Impact of lubiprostone on gastric-emptying profile and the possible effect of concomitant domperidone in healthy adults
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BACKGROUND: Lubiprostone is effective for patients with chronic constipation. This agent sometimes causes upper gastrointestinal symptoms, such as nausea, which is one of the chief reasons for discontinuation. However, the etiology of and strategy against bothersome gastrointestinal symptoms of lubiprostone remain unclear. AIMS: The goal of this study was to investigate the influence of lubiprostone on the gastric-emptying profile of healthy adults. The effect of domperidone on gastric emptying and gastrointestinal symptoms after lubiprostone administration were also assessed. MATERIALS AND METHODS: 80 healthy male participants underwent 13C acetate breath testing to evaluate gastric emptying. The test meal comprised 200 kcal of a standard liquid nutrient. Each participant underwent 3 random breath tests with: 1) no premedication; 2) 24 µg of lubiprostone 30 minutes prior to the study; and 3) 24 µg of lubiprostone plus 10 mg of domperidone 30 minutes prior to the study. Gastrointestinal symptoms (heartburn, regurgitation, epigastric pain, fullness, distress feeling) during testing were evaluated using a 7-point scoring system. RESULTS: Gastric emptying was significantly delayed by the administration of lubiprostone. Among all 8 subjects, 4 reported heartburn after taking lubiprostone, whereas this symptom was not found when subjects received concomitant domperidone. However, gastric emptying showed little change between lubiprostone alone and lubiprostone plus domperidone. CONCLUSION: Lubiprostone delayed gastric emptying of liquid in healthy adults, which could be associated with the gastrointestinal symptoms caused by the agent. Domperidone seemed effective against such gastrointestinal symptoms after administration of lubiprostone. This effect seemed unrelated to gastric motility.
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Extensive gastric mucosal atrophy is a possible predictor of clinical effectiveness of acotiamide in patients with functional dyspepsia
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BACKGROUND: Acotiamide is known as an effective agent for functional dyspepsia. However, clinical factors related to its effectiveness have not been fully elucidated, so it is difficult to predict the drug's effectiveness prior to its administration in patients. AIMS: The present retrospective study was conducted to examine the relationship between clinical factors and the effectiveness of acotiamide for functional dyspepsia. MATERIALS AND METHODS: The study subjects were 149 patients with functional dyspepsia who were prescribed acotiamide. Based on medical records and clinical factors, including endoscopic findings, the effectiveness of acotiamide was investigated. RESULTS: Significant clinical factors associated with acotiamide's effectiveness were identified. These included postprandial syndrome, concomitant mental disorder, and extensive gastric mucosal atrophy. On multiple regression analysis, extensive gastric mucosal atrophy showed the strongest relationship with the clinical effectiveness of acotiamide; the other significant factor was concomitant mental disorder. CONCLUSION: Although the pathophysiology of the relationship between mucosal atrophy and acotiamide remains uncertain, a decrease in hormonal secretion, such as that of ghrelin, may be a possible mechanism.
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Gastrointestinal bleeding risk of non-vitamin K oral anticoagulants is similar to warfarin - a Japanese retrospective cohort study
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BACKGROUND AND AIM: Although several non-vitamin K oral anticoagulants have been developed to prevent cardiogenic thrombosis, the status of hemorrhagic complications in the clinical setting among Asian populations, including Japan, remains unclear. We conducted this retrospective cohort study to clarify the current status of hemorrhagic events during antithrombotic therapy with non-vitamin K oral anticoagulants, with particular focus on gastrointestinal bleeding. METHODS: Medical charts of 475 patients prescribed dabigatran, rivaroxaban, or apixaban between April 2011 and September 2014 were reviewed to examine whether any hemorrhagic events occurred, compared with 135 patients who received warfarin between April 2009 and March 2011. RESULTS: Incidences of total and actionable hemorrhage in patient taking non-vitamin K oral anticoagulants were 13.8% per year and 4.6% per year, respectively, showing no significant differences from those in warfarin users (9.3% per year and 5.0% per year, respectively). In addition, actionable gastrointestinal hemorrhage occurred at similar rates in non-vitamin K oral anticoagulants users (2.1% per year) and warfarin users (1.5% per year). Most hemorrhages were from the lower gastrointestinal tract, and considerable events involved perianal bleeding. Multiple regression analysis showed that age, concomitant dual antiplatelet therapy, and concomitant nonsteroidal anti-inflammatory drug therapy were significant factors related to actionable gastrointestinal bleeding. CONCLUSIONS: Risk of gastrointestinal hemorrhage in patients taking non-vitamin K oral anticoagulants was similar to that in patients taking warfarin. The dominant bleeding site was the lower gastrointestinal tract.
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Is narrow-band imaging useful for histological evaluation of gastric mucosa-associated lymphoid tissue lymphoma after treatment?

