齊藤 景子

BACKGROUND: Laterally spreading tumors (LSTs) are generally defined as lesions >10 mm in diameter, are characterized by lateral expansion along the luminal wall with a low vertical axis. In contrast to other forms of tumor, LSTs are generally considered to have a superficial growth pattern and the potential for malignancy. We focused on this morphological character of LSTs, and analyzed the gene expression profile of LSTs. METHODS: The expression of 168 genes in 41 colorectal tumor samples (17 LST-adenoma, 12 LST-carcinoma, 12 Ip [pedunculated type of the Paris classification)-adenoma, all of which were 10 mm or more in diameter] was analyzed by PCR array. Based on the results, we investigated the expression levels of genes up-regulated in LST-adenoma, compared to Ip-adenoma, by hierarchical and K-means clustering. To confirm the results of the array analysis, using an additional 60 samples (38 LST-adenoma, 22 Ip-adenoma), we determined the localization of the gene product by immunohistochemical staining. RESULT: The expression of 129 genes differed in colorectal tumors from normal mucosa by PCR array analysis. As a result of K-means clustering, the expression levels of five genes, AKT1, BCL2L1, ERBB2, MTA2 and TNFRSF25, were found to be significantly up-regulated (p < 0.05) in LST-adenoma, compared to Ip-adenoma. Immunohistochemical analysis showed that the BCL2L1 protein was significantly and meaningfully up-regulated in LST-adenoma compared to Ip-adenoma (p = 0.010). With respect to apoptosis status in LST-Adenoma, it assumes that BCL2L1 is anti-apoptotic protein, the samples such as BCL2L1 positive and TUNEL negative, or BCL2L1 negative and TUNEL positive are consistent with the assumption. 63.2 % LST-adenoma samples were consistent with the assumption. CONCLUSIONS: LSTs have an unusual profile of gene expression compared to other tumors and BCL2L1 might be concerned in the organization of LSTs.

BACKGROUND: It is well known that in patients with sporadic nonampullary duodenal adenoma/carcinoma (SNADA) with no polyposis syndrome, including familial adenomataous polyposis, the rates of colorectal adenoma/carcinoma are high. However, the prevalence rates of other tumor types, for example, gastric cancer, in SNADA patients remain unknown. In this study, we aimed to analyze the prevalence rate of comorbid diseases in SNADA patients. METHODS: We retrospectively analyzed 78 patients with SNADA treated by endoscopic resection between May 2005 and September 2014 at our institution. RESULTS: Overall, 51 of the 78 (65.4%) SNADA patients had comorbid colorectal adenoma/carcinoma. Further, 10 of the 78 (12.8%) SNADA patients had comorbid gastric cancer, and all of them were positive for Helicobacter pylori infection. SNADA lesions were located significantly more frequently at the oral side of the major papilla in patients with H. pylori infection than in those without H. pylori infection (27 of 36 [75.0%] vs. 19 of 42 [45.2%], p = 0.008, chi-square test). In contrast, SNADA lesions were located significantly more frequently at the anal side of the major papilla in patients with colorectal adenoma/carcinoma than in those without colorectal adenoma/carcinoma (27 of 51 [52.9%] vs. 5 of 27 [18.5%], p = 0.003, chi-square test). CONCLUSION: SNADA patients showed comorbidity with not only colorectal adenoma/carcinoma but also gastric cancer. H. pylori infection is known to cause gastric cancer and may influence tumorigenesis of SNADA lesions at the oral side of the major papilla.

