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Background. We reported that deficiency of the eNOS protein exacerbates colitis induced by dextran sodium sulfate (DSS-induced colitis). However, the role of eNOS in colitis remains controversial. Therefore, we studied how over-expression of eNOS affected this inflammatory condition, using vascular endothelial cells and mice as in vitro and in vivo models, respectively. Furthermore, we investigated the influence of a polymorphism in the eNOS gene on the clinical features of ulcerative colitis (UC). Methods. We examined the effect of eNOS overexpression on the expression of adhesion molecules in the endothelium and assessed the degree of DSS-induced colitis in eNOS transgenic (eNOS-Tg) mice. We also investigated the relationship between a polymorphism in the eNOS gene and clinical features of patients with UC. Results. The expression of adhesion molecules, under inflammatory conditions, was attenuated in eNOS gene-transfected vascular endothelial cells, as measured by western blot analysis. Symptoms of DSS-induced colitis were likewise attenuated in eNOS-Tg mice, which exhibited lower weight loss, mortality, histological damage (by inflammation score and crypt damage score), and colonic myeloperoxidase activity, tumor necrosis factor-α expression, and MAdCAM-1 expression than in wild-type mice. Furthermore, there was a significant relationship between intractable cases of UC and a polymorphism in the eNOS gene promoter (c.-786 T > C) that decreases eNOS expression. Conclusion. The eNOS gene plays an important role in the regulation of colonic inflammation. The level of eNOS expression may be a predictive marker for prognosis of UC, and eNOS expression may be a novel therapeutic target. [ABSTRACT FROM AUTHOR]

This study was performed to define the biologically active growth modulators in human gastric juice. Mitogenic activity was evaluated by the incorporation of [3H]thymidine into 3T3 fibroblasts. A negative correlation was observed between pH and mitogenic activity in gastric juice (r = -0.45, P < 0.01). The concentrations of epidermal growth factor (EGF), transforming growth factor-alpha and -beta 1 (TGF-alpha and -beta 1), platelet-derived growth factor (PDGF), and basic fibroblast growth factor (bFGF) in gastric juice did not explain these changes in mitogenic activity. Gel filtration identified growth-stimulating activity due to small molecule mitogens (less than 13 kDa), and growth inhibitory activity only in neutral samples due to a macromolecular substance (larger than 240 kDa) susceptible to trypsin digestion and heat and acid treatments. We conclude that acidity-dependent changes in mitogenic activity observed in this study are due to appearance of acid-unstable, high-molecular-weight, growth-inhibitory substance. [ABSTRACT FROM AUTHOR]

SATB2 has been reported to be highly specific for lower gastrointestinal tract tumors. On the basis of its ileum-colon conversion effects, which involve the activation of colonic genes in cooperation with CDX2 and HNF4A, we hypothesized that SATB2 and CDX2 might define the characteristics of colorectal cancers (CRCs). In the present study, the clinicopathologic and immunohistochemical characteristics of 269 CRCs were analyzed according to SATB2 and CDX2 expression. CRCs with SATB2- and/or CDX2- phenotypes showed associations with poorly differentiated histotypes ( P <0.00001), mucus production ( P =0.0019), and mismatch repair-deficient phenotypes ( P <0.00001). SATB2-/CDX2- CRCs were significantly associated with CK20-negativity, with or without CK7 expression ( P <0.00001), as well as with MUC5AC-positivity ( P <0.00001), and CD10-negativity ( P =0.00047). Negativity for SATB2 or CDX2 was associated with the expression of PD-L1 in both all CRC ( P <0.00001) and mismatch repair-proficient CRC ( P =0.000091). Multivariate Cox hazard regression analysis identified negativity for SATB2 and/or CDX2 as potential independent risk factors for patients with CRC. Regarding the diagnostic utility of SATB2, all of the 44 CRC metastases could be diagnosed as colorectal in origin if the immunohistochemical phenotypes (including CK7, CK20, and p53) of the primary lesions and patient history were considered. Among the other 684 tumors, we were unable to distinguish a case of CK7-/CK20+/CDX2+/SATB2+ ovarian mucinous cystadenocarcinoma from metastatic CRC without the patient history and clinical information., Competing Interests: The authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

