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A ''stilling basin'' is a structure used downstream of a dam to reduce energy flow and prevent damage to the dam structure or erosion downstream. The literature on energy dissipation in stilling basins has identified mechanisms such as abrupt drops, sudden enlargements, steps, and cross walls. However, the combined effects of these mechanisms in a comprehensive experimental approach have not been thoroughly studied. This experimental study explores flow behavior within an in-ground stilling basin (ISB). In contrast to previous studies, this study systematically investigated the interaction between geometric parameters and flow behavior. Five types of hydraulic jumps were identified based on their surface patterns and water flow profiles. Among these, the steady submerged hydraulic jump is the most effective for reducing the flow velocity, maintaining stability, and ensuring symmetry. This study also highlights that the height of the cross-wall influences the flow pattern in the ISB more than variations in upstream conditions, such as the Froude number. Increasing the length of the ISB reduces the flow stability. Furthermore, incorporating free spaces in the ISB design improves flow stability and symmetry while offering additional benefits, such as better flushing efficiency, fish passage, and improved downstream flow conditions, which have not been fully addressed in prior studies. The results of this study provide the foundation for practical recommendations and design guidelines for ISBs in flood mitigation systems.

Background: There are many reports on the choice of treatment for and prognosis of left-sided obstructive colorectal cancer; however, few studies have focused on the prognostic factors of left-sided obstructive colorectal cancer. Therefore, we analyzed the prognostic factors using a post hoc analysis of a retrospective multicenter study in Japan. Methods: A total of 301 patients were enrolled in this study to investigate the prognostic factors for relapse-free survival. The relationships between sex, age, decompression for bridge to surgery, depth of invasion, lymph node metastasis, postoperative complications, adjuvant chemotherapy, carcinoembryonic antigen, carbohydrate antigen 19-9, neutrophil-to-lymphocyte ratio, and relapse-free survival were examined. Results: No change in the decompression method, T3 cancer, negative postoperative complications (grades 0–1 of Clavien-Dindo classification), and adjuvant chemotherapy during Stage III indicated a significantly better prognosis in a Cox univariate analysis. Lymph node metastasis was not selected as a prognostic factor. Excluding patients with <12 harvested lymph nodes (possible stage migration), lymph node metastasis was determined as a prognostic factor. In a Cox multivariate analysis, change in the decompression method, depth of invasion, lymph node metastasis (excluding N0 cases with <12 harvested lymph nodes), and adjuvant chemotherapy were prognostic factors. Conclusions: Similar to those in nonobstructive colorectal cancer, depth of invasion and lymph node metastasis were prognostic factors in left-sided obstructive colorectal cancer, and patients with <12 dissected lymph nodes experienced stage migration. Stage migration may result in disadvantages, such as not being able to receive adjuvant chemotherapy. [ABSTRACT FROM AUTHOR]

Abstract Background Membrane-anchored heparin-binding epidermal growth factor-like growth factor (proHB-EGF) yields soluble HB-EGF, which is an epidermal growth factor receptor (EGFR) ligand, and a carboxy-terminal fragment of HB-EGF (HB-EGF-CTF) after ectodomain shedding. We previously reported that HB-EGF-CTF and unshed proHB-EGF which has the cytoplasmic domain of proHB-EGF (HB-EGF-C), translocate from the plasma membrane to the nucleus and regulate cell cycle after shedding stimuli. However, the significance of nuclear exported HB-EGF-C in human gastric cancer is unclear. Methods We investigated the relationship between intracellular localization of HB-EGF-C and clinical outcome in 96 gastric cancer patients treated with gastrectomy. Moreover, we established stable gastric cancer cell lines overexpressing wild-type HB-EGF (wt-HB-EGF) and mutated HB-EGF (HB-EGF-mC), which prevented HB-EGF-C nuclear translocation after shedding. Cell motility between these 2 gastric cancer cell lines was investigated using a transwell invasion assay and a wound healing assay. Results Of the 96 gastric cancer cases, HB-EGF-C immunoreactivity was detected in both the nucleus and cytoplasm in 19 cases (19.8 %) and in the cytoplasm only in 25 cases (26.0 %). The nuclear immunoreactivity of HB-EGF-C was significantly increased in stage pT3/4 tumors compared with pT1/2 tumors (T1/2 vs. T3/4: 11.1 % vs. 36.4 %, P Conclusions Both the function of HB-EGF as an EGFR ligand and a novel signal for HB-EGF-C nuclear translocation induce gastric cancer growth, whereas HB-EGF-C nuclear translocation independently plays a critical role in gastric cancer invasion. The present study demonstrated that HB-EGF-C nuclear translocation might be crucial in gastric cancer invasion. HB-EGF-C nuclear translocation may offer a prognostic marker and a new molecular target for gastric cancer therapy.

Background and study aims Although deep vein thrombosis (DVT) and pulmonary embolism (PE) are major postoperative complications, risk of DVT/PE after endoscopic procedures remains unknown. This study aimed to identify risks of DVT/PE after colorectal endoscopic submucosal dissection (ESD) and double-balloon endoscopy (DBE). Patients and methods Patients who were scheduled to undergo DBE and colorectal ESD were prospectively enrolled in this study. Before enrollment, all patients were confirmed to have no DVT on whole-leg ultrasonography (US) or contrast-enhanced computed tomography (CECT). All patients routinely underwent whole-leg US after ESD or DBE. The primary endpoint was incidence of DVT after colorectal ESD and DBE. The preplanned sample size was 170 patients in the colorectal ESD group and 75 in the DBE group. Results Between September 2020 and June 2022, 170 patients who had colorectal ESD and 75 who had DBE were recruited for this study; however, 238 patients (ESD, n = 167; DBE, n = 71) were analyzed. Of these 238 patients, DVT occurred in only one patient after colorectal ESD and incidence of DVT was 0.4% (95% confidence interval [CI] 0-1.2) in total, including 0.6% (95% CI 0-1.8) after colorectal ESD and 0% after DBE. Conversely, no PE occurred in the entire cohort. Conclusions This prospective study demonstrated that risk of DVT/PE following highly invasive endoscopic procedures including colorectal ESD and DBE is very low., Competing Interests: Conflict of Interest The authors declare that they have no conflict of interest., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

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.)