Irsogladine maleate (2,4-diamino-6-[2,5-dichlorophenyl]-s-triazine maleate; IM), an anti-peptic ulcer drug, may have a protective effect on the gastrointestinal mucosa. This study investigated the effects of IM on spontaneous colitis in interleukin-10 gene-deficient (IL-10(-/-)) mice. Five-week-old IL-10(-/-) mice were fed a control diet or one containing 100 ppm of IM for 10 weeks. Colonic tissues were evaluated morphologically and histologically. J774A.1 murine monocyte/macrophage cells were incubated with IM after lipopolysaccharide stimulation. mRNA expression was assessed by quantitative polymerase chain reaction (PCR) and protein concentration by enzyme-linked immunosorbent assay (ELISA). Colonic length, weight, and histological scores clearly demonstrated that spontaneous colitis was prevented in IL-10(-/-) mice fed a diet containing IM compared with those fed control diet. Levels of tumor necrosis factor-alpha (TNF-α) (-2.5-fold), IL-1β (-5.4), interferon-gamma (IFN-γ) (-4.5), IL-17 (-113.0), IL-12p35 (-21.0), IL-12p40 (-3.4), and IL-23p19 (-4.2) mRNA expression were significantly decreased in the colonic tissues of IM-treated animals, suggesting that oral treatment with IM suppressed the T-helper (Th)1/Th17 immune response in the colonic mucosa. An in vitro study using monocyte/macrophage cells to clarify the pharmacological action of IM indicated that IL-12p40 and IL-23p19 mRNA expression levels were dose-dependently decreased by IM treatment. ELISA showed that IL-12p40 and IL-23 protein secretion were significantly decreased by IM in a dose-dependent manner. Oral treatment with IM prevented spontaneous colitis in IL-10(-/-) mice by suppressing the colonic mucosal Th1/Th17 immune response through inhibition of IL-12 and -23 production in monocyte/macrophage cells.

AIM: To investigate the optimum period of treatment for post endoscopic submucosal dissection (ESD) ulcers. METHODS: Patients who underwent ESD for gastric cancer were randomized to two groups and treated with esomeprazole 20 mg per day for 4 wk (4W group) or 2 wk (2W group). At 4 wk after ESD, we measured the size of the artificial ulcers by endoscopy and determined the ulcer healing rate, compared with the size of the ESD specimens. This randomized controlled trial study was approved by our ethics committee and registered in the UMIN Clinical Trial Registry. RESULTS: A total of 60 consecutive patients were included in the study. All patients received rebamipide 300 mg per day for 4 wk. One patient in 2W group who showed bleeding within two weeks and received endoscopic treatment was excluded from further analysis. The numbers of patients with ulcers in the healing/scar stage in the 2W and 4W groups at 4 wk after ESD were 20/6 and 28/5, respectively, with no significant difference. The ulcer healing rate in the 2W and 4W groups were 96.1% [95% confidence interval (CI): 94.6%-97.55] vs 94.8% (95%CI: 92.6%-97.1%), respectively, with no statistical difference (UMIN000006951). CONCLUSION: Two-wk treatment with a proton pump inhibitor is as effective as four-week treatment for healing post ESD ulcers.

BACKGROUND: Endoscopic submucosal dissection (ESD) has become widely accepted as a standard treatment for gastric epithelial neoplasms. Antithrombotic agents are widely used to prevent thromboembolic disease. However, the feasibility of endoscopic procedures for patients using such agents has been rarely investigated. The aim of this study was to identify risk factors for post-operative bleeding after gastric ESD and to evaluate the relationship between the use of antithrombotic agents and post-operative bleeding. METHODS: From June 2005 to March 2014, 413 patients with 425 gastric neoplasms were treated by ESD. The demographic and clinical parameters associated with post-operative bleeding were investigated. 83 patients receiving antithrombotic agents were separately assessed using various methods of administration during the ESD procedure. Post-operative bleeding that occurred within 5 days of ESD was defined as early post-operative bleeding, whereas subsequent bleeding was defined as delayed bleeding. RESULTS: The overall post-operative bleeding rate was 4.7%. In patients with continued low-dose aspirin (LDA), heparin replacement (HR), or continued LDA along with HR, post-operative bleeding rates were 9.5%, 23.8%, and 25.0%, respectively. On multivariate analysis, a specimen size of ≥40 mm was a risk factor for early post-operative bleeding [odds ratio (OR) 6.08, 95% CI: 1.74-21.27], and HR and chronic kidney disease (CKD) requiring hemodialysis were risk factors for delayed bleeding (OR 12.23, 95% CI: 2.63-56.77 and OR 28.35, 95% CI: 4.67-172.11, respectively). Continued LDA was not a risk factor for post-operative bleeding. CONCLUSIONS: Large specimen size is a risk factor for early post-operative bleeding, and HR and CKD requiring hemodialysis are risk factors for delayed bleeding. Patients with risk factors should be carefully watched, allowing for the timing of post-operative bleeding after ESD.