The Japan Gastroenterological Association (JGA) published the first version of clinical guidelines for chronic diarrhea 2023. These guidelines describe the definition, classification, diagnostic criteria, diagnostic testing methods, epidemiology, pathophysiology, and treatment of chronic diarrhea, and provide flowcharts for the diagnosis and treatment of chronic diarrhea based on the latest evidence. Treatment for chronic diarrhea begins by distinguishing secondary chronic constipation with a clear etiology, such as drug-induced diarrhea, food-induced diarrhea, systemic disease-associated diarrhea, infection-associated diarrhea, organic disease-associated diarrhea, and bile acid diarrhea. The first line of treatment for chronic diarrhea in the narrow sense, defined in these guidelines as functional diarrhea in routine medical care, is lifestyle modification and dietary therapy. The first medicines to be considered for oral treatment are probiotics for regulating the gut microbiome and anti-diarrheals. Other medications, such as 5HT3 receptor antagonists, anticholinergics, Kampo medicine, psychotherapy, antibiotics, bulking agents, adrenergic agonists, and somatostatin analogs, lack sufficient evidence for their use, highlighting a challenge for future research. This Clinical Guidelines for Chronic Diarrhea 2023, which provides the best clinical strategies for treating chronic diarrhea in Japan, will also be useful for medical treatment worldwide., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

The Japan Gastroenterological Association published the first version of its clinical guidelines for chronic constipation 2023. Based on the latest evidence, these guidelines describe the definition, classification, diagnostic criteria, diagnostic testing methods, epidemiology, pathophysiology, and treatment of chronic constipation. They include flowcharts for both diagnosis and treatment of chronic constipation. In the treatment of chronic constipation, the first step involves differentiating between secondary forms, such as organic disease-associated constipation, systemic disease-associated constipation, and drug-induced constipation. The next step is to determine whether the chronic constipation stems from a motility disorder, a form of primary chronic constipation. For functional constipation and constipation-predominant irritable bowel syndrome, treatment should be initiated after evaluating symptoms like reduced bowel movement frequency type or defecation difficulty type. The first line of treatment includes the improvement of lifestyle habits and diet therapy. The first drugs to consider for oral treatment are osmotic laxatives. If these are ineffective, secretagogues and ileal bile acid transporter inhibitors are candidates. However, stimulant laxatives are exclusively designated for as-needed use. Probiotics, bulk-forming laxatives, prokinetics, and Kampo medicines, for which there is insufficient evidence, are considered alternative or complementary therapy. Providing the best clinical strategies for chronic constipation therapy in Japan, these clinical guidelines for chronic constipation 2023 should prove useful for its treatment worldwide., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Background and Purpose: Formulary systems play a crucial role in healthcare organizations by promoting collaboration and ensuring the rational and cost-effective utilization of medications. With a rise in pharmacist involvement in hospital formulary management, this study aims to describe the components of an online formulary exercise, assess fifth-year students' perceptions of this exercise, and evaluate its effectiveness in understanding formulary management and the pharmacist's role., Educational Activity and Setting: The online formulary exercise was initiated during hospital practice training at Kitasato University Hospital since October 2021. Students underwent reading assignments and a pre-test before participating in the program. The one-day program included a pre-practice test, 1.5 h of pre-recorded video lectures, 2.5 h of two small group discussions, a 1-h individual assignment creating a proton pump inhibitor comparison chart, 30 min of group presentations, and feedback from clinical faculty. Post-program assessments comprised a test, evaluations, and surveys on difficulty, necessity, and impressions. Analysis involved descriptive methods and thematic analysis for free-form responses, and a Friedman test for test scores., Findings: The surveys conducted between July 2022 and February 2023 were compiled and analyzed. This study assessed the impact of an online formulary exercise program on 100 participants, revealing an improvement in formulary understanding (97%) and a high recommendation rate (92%). Test performance demonstrated an improvement (p < 0.05, r = 0.85), with students recognizing the importance of contributing to the reduction of healthcare costs. The program positively influenced students' formulary knowledge and readiness for pharmacist roles., Summary: This online formulary exercise provided a valuable opportunity for students to learn about formulary management. The use of survey results and test scores demonstrated the positive impact of both pre-assignments and exercise on students' comprehension of formulary, enhancing not only their understanding but also fostering a sense of responsibility as future pharmacists., Competing Interests: Declaration of competing interest The authors declare no conflict of interest. There are no financial conflicts of interest to disclose. This study did not receive any funding., (Copyright © 2023. Published by Elsevier Inc.)