Background: Recently, there has been a significant increase in the utilization of self-expandable metallic stents (SEMSs) for treating malignant colorectal obstructions through colorectal stenting. The mechanical properties of SEMSs are usually considered to affect clinical outcomes of patients with malignant colorectal obstructions. Methods : This single-arm, prospective, multicenter study of SEMS with a lower axial force and high axial force zero-border included 200 patients with malignant colorectal obstruction. Technical and clinical success, stent patency, and adverse events associated with SEMS placement were evaluated. Results: One patient was excluded, and 199 patients were evaluated. The treatment intent was bridge-to-surgery in 129 and palliation in 70 patients. Technical and clinical success rates were 99.5% and 97.0%, respectively. The percentage of the ColoRectal Obstruction Scoring System scores of 3 or higher improved significantly from 19.2% before placement to 93.9% after placement. Clinical success was not achieved in five patients due to insufficient stent expansion in four patients and stent occlusion in one patient. Only one patient underwent emergency surgery for perforation of the proximal colon, far from where the stent was placed; the rescue procedure was not performed, despite no improvement in proximal dilatation due to insufficient stent expansion. Among the palliation cohort, 15 patients received chemotherapy, including molecular-targeted agents such as bevacizumab. There were no fatal cases related to stent placement. Conclusions : For management of malignant colorectal obstruction, this newly developed SEMS with low axial force and a high axial force zero-border showed high technical and clinical success rates, and an extremely low perforation rate (0.5%).

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.)

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.)

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.)

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.)

A 54-year-old man was referred to our hospital because of a suspected esophageal submucosal tumor on upper gastrointestinal radiography. Contrast-enhanced computed tomography showed a 52 mm homogeneous mass attached to the lower thoracic esophagus. Esophagogastroduodenoscopy revealed a 50 mm submucosal tumor in the lower esophagus, and endoscopic ultrasonography (EUS) showed a continuous hypoechoic lesion in the esophageal muscularis propria. Contrast-enhanced harmonic EUS revealed a non-echogenic area. T1 and T2 magnetic resonance imaging revealed a high-signal lesion. Based on imaging studies, an esophageal duplication cyst was diagnosed. Although asymptomatic, the patient underwent video-assisted thoracic surgery because of the possibility of rupture and the appearance of symptoms due to a future infection or enlargement, although this was not noted before. In our case, the esophageal duplication cyst appeared as a hypoechoic mass, requiring differentiation from submucosal tumor other than the cyst. Histologically, the cyst was covered by two layers of muscle covered by the chorioepithelial columnar epithelium. EUS fine-needle aspiration is effective in diagnosing submucosal tumor but also carries the risk of infection. Contrast-enhanced ultrasonography was used in this case to observe the interior and reach a preoperative diagnosis. Contrast-enhanced harmonic EUS appears to be effective in examining the interior of submucosal tumor lesions noninvasively., Competing Interests: None., (© 2023 The Authors. DEN Open published by John Wiley & Sons Australia, Ltd on behalf of Japan Gastroenterological Endoscopy Society.)

Background: Self-expanding metallic stent (SEMS) and trans-anal colorectal tube (TCT) are alternative treatments to conventional emergency surgery for non-right-sided obstructive colon cancer (NROCC). However, the one with better short- and long-term outcomes remains controversial. Thus, this multicenter case-control study aimed to analyze and compare SEMS and TCT for NROCC., Methods: Patients with stage II/III NROCC who underwent surgery between January 2010 and December 2019 at either of the eight selected Japanese affiliate hospitals were, retrospectively, reviewed. Baseline characteristics between the SEMS and TCT groups were adjusted by propensity score (PS) matching., Results: Among 239 reviewed patients (SEMS: 76, TCT: 163), 180 were finally included in two well-balanced cohorts through PS: SEMS group (65 patients) and TCT group (115 patients). Technical success, clinical success, morbidity, and short-term mortality were not significantly different between the two groups. SEMS placement achieved significantly higher rates for primary resection/anastomosis without stoma (SEMS: 90.8% vs. TCT: 77.4%, p < 0.001) and laparoscopic surgery (SEMS: 64.6% vs. TCT: 43.5%, p < 0.001) than TCT placement. However, 5-year overall survival (SEMS: 83.7% vs. TCT: 86.4%; p = 0.822) and 5-year relapse-free survival (SEMS: 64.7% vs. TCT: 66.4%; p = 0.854) showed no significant differences between these groups., Conclusions: Both SEMS and TCT revealed similar long-term outcomes, but SEMS placement was better in achieving primary resection/anastomosis and laparoscopic surgery in patients with stage II/III NROCC., (© 2023. Japanese Society of Gastroenterology.)

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.

Purpose: The standard first-line treatment for human epidermal growth factor receptor type 2 (HER2)-positive advanced gastric cancer (AGC) is trastuzumab in combination with cisplatin and fluoropyrimidines. We evaluated the efficacy and safety of S-1 and oxaliplatin (100 mg/m 2 ) (SOX100) combined with trastuzumab, a monoclonal antibody against HER2 for HER2-positive AGC., Methods: In this single-arm, multicenter phase II study, patients with HER2-positive AGC received S-1 (80-120 mg per day) orally on days 1-14, oxaliplatin (100 mg/m 2 ) intravenously on day 1, and trastuzumab (8 mg/kg on day 1 of the first cycle, followed by 6 mg/kg every 3 weeks) intravenously. The primary end point was 1-year survival rate. The secondary end points included overall survival (OS), progression-free survival (PFS), overall response rate (ORR), and safety., Results: A total of 25 patients from six centers were enrolled from December 2015 to March 2020. In the 25 patients evaluable for analysis, the 1-year survival rate was 70.8% [90% confidence interval (CI) = 55.5-86.1%], whereas the median OS, PFS, and ORR were 17.8 (95% CI 10.5-22.9) months, 7.6 (95% CI 5.0-10.9) months, and 75.0% (95% CI 53.3-90.2), respectively. Major grade 3/4 adverse events included anorexia (20%), anemia (16%), peripheral sensory neuropathy (16%), and diarrhea (15%)., Conclusion: SOX100 combined with trastuzumab was effective with a favorable safety profile in patients with HER2-positive AGC., (© 2021. Springer Science+Business Media, LLC, part of Springer Nature.)

