Antacids and reflux esophagitis as a risk factor for gastric neoplasm of fundic-gland type: A retrospective, matched case-control study.

BACKGROUND AND AIM: Since the first report of gastric adenocarcinoma of the fundic-gland type in 2010, the clinicopathological characteristics of gastric neoplasm of the fundic-gland type (GNFG) have become clearer; however, their risk factors remain unclear. This exploratory study aimed to identify the risk factors for GNFG. METHODS: We conducted a single-center, retrospective, matched case-control study using medical information recorded at our health management center from January 2014 to July 2023. During this period, 39 240 people underwent upper gastrointestinal endoscopy. GNFG were extracted as cases and matched to controls, according to age and sex, in a 1:8 ratio, excluding those with a history of gastrointestinal surgery and those with a history or comorbidity of cancer. Univariate analysis was used to compare patient background and endoscopic findings. Multivariable analysis was performed, adjusting for factors with P values < 0.1 and antacid use. RESULTS: A total of 20 GNFG cases and 160 matched healthy controls were included. In the univariate analysis, only reflux esophagitis was significantly more common in GNFG (40.0% vs 18.1%; P = 0.036). Factors antacids and duodenitis had P values < 0.1. Logistic regression analysis was performed, adjusting for antacids, reflux esophagitis, and duodenitis. Antacids and reflux esophagitis were the independent risk factors for GNFG (odds ratio = 3.68 [95% confidence interval: 1.04-11.91] and 3.25 [95% confidence interval: 1.11-9.35]). CONCLUSIONS: Although the sample of patients with GNFG was small, antacids and reflux esophagitis were identified as a risk factor. The pathogenesis of antacids and reflux esophagitis may be involved in the development of GNFG.

Guidelines for endoscopic balloon dilation in treating Crohn's disease-associated small intestinal strictures (supplement to the Clinical Practice Guidelines for Enteroscopy).

Balloon-assisted enteroscopy allows endoscopic treatments in the deeper segments of the small bowel. Endoscopic balloon dilation has become a popular minimally invasive alternative for the treatment of Crohn's disease-associated small intestinal strictures. As a supplement to the Clinical Practice Guidelines for Enteroscopy, the Japan Gastroenterological Endoscopy Society's Working Committee has developed the present "Guidelines for endoscopic balloon dilation in treating Crohn's disease-associated small intestinal strictures," based on new scientific techniques and evidence. The guidelines cover standard procedures for the insertion route of the balloon endoscope, bowel preparation, indications, procedure-related complications, efficacy, target diameter and duration, management of multiple strictures, and the current state of combined and alternative treatments. Unresolved future research questions are also listed in this guideline.

Clipping with double-balloon endoscopy for small intestinal venous malformations in a patient with blue rubber bleb nevus syndrome.

Blue rubber bleb nevus syndrome (BRBNS) is a rare syndrome characterized by venous malformations in the skin and gastrointestinal tract, especially in the small intestine. Patients with BRBNS have increased risks of gastrointestinal hemorrhage and anemia. This is the first report in the English literature on BRBNS with hemangiomas in the small intestine that were treated successfully by endoscopic clipping using double-balloon endoscopy. A 25-year-old Japanese man presented to a local clinic with dyspnea, fatigue, and a hemoglobin level < 5 g/dL. The diagnosis was iron deficiency anemia. Since childhood, he had had a hemangioma in the shoulder joint and hemangiomas in the skin on the left arm. However, neither upper nor lower gastrointestinal endoscopy showed any lesions and he was referred to us for further evaluation and treatment of the anemia. Small bowel capsule endoscopy (SBCE) revealed hemangiomas in the small intestine, one of which was bleeding. Transanal DBE revealed a 10-mm bluish-purple hemangioma with erosion on the surface, which became smaller after application of five clips. Follow-up SBCE on day 50 showed that the hemangioma had completely disappeared. Clipping may be a safe and effective treatment for small bowel hemangioma in BRBNS.

Evaluation of personal exposure of workers to indium concentrations in total dust and its respirable fraction at three Japanese indium plants.

