Tag-less patency capsule for suspected small bowel stenosis: Nationwide multicenter prospective study in Japan.

STUDY AIMS: The PillCam patency capsule (PPC) is an Agile tag-less patency capsule used to evaluate gastrointestinal (GI) patency. We determined the appropriate use of PPC to preclude subsequent small bowel capsule endoscopy (SBCE) retention. METHODS: This prospective multicenter study consecutively enrolled patients indicated for SBCE with suspected or established small bowel stenosis. Excretion of an intact PPC or its radiologic visualization in the large bowel was considered GI patency. Primary and secondary study endpoints were SBCE retention rates in patients with confirmed patency and identification of factors associated with patency and SBCE retention, respectively. RESULTS: Of 1096 patients enrolled in the study, patency was confirmed in 976 (89.1%). PPC excretion occurred in 579 patients. Of the remaining 517 patients, patency was confirmed using imaging modalities in 401 (77.5%). SBCE retention occurred in five (0.51%) of 963 patients who underwent SBCE: 1.0% in established Crohn's disease (CD) patients, 0% in suspected CD, 0% in tumors, and 1.6% in patients with obscure GI bleeding, for which PPC localization had been radiographically misinterpreted. The non-confirmation of patency was associated with established CD, stenosis identified using imaging modalities, abdominal fullness, serum albumin levels <4.0 g/dL, and previous small bowel obstruction (adjusted odds ratios: 4.21, 2.60, 2.47, 2.12, and 2.00; 95% confidence intervals: 2.62-6.78, 1.62-4.17, 1.43-4.27, 1.32-3.40, and 1.15-3.47, respectively). CONCLUSIONS: The PillCam™ patency capsule helped preclude SBCE retention in most patients, but its accurate localization was essential for cases without excretion (Study registered the University Hospital Medical Information Network, #UMIN000010513).

Assessment of an electronic learning system for colon capsule endoscopy: a pilot study.

BACKGROUND: Training for colon capsule endoscopy (CCE) procedures is currently performed as a lecture and hands-on seminar. The aims of this pilot study were to assess the utility of an electronic learning system for CCE (ELCCE) designed for the Japanese Association for Capsule Endoscopy using an objective scoring engine, and to evaluate the efficacy of ELCCE on the acquisition of CCE reading competence. METHODS: ELCCE is an Internet-based learning system with the following steps: step 1, introduction; step 2, CCE reading competence assessment test (CCAT), which evaluates the competence of CCE reading prior to training; step 3, learning reading theory; step 4, training with guidance; step 5, training without guidance; step 6, final assessment; and step 7, the same as step 2. The CCAT, step 5 and step 6 were scored automatically according to: lesion detection, diagnosis (location, size, shape of lesion), management recommendations, and quality of view. Ten trainee endoscopists were initially recruited (cohort 1), followed by a validating cohort of 11 trainee endoscopists (cohort 2). RESULTS: All but one participant finished ELCCE training within 7 weeks. In step 6, accuracy ranged from 53 to 98 % and was not impacted by step 2 pretest scores. The average CCAT scores significantly increased between step 2 pretest and step 7 in both cohorts, from 42 ± 18 % to 79 ± 15 % in cohort 1 (p = 0.0004), and from 52 ± 15 % to 79 ± 14 % in cohort 2 (p = 0.0003). CONCLUSIONS: ELCCE is useful and effective for improving CCE reading competence.

Relationship between the degree of endoscopic atrophy of the gastric mucosa and carcinogenic risk.