BACKGROUND AND AIM: Capsule endoscopy (CE) is now widely accepted as a first-line diagnostic modality for obscure gastrointestinal bleeding (OGIB), with a high diagnostic yield compared to other modalities. However, even after negative CE examination, re-bleeding is often known to occur. The aim of the present study was to identify predictive factors of re-bleeding after negative CE, and to clarify the clinical utility of double-balloon enteroscopy (DBE) after negative CE for OGIB. METHODS: Two hundred and sixty patients who underwent CE for OGIB between October 2007 and September 2012 were included, and followed up for at least 1 year after CE examination. Demographic and clinical parameters associated with re-bleeding after negative CE were investigated. RESULTS: A total of 154 patients (59.2%) had negative findings. Thirteen of those patients (8.4%) had one or more re-bleeding episodes during the follow-up period. In comparing patients with and without re-bleeding, Cox hazard regression analysis revealed that advanced age was a predictive factor for re-bleeding after negative CE (hazard ratio 1.05 [1.01-1.10], P = 0.03). Subsequent DBE for reasons other than re-bleeding was carried out in 51 patients (33.1%). Mucosal lesions (ulcer or multiple erosions) were subsequently detected in seven patients (13.7%), and endoscopic therapies were carried out in two patients (3.9%). CONCLUSIONS: In patients of advanced age, more extensive follow up is needed, even if the CE result is negative. In addition, DBE subsequent to negative CE may be useful to detect lesions that were overlooked on CE.

A 75-year-old man who had undergone partial gastrectomy was referred to our hospital due to worsening leg edema, loose stools and malnutrition. Double balloon enteroscopy followed by insertion of an indwelling ileus tube was performed to investigate the microbial flora and for washing inside the blind loop. Trophozoites of Giardia were detected in the sampled fluid from the blind loop and DNA analysis disclosed an assemblage of genotype A-II of Giardia duodenalis. Treatment with oral metronidazole was effective. This case emphasizes the importance of a correct diagnosis when treating patients with blind loop syndrome in the digestive tract.

健常成人男性12名を対象にクエン酸モサプリドを2週間投与し、投与前後の血漿活性型GLP-1および血清インスリン濃度を比較検討した。その結果、モサプリドの2週間投与は、食後90分値における血漿活性型GLP-1、血清インスリン濃度を有意に上昇させ、近位消化管における消化管甘味受容体を増加させることが明らかとなった。さらに、モサプリドが消化管甘味受容体発現を増加させることにより、食後の時相におけるL細胞内の信号伝達系を亢進させ、結果として食後血漿活性型GLP-1濃度の上昇につながっている可能性が示唆された。

BACKGROUND: We previously showed that fibrocytes, a hematopoietic stem cell source of fibroblasts/myofibroblasts, infiltrated the colonic mucosa of a murine colitis model. AIM: We investigated whether fibrocytes were involved in the pathogenesis of Crohn's disease. METHODS: Human surgical intestinal specimens were stained with anti-leukocyte-specific protein 1 and anti-collagen type-I (ColI) antibodies. Circulating fibrocytes in the human peripheral blood were quantified by fluorescence-activated cell sorting with anti-CD45 and anti-ColI antibodies. Cultured human fibrocytes were prepared by culturing peripheral CD14(+) monocytes. RESULTS: In the specimens of patients with Crohn's disease, the fibrocyte/total leukocyte percentage was significantly increased in inflammatory lesions (22.2 %, p < 0.01) compared with that in non-affected areas of the intestine (2.5 %). Interestingly, the percentage in fibrotic lesions was similar (2.2 %, p = 0.87) to that in non-affected areas. The percentages of circulating fibrocytes/total leukocytes were significantly higher in patients with Crohn's disease than in healthy controls. Both CXC-chemokine receptor 4(+) and intercellular adhesion molecule 1(+) fibrocyte numbers were significantly increased in Crohn's disease, suggesting that circulating fibrocytes have a higher ability to infiltrate injured sites and traffic leukocytes. In cultured fibrocytes, lipopolysaccharide treatment remarkably upregulated tumor necrosis factor (TNF)-α mRNA (17.0 ± 5.7-fold) and ColI mRNA expression (12.8 ± 5.7-fold), indicating that fibrocytes stimulated by bacterial components directly augmented inflammation as well as fibrosis. CONCLUSIONS: Fibrocytes are recruited early in the inflammatory phase and likely differentiate into fibroblasts/myofibroblasts until the fibrosis phase. They may enhance inflammation by producing TNF-α and can directly augment fibrosis by producing ColI.