Colonic diverticular bleeding (CDB) is the most frequent cause of acute lower gastrointestinal bleeding. The aim of this study was to evaluate the efficacy and safety of transcatheter arterial embolization (TAE) for CDB as first-line treatment with extravasation on contrast-enhanced computed tomography (CECT), compared with endoscopic hemostasis. Three Japanese institutions participated in this retrospective cohort study. Data from consecutive patients admitted with a diagnosis of CDB with extravasation on CECT were reviewed. One hospital performed TAE and the others conducted urgent colonoscopy (CS) as the first-line treatment for CDB with extravasation on CECT. The primary outcome was rebleeding rate within 30 days after first-line treatment. In total, 165 CDB cases with extravasation on CECT (TAE group, n = 39; CS group, n = 126) were analyzed in this study. The rebleeding rate within 30 days was significantly lower in the TAE group (7.69%) than in the CS group (23.02%; P = .038). The bleeding point detection rate was significantly higher in the TAE group (89.74%, 35/39) than in the CS group (37.30%, 47/126; P < .0001). Even in those cases in which a bleeding point was detected, the rebleeding rate was significantly lower in the TAE group (0%) than in the endoscopic hemostasis-success group (23.91%; P = .005). No severe complications of Grade 3 or more were seen with TAE. We showed that TAE is an effective, safe hemostatic method, and a useful alternative to endoscopic hemostasis for first-line treatment of CDB., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Herein, we describe a case of olmesartan-related sprue-like enteropathy in which improvement in villous atrophy was confirmed by small-bowel capsule endoscopy (CE). We successfully treated a 66-year-old man with a chief complaint of loose diarrhea. The patient had persistent watery diarrhea 10 times a day and experienced a weight loss of 9 kg in 3 months. An abdominal computed tomography scan showed fluid retention in the small intestine. Blood test results revealed no inflammatory reaction. Esophagogastroduodenoscopy detected villous atrophy in the stomach and duodenum. Moreover, small-bowel CE showed villous atrophy in about two-thirds of the small intestine. Based on other examinations, hyperthyroidism, intestinal tuberculosis, intestinal amyloidosis, and intestinal malignant lymphoma were ruled out. Therefore, the patient was suspected of having an olmesartan-related sprue-like disease. Early after discontinuation of medication, diarrhea symptoms improved, and a repeat CE indicated improvements in small intestinal villous atrophy. Since the patient had been administered olmesartan for a long time and CE showed villous atrophy throughout the small bowel, we suspected him of having the olmesartan-associated sprue-like disease. The findings of gastric mucosa atrophy on esophagogastroduodenoscopy may lead to an early diagnosis of this disease. Olmesartan-related sprue-like enteropathy should be considered as a differential diagnosis in patients with chronic severe watery diarrhea., Competing Interests: None., (© 2022 The Authors. DEN Open published by John Wiley & Sons Australia, Ltd on behalf of Japan Gastroenterological Endoscopy Society.)

Background/aims: Detailed evaluations of overlapping constipation and gastroesophageal reflux disease (GERD) have not been conducted in Japan. The REACTION-J2 study examined the overlap of these diseases in Japan., Methods: This internet-based survey recruited participants from general public survey panels. Questions included demographic and medical data and assessments based on validated measures for constipation and GERD. Associations between background factors affecting constipation/GERD overlap, disease measures, and treatment were also evaluated., Results: Among 10 000 survey responses received, functional constipation (Rome IV diagnostic criteria) was reported by 439 participants; chronic constipation (Japanese guidelines) by 3804 participants; and subjective constipation symptoms by 2563 participants. The number of participants with constipation/GERD overlap ranged from 73 to 1533 depending on the criteria used. Regardless of the definition used, all GERD groups had significantly higher odds of being constipated than non-GERD participants: the OR (95% CI) for all 9 combinations of definitions ranged between 1.56 (1.21, 2.01) and 2.67 (2.44, 2.92) (all P ≤ 0.001). Straining, hard stools, and sensations of incomplete evacuation and anorectal obstruction/blockage, according to chronic constipation criteria, were common. Participants with constipation/GERD overlap had poorer quality of life ( P < 0.001) and worse GERD symptom scores ( P < 0.001). The frequency of abnormal stools was highest ( P < 0.001) in the constipation/GERD overlap group. In the overlap group, 52.4% and 26.0% used gastric and constipation medication, respectively., Conclusion: Individuals with constipation/GERD overlap tend to have worsened symptoms and quality of life.

A 62-year-old man was referred to our hospital because of abdominal pain. Computed tomography revealed an approximately 7-cm-diameter tumor in the left abdomen with metastatic lymph nodes, an approximately 1-cm-diameter round tumor in contact with the subclavian artery in the apical lobe of the right lung, and mediastinal lymph node enlargement in contact with the superior vena cava. Esophagogastroduodenoscopy and colonoscopy revealed no abnormalities. Double-balloon endoscopy revealed a whole circumferential ulcer in the jejunum approximately 20 cm from the ligament of Treitz. Biopsy analysis of an ulcer specimen revealed a poorly differentiated carcinoma. Immunohistochemical staining of the specimen showed that it was positive for thyroid transcription factor 1 and cytokeratin 7 and negative for cytokeratin 20, GATA-binding protein 3, caudal-type homeobox protein 2, and paired box 8. Positron emission tomography revealed positive findings in the small-intestinal tumor, nearby mesenteric lymph nodes, lymph nodes around the abdominal aorta, lung tumor, and mediastinal lymph node in the apical lobe of the right lung. Accordingly, the patient was diagnosed as having a lung carcinoma with small-intestinal metastasis (T1b, N3, M1c; cStage IVB). Pathological examination helped distinguish the primary small-intestinal tumor from the metastatic small-intestinal tumor and detect the tumor origin., Competing Interests: The authors declare no conflicts of interest pertaining to this manuscript., (Copyright © 2022 by S. Karger AG, Basel.)