Evidence for the tumour-supporting capacities of the tumour stroma has accumulated rapidly in colorectal cancer (CRC). Tumour stroma is composed of heterogeneous cells and components including cancer-associated fibroblasts (CAFs), small vessels, immune cells, and extracellular matrix proteins. The present study examined the characteristics of CAFs and collagen, major components of cancer stroma, by immunohistochemistry and Sirius red staining. The expression status of five independent CAF-related or stromal markers, decorin (DCN), fibroblast activation protein (FAP), podoplanin (PDPN), alpha-smooth muscle actin (ACTA2), and collagen, and their association with clinicopathological features and clinical outcomes were analysed. Patients with DCN-high tumours had a significantly worse 5-year survival rate (57.3% versus 79.0%; p = 0.044). Furthermore, hierarchical clustering analyses for these five markers identified three groups that showed specific characteristics: a solid group (cancer cell-rich, DCN Low PDPN Low ); a PDPN-dominant group (DCN Mid PDPN High ); and a DCN-dominant group (DCN High PDPN Low ), with a significant association with patient survival (p = 0.0085). Cox proportional hazards model identified the PDPN-dominant group (hazard ratio = 0.50, 95% CI = 0.26-0.96, p = 0.037) as a potential favourable factor compared with the DCN-dominant group. Of note, DCN-dominant tumours showed the most advanced pT stage and contained the lowest number of CD8+ and FOXP3+ immune cells. This study has revealed that immunohistochemistry and special staining of five stromal factors with hierarchical clustering analyses could be used for the prognostication of patients with CRC. Cancer stroma-targeting therapies may be candidate treatments for patients with CRC., (© 2024 The Author(s). The Journal of Pathology: Clinical Research published by The Pathological Society of Great Britain and Ireland and John Wiley & Sons Ltd.)

Background: Constipation causes substantial morbidity worldwide. Methods: This survey assessed constipation-related factors in Japan using the Japanese version of the Irritable Bowel Syndrome Quality of Life (IBS-QOL-J) instrument. We also examined the relationship among laxative type, Bristol Stool Form Scale (BSFS) scores, and treatment cost. Finally, we examined differences in satisfaction scores according to laxative type, treatment type, treatment cost, and BSFS score. Results: IBS-QOL-J was higher among those taking salt and/or irritation laxatives. Those paying >JPY 5000 (USD 50.00) had the lowest IBS-QOL-J. IBS-QOL-J was significantly lower among those with a BSFS score of 1 or 2 (severe constipation). Conclusions: This study's findings suggest that a variety of factors, including treatment type and cost, are associated with defecation satisfaction. Those who had hard stools, used multiple laxatives, or spent more on treatment were less satisfied. Future strategies should target therapies that do not require multiple laxatives with lower treatment costs. Adequate defecation with a small number of appropriate laxatives at minimal cost appears to improve defecation satisfaction. It is desirable to identify appropriate laxatives and improve dietary habits and exercise routines. It is also necessary to stop blindly increasing laxative usage and properly diagnose constipation disorders such as anatomical abnormalities other than functional constipation.