This study aimed to evaluate personal exposures of 27 workers to indium compounds as "total" dust and its "respirable" fraction in their breathing zones at 3 Japanese indium plants. Eight-hour time-weighted average (TWA) indium concentrations of personal exposure to dust collected in sampling periods of 6 h or longer were determined by ICP-MS. The arithmetic means of exposure concentrations were 0.095 mg indium (In)/m3, when sampled as total dust, and 0.059 mg In/m3, as respirable fraction. ACGIH's TLV-TWA of 0.1 mg In/m3 for total particulate matter and Acceptable Exposure Concentration Limit (AECL) of 3×10-4 mg In/m3 for the respirable fraction notified by the Japanese Ministry of Health, Labour and Welfare were used to evaluate the exposure concentrations. Twenty-five out of 27 workers were exposed to indium concentrations lower than TLV-TWA, while all of the workers were exposed to the indium concentrations higher than AECL. We noted that there was a large discrepancy between the two occupational exposure limits referred to in this report, and these differences were attributed to the sampling strategies and health effects used as the prevention targets. Carcinogenicity of the respirable fraction of indium-containing particulates was considered in setting AECL, whereas it was not in ACGIH's TLV.

Quantitative assessment of occupational exposure to total indium dust in Japanese indium plants.

This study quantitatively assessed personal exposure of 86 workers to indium compounds as total dust at 11 Japanese indium plants. The personal exposures to indium concentrations in the breathing zone during an 8 h work-shift were determined by ICP-MS. The arithmetic mean indium concentration of all the workers was 0.098 mg Indium (In)/m3, with individual values ranging from 0.0001 to 1.421 mg In/m3. There were 11 workers whose exposure to indium concentrations exceeded the American Conference of Governmental Industrial Hygienists' Threshold Limit Value-Time Weighted Average (TLV-TWA) of 0.1 mg In/m3. Based on the condition TLV-TWA

Assessment of workplace air concentrations of formaldehyde during and before working hours in medical facilities.

Workplace air concentrations of formaldehyde (FA) in medical facilities where FA and FA-treated organs were stored and handled were measured before and during working hours and assessed by the official method specified by Work Environment Measurement Law. Sixty-percent of the total facilities examined were judged as inappropriately controlled work environment. The concentrations of FA before working hours by spot sampling were found to exceed 0.1 ppm in some facilities, and tended to increase with increasing volume of containers storing FA and FA-treated materials. Regression analysis revealed that logarithmic concentrations of FA during working hours by the Law-specified analytical method were highly correlated with those before working hours by spot sampling, suggesting the importance for appropriate storing methods of FA and FA-treated materials. The concentrations of FA during working hours are considered to be lowered by effective ventilation of FA-contaminated workplace air and appropriate storage of FA and FA-treated materials in plastic containers in the medical facilities. In particular, such improvement by a local exhaust ventilation system and tightly-sealed containment of FA-treated material were urgently needed for the dissecting room where FA-treated cadavers were prepared and handled for a gross anatomy course in a medical school.

Magnetic resonance evaluation for small bowel strictures in Crohn's disease: comparison with balloon enteroscopy.

BACKGROUND: Magnetic resonance (MR) imaging is the recommended technique for detection of small bowel lesions in Crohn's disease. We aimed to evaluate the impact of stricture findings obtained by MR imaging on patient outcomes using balloon-assisted enteroscopy (BAE) as a reference. METHODS: Two hundred Crohn's disease patients undergoing both MR enterocolonography and BAE were prospectively followed up for at least 1 year. The presence of strictures detected by MR enterocolonography was compared with endoscopic findings. Moreover, the relationship between MR findings and surgery was evaluated. RESULTS: The accuracy of MR imaging for detection of small bowel strictures was defined by a sensitivity of 60.6% and a specificity of 93.4%. Major strictures (diameter less than 10 mm or with internal fistula), long strictures (length 10 mm or greater), and prestenotic dilatation were predictors of stricture detection by MR imaging (P = 0.001, 0.017, and 0.002 respectively). Surgery was performed in 31.6% of patients (18 of 57) in the MR-positive-BAE-positive stricture group and in 10.8% of patients (4 of 37) in the MR-negative-BAE-positive stricture group. Multiple regression analysis showed MR-positive-BAE-positive strictures were an independent risk factor for surgery (P = 0.002 at 6 months and P < 0.001 at 1 year). The surgery-free rate in the MR-negative-BAE-positive stricture group was significantly lower than that in nonstricture group at 1 year (P = 0.001). CONCLUSIONS: The specificity of MR imaging for detection of small bowel strictures was clinically sufficient, and the MR procedure could detect critical strictures, which was a predictive factor for surgery. But MR-negative-BAE-positive strictures were also associated with an increased risk compared with no strictures after 1 year of follow-up.