Gastric plexiform fibromyxoma is extremely rare. In our case, upper gastrointestinal endoscopy of a 41-year-old woman patient revealed a 1-cm submucosal tumor (SMT) in the greater curvature of the lower body of the stomach. On contrast-enhanced computed tomography, the tumor was hypervascular in the arterial phase with continuous enhancement in the post-venous phase. On endoscopic ultrasonography, it had a low echo pattern. The preoperative diagnosis was a gastric SMT with a rich vasculature; however because the biosy specimen did not contain tumor tissue, a malignant tumor could not be excluded. The patient underwent nonexposed endoscopic wall-inversion surgery (NEWS), and the tumor was completely resected. Immunohistochemical examination revealed that the tumor was positive for D2-40 and α-smooth muscle actin, but negative for c-kit, discovered on gastrointestinal stromal tumor-1, desmin, S100, Melan-A, signal transducer and activator of transcription 6, insulinoma-associated protein 1, CXCL13, ETS transcription factor, follicular dendritic cell, anaplastic lymphoma kinase, human melanoma black, h-caldesmon, and CD1a, 10, 21, 23, 31, 34, 68, and 163. Approximately, 1-2% of the tumor cell nuclei were Ki-67-positive. Finally, we diagnosed the tumor as a plexiform fibromyxoma. In conclusion, NEWS is an effective method for the treatment of SMTs with a diameter of <3 cm., Competing Interests: The authors declare that they have no conflict of interest., (Copyright © 2022 by S. Karger AG, Basel.)

p53 immunohistochemistry is considered an accurate surrogate marker reflecting the underlying TP53 mutation status and has utility in tumor diagnostics. In the present study, 269 primary CRCs were immunohistochemically evaluated for p53 expression to assess its utility in diagnostic pathology and prognostication. p53 expression was wild-type in 59 cases (23%), overexpressed in 143 cases (55%), completely lost in 50 cases (19%), and cytoplasmic in 10 cases (4%). p53 immunoreactivity was associated with tumor size (p = 0.0056), mucus production (p = 0.0015), and mismatch repair (MMR) system status (p < 0.0001). Furthermore, among CRCs with wild-type p53 expression, a significantly higher number of cases had decreased CDX2 than those with p53 overexpression (p = 0.012) or complete p53 loss (p = 0.043). In contrast, among CRCs with p53 overexpression, there were significantly fewer ALCAM-positive cases than p53 wild-type cases (p = 0.0045). However, no significant association was detected between p53 immunoreactivity and the “stem-like” immunophenotype defined by CDX2 downregulation and ALCAM-positivity. Multivariate Cox hazards regression analysis identified tubular-forming histology (hazard ratio [HR] = 0.17, p < 0.0001), younger age (HR = 0.52, p = 0.021), and female sex (HR = 0.55, p = 0.046) as potential favorable factors. The analysis also revealed complete p53 loss (HR = 2.16, p = 0.0087), incomplete resection (HR = 2.65, p = 0.0068), and peritoneal metastasis (HR = 5.32, p < 0.0001) as potential independent risk factors for patients with CRC. The sub-cohort survival analyses classified according to chemotherapy after surgery revealed that CRC patients with wild-type p53 expression tended to have better survival than those with overexpression or complete loss after chemotherapy. Thus, immunohistochemistry for p53 could be used for the prognostication and chemotherapy target selection of patients with CRC.

Background: Functional constipation (FC), a functional bowel disorder with symptoms of constipation, has considerable impact on quality of life. As data regarding its prevalence and epidemiology are lacking, this study aimed to evaluate the prevalence, population composition, lifestyle, quality of life, and clinical characteristics of these individuals by comparing people with and without FC. These parameters were also compared among individuals with strong and weak awareness of constipation., Methods: An internet survey was conducted among 10,000 individuals aged 20-69 years from the general Japanese population; they were registered with an internet survey company. The following data were obtained: age, sex, educational history, occupation, residence, history of other diseases, lifestyle (including smoking/drinking habits using the Japanese Health Practice Index, medication use, symptoms of constipation according to the Rome III criteria, stool types according to the Bristol stool scale, and use of laxatives, including the place of purchase and cost per month or acceptable cost per month. The 8-item Short Form Health Survey Questionnaire was also used; FC was diagnosed based on Rome III criteria. All respondents were classified according to their awareness of constipation (i.e. strong or weak), and their characteristic features were compared., Results: The data of 3000 respondents were evaluated; 262 (8.7%) had FC, which was common among older adults, women, and homemakers. FC was associated with changes in the frequency of bowel movement, sensation of incomplete or scanty evacuation, and the use of manual maneuvers; these are consequential clinical symptoms of FC. These individuals frequently skipped breakfast, had insufficient sleep, had more severe constipation, and had purchased laxatives in pharmacies or online more often than those without FC. A strong awareness of constipation was significantly more prevalent among women and homemakers. A history of anemia and cardiovascular disease was significantly more frequent in the strong awareness group, whereas a history of hypertension was more frequent in the weak awareness group., Conclusions: Appropriate and comprehensive management should be provided for FC, based on the understanding of its characteristic features and considering the symptoms and lifestyle., (© 2022. The Author(s).)

Dysregulation of mitochondrial quality control has been reported to be associated with cancer and degenerative diseases. SPATA18 (spermatogenesis-associated 18, also known as Mieap) encodes a p53-inducible protein that can induce lysosome-like organelles within mitochondria that eliminate oxidized mitochondrial proteins and has tumor suppressor functions in mitochondrial quality control. In the present study, 268 primary colorectal cancers (CRCs) were evaluated immunohistochemically for SPATA18 expression to assess its predictive utility and its association with cellular proliferation activity. Furthermore, the association with p53 immunoreactivity, a surrogate marker for TP53 mutation, was analyzed. Non-neoplastic colonic mucosa showed cytoplasmic SPATA18 expression. Seventy-two percent of the lesions (193/268) displayed high SPATA18 expression in the cytoplasm of CRC cells. Univariate analyses revealed significant associations between SPATA18 expression and tumor size (p < 0.0001), histological differentiation (p = 0.0017), and lymph node metastasis (p = 0.00039). The log-rank test revealed that patients with SPATA18-high CRCs had significantly better survival than SPATA18-low patients (p < 0.0001). Multivariate Cox hazards regression analysis identified tubular-forming histology (hazard ratio [HR] = 0.25), age < 70 years (HR = 0.50), and SPATA18-high (HR = 0.55) as potential favorable factors. Lymph node metastasis (HR = 1.98) and peritoneal metastasis (HR = 5.45) were cited as potential independent risk factors. Cellular proliferation activity was significantly higher in SPATA18-high tumors. However, no significant correlation was detected between SPATA18 expression and p53 immunoreactivity or KRAS/BRAF mutation status. On the basis of our observations, SPATA18 immunohistochemistry can be used in the prognostication of CRC patients.