BACKGROUND AND AIM: Gastric ulcer healing is a complex process involving cell proliferation and tissue remodeling. Sonic hedgehog (Shh) activates the Shh signaling pathway, which plays a key role in processes such as tissue repair. Shh and interleukin 1β (IL1β) have been reported to influence the proliferation of gastric mucosa. We evaluated the relationships between the speed of gastric ulcer healing and the levels of expression of Shh and IL1β. METHODS: The study included 45 patients (mean age 71.9 ± 9.0 years; M/F, 30/15) who underwent endoscopic submucosal dissection (ESD) for gastric cancer, followed by standard dose of oral proton-pump inhibitor for 4 weeks. Subsequently, the size of ESD-induced artificial ulcers were measured to determine the speed of gastric ulcer healing, and regenerating mucosa around the ulcers and appropriately matched controls were collected from patients by endoscopic biopsy. Polymerase chain reaction (PCR) array analysis of genes in the Shh signaling pathway was performed, and quantitative reverse transcription (RT)-PCR was used to measure IL1β mRNA. RESULTS: The levels of Shh and IL1β mRNA were 3.0 ± 2.7-fold and 2.5 ± 2.5-fold higher, respectively, in regenerating mucosa of artificial ulcers than in appropriately matched controls, with the two being positively correlated (r = 0.9, P < 0.001). Shh (r = 0.8, P < 0.001) and IL1β (r = 0.7, P < 0.005) expression was each positively correlated with the speed of gastric ulcer healing, but multivariate analysis showed that Shh expression was the only significant parameter (P = 0.045). CONCLUSIONS: Expression of Shh was correlated with the speed of gastric ulcer healing, promoting the regeneration of gastric mucosa.

Objectives. The aim of this study was to investigate and compare the eradication rate of Helicobacter pylori as the third-line triple therapy with rabeprazole (RPZ) + amoxicillin (AMPC) + levofloxacin (LVFX) and high-dose RPZ + AMPC. Methods. 51 patients who failed Japanese first-line (proton pump inhibitor (PPI) + AMPC + clarithromycin) and second-line (PPI + AMPC + metronidazole) eradication therapy were randomly assigned at a 1 : 1 ratio to one of the following third-line eradication groups: (1) RAL group: RPZ 10 mg (b.i.d.), AMPC 750 mg (b.i.d.), and LVFX 500 mg (o.d.) for 10 days; (2) RA group: RPZ 10 mg (q.i.d.) and AMPC 500 mg (q.i.d.) for 14 days. Patients who failed to respond to third-line eradication therapy received salvage therapy. Results. The rates of eradication success, based on intention to treat (ITT) analysis, were 45.8% in the RAL group and 40.7% in the RA group. The overall eradication rates were 73.9% in the RAL group and 64.0% in the RA group. There was no significant difference between the two groups. Conclusions. The third-line triple therapy with RPZ, AMPC, and LVFX was as effective as that with high-dose RPZ and AMPC.