PGE2 is a direct and robust mediator of anion/fluid secretion by human intestinal epithelial cells.

Intestinal epithelial cells (IECs) play an indispensable role in maintaining body fluid balance partly through their ability to regulate anion/fluid secretion. Yet in various inflammatory gastrointestinal diseases, over-secretion of anions results in symptoms such as severe diarrhoea. Endogenous mediators, such as vasoactive intestinal peptide or prostaglandin E2 (PGE2), regulate intestinal anion/fluid secretion, but their direct effect on purified human IECs has never been described in detail. Based on a previously described intestinal organoid swelling model, we established a 3D-scanner-assisted quantification method to evaluate the anion/fluid secretory response of cultured human IECs. Among various endogenous secretagogues, we found that PGE2 had the lowest EC50 value with regard to the induction of swelling of the jejunal and colonic organoids. This PGE2-mediated swelling response was dependent on environmental Cl- concentrations as well as on several channels and transporters as shown by a series of chemical inhibitor studies. The concomitant presence of various inflammatory cytokines with PGE2 failed to modulate the PGE2-mediated organoid swelling response. Therefore, the present study features PGE2 as a direct and robust mediator of anion/fluid secretion by IECs in the human intestine.

Reduced Human α-defensin 6 in Noninflamed Jejunal Tissue of Patients with Crohn's Disease.

BACKGROUND: Mucosal barrier dysfunction is considered a critical component of Crohn's disease (CD) pathogenesis after the identification of susceptibility genes. However, the precise mechanism underlying mucosal barrier dysfunction has not yet been elucidated. We therefore aimed to elucidate the molecular mechanism underlying the expression of human α-defensin 6 (HD6) in patients with CD. METHODS: HD6 expression was induced by the transfection of an atonal homolog 1 (Atoh1) transgene and was assessed by reverse transcription polymerase chain reaction. The HD6 promoter region targeted by Atoh1 and ß-catenin was determined by reporter analysis and chromatin immunoprecipitation assay. HD5/HD6/Atoh1/ß-catenin expression in noninflamed jejunal samples collected by balloon endoscopy from 15 patients with CD and 9 non-inflammatory bowel disease patients were assessed by immunofluorescence. RESULTS: Both promoter activity and gene expression of HD6 was significantly upregulated by the Atoh1 transgene in human colonic cancer cell line. We identified a TCF4 binding site and an E-box site, critical for the regulation of HD6 transcriptional activity by directly binding of Atoh1 in the 200-bp HD6 promoter region. The treatment with ß-catenin inhibitor also decreases HD6 promoter activity and gene expression. Moreover, HD6 expression, but not HD5 expression, was found to be decreased in noninflamed jejunal regions from patients with CD. In HD6-negative crypts, nuclear accumulation of ß-catenin was impaired. CONCLUSIONS: HD6 expression was found to be regulated by cooperation between Atoh1 and ß-catenin within the HD6 promoter region. Downregulation of HD6 in noninflamed mucosa may contribute to mucosal barrier dysfunction of patients with CD.

Comparison of magnetic resonance and balloon enteroscopic examination of the small intestine in patients with Crohn's disease.