Colorectal cancer (CRC) is one of the most common gastrointestinal cancers worldwide, with high morbidity and mortality rates. The evidence for the tumor-supporting capacities of cancer-associated fibroblasts (CAFs) that modulate cancer cell proliferation, invasion, metastasis, and tumor immunity, including in CRC, has been attracting attention. The present study examined the expression status of CD70 and POSTN in CRC and analyzed their association with clinicopathological features and clinical outcomes. In the present study, in total 15% (40/269) and 44% (119/269) of cases exhibited CD70 and POSTN expression on CAFs, respectively. Co-expression of CD70 and POSTN was detected in 8% (21/269) of patients. Fluorescent immunohistochemistry identified the co-expression of CD70 and POSTN with FAP and PDPN, respectively. ACTA2 was not co-expressed with CD70 or POSTN in CRC CAFs. CRC with CD70+/POSTN+ status in CAFs was significantly associated with distant organ metastasis ( p = 0.0020) or incomplete resection status ( p = 0.0011). CD70+/POSTN+ status tended to associate with advanced pT stage ( p = 0.032) or peritoneal metastasis ( p = 0.0059). Multivariate Cox hazards regression analysis identified CD70+/POSTN+ status in CAFs [hazard ratio (HR) = 3.78] as a potential independent risk factor. In vitro experiments revealed the activated phenotypes of colonic fibroblasts induced by CD70 and POSTN, while migration and invasion assays identified enhanced migration and invasion of CRC cells co-cultured with CD70- and POSTN-expressing colonic fibroblasts. On the basis of our observations, CD70 and POSTN immunohistochemistry can be used in the prognostication of CRC patients. CRC CAFs may be a promising target in the treatment of CRC patients.

Background and Aims: Acute lower gastrointestinal bleeding (ALGIB) increase with age and the administration of antiplatelet drugs. Colonic diverticular bleeding (CDB) is the most common cause of ALGIB, and endoscopic hemostasis is an effective treatment for massive CDB. But in patients without extravasation on contrast-enhanced computed tomography (CECT), the efficacy of urgent colonoscopy (UCS) is controversial from the point of the clinical course, including rebleeding rate. We aimed to establish a potential strategy including UCS for CDB patients without extravasation on CECT., Patients and Methods: Patients from two centers treated for CDB without extravasation on CECT between July 2014 and July 2019 were retrospectively identified (n = 282). Seventy-four underwent UCS, and 208 received conservative management. We conducted two analyses. The first analysis investigates the risk factors of rebleeding rate within 5 days after administration (very early rebleeding), and no UCS (NUCS) was not the independent factor of the very early rebleeding. The second analysis is whether UCS positively influenced the clinical course after hospitalization., Results: The prevalence of very early rebleeding and early rebleeding (6-30 days from admission), patients requiring blood transfusion within 0-5 days and 6-30 days post-admission, and duration of hospitalization were examined as clinical course factors between UCS and NUCS group. There was no significant difference between the UCS and non-UCS groups in the clinical course factors. UCS for the CDB patients without extravasation was not improved rebleeding rate and clinical course., Conclusions: UCS is not necessary in case ofCDB patient without extravasation on CECT., Competing Interests: Declaration of competing interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

This study investigated the trends in idiopathic peptic ulcers, examined the characteristics of refractory idiopathic peptic ulcer, and identified the optimal treatment. The characteristics of 309 patients with idiopathic peptic ulcer were examined. We allocated idiopathic peptic ulcers that did not heal after 8 weeks' treatment (6 weeks for duodenal ulcers) to the refractory group and those that healed within this period to the healed group. The typical risk factors for idiopathic peptic ulcer (atherosclerosis-related underlying disease or liver cirrhosis complications) were absent in 46.6% of patients. Absence of gastric mucosal atrophy (refractory group: 51.4%, healed group: 28.4%; p  = 0.016), and gastric fundic gland polyps (refractory group: 17.6%, healed group: 5.9%; p  = 0.045) were significantly more common in the refractory group compared to the healed group. A history of H. pylori eradication (refractory group: 85.3%, healed group: 66.0%; p  = 0.016), previous H. pylori infection (i.e., gastric mucosal atrophy or history of H. pylori eradication) (refractory group: 48.5%, healed group: 80.0%; p  = 0.001), and potassium-competitive acid blocker treatment (refractory group: 28.6%, healed group, 64.1%; p  = 0.001) were significantly more frequent in the healed group compared to the refractory group. Thus, acid hypersecretion may be a major factor underlying the refractoriness of idiopathic peptic ulcer., Competing Interests: No potential conflicts of interest were disclosed., (Copyright © 2024 JCBN.)