BACKGROUND: The relationship between Helicobacter pylori infection and gastric cancer has been demonstrated, and the risk of gastric cancer occurrence is known to increase with the progression of atrophic changes associated with chronic gastritis. Endoscopic evaluation of the degree and extent of atrophy of the gastric mucosa is a simple and very important means of identifying a group at high risk for gastric cancer. This study aimed to clarify the carcinogenic risk in relation to the degree of atrophy. METHODS: A total of 27,777 patients (272 with early gastric cancer and 135 with advanced gastric cancer) were included in this study. Endoscopically evaluated atrophy of the gastric mucosa was classified as C-0 to O-3 according to the Kimura and Takemoto classification system. RESULTS: The cancer detection rate in relation to the degree of gastric mucosal atrophy was 0.04% (2/4,183 patients) for C-0, 0% (0/4,506) for C-1, 0.25% (9/3,660) for C-2, 0.71% (21/2,960) for C-3, 1.32% (75/5,684) for O-1, 3.70% (140/3,780) for O-2 and 5.33% (160/3,004) for O-3. As to the proportions of differentiated and undifferentiated cancers, the latter were relatively frequent in the C-0 to C-2 groups, but differentiated cancers became predominant as atrophy progressed. On the other hand, the number of both differentiated and undifferentiated cancers detected increased as gastric mucosal atrophy progressed. In addition, open-type atrophy was found in 29 (96.7%) of 30 patients with synchronous multiple gastric cancers and in all 20 patients with metachronous multiple gastric cancers. CONCLUSION: Endoscopic evaluation of gastric mucosal atrophy can provide a simple and reliable predictive index for both current and future carcinogenic risk.

Evaluation of a novel high-resolution magnifying videoendoscope that is capable of photodynamic diagnosis and therapy for gastric cancer.

OBJECTIVE: To evaluate the usefulness of a novel high-resolution magnifying videoendoscope called the XG-0001 (Fujifilm, Tokyo, Japan) that is capable of PDD and PDT in experimental and clinical situations. MATERIALS AND METHODS: The fluorescences of three photosensitizers (i.e., porfimer sodium (Photofrin), protoporphyrin IX and talaporfin sodium (Laserphyrin)) were studied experimentally via excitation with a purple diode laser (VDL, wavelength 405nm). Five consecutive patients with superficial early gastric cancer not indicated for surgery or other curative endoscopic treatment due to complicated serious diseases were enrolled in this study. After close endoscopic examinations, 2mg/kg of Photofrin were intravenously injected into the patients for PDT, and 5-aminolevulinic acid (ALA; 15-20mg/kg) was orally taken for PDD. PDD using VDL and PDT using an excimer-dye laser (630nm, 4mJ, 60Hz) were performed with the XG-0001. RESULTS: Photofrin and Laserphyrin had experimentally the lowest and highest fluorescence intensities, respectively. The five patients comprised four men and one woman with a mean age 75.2 year and an age range of 56-83 years. Two additional cancerous lesions were newly detected by magnifying pharmacoendoscopy. In each patient, PDD was successfully performed. PDT could also safely performed and CR was obtained in 71.4% (5/7) of the cancerous lesions in five patients, and no serious complications were encountered. CONCLUSION: The XG-0001, which is based on a simultaneous videoendoscopy method that uses an RGB color chip CCD, proved extremely useful in routine use and also in PDD and PDT for gastric cancer.

Consensus of the present and prospects on endoscopic diagnosis and treatment in East asian countries.

Background and Aim. New diagnostic or therapeutic methods in endoscopy have been used. Current clinical application of these procedures is not well known. The aim of this study is to investigate the present situation on endoscopic diagnosis and treatment of gastrointestinal disorders in East Asian countries. Method. A representative member from the International Gastrointestinal Consensus Symposium Committee provided a questionnaire to physicians in China, Indonesia, Japan, Korea, the Philippines, and Thailand. Results. In total, 514 physicians including gastroenterologists, surgeons, and general practitioners enrolled. The most frequently occurring disorder as the origin of upper gastrointestinal bleeding is gastric ulcer. Capsule endoscopy is selected as the first choice for the diagnosis of small intestine bleeding. The second choice was double-balloon endoscopy or angiography. For patients with gastric adenoma, the number of physicians who choose endoscopic mucosal resection is larger than those selecting endoscopic submucosal dissection (ESD) in China, Indonesia, the Philippines, and Thailand. ESD is chosen first in Japan and Korea. Conclusion. New instruments or techniques on endoscopy have not come into wide use yet, and there is diversity in the situation on it in Asian countries. We should unify the endoscopic diagnostic criteria or treated strategy in patients with GI disease.