BACKGROUND AND AIM: Endoscopic diagnosis of stomach mucosa-associated lymphoid tissue (MALT) lymphoma is often difficult because few specific findings are indicated. Even when MALT lymphoma is suspected by endoscopy, it is still difficult to make a definitive diagnosis by biopsy because lymphoma cells sometimes distribute unevenly. We previously reported that a tree-like appearance (TLA) is a characteristic finding of MALT lymphoma by narrow-band imaging (NBI) magnifying endoscopy and it is valuable in the selection of an optimal biopsy site in MALT lymphoma. Here, we study the frequency of TLA and evaluate the relationship between the response to eradication therapy and TLA in MALT lymphoma. METHODS: We retrospectively examined the clinical background, endoscopic findings, response to eradication therapy, and Helicobacter pylori infection status of 16 patients diagnosed with MALT lymphoma who were referred to our hospital from April 2007 to August 2012. The regimen for eradicationtherapy consisted of rabeprazole, with amoxicillin and clarithromycin, all given for 7 days. RESULTS: TLA was found in 75% (12/16) and H. pylori infection in 75% (12/16) of patients diagnosed with MALT lymphoma by NBI magnifying endoscopy. In all complete regression (CR) patients after eradication treatment, the TLA finding had disappeared (100%); however, in the non-CR patients, TLA remained the same as before the eradication therapy (P=0.002). CONCLUSION: These results suggest that NBI magnifying endoscopy may be useful not only in the diagnosis but also in the evaluation of the response to eradication therapy of MALT lymphoma of the stomach.

Different healing process of esophageal large mucosal defects by endoscopic mucosal dissection between with and without steroid injection in an animal model.

BACKGROUND: Stricture formation is one of the major complications after endoscopic removal of large superficial squamous cell neoplasms of the esophagus, and local steroid injections have been adopted to prevent it. However, fundamental pathological alterations related to them have not been well analyzed so far. The aim of this study was to analyze the time course of the healing process of esophageal large mucosal defects resulting in stricture formation and its modification by local steroid injection, using an animal model. METHODS: Esophageal circumferential mucosal defects were created by endoscopic mucosal dissection (ESD) for four pigs. One pig was sacrificed five minutes after the ESD, and other two pigs were followed-up on endoscopy and sacrificed at the time of one week and three weeks after the ESD, respectively. The remaining one pig was followed-up on endoscopy with five times of local steroid injection and sacrificed at the time of eight weeks after the ESD. The esophageal tissues of all pigs were subjected to pathological analyses. RESULTS: For the pigs without steroid injection, the esophageal stricture was completed around three weeks after the ESD on both endoscopy and esophagography. Histopathological examination of the esophageal tissues revealed that spindle-shaped α-smooth muscle actin (SMA)-positive myofibroblasts arranged in a parallel fashion and extending horizontally were identified at the ulcer bed one week after the ESD, and increased contributing to formation of the stenotic luminal ridge covered with the regenerated epithelium three weeks after the ESD. The proper muscle layer of the stricture site was thinned with some myocytes which seemingly showed transition to the myofibroblast layer. By contrast, for the pig with steroid injection, esophageal stricture formation was not evident with limited appearance of the spindle-shaped myofibroblasts, instead, appearance of stellate or polygocal SMA-positive stromal cells arranged haphazardly in the persistent granulation tissue of the ulcer site. CONCLUSIONS: Proliferation of spindle-shaped myofibroblasts arranged in a parallel fashion is likely to play an important role in stricture formation after circumferential mucosal defects by esophageal ESD, which may be related to the thinning of the proper muscle layer in the healing course of the defects. Local steroid injection seems to be effective to prevent the stricture through the modification of this process.