Gastroesophageal reflux disease (GERD) is caused by the reflux of gastric contents into the esophagus due to a decline in esophageal clearance and anti-reflux barrier mechanisms. Mucosal injury is caused by a combination of gastric juice directly damaging the esophageal mucosa and the immune and inflammatory mechanism in which inflammatory cytokines released from the esophageal mucosal epithelium cause neutrophil migration, triggering inflammation. Gastric secretion inhibitors are the first-line treatment for GERD, but they can be combined with prokinetic agents and Chinese herbal remedies. However, pharmacotherapy cannot improve anatomical problems or prevent physical causes of GERD, such as reflux of non-acidic contents. Therefore, surgery can be warranted, depending on the pathology. Intraluminal endoscopic therapy, which is both less invasive and more effective than surgery, was recently developed and applied in Europe and the United States. In Japan, intraluminal endoscopic therapies, such as anti-reflux mucosectomy, anti-reflux mucosal ablation, and endoscopic submucosal dissection, for GERD have been independently developed.

The present study analyzed the expression of five independent immunohistochemical markers, CD4, CD8, CD66b, CD68, and CD163, on immune cells within the colorectal cancer (CRC) tumor microenvironment (TME). Using hierarchical clustering, patients were successfully classified according to significant associations with clinicopathological features and/or survival. Patients with mismatch repair-proficient (pMMR) CRC were categorized into four groups with survival differences (p = 0.0084): CD4 Low , CD4 High , MΦ High , and CD8 Low . MΦ High tumors showed significantly higher expression of CD47 (p < 0.0001), a phagocytosis checkpoint molecule. These tumors contained significantly greater numbers of PD-1+ (p < 0.0001), TIM-3+ (p < 0.0001), and SIRPA+ (p < 0.0001) immune cells. Notably, 10% of the patients with pMMR CRC expressed PD-L1 (CD274) on tumor cells with significantly worse survival (p = 0.00064). The Cox proportional hazards model identified MΦ High (hazard ratio [HR] = 2.02, 95%, p = 0.032), CD8 Low (HR = 2.45, p = 0.011), and tumor PD-L1 expression (HR = 2.74, p = 0.0061) as potential risk factors. PD-L1-PD-1 and/or CD47-SIRPA axes targeting immune checkpoint therapies might be considered for patients with pMMR CRC according to their tumor cells and tumor immune microenvironment characteristics., (© 2023 Japanese Society of Pathology and John Wiley & Sons Australia, Ltd.)

Objective Vonoprazan (VPZ), clarithromycin (CAM), metronidazole (MNZ) and VPZ, MNZ, and sitafloxacin (STFX) regimen are all established Helicobacter pylori eradication therapies for patients with penicillin allergy in Japan. However, no study has assessed the efficacy of a VPZ, CAM, and MNZ (VCM) regimen in patients with clarithromycin resistance (CAM-R). We therefore assessed the efficacy of a VCM regimen for treating H. pylori infection in patients with CAM-R and penicillin allergy. Methods Fifty-three patients with penicillin allergy who received H. pylori eradication therapy were retrospectively analyzed. Eight patients received a 7-day proton-pump inhibitor, CAM, and MNZ (PCM) regimen; 35 patients [11 CAM-R, and 10 with clarithromycin sensitivity (CAM-S)] received 7-day VCM regimens; and 10 patients received 7-day VPZ, MNZ, and STFX (VMS) regimens. A 13 C-urea breath test was used to determine eradication. The efficacy of eradication was evaluated via both intention-to-treat (ITT) and per-protocol (PP) analyses. Results According to ITT and PP analyses, eradication rates (ERs) with PCM, VCM, and VMS therapies were 50.0% and 50.0%, 94.3% and 100%, and 90% and 90%, respectively. Treatment was successful in all patients with CAM-S. For patients with CAM-R, treatment was successful in 10 patients, and 1 patient discontinued treatment owing to an adverse event. According to ITT and PP analyses, ERs were 90.9% and 100% in CAM-R, and were 100% and 100% in CAM-S, respectively. Conclusion The VCM regimen for H. pylori eradication may be a viable candidate therapy for patients with penicillin allergy, regardless of CAM-R.