Management of obscure gastrointestinal bleeding based on the classification of capsule endoscopic bleeding findings.

BACKGROUND: Double-balloon endoscopy (DBE) and capsule endoscopy (CE) have been useful in managing obscure gastrointestinal bleeding (OGIB). However, DBE is invasive, complex and time-consuming, therefore indications should probably be selective. The aim of this study was to evaluate the usefulness of the classification of the CE bleeding findings for determining the indications and timing of DBE in patients with OGIB. METHODS: From February 2003 to January 2009, 123 patients with OGIB who underwent CE were included in this study. These CE findings were classified based on the bleeding source. Type CE-I, II, III, IV and 0 indicate active bleeding, previous bleeding, lesions without active bleeding, a lesion outside of the small bowel, and no findings, respectively. We compared diagnostic yield and outcome between the classification and the findings of DBE or enteroclysis. RESULTS: Comparisons of the positive findings rate with DBE or enteroclysis, the treatment rate and the rebleeding rate with the classification showed: CE-Ia, 100% (6/6), 50% (3/6), 33.3% (2/6); Ib, 66.7% (4/6), 0% (0/6), 16.7% (1/6); IIa, 33.3% (1/3), 33.3% (1/3), 33.3% (1/3); IIb, 53.8% (7/13),15.4% (2/13), 30.8% (4/13); III, 100% (84/84), 9.5% (8/84), 8.3% (7/84); IV, 100% (2/2), 50% (1/2), 0% (0/2); and 0, 0% (0/9), 0% (0/9), 0% (0/9), respectively. CONCLUSIONS: The proportion of patients requiring treatment, the positive findings rate with DBE or enteroclysis and the rebleeding rates tended to be higher in the higher ranked classification types (CE-I>II>III>IV>0). These findings suggest that the classification can provide useful information on determining the indications and timing of DBE.

[Recent progress of capsule endoscopy].

Capsule endoscopy is a swallowable pill sized endoscope to visualize the inside of gastrointestinal (GI) tract. Therefore, it is a non-invasive and comfortable examination tool for the patients suffering from disorders of GI tract. New capsule endoscopy for not only small bowel but also esophagus and colon has been in practical use, and several kinds of new capsule shaped equipments are developed recently. In this paper, we introduced a second generation of capsule endoscopy, especially PillCam COLON2 manufactured by Given Imaging Ltd., and new capsules such as Agile Patency Capsule, SmartPill and intelligent Pill (iPill).

A 2008 questionnaire-based survey of gastroesophageal reflux disease and related diseases by physicians in East Asian countries.

BACKGROUND/AIMS: Gastroesophageal reflux disease (GERD) is a common gastrointestinal disease. This study was designed to examine current epidemiology, diagnosis, management, and treatment of patients diagnosed with GERD by surveying physicians in several East Asian countries. METHODS: A questionnaire-based survey was completed in six countries including China, Indonesia, Japan, Korea, the Philippines, and Thailand between July 2008 and December 2008. RESULTS: In total, 876 physicians participated in the study. Most physicians in all countries, except Japan, frequently used international guidelines for the care of GERD patients, whereas approximately half of Japanese physicians did not use such guidelines. GERD was common among many patients, but Barrett's esophagus, particularly the long-segmental type, was rare. The incidence of esophageal cancer, particularly adenocarcinoma, was high in China, but low in other countries. Most physicians diagnosed GERD based on symptoms, followed by endoscopy in Japan and Korea, or in other countries, by the proton-pump inhibitor (PPI) test. Heartburn was recognized as the chief complaint in all countries except Korea. Most physicians in all countries used PPI as the first-line of treatment for GERD. Increasing the PPI dose was the treatment of choice for PPI-refractory erosive esophagitis in Korea, the Philippines, and Thailand. In contrast, in other countries, physicians used a combination of PPI and other drugs to treat PPI-refractory erosive esophagitis. Prescription of antidepressant drugs increased for PPI-refractory nonerosive reflux disease compared with PPI-refractory erosive esophagitis. CONCLUSION: The findings in the present survey are useful to understand the current epidemiology, diagnosis, and treatment of GERD in East Asian countries.