(1) Background: Additional surgical resection after endoscopic resection (ER) is recommended for patients with submucosal invasive colorectal cancer (pT1 CRC) who have risk factors for lymph node metastasis (LNM) (high-risk pT1 CRC). This study aimed to identify risk factors for LNM and metastatic recurrence and to determine the low-risk population for whom additional surgery can be omitted among high-risk pT1 CRCs. (2) Methods: We retrospectively identified 404 patients with pT1 CRC who underwent ER or surgery, and patients were divided into three groups: low-risk ( n = 79); high-risk pT1 with ER ( n = 40); and high-risk with surgery ( n = 285). We also enrolled another 64 patients with high-risk pT1 CRC in an independent validation cohort. (3) Results: In the high-risk with surgery group, LNM was seen in 11.2%, and vascular and lymphatic invasions were significantly independent risk factors for LNM on multivariate analysis. No LNMs were observed in pT1 CRCs with a negative vertical margin and SM invasion depth ≤2000 µm that had no other risk factors except for budding. Five patients developed metastatic recurrence in the high-risk with surgery group, and rectal cancer and undifferentiated histology were significantly independent risk factors for poor relapse-free survival. No LNM or recurrent cases were seen in high-risk pT1 CRCs that met these criteria: differentiated adenocarcinoma, no lymphovascular invasion, colon cancer, SM invasion depth ≤2000 μm, and a negative vertical margin, which were validated in an independent validation cohort. (4) Conclusions: Completion surgery may be skipped for high-risk pT1 CRCs that meet our proposed criteria.

Colorectal cancer (CRC) is one of the most frequent gastrointestinal malignancies with high morbidity and mortality rates. Several biological markers for the prognostication of patient outcome of CRCs are available. Recently, our group identified two favorable factors for the survival of CRC patients: PDZ-binding kinase (PBK) and phospho-histone H3 (PHH3). Both showed a significant inverse association to pT stage. The aim of this study was to uncover the mechanism through which these cellular proliferation-associated protein expressions lead to favorable clinical outcome in CRC patients. We first confirmed co-expression of PBK and PHH3 in CRC cells. Further investigation showed that aberrantly expressed PBK up-regulated the cellular proliferation of CRC cells with accumulation of PHH3. The PBK inhibitor OTS514 suppressed cellular proliferation of CRC cells through down-regulation of PHH3 and induction of apoptosis. In vitro studies revealed that PBK suppressed the migration and invasion of CRC cells with suppression of Wnt/β-catenin signaling and CDH1 stabilization. Exogeneous PBK up-regulated the phosphorylated CDH1 at S840, S846, and S847 residues in cultured cells. Recombinant PBK directly phosphorylated HH3; however, it failed to phosphorylate CDH1 directly in vitro . The present study demonstrated the association of two markers PBK and PHH3 in CRC. We further identified one of the potential mechanisms by which higher expression of these cellular proliferation-associated proteins leads to the better survival of CRC patients, which likely involves PBK-mediated suppression of the migration and invasion of CRC cells. Our findings suggest that PBK-targeting therapeutics may be useful for the treatment of CRC patients with PBK-expressing tumors., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Koshino, Nagano, Ota, Hyodo, Ueki, Komura, Sugimura-Nagata, Ebi, Ogasawara, Kasai, Hosokawa, Kasugai, Takahashi and Inaguma.)

Background: We had previously reported that the administration of Gastrografin through a nasogastric tube (NGT-G) followed by long tube (LT) strategy could be a novel standard treatment for adhesive small bowel obstruction (ASBO); however, the long-term outcomes after initial improvement remain unknown. This study aimed to analyze the long-term outcomes of first-line NGT-G., Methods: Enrolled patients with ASBO were randomly assigned to receive LT or NGT-G between July 2016 and November 2018. Thereafter, the cumulative surgery rate, cumulative recurrence rate, and overall survival (OS) rate were analyzed. In addition, subset analysis was conducted to determine the cumulative recurrence rate according to colonic contrast with Gastrografin at 24 h., Results: A total of 223 patients (LT group, n = 111; NGT-G group, n = 112) were analyzed over a median follow-up duration of 550 days. The cumulative 1-year surgery rates, cumulative 1-year recurrence rates, and 1-year OS rates in the LT and NGT-G groups were 18.8% and 18.1%, 30.0% and 31.7%, and 99.1% and 96.6%, respectively; no significant differences were observed between both groups. In the NGT-G group, a negative colonic contrast at 24 h demonstrated a higher tendency for future recurrence compared with a positive colonic contrast at 24 h (1-year recurrence rate: negative contrast, 46.9% vs positive contrast, 27.6%)., Conclusions: Gastrografin through a nasogastric tube followed by LT can be a promising treatment strategy for ASBO, with long-term efficacies equivalent to initial LT placement., (© 2021 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Background/aims: Chronic constipation and lifestyle factors can affect sleep quality. We evaluated the relationship between chronic constipation and sleep in the Japanese population., Methods: This cross-sectional internet-based survey included 3000 subjects with constipation, classified according to sleep status (good/poor). Primary endpoints were Bristol stool form scale (BSFS) score and correlations between sleep disorder criteria of the Pittsburgh Sleep Quality Index (PSQI) and sleep status (good/poor sleep). Secondary endpoints included correlations between quality of life (QOL) and mood, medical, lifestyle, and sleep factors., Results: The proportion of participants with BSFS category 4 (normal stool) was significantly higher in the good sleep group ( P < 0.001). Sleep disturbance ( P < 0.05), sleep quality, and duration, use of hypnotic medication, and daytime dysfunction of PSQI (all P < 0.001) significantly correlated with poor sleep. In the poor sleep group, QOL was significantly worse and anxiety and depression levels were significantly higher (all P < 0.001) compared with the good sleep group. Anemia and smoking (both P < 0.05), recent body weight increases, and poor eating habits (all P < 0.001) were significantly higher in the poor sleep group. Male sex, onset associated with change in frequency of stools, sensation of incomplete evacuation for at least 25% of defecations, and manual maneuvers to facilitate at least 25% of defecations correlated with poor sleep., Conclusions: Subjects with constipation and poor sleep experienced severe symptoms and had poor QOL. These data support the need for a multifocal treatment approach, including lifestyle advice and pharmacotherapy.