BACKGROUND & AIMS: Magnetic resonance (MR) enterography is a recommended imaging technique for detecting intestinal involvement in Crohn's disease (CD). However, the diagnostic accuracy of MR enterography has not been compared directly what that of enteroscopy of the jejunum and proximal ileum. We evaluated the usefulness of MR enterocolonography (MREC) by comparing its findings with those from balloon-assisted enteroscopy. METHODS: In a prospective study, MREC and enteroscopy were performed within 3 days of each other on 100 patients. Ulcerative lesions and all mucosal lesions were evaluated. Physicians and radiologists were blinded to results from other studies. Findings from MREC were compared directly with those from enteroscopy; the sensitivity and specificity with which MREC detected CD lesions were assessed. RESULTS: MREC detected ulcerative lesions and all mucosal lesions in the small intestine with 82.4% sensitivity (95% confidence interval [CI], 75.4%-87.7%) and 67.5% sensitivity (95% CI, 63.1%-70.0%); specificity values were 87.6% (95% CI, 83.7%-90.6%) and 94.8% (95% CI, 90.1%-97.5%). MREC detected major stenosis with 58.8% sensitivity (95% CI, 37.6%-77.2%) and 90.0% specificity (95% CI, 88.4%-91.5%) and all stenoses with 40.8% sensitivity (95% CI, 30.8%-49.4%) and 93.7% specificity (95% CI, 91.1%-95.9%). CONCLUSIONS: MREC is useful for detecting active lesions in the small intestine. However, MR imaging is less sensitive for detecting intestinal damage, such as stenoses. Enteroscopy is preferred for identifying intestinal damage. Suitable imaging approaches should be selected to assess CD lesions in deep small intestine.

Lineage-specific expression of bestrophin-2 and bestrophin-4 in human intestinal epithelial cells.

Intestinal epithelial cells (IECs) regulate the absorption and secretion of anions, such as HCO3(-) or Cl(-). Bestrophin genes represent a newly identified group of calcium-activated Cl(-) channels (CaCCs). Studies have suggested that, among the four human bestrophin-family genes, bestrophin-2 (BEST2) and bestrophin-4 (BEST4) might be expressed within the intestinal tissue. Consistently, a study showed that BEST2 is expressed by human colonic goblet cells. However, their precise expression pattern along the gastrointestinal tract, or the lineage specificity of the cells expressing these genes, remains largely unknown. Here, we show that BEST2 and BEST4 are expressed in vivo, each in a distinct, lineage-specific manner, in human IECs. While BEST2 was expressed exclusively in colonic goblet cells, BEST4 was expressed in the absorptive cells of both the small intestine and the colon. In addition, we found that BEST2 expression is significantly down-regulated in the active lesions of ulcerative colitis, where goblet cells were depleted, suggesting that BEST2 expression is restricted to goblet cells under both normal and pathologic conditions. Consistently, the induction of goblet cell differentiation by a Notch inhibitor, LY411575, significantly up-regulated the expression of not BEST4 but BEST2 in MUC2-positive HT-29 cells. Conversely, the induction of absorptive cell differentiation up-regulated the expression of BEST4 in villin-positive Caco-2 cells. In addition, we found that the up- or down-regulation of Notch activity leads to the preferential expression of either BEST4 or BEST2, respectively, in LS174T cells. These results collectively confirmed that BEST2 and BEST4 could be added to the lineage-specific genes of humans IECs due to their abilities to clearly identify goblet cells of colonic origin and a distinct subset of absorptive cells, respectively.

Histological diagnosis of follicular lymphoma by biopsy of small intestinal normal mucosa.

Due to advances in double-balloon endoscopy, various types of malignant lymphoma of the small intestine have been observed at very early stages. We report here that after remission of diffuse large B-cell lymphoma, follicular lymphoma recurred in the mucosa of the small intestine. Furthermore, these lesions were diagnosed by biopsy from normal mucosa as diminutive erosions and reddish looking. If a small intestinal lesion is suspected of being a malignant lymphoma, a double-balloon endoscopy should be carried out, and a biopsy should be taken and inspected.

Endoscopic ultrasound with double-balloon endoscopy for the diagnosis of inverted Meckel's diverticulum: a case report.

