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).

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.

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.

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.

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.

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.

Mutational analysis of the BRAF gene in colorectal mucinous carcinoma in association with histological configuration.

Genetic alterations and their association with clinicopathological features in colorectal mucinous carcinoma (MC) remain unknown. In particular, little is known about the mutational status of the BRAF gene, which is activated by oncogenic Ras. This study aimed to evaluate the status of BRAF together with K-ras, p53 and mismatch-repair deficiency to clarify their association with tumorigenesis of colorectal MC. BRAF and K-ras mutations were determined in 43 colorectal MCs by direct sequencing. p53 alteration was investigated immunohistochemically. The status of mismatch-repair deficiency was assessed by microsatellite analyses and immunohistochemistry for hMLH1. We also examined the association between these molecular alterations and clinicopathological features including histological configuration. BRAF mutation was detected in 4 (9.3%) tumors and was located at codon 599 of exon 15 in all cases. K-ras mutation was detected in 13 tumors (30.2%). No BRAF and K-ras mutations were identified simultaneously in the same tumor. The incidence of mismatch-repair deficiency tended to be higher in MC with BRAF mutation than without. In terms of histological configuration, we classified the cases according to growth type by tumor edge morphology. All MCs with BRAF mutation and 9 of 13 MCs (69.2%) with K-ras mutation were classified as polypoid type. BRAF and K-ras mutation did not affect patient prognosis, but non polypoid type was significantly more aggressive than polypoid type. Our findings indicate that BRAF mutation plays an important role in the tumorigenesis of colorectal MC and in tumor edge morphology, similar to K-ras mutation.

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.

Prediction of colorectal neoplasia by quantitative methylation analysis of estrogen receptor gene in nonneoplastic epithelium from patients with ulcerative colitis.

PURPOSE: The incidence of colorectal neoplasia has increased among patients with longstanding and extensive ulcerative colitis (UC). Therefore, surveillance colonoscopy has been widely recommended. However, there is controversy about the impact of cancer surveillance, and ways to improve its effectiveness are being sought. The estrogen receptor (ER) gene shows age-related methylation in the colorectal epithelium and is frequently methylated in colorectal neoplasia, suggesting that ER methylation occurs early in the process of colorectal tumorigenesis. EXPERIMENTAL DESIGN: To clarify whether methylation analysis of the ER gene in nonneoplastic epithelium can help predict an increased risk for UC-associated neoplasia, a total of 105 nonneoplastic colorectal epithelia from 18 patients with longstanding and extensive UC, including 8 patients with neoplasia and 10 patients without neoplasia, were analyzed. In all patients, multiple samples were taken from six regions of the colorectum. The combined bisulfite restriction analysis method was used to determine the methylation status of the ER gene. RESULTS: The mean methylation level of the ER gene was 25.4% in the nonneoplastic epithelia from UC patients with neoplasia, whereas it was only 4.0% in those without neoplasia (P<0.001). The methylation level of the ER gene in UC patients with neoplasia was significantly higher than in UC patients without neoplasia throughout the colorectum except for the cecum. In UC patients with neoplasia, the mean ER methylation level in the distal colon (36.1%) was significantly higher than in the proximal colon (14.6%; P<0.001). CONCLUSIONS: These results suggest that the analysis of ER gene methylation in nonneoplastic colorectal epithelium could have the potential to be a useful adjunct for identifying individuals with longstanding and extensive UC who are at increased risk of neoplasia and contribute to more effective cancer surveillance.

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.

Protective effect of central thyrotropin-releasing hormone analog on cerulein-induced acute pancreatitis in rats.

Central neuropeptides play a role in many physiological functions through the autonomic nervous system. We have recently demonstrated that central injection of a thyrotropin-releasing hormone (TRH) analog increases pancreatic blood flow through vagal and nitric oxide-dependent pathways. In this study, the central effect of a TRH analog on experimental acute pancreatitis was investigated in rats. Acute pancreatitis was induced by two intraperitoneal injections of cerulein (40 microg/kg) at 1-h interval. Either stable TRH analog, RX 77368 (5-100 ng), or saline was injected intracisternally 15 min before the first cerulein injection under ether anesthesia. Serum amylase level was measured before and 5 h after the first cerulein injection. Pancreatic wet/dry weight ratio and histological changes were also evaluated. Intracisternal TRH analog inhibited cerulean-induced elevation of serum amylase level, increase in pancreatic wet/dry weight ratio and pancreatic histological changes, such as interstitial edema, inflammation and vacuolization. The pancreatic cytoprotection induced by central TRH analog was abolished by subdiaphragmatic vagotomy and N(G)-nitro-L-arginine-methyl ester (L-NAME), but not by 6-hydroxydopamine (6-OHDA). Intravenous administration of the TRH analog did not influence cerulein-induced acute pancreatitis. These results indicate that the TRH analog acts in the central nervous system to protect against acute pancreatitis through vagal and nitric oxide-dependent pathways.

[Capsule endoscopy].

Wireless capsule endoscopy is a new diagnostic tool in which a disposable video capsule is swallowed by the patient. This examination enables visualization of the small intestine that is not within the reach of conventional upper and lower endoscopy. The best indications include an obscure source of gastrointestinal bleeding, Crohn's disease, and small intestinal tumors. The disadvantage that biopsy cannot be performed is compensated for by employing double-balloon endoscopy. In particular, this examination can identify the origin of bleeding and diagnose the underlying disease, leading to prompt surgical treatment with better results. In future, capsule endoscopy will become a necessary examination for diagnosing digestive tract disease.