Purpose: Endoscopic clipping closure after colorectal endoscopic submucosal dissection (ESD) did not reduce the incidence of post-ESD coagulation syndrome (PECS) in our recent randomized controlled trial (RCT); however, the definition of PECS is still controversial. The aim of this study is to establish optimal definition of PECS with additional analysis of RCT based on another definition., Methods: In this multicenter, single-blind RCT, individuals were randomly assigned to colorectal ESD followed by endoscopic clipping closure or non-closure. In this post hoc analysis, the definition of PECS was modified as both localized abdominal pain on visual analogue scale and inflammatory response (fever or leukocytosis), from either localized abdominal pain or inflammatory response in the original study. All participants underwent a computed tomography after ESD, and PECS was classified into type I, conventional PECS without extra-luminal air, and type II, PECS with peri-luminal air., Results: A total of 155 patients (84 in the non-closure group and 71 in the closure group) were analyzed. As a result of criteria modification, 21 type I PECS and four type II PECS cases in the original study, which included patients with clear pain and inflammatory response, were downgraded to no adverse event and simple peri-luminal air, respectively. The frequency of PECS showed no significant difference between non-closure and closure groups., Conclusion: Clipping closure after colorectal ESD does not reduce the incidence of PECS regardless of the diagnostic criteria. Either localized abdominal pain or inflammatory response might be optimal criteria of PECS (UMIN000027031)., Trial Registration Number: UMIN000027031 DATE OF REGISTRATION: April 18, 2017.

Colorectal cancer (CRC) is one of the most frequent gastrointestinal cancers worldwide, with high morbidity and mortality rates. Despite numerous attempts to identify prognostic markers for the CRC patients, the significance of the association of cellular proliferation markers with survival is controversial. Here we used immunohistochemistry to detect four markers of cellular proliferation expressed in primary CRC tissue specimens (n = 269) to assess their potential to serve as prognostic factors. CRC cells variably expressed phospho-histone H3 (PHH3) (range, 0-76 per high-powered field (HPF); median, 7 per HPF), cyclin A (CCNA) (range, 11.3-73.7%; median, 32%), geminin (GMNN) (range, 7.8-82.0%; median, 37.1%), and marker of proliferation Ki-67 (MKI67) (range, 4.9-96.6%; median, 49.6%). Among them, patients with PHH3-high (≥7 per HPF) tumors uniquely experienced significantly longer 5-year survival than those with PHH3-low (≤6 per HPF) (81.8% vs. 65.5%; P = 0.0047). Multivariable Cox hazards regression analysis identified PHH3-high (hazard ratio, 0.54; 95% confidence interval, 0.31-0.92; P = 0.025) as potential favorable factors. PHH3 levels inversely associated with pT stage (P < 0.0001) and were significantly and inversely associated with tumor diameter (ρ = -0.314, P < 0.0001). These findings support the use of PHH3 immunohistochemistry for predicting the prognoses of patients with CRC., (© 2021 Japanese Society of Pathology and John Wiley & Sons Australia, Ltd.)

Despite the confirmed anti-cancer effects of T-cell immune checkpoint inhibitors, in colorectal cancer (CRC) they are only effective in a small subset of patients with microsatellite-unstable tumors. Thus, therapeutics targeting other types of CRCs or tumors refractory to T-cell checkpoint inhibitors are desired. The binding of aberrantly expressed CD47 on tumor cells to signal regulatory protein-alpha (SIRPA) on macrophages allows tumor cells to evade immune destruction. Based on these observations, drugs targeting the macrophage checkpoint have been developed with the expectation of anti-cancer effects against T-cell immune checkpoint inhibitor-refractory tumors. In the present study, 269 primary CRCs were evaluated immunohistochemically for CD47, SIRPA, CD68, and CD163 expression to assess their predictive utility and the applicability of CD47-SIRPA axis-modulating drugs. Thirty-five percent of the lesions (95/269) displayed CD47 expression on the cytomembrane of CRC cells. CRCs contained various numbers of tumor-associated immune cells (TAIs) with SIRPA, CD68, or CD163 expression. The log-rank test revealed that patients with CD47-positive CRCs had significantly worse survival than CD47-negative patients. Multivariate Cox hazards regression analysis identified tubular-forming histology (hazard ratio (R) = 0.23), age < 70 years (HR = 0.48), and high SIRPA-positive TAI counts (HR = 0.55) as potential favorable factors. High tumor CD47 expression (HR = 1.75), lymph node metastasis (HR = 2.26), and peritoneal metastasis (HR = 5.80) were cited as potential independent risk factors. Based on our observations, CD47-SIRPA pathway-modulating therapies may be effective in patients with CRC.

Aseptic abscesses (AAs) are extraintestinal manifestations of inflammatory bowel disease (IBD). IBD-associated AAs are rare in Japan. We treated a 45-year-old man with ulcerative colitis (UC)-associated AAs. During remission, multiple progressive abscesses were detected in the spleen; he underwent splenectomy because an infectious disease was suspected. Although his condition improved temporarily after splenectomy, a large liver abscess was noted, and a diagnosis of UC-associated AAs was made. Granulocytapheresis (GCAP) and infliximab (IFX) administration resolved the abscess. This is the first reported case of UC-associated AAs in a Japanese patient treated by splenectomy, GCAP, and IFX.