Detailed evaluations of body mass index (BMI) and stool form based on the Bristol Stool Form Scale (BSFS) in individuals with constipation, gastroesophageal reflux disease (GERD), and concomitant constipation and GERD have not been performed in Japan. This study was an internet survey conducted to examine the relationships between BMI and constipation, GERD, stool forms based on the BSFS, and education level. This internet-based survey recruited participants from general public survey panels. 10,000 individuals meeting the eligibility criteria were enrolled. Questions included demographics, medical data, and assessments based on validated measures for constipation and GERD. BMI was significantly lower in males with versus without constipation. BMI was significantly higher with GERD both males and females. Mean BMI increased from the BSFS-1/2 group through the BSFS-3/4/5 to the BSFS-6/7 groups in both sexes. BMI was highest in individuals with a maximum education level of junior high school and second highest in individuals completing high school. This is the first real-world survey that closely examines the relationship between BMI and stool forms of individuals in Japan. When the BMI increased, stool forms varied from hard to watery in Japanese people. BMI was related with education level in Japan. (Trial registration: UMIN000039688)., Competing Interests: NO received expenses reimbursement related to this study from EA Pharma Co., Ltd. KK received expenses reimbursement related to this study from EA Pharma Co., Ltd.; research funding from EA Pharma Co., Ltd.; and scholarship donations from AstraZeneca and Daiichi Sankyo Co., Ltd., (Copyright © 2023 JCBN.)

Background: Helicobacter pylori infection is a well-known risk factor for gastric cancer. However, the contribution of germline pathogenic variants in cancer-predisposing genes and their effect, when combined with H. pylori infection, on the risk of gastric cancer has not been widely evaluated., Methods: We evaluated the association between germline pathogenic variants in 27 cancer-predisposing genes and the risk of gastric cancer in a sample of 10,426 patients with gastric cancer and 38,153 controls from BioBank Japan. We also assessed the combined effect of pathogenic variants and H. pylori infection status on the risk of gastric cancer and calculated the cumulative risk in 1433 patients with gastric cancer and 5997 controls from the Hospital-based Epidemiologic Research Program at Aichi Cancer Center (HERPACC)., Results: Germline pathogenic variants in nine genes ( APC , ATM , BRCA1 , BRCA2 , CDH1 , MLH1 , MSH2 , MSH6 , and PALB2 ) were associated with the risk of gastric cancer. We found an interaction between H. pylori infection and pathogenic variants in homologous-recombination genes with respect to the risk of gastric cancer in the sample from HERPACC (relative excess risk due to the interaction, 16.01; 95% confidence interval [CI], 2.22 to 29.81; P = 0.02). At 85 years of age, persons with H. pylori infection and a pathogenic variant had a higher cumulative risk of gastric cancer than noncarriers infected with H. pylori (45.5% [95% CI, 20.7 to 62.6] vs. 14.4% [95% CI, 12.2 to 16.6])., Conclusions: H. pylori infection modified the risk of gastric cancer associated with germline pathogenic variants in homologous-recombination genes. (Funded by the Japan Agency for Medical Research and Development and others.)., (Copyright © 2023 Massachusetts Medical Society.)