INTRODUCTION: Inverted Meckel's diverticulum has usually been misdiagnosed in the cases based on computed tomography images presented in the literature. The final diagnosis was made intra-operatively or by pathology reports after surgery. Despite this, preoperative diagnosis could be made successfully by using endoscopic ultrasound with double-balloon endoscopy prior to surgery. CASE PRESENTATION: A 60-year-old Japanese woman with severe anemia complained of several episodes of black stool over the preceding 2 years. Abdominal computed tomography showed a 3.0-cm low-density tumor in the ileum, suggesting a diagnosis of intestinal lipoma. Examination of the tumor by endoscopic ultrasound with double-balloon endoscopy revealed a hypo-echoic layer corresponding to the muscularis propria, and a hyper-echoic layer corresponding to the fat tissue. These findings, which suggested that the tumor included areas outside the intestinal serosa, are not typical for a lipoma, despite the existence of a hyper-echoic layer corresponding to fatty tissue. We then considered a diagnosis of inverted Meckel's diverticulum. CONCLUSION: Lipoma and inverted Meckel's diverticulum are difficult to differentially diagnose by computed tomography. Polypectomy is the preferred therapeutic approach when a lipoma is present; however, polypectomy in a patient with Meckel's diverticulum requires full-thickness resection. Situations where polypectomy is performed without preparing for full-thickness resection can be avoided by first making a precise diagnosis using double-balloon endoscopy and endoscopic ultrasound.

Modified single-operator method for double-balloon endoscopy.

Applications of double-balloon endoscopy (DBE) have expanded widely to areas beyond small-intestine endoscopy. Two endoscopists are required for standard insertion, but it is preferable to have DBE carried out by one endoscopist to optimize control of the procedure and because of human resources issues. We previously reported on the Single-Operator Method, but here we describe newly modified insertion techniques that facilitate and enhance the performance of DBE by a single endoscopist. Our new technique consists of Hooking Technique, Outside Support, Grasp Scope and Overtube, Continuous Overtube Infusion and Double-Overtube Method. These new techniques make it easier to carry out the Single-Operator Method.

Magnetic resonance enterocolonography is useful for simultaneous evaluation of small and large intestinal lesions in Crohn's disease.

BACKGROUND: We developed novel magnetic resonance enterocolonography (MREC) for simultaneously evaluating both small and large bowel lesions in patients with Crohn's disease (CD). The aim of this study was to evaluate the diagnostic performance of MREC by comparing results of this procedure to those of endoscopies for evaluating the small and large bowel lesions of patients with CD. METHODS: Thirty patients with established CD were prospectively examined by newly developed MREC. Patients underwent ileocolonoscopy (ICS) (24 procedures) or double-balloon endoscopy (DBE) (10 procedures) after MREC on the same day. Two gastroenterologists and two radiologists who were blinded to the results of another study evaluated endoscopy and MREC findings, respectively. RESULTS: In colonic lesions the sensitivities of the MREC for deep mucosal lesions (DML), all CD lesions, and stenosis were 88.2, 61.8, and 71.4%, respectively, while the specificities were 98.1, 95.3, and 97.7%, respectively. In small intestinal lesions, MREC sensitivities for DML, all CD lesions, and stenosis were 100, 85.7, and 100%, respectively, while specificities were 100, 90.5, and 93.1%, respectively. Endoscopic scores were significantly correlated with MREC scores. Eleven (46%) of the 24 patients who were clinically not suspected to show stricture were observed to demonstrate stricture by radiologists. CONCLUSIONS: Our results demonstrated that MREC can simultaneously detect the CD lesions of the small and large intestine. MREC can be performed without radiation exposure, the use of enema, or the placement of a naso-jejunal catheter. MREC and endoscopy have comparable abilities for evaluating mucosal lesions of patients with CD.

Longitudinal cell formation in the entire human small intestine is correlated with the localization of Hath1 and Klf4.