Background: With the goal of discovering non-invasive biomarkers for early diagnosis of GC, we conducted a case-control study utilising urine samples from individuals with predominantly early GC vs. healthy control (HC)., Methods: Among urine samples from 372 patients, age- and sex-matched 282 patients were randomly divided into three groups: 18 patients in a discovery cohort; 176 patients in a training cohort and 88 patients in a validation cohort., Results: Among urinary proteins identified in the comprehensive quantitative proteomics analysis, urinary levels of TFF1 (uTFF1) and ADAM12 (uADAM12) were significantly independent diagnostic biomarkers for GC, in addition to Helicobacter pylori status. A urinary biomarker panel combining uTFF1, uADAM12 and H. pylori significantly distinguished between HC and GC patients in both training and validation cohorts. On the analysis for sex-specific biomarkers, this combination panel demonstrated a good AUC of 0.858 for male GC, whereas another combination panel of uTFF1, uBARD1 and H. pylori also provided a good AUC of 0.893 for female GC. Notably, each panel could distinguish even stage I GC patients from HC patients (AUC = 0.850 for males; AUC = 0.845 for females)., Conclusions: Novel urinary protein biomarker panels represent promising non-invasive biomarkers for GC, including early-stage disease.

Background: Gastrointestinal decompression is generally applied to a non-strangulated acute small bowel obstruction (NSASBO). Although long tube (LT) placement and administration of Gastrografin through a nasogastric tube (NGT-G) have shown advantages over NGT alone in previous studies, no studies appear to have compared LT and NGT-G., Methods: In this multicenter, randomized controlled trial, patients with NSASBO were randomly assigned to receive LT or NGT-G between July 2016 and November 2018 at 11 Japanese institutions. The primary endpoint was non-inferiority of NGT-G compared to LT for non-surgery rate, and the lower limit of the 95% confidence interval for the non-surgery rate (-15%) was set as the lower margin for inferiority of NGT-G compared to LT., Results: In total, 223 patients (LT group, n = 111; NGT-G group, n = 112) were analyzed in the present trial. The non-surgery rate was 87.4% in the LT group and 91.1% in the NGT-G group, with a 3.7% difference between NGT-G and LT (95.3%CI - 5.55 to 12.91; non-inferiority P = 0.00002923). On the other hand, the non-surgery rate with pure NGT-G alone (76.8%) that represents non-cross-over NGT-G without subsequent LT was significantly lower than that with LT (P = 0.039). Median procedure time was significantly shorter with NGT-G (1 min) than with LT (25 min; P < 0.001), whereas no significant differences in mortality or hospital stay were noted between groups., Conclusion: NGT-G is an effective alternative to LT as a first-line treatment for NSASBO. A sequential strategy comprising NGT-G followed by LT might offer a new standard for NSASBO., Clinical Trials Registration: This trial was registered with the University Hospital Medical Information Network Clinical Trials Registry (umin.ac.jp/ctr Identifier: UMIN000022669) prior to the start of this trial.

Background and Aims: Post endoscopic submucosal dissection coagulation syndrome (PECS) occasionally occurs after colorectal endoscopic submucosal dissection (ESD), presenting with localized abdominal pain and inflammation. We conducted a randomized controlled trial (RCT) to assess the usefulness of endoscopic clipping closure to prevent PECS and delayed perforation (DP)., Methods: This is a multicenter, single-blind RCT. Prospectively enrolled patients undergoing colorectal ESD were randomly allocated to endoscopic clipping closure and nonclosure after ESD, stratifying by institution and tumor size. All participants underwent a computed tomography scan after ESD. PECS was defined as visual analog scale (VAS) ≥30 mm, an increase in VAS ≥20 mm from baseline, body temperature ≥37.5°C or white blood cells ≥10,000/μL after colorectal ESD. DP was defined as PECS accompanied by extraluminal air. The preplanned sample size was 320 patients, and the primary endpoint was the rate of PECS/DP., Results: At the planned interim analysis, this trial was terminated by recommendation of the independent data and safety monitoring committee because conditional power with superiority was lower than the preplanned futility limit. Finally, 155 patients were analyzed. The rate of PECS/DP was 16% (95% confidence interval [CI], 8%-23%) in the nonclosure group and 24% (95% CI, 14%-34%) in the closure group (P = .184). All cases of DP were within minor criteria, and all PECS/DP patients were managed conservatively without surgical treatment. Simple periluminal air without PECS was observed in 16% (95% CI, 8%-23%) in the nonclosure group and 10% (95% CI, 3%-17%) in the closure group., Conclusion: Endoscopic clipping closure could not reduce the high incidence of PECS/DP after colorectal ESD. (University Hospital Medical Network Clinical Trials Registry number: UMIN000027031.)., (Copyright © 2020 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.)

Atrial fibrillation (AF) is the most common cardiac arrhythmia, and radiofrequency catheter ablation (RFCA) for pulmonary vein isolation is a well-established therapeutic modality for AF. Transient gastroparesis rarely complicates RFCA. We report two cases of RFCA-induced transient gastroparesis, effectively treated with mosapride citrate administration. Case 1. Computed tomography (CT) performed 4 days after RFCA revealed marked gastric dilatation without any gastric or intestinal obstruction. The patient was fasting and was administered mosapride citrate (5 mg thrice a day). The patient's symptoms improved 6 days later, and CT revealed no gastric dilatation. Esophagogastroduodenoscopy revealed gastric peristalsis without residual food in the stomach. Case 2. CT performed 8 days after RFCA revealed marked gastric dilatation without any gastric or intestinal obstruction. The patient was fasting and was administered pantothenic acid (500 mg/day intravenously for 7 days). However, symptoms persisted, and CT revealed residual food in the stomach. The patient was subsequently administered mosapride citrate (5 mg thrice a day). The patient's symptoms improved 4 days later, and contrast-enhanced gastric X-ray using amidotrizoate meglumine revealed gastric peristalsis, passage of amidotrizoate meglumine into the duodenum, and no gastric dilatation. Mosapride citrate is useful to treat RFCA-induced gastroparesis.

Duodenal gangliocytic paragangliomas are extremely rare. A 79-year-old woman underwent gastrointestinal endoscopy for screening prior to resection of gallbladder carcinoma. Gastrointestinal endoscopy revealed a 5-mm submucosal tumor in the second portion of the duodenum. Contrast-enhanced computed tomography revealed no tumor or metastasis. Endoscopic ultrasonography revealed low echo pattern of the tumor. Histopathological examination of the biopsy specimen revealed proliferation of three types of cells (epithelioid cells, spindle cells, and ganglion cells). Immunohistochemical examination revealed that the tumor was positive for S-100 and synaptophysin. The preoperative diagnosis was gangliocytic paraganglioma. The tumor was completely resected by endoscopic mucosal resection (EMR). In conclusion, an early stage of gangliocytic paraganglioma of the duodenum could be resected using EMR.