A 46-year-old man, receiving continuous steroid therapy for refractory ulcerative colitis with an insufficient response to anti-tumor necrosis factor-α therapy, presented with left buttock pain. He was diagnosed with steroidal left femoral head necrosis, and total proctocolectomy with permanent ileostomy was performed. At 6 months postoperatively, the patient developed general fatigue, abdominal pain, and severe ileostomy diarrhea. Computed tomography revealed continuous intestinal edema from the descending duodenal leg to the upper jejunum. Gastrointestinal endoscopy revealed deep ulcers, coarse mucosa, and duodenal erosion. Based on clinical progress, findings, and pathology, the patient was diagnosed with ulcerative colitis-related postoperative enteritis. Although 5-aminosalicylic acid treatment was initiated, his symptoms persisted, bloody diarrhea from colostomy was observed. Subsequently, granulocyte and monocyte apheresis treatment was added. Symptoms and endoscopic findings improved with granulocyte and monocyte apheresis. Azathioprine was introduced as maintenance therapy, and no sign of recurrence was observed. Although ulcerative colitis-related postoperative enteritis has no definitive treatment, granulocyte and monocyte apheresis may be considered for initial treatment., (© 2022. Japanese Society of Gastroenterology.)

Evidence for the tumor-supporting capacities of cancer-associated fibroblasts (CAFs) has rapidly been accumulating. To uncover clinicopathological importance of periostin (POSTN) expression in colorectal cancer (CRC), the present study immunohistochemically examined its expression status. Furthermore, to reveal its mechanisms involved, molecular experiments were performed. In CRC tissues, 44% of the cases (119/269) exhibited POSTN expression in the CAFs. In contrast, CRC cells expressed POSTN at almost undetectable levels. Survival analyses identified that patients with POSTN-positive CRC had a significantly worse 5-year survival rate (63.2% vs. 81.2%; p = 0.011). Univariate analyses revealed that POSTN positivity was associated with peritoneal ( p = 0.0031) and distant organ metastasis ( p < 0.001). Furthermore, immunohistochemical analyses identified a significant association between POSTN and p53 complete loss status in CRC cells. Decorin and fibroblast activation protein expression in CAFs was also associated with POSTN. POSTN significantly enhanced the migration of both CRC cells and fibroblasts with FAK and AKT or STAT3 activation, and co-culture assays demonstrated the communication between CRC cells and fibroblasts, which enhanced STAT3 activation in fibroblasts. On the basis of our results, we speculated that stromal POSTN accelerated metastasis via stromal remodeling capacity and activated the migration of both tumor and stromal cells.

Background: The risk of bleeding after gastric endoscopic submucosal dissection (ESD) in antithrombotic agent users has increased, and its management remains a problem. Second-look endoscopy (SLE) following gastric ESD in antithrombotic agent users may be effective in preventing delayed bleeding, but this requires elucidation. Therefore, this study aimed to investigate the efficacy of SLE in reducing bleeding after gastric ESD in patients receiving antithrombotic agents., Methods: This retrospective cohort study was conducted at 19 referral hospitals in Japan. A total of 1,245 patients who were receiving antithrombotic agents underwent gastric ESD between January 2013 and July 2018. The incidence of delayed bleeding was compared between SLE and non-SLE groups using propensity score matching analysis., Results: Overall, 858 patients (SLE group, 657 patients; non-SLE group, 201 patients) were analyzed. After matching, 198 pairs were created. Delayed bleeding occurred in 10 patients (5.1%) in the SLE group and 16 patients (8.1%) in the non-SLE group [odds ratio (OR) 0.605, 95% confidence interval (CI) 0.23-1.46, p = 0.310]. In the subgroup analysis, SLE reduced the incidence of delayed bleeding in patients receiving heparin bridging therapy (6.3% and 40.0%, respectively; p = 0.004). In the SLE group, prophylactic coagulation did not significantly reduce delayed bleeding compared to the no treatment group (14.6% and 8.6%, respectively; p = 0.140)., Conclusions: SLE was ineffective in reducing bleeding after gastric ESD in antithrombotic agent users, overall. A prospective comparative study is warranted to definitively evaluate the effectiveness of SLE in reducing bleeding in high-risk patients., (© 2022. The Author(s) under exclusive licence to The International Gastric Cancer Association and The Japanese Gastric Cancer Association.)