A questionnaire-based survey on the prescription of non-steroidal anti-inflammatory drugs by physicians in East Asian countries in 2007.

BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) and aspirin are widely used clinically but increase the risk of gastrointestinal (GI) complications. AIM: To examine the current prescription of NSAIDs and comedication to prevent GI complications from NSAIDs within East Asia by means of a questionnaire survey. METHODS: Representative members of the Committee of the International Gastrointestinal Consensus Symposium provided a questionnaire to physicians in 6 East Asian countries. RESULTS: A total of 1,568 physicians participated in this survey. Most physicians prescribed nonselective NSAIDs, cyclooxygenase-2 inhibitors (COXIBs) or aspirin for more than 5 patients per week in all countries, with the exception of the prescription of COXIBs in Japan. Of the nonselective NSAIDs, the drug most frequently prescribed as a first choice was loxoprofen (34%), which was mainly prescribed in Japan, followed by diclofenac (30%). The frequency of prescription of comedication with nonselective NSAIDs was higher compared with that for selective COXIBs or aspirin. Physicians in the northern region (China, Japan and Korea) preferred mucoprotective drugs for comedication with NSAIDs or aspirin, while those in southern region (Indonesia, Philippines and Thailand) frequently used proton-pump inhibitors. CONCLUSION: Among East Asian countries, there are both similarities and differences in the prescription of NSAIDs and of comedication to prevent GI complications.

Capsule endoscopy: past, present, and future.

A capsule endoscope is a swallowable wireless miniature camera for getting images of the gastrointestinal (GI) mucosa. The initial capsule endoscope model was developed by Given Imaging and approved in Western countries in 2001. Before the introduction of capsule endoscopy (CE) and double-balloon endoscopy (DBE), there was no effective modality for the evaluation and management of patients with obscure GI bleeding. Obscure GI bleeding is defined as bleeding of unknown origin that persists or recurs after a negative initial or primary endoscopy (colonoscopy or upper endoscopy) result. The first capsule endoscope model, which is now regarded as a first-line tool for the detection of abnormalities of the small bowel, was the PillCam SB. It was approved in Japan in April 2007. The main indication for use of the PillCam SB is obscure GI bleeding. Almost the only complication of CE is capsule retention, which is the capsule remaining in the digestive tract for a minimum of 2 weeks. A retained capsule can be retrieved by DBE. There are some limitations of CE in that it cannot be used to obtain a biopsy specimen or for endoscopic treatment. However, the combination of a PillCam SB and DBE seems to be the best strategy for management of obscure GI bleeding. Recently, several new types of capsule endoscope have been developed, such as Olympus CE for the small bowel, PillCam ESO for investigation of esophageal diseases, and PillCam COLON for detection of colonic neoplasias. In the near future, CE is expected to have a positive impact on many aspects of GI disease evaluation and management.

Proton pump inhibitors and recurrent bleeding in peptic ulcer disease.

Peptic ulcer disease (PUD) is one of the main lesions responsible for upper gastrointestinal (GI) bleeding, as well as esophageal varices and Mallory-Weiss tear. Helicobacter pylori and non-steroidal anti-inflammatory drugs (NSAIDs)/aspirin are the major responsible causes. In cases of upper GI bleeding, urgent endoscopy is performed after stabilization of vital signs. There are several modalities for controlling bleeding in PUD, such as ethanol injection or hypertonic saline with epinephrine. Recurrent bleeding occurs in 20% of patients after endoscopic therapy. The combination of endoscopic intervention and a proton pump inhibitor (PPI) is necessary to achieve hemostasis of active bleeding. It has been reported that high-dose omeprazole (80 mg bolus injection, then 8 mg/h continuous infusion for 72 h, then 40 mg/day orally for 1 week) can reduce recurrent bleeding, the need for surgery and mortality from hemorrhagic shock in patients with high-risk peptic ulcer bleeding, as compared with standard-dose omeprazole. The metabolism of PPIs is dependent upon P450 2C19 genotypes and the clinical usefulness of genotypic analysis remains to be determined.