The role of enterobacterial flora in the onset and progression of inflammatory bowel diseases is a topic of considerable interest. Here, we assessed the association among enterobacterial flora, dietary factors, and ulcerative colitis (UC) progression. Forty-six patients with UC who were diagnosed as being in remission were enrolled. We collected each patient's stool sample one or two days before diagnostic colonoscopy. After colonoscopy, we observed the patients for one year and then retrospectively divided them into two groups: remission ( n  = 39) and relapse ( n  = 7) groups, depending on whether the relapse occurred during the follow-up period, and analyzed the relationship among patient characteristics, dietary factors, enterobacterial flora, and UC relapse. Overall, there were no significant differences in bacterial community populations between the remission and relapse groups, except that the order Lactobacillales was detected at a significantly higher rate in the relapse than in the remission group (100% vs 71.4%, p <0.05). Vitamin C intake was significantly higher in the remission than in the relapse group ( p <0.05). Although there were no obvious differences in enterobacterial flora between the remission and relapse groups, there was a relationship among enterobacterial flora, diet, and UC progression. Given that the enterobacterial flora was only analyzed at the initiation of the study, we conclude that in future analyses, enterobacterial flora should be sampled at numerous time points to examine its role in UC progression. Further long-term longitudinal studies examining enterobacterial flora, dietary factors, and UC progression are also required., Competing Interests: KK received lecture fees from Daiichi Sankyo Co., Ltd., Astra Zeneca Co., Ltd., EA Pharma Co., Ltd., Mylan Co., Ltd., Sanwa Kagaku Kenkyusho Co., Ltd., and Takeda Pharmaceutical Co., Ltd. KK received research grants from Astellas Co., Ltd., Daiichi Sankyo Co., Ltd., EA Pharma Co., Ltd., Mitsubishi Tanabe Pharma Co., Ltd., and Takeda Pharmaceutical Co., Ltd. The other authors have no conflicts of interest to declare., (Copyright © 2020 JCBNCopyright © 2020 JCBN.)

Mesothelin (MSLN) is a glycophosphatidylinositol (GPI)-linked cell surface protein that is highly expressed in several types of malignant tumor, including malignant pleural mesothelioma, ovarian cancer and pancreatic adenocarcinoma. Recently, a comprehensive immunohistochemical study using MN-1 monoclonal antibody identified a significant number of colorectal tumors in which MSLN was expressed. However, the clinicopathological profiles and survival of patients with MSLN-positive colorectal cancer have not been fully analyzed. In the current study, the expression of MSLN in 270 primary and 44 metastatic colorectal tumors was immunohistochemically analyzed to determine the clinical usefulness of MSLN immunohistochemistry and to identify potential candidates for future anti-MSLN therapy. In vitro experiments using colon cancer cell lines were performed to investigate the biological significance of MSLN expression in tumors. The results of univariate analyses identified a significant correlation between MSLN expression and females (P=0.0042). Furthermore, an inverse correlation between MSLN expression and solid/sheet-like proliferation (P=0.014) was also revealed. Additionally, overall survival was significantly shorter in patients with diffuse luminal/membranous expression of MSLN (P=0.018). Multivariable Cox hazards regression analysis revealed diffuse MSLN expression (hazard ratio, 2.26; 95% confidence interval, 1.04-4.91; P=0.039) as a potential risk factor. When comparing primary CRCs and the metastasis of each, a weakly positive correlation was identified for MSLN positivity (% positive cells; R=0.484; P<0.0001). The in vitro experiments revealed a positive role for MSLN in colon cancer cell proliferation. Thus, MSLN immunohistochemistry may be useful in the prognostication of patients with CRC. The results demonstrated that significant numbers of patients with MSLN-positive CRC exhibiting metastasis could be targeted by anti-MSLN therapies., (Copyright: © Inoue et al.)

We experienced marked efficacy with steroid treatment of three patients with jackhammer esophagus (JHE). An esophageal biopsy revealed eosinophilic esophagitis (EoE) in two patients. One of the patients without EoE had eosinophilia and an increased serum immunoglobulin E level, and endoscopic ultrasonography revealed thickening of the esophageal muscularis propria. Esophageal manometry was used to diagnose all cases of JHE. Treatment consisted of steroid administration, which improved the symptoms and resolved the esophageal muscularis propria thickening in all patients. The esophageal manometry findings also normalized following treatment. Allergic diseases, including EoE, were assumed to have caused JHE.

Recent studies have shown that colorectal serrated lesions, which include sessile serrated adenomas (SSAs) and traditional serrated adenomas (TSAs), are precursors of colorectal cancer. However, the molecular mechanisms underlying the carcinogenesis, particularly in TSAs, remain largely uncharacterized. To clarify their molecular and clinicopathological characteristics, we performed mutation and methylation analyses of cancer-associated genes in 78 serrated lesions, including TSAs, SSAs and microvesicular hyperplastic polyps. Target exon sequence analysis was performed with 39 genes, including genes known to be frequently mutated in colorectal cancers and/or serrated lesions. We also used bisulfite pyrosequencing to assess the methylation status of various cancer-associated genes and marker genes of the CpG island methylator phenotype (CIMP). The prevalence of mutations in genes associated with Wnt signaling was significantly higher in TSAs than SSAs (65% vs. 28%, p < 0.01). Among those, RNF43 mutations were observed in 38% of TSAs and 17% of SSAs. In immunohistochemical studies of 39 serrated lesions, the prevalence of abnormal nuclear β-catenin accumulation was significantly higher in TSAs (57%) than SSAs (8%) (P = 0.01). SMOC1 methylation was detected in 54% of TSAs but in no SSAs (p < 0.01). Additionally, SMOC1 methylation was more prevalent among TSAs with KRAS mutation (82%) than with BRAF mutation (38%, p = 0.03). Lesions with CIMP-high or RNF43 mutations were detected only in TSAs with BRAF mutation, suggesting two distinct carcinogenic pathways in TSAs. Mutations in genes associated with Wnt signaling play a greater role in the carcinogenesis of TSAs than SSAs., Competing Interests: The authors have declared that no competing interests exist.