We encountered a rare case of severe diffuse duodenitis associated with ulcerative colitis (UC). A 23-year-old man underwent total proctocolectomy with ileal J-pouch anal anastomosis for UC. He suffered from severe abdominal pain, fever and bloody diarrhea for six months after the surgery. Upper double-balloon enteroscopy disclosed severe diffuse duodenitis, of which the findings were endoscopically and histologically similar to those of colonic lesions of UC. Although the administration of prednisolone was ineffective, treatment with intravenous tacrolimus markedly improved the clinical findings. This is the first report of the successful treatment of severe UC-associated diffuse duodenitis with intravenous tacrolimus.

Arterio enteric fistulas (AEFs) are rare. We herein report a case of a primary arterio enteric fistula of the rectum associated with Takayasu arteritis. A 77-year-old woman presented with acute massive hematochezia and was taken to our hospital. Colonoscopy revealed pulsatile extrinsic rectal wall compression with an exposed blood vessel. Transvaginal ultrasonography and Doppler ultrasound revealed a localized vascular growth laying on the dorsal surface of the uterus that showed an arterial blood-flow signal. We diagnosed the patient to have a pelvic aneurism that had formed a fistula within the rectal wall. We eliminated the aneurysm by ligating the drainage and feeder arteries. Following surgery, the patient did not experience any relapses of hematochezia.

BACKGROUND: When treating patients with severe ulcerative colitis (UC), accurate prediction of drug efficacy contributes to early clinical decision-making. AIM: To identify predictive factors and to develop a reliable prediction formula and a decision tree of response to intravenous ciclosporin treatment for severe UC. METHODS: Patients included in this study were those diagnosed with refractory severe UC who had undergone ciclosporin treatment between December 2004 and March 2011 at a tertiary referral centre in Japan. Demographic and clinical parameters from all patients were analysed by multivariate statistics. RESULTS: Fifty-two patients were included in this study (36.5% men with an average age of ciclosporin initiation of 40.2 ± 15.6 years). Thirty-four patients (65.4%) were responders to the treatment with ciclosporin and avoided colectomy, 18 patients (34.6%) were nonresponders and underwent colectomy. Stepwise multiple logistic regression analysis identified four independent predictive factors of response to intravenous ciclosporin: age at hospitalisation (AGE), platelet count (×10(4) /μL) on the first day (PLA), Lichtiger score on the third day (LIC) and total protein (g/dL) on the third day minus total protein on the first day (ΔTP). The calculation formula (8.5 - 0.16 × AGE + 0.21 × PLA - 0.61 × LIC + 2.3 × ΔTP < 0) predicted colectomy with an accuracy of 88.5% and the decision tree predicted colectomy with an accuracy of 90.4%. CONCLUSION: The novel calculation formula and the decision tree effectively predict the clinical outcome of ciclosporin treatment for severe ulcerative colitis as early as on day 3 after starting ciclosporin treatment.

BACKGROUND AND OBJECTIVES: Genome-wide association studies have revealed a link between autophagy-related (ATG) genes and susceptibility to Crohn's disease. This suggests underlying involvement of autophagy impairment in the pathogenesis of Crohn's disease. This study was performed to investigate the pathophysiological importance of autophagy impairment in intestinal epithelial cells exposed to TNF-α. METHODS: Human colonic epithelial cells (HT-29) and rat small intestinal epithelial cells (IEC-18) were used. Formation of phosphatidylethanolamine-conjugated microtubule-associated protein light chain 3 (LC3-II) was monitored as a marker of autophagy. Autophagy was inhibited using 3-methyladenine or short interfering RNA targeting ATG5 and ATG16L1. RESULTS: TNF-α treatment elicited a significant dose-dependent increase in LC3-II protein levels, thus autophagy is induced in the presence of TNF-α. Combined autophagy inhibition and TNF-α treatment induced a marked increase in the number of detached cells and a decrease in activated integrin β1 protein levels. Trypan blue staining indicated 70-80 % of the detached cells were alive, suggesting that these cells became detached not because they were killed but because of dysfunction of cellular adhesion. CONCLUSIONS: This is the first study indicating that intestinal epithelial cells with impaired autophagy lose their adhesive capacity in the presence of TNF-α. These observations indicate that impairment of autophagy leads to disruption of the intestinal epithelial cell layers in TNF-α-rich environments.