Selection of anticoagulants for leukocytapheresis therapy in cases of active ulcerative colitis.

BACKGROUND AND AIM: Leukocytapheresis (LCAP) is an extracorporeal leukocyte removal therapy that removes immunocompetent leukocytes from the peripheral blood. Nafamostat mesilate (NM) is the most commonly used anticoagulant for LCAP due to various benefits associated with its use, such as a reduced likelihood of bleeding and minimization of adverse reactions caused by contact between blood and the LCAP device. However, adverse reactions have also been reported with NM administration. We reviewed the safety of anticoagulants other than NM, from the perspective of bradykinin production and the consequent drop in blood pressure during treatment. METHODS: For each of 10 patients with ulcerative colitis, we used four types of anticoagulants sequentially [NM (30-50 mg), heparin, low-molecular-weight heparin (LMWH) and NM (1 mg), and LMWH] for LCAP. We then examined the changes in the blood bradykinin concentrations from the perspective of adverse reactions during LCAP. RESULTS: The bradykinin production levels from Cellsorba EX varied, depending on the type of anticoagulant used. NM alone (30-50 mg) or LMWH + NM (1 mg) inhibited bradykinin production, whereas heparin alone or LMWH alone significantly accelerated it. However, an excessive fall of blood pressure was not noted in any of the cases. Use of LMWH alone was frequently associated with pressure elevations in the column. CONCLUSIONS: Given the significant benefits of minimized adverse reactions of LCAP and of continuation of LCAP, we suggest that an appropriate selection of the anticoagulant(s) may allow safer execution of LCAP.

Rebamipide, a gastro-protective and anti-inflammatory drug, promotes gastric ulcer healing following eradication therapy for Helicobacter pylori in a Japanese population: a randomized, double-blind, placebo-controlled trial.

BACKGROUND: One week of Helicobacter pylori eradication therapy is insufficient for healing of gastric ulcers. We examined the efficacy of rebamipide in gastric ulcer healing following 1 week of eradication therapy in a randomized, double-blind, placebo-controlled trial. METHODS: Patients with H. pylori-positive gastric ulcer were enrolled and received 1 week of eradication therapy, followed by 100 mg of rebamipide or placebo for 7 weeks. The primary end point was the gastric ulcer healing rate. RESULTS: Of the 309 patients entered in the trial, 301 completed H. pylori eradication therapy; 154 patients took rebamipide, and 147 took placebo. The healing rate in the rebamipide group was higher than that in the placebo group in the per-protocol analysis-80.0% (104/130) versus 66.1% (82/124) [95% confidence interval (CI), 3.1-24.7; P = 0.013)-and in a full analysis-70.1% (108/154) versus 60.5% (89/147) (95% CI, -1.1 to 20.3; P = 0.080). CONCLUSIONS: Compared with placebo, rebamipide significantly promoted gastric ulcer healing following 1 week of eradication therapy.

Up-regulation of TFF1 (pS2) expression by TNF-alpha in gastric epithelial cells.