BACKGROUND: Double balloon endoscopy (DBE) enables the observation and collection of viable specimens from the entire intestine, thereby allowing more detailed investigation of how the structure and function of the human small intestine are regulated. The present study aimed to elucidate the regulation of cell formation in the human small intestine using biopsy specimens collected from an entire individual small intestine by DBE. METHODS: The expression and the localization of representative genes for the differentiation program were analyzed in the entire small intestine of 10 patients. The functional correlation between Hath1 and Klf4 was analyzed in an intestinal cell line by using a Tet-On system. RESULTS: In longitudinal cell formation in the small intestine, it was shown that goblet cells, but not Paneth cells, increased toward the ileum in each individual small intestine. Immunohistochemistry showed that Hath1-expressing cells migrated from the base of the crypt to the top of the villi in the terminal ileum, while Klf4-expressing cells migrated from the top of the villus, resulting in the colocalization of Hath1 and Klf4 in the terminal ileum. Coexpression of Hath1 and Klf4 upregulated the expression of phenotypic genes for goblet cells following the downregulation of those for Paneth cells. CONCLUSIONS: Using mapping biopsy by DBE, we have demonstrated, for the first time, the molecular basis of the villus structure in the entire human small intestine in vivo. The present study showed that longitudinal cell formation was regulated by the colocalization of Hath1 and Klf4 that converted Paneth cell differentiation into goblet cell differentiation.

Extranodal NK/T cell lymphoma, nasal type, of the small intestine diagnosed by double-balloon endoscopy.

Extranodal NK/T-cell lymphoma (ENKL), nasal type, is rare and the small intestine is quite extraordinary as a primary lesion site. We report a 47-year-old man with ENKL of the small intestine. He was referred to our hospital because of bloody stool and the diagnosis was made by double-balloon endoscopy (DBE) of the small intestine without surgical procedure. His clinical stage was IVB and he was categorized in group 4 by prognostic index of ENKL. He went into complete remission (CR) after intensive chemotherapy (DeVIC) and subsequently underwent allogeneic bone marrow transplantation (BMT). Although he remained in CR for about 8 months after BMT, he died of disease recurrence 14 months after the diagnosis was made. ENKL of the small intestine follows a highly aggressive course. We describe the usefulness of DBE for diagnosis and management for ENKL of the small intestine. Additional cases, however, should be accumulated to establish optimal treatment strategy.

Single-operator double-balloon endoscopy (DBE) is as effective as dual-operator DBE.

BACKGROUND AND STUDY AIMS: Double-balloon endoscopy (DBE) is a new device that allows diagnosis and treatment throughout the entire small intestine. Although the originally described method requires two operators, we have recently developed a method to perform DBE by a single operator. We here assessed the clinical usefulness of this one-person method in comparison to the conventional two-person DBE. PATIENTS AND METHODS: One hundred sixty-two patients (102 men and 60 women, mean age 59 years) underwent 303 DBE procedures. Total observation time, completion rate of total intestinal and colonic observation, lesion-discovery rate, and complication rate were retrospectively compared between the one-person method and the conventional two-person method of DBE. The one-person method consists of the Grip and Pinch technique and Keep (or Hold) and Slide technique. RESULTS: The total observation times were 95.5 +/- 35.1 min and 96.7 +/- 47.5 min by one-person and two-person antegrade DBE, respectively, and 103 +/- 29.8 min and 111 +/- 30.1 min by one-person and two-person retrograde DBE, respectively. The completion rate for examination of the entire small intestine was 74.2% in one-person DBE and 76.5% in two-person DBE, respectively. The lesion-discovery rate was 69.0% in one-person DBE and 65.5% in two-person DBE, respectively. No significant differences between two methods were found in all measures. Also, no difference was observed in complication rate of the two methods. CONCLUSIONS: The single-operator method for DBE was as efficient as the dual-operator DBE without any higher risk of complications and, therefore, could replace the conventional dual-operator method in the future.

[A case report: Severe bone marrow suppression caused by 6-mercaptopurin in Crohn's disease patient].

A 23-year-old man was admitted for treatment of acute exacerbation of ileitis and perianal abscess caused by Crohn's disease. After incision and drainage of the abscess, coupled with antibiotic therapy, 6-mercaptopurine (6-MP) was commenced. His white blood cell (WBC) count on day 12 after initiation of 6-MP was not decreased. However, on day 24 he was re-admitted because of severe myelosuppression (WBC: 300/microl), which was complicated by the recurrence of the perianal abscess. Myelosuppression was prolonged and required the administration of granulocyte colony stimulating factor (G-CSF). G-CSF was continued for 17 days to achieve recovery of his WBC count to a normal level.