BACKGROUND AND AIM: TFF1 (pS2) is expressed at a high level in gastric epithelial cells and plays an important role in protecting the gastric mucosa. However, the regulatory mechanisms of TFF1 expression are not fully understood. The aim of this study was to investigate the effect of TNF-alpha, a representative proinflammatory cytokine, on TFF1 expression. METHODS: MKN45 and AGS cells, derived from human gastric carcinoma, were used. Endogenous TFF1 mRNA expression was analyzed by real-time quantitative RT-PCR. The sequences of the human TFF1 promoter were cloned into the pGL3-basic vector and reporter gene assays were performed. Nuclear factor (NF)-kappaB activity was monitored using a reporter vector that contained multiple copies of NF-kappaB responsive element upstream of the luciferase gene. Interaction between NF-kappaB and TFF1 cis-element was examined by electophoretic mobility shift assay (EMSA). RESULTS: TNF-alpha activated NF-kappaB and up-regulated endogenous TFF1 mRNA expression as well as the transcription of the TFF1 reporter genes in a dose-dependent manner. IL-1beta, another proinflammatory cytokine, also up-regulated TFF1 expression. TNF-alpha responsive element was mapped between -342 and -147 of the human TFF1 promoter and a putative NF-kappaB binding site was identified at -231. When this element was deleted, the reporter genes became almost insensitive to TNF-alpha treatment. EMSA showed binding of NF-kappaB to this element. CONCLUSIONS: Inflammatory stimuli that activate NF-kappaB appear to up-regulate TFF1 expression in gastric epithelial cells. This mechanism may aid in the protection of the gastric mucosa under inflammatory conditions.

Comparison between endoscopic papillary balloon dilatation and endoscopic sphincterotomy for the treatment of common bile duct stones.

BACKGROUND: This study was designed to evaluate the therapeutic outcome and early postoperative complications, especially pancreatitis, of endoscopic papillary balloon dilation (EPBD) and endoscopic sphincterotomy (EST) in patients with common bile duct stones in our department. METHODS: One hundred eighty patients with common bile duct stones were randomized to undergo EPBD or EST. An 8-mm dilatation balloon was used for EPBD. Modified Cotton's criteria, in which relatively mild pancreatitis is also included as a complication, were used to determine the incidence of postoperative complications. RESULTS: The rate of complete removal of stones was significantly higher in the EST group (95.6%) than in the EPBD group (86.6%); for stones less than 10 mm in diameter, however, the rate with EPBD (93.8%) was almost equivalent to that with EST (98.1%). According to modified Cotton's criteria, the incidence of postoperative pancreatitis was significantly higher in the EPBD group (16.7%) than in the EST group (6.7%). Bleeding was encountered in one patient (1.1%) in the EST group, but in none in the EPBD group. No fatal complication occurred in either the EPBD or the EST group. CONCLUSIONS: Although EPBD appears to be comparable to EST for removal of small common bile duct stones, mild postoperative pancreatitis is more likely to occur with EPBD than with EST.

Peroxisome proliferator-activated receptor gamma (PPARgamma) regulates trefoil factor family 2 (TFF2) expression in gastric epithelial cells.

Although trefoil factor family 2 (TFF2) plays a critical role in the defense and repair of gastric mucosa, the regulatory mechanism of TFF2 expression is not fully understood. In this study, we investigated the regulation of TFF2 expression by peroxisome proliferator-activated receptor gamma (PPARgamma) in gastric epithelial cells. MKN45 gastric cells were used. TFF2 mRNA expression was analyzed by real-time quantitative RT-PCR. The promoter sequence of the human TFF2 gene was cloned into pGL3-basic vector for reporter gene assays. Ciglitazone was mainly used as a specific PPARgamma ligand. MKN45 cells expressed functional PPARgamma proteins. Endogenous TFF2 mRNA expression and TFF2 reporter gene transcription was significantly up-regulated by ciglitazone in a dose-dependent manner. Reporter gene assays showed that two distinct cis-elements are involved in the response to PAPRgamma activation. Within one of these element (nucleotides -558 to -507), we identified a functional peroxisome proliferator responsive element (PPRE) at -522 (5'-GGGACAAAGGGCA-3'). Electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) assay confirmed the binding of PPARgamma to this sequence. Another element (nucleotides -407 to -358) appeared to be a composite enhancer element indirectly regulated by PPARgamma and a combination of these two cis-elements was required for the full response of the human TFF2 gene expression to PPARgamma. These data demonstrate that human TFF2 gene is a direct target of PPARgamma in gastric epithelial cells. Since TFF2 is a critical gastroprotective agent, PPARgamma may be involved in the gastric mucosal defense through regulating TFF2 expression in humans.