Prospective study of the evaluation of the usefulness of tumor typing by narrow band imaging for the differential diagnosis of gastric adenoma and well-differentiated adenocarcinoma.

BACKGROUND AND AIM: Presently, the differential diagnosis of gastric adenoma and well-differentiated adenocarcinoma by endoscopy is very difficult. We carried out magnifying endoscopy with narrow band imaging (NBI) in lesions that required discrimination between gastric adenoma and well-differentiated adenocarcinoma, and prospectively evaluated whether the tumor typing that we propose is useful for their differential diagnosis. METHODS: The materials were 93 lesions that required differential diagnosis between gastric adenoma and well-differentiated adenocarcinoma among the gastric epithelial tumors for which endoscopic treatment was planned at three facilities during the 14 months between November 2008 and December 2009. According to the typing method proposed by our facility based on images of the mucosal ultrastructure and microvessels obtained by magnified endoscopy combined with NBI, type I-II and type III-V lesions were diagnosed as gastric adenoma and well-differentiated adenocarcinoma, respectively, before endoscopic treatment, and the accuracy of the diagnoses were prospectively examined by comparing them with the postoperative pathological findings. RESULTS: Of the 93 lesions, 87 could be typed into the five types of our typing method, but six lesions could not be classified. The 87 lesions consisted of 16 type I, 12 type II, 29 type III, 27 type IV, and three type V lesions. The percentages of accurate preoperative diagnoses of types I-II as adenoma and types III-V as well-differentiated adenocarcinoma were 79% and 93%, respectively. CONCLUSIONS: The tumor typing based on NBI was useful for the endoscopic differentiation of gastric adenoma and well-differentiated adenocarcinoma.

Identification of HLA-A2-restricted CD8(+) cytotoxic T cell responses in primary biliary cirrhosis: T cell activation is augmented by immune complexes cross-presented by dendritic cells.

Primary biliary cirrhosis (PBC) is characterized by an intense biliary inflammatory CD4(+) and CD8(+) T cell response. Very limited information on autoantigen-specific cytotoxic T lymphocyte (CTL) responses is available compared with autoreactive CD4(+) T cell responses. Using peripheral blood mononuclear cells (PBMCs) from PBC, we identified an HLA-A2-restricted CTL epitope of the E2 component of pyruvate dehydrogenase (PDC-E2), the immunodominant mitochondrial autoantigen. This peptide, amino acids 159-167 of PDC-E2, induces specific MHC class I-restricted CD8(+) CTL lines from 10/12 HLA-A2(+) PBC patients, but not controls, after in vitro stimulation with antigen-pulsed dendritic cells (DCs). PDC-E2-specific CTLs could also be generated by pulsing DCs with full-length recombinant PDC-E2 protein. Furthermore, using soluble PDC-E2 complexed with either PDC-E2-specific human monoclonal antibody or affinity-purified autoantibodies against PDC-E2, the generation of PDC-E2-specific CTLs, occurred at 100-fold and 10-fold less concentration, respectively, compared with soluble antigen alone. Collectively, these data demonstrate that autoantibody, helper, and CTL epitopes all contain a shared peptide sequence. The finding that autoantigen-immune complexes can not only cross-present but also that presentation of the autoantigen is of a higher relative efficiency, for the first time defines a unique role for autoantibodies in the pathogenesis of an autoimmune disease.

Diagnosis of elevated-type early gastric cancers by the optimal band imaging system.

BACKGROUND: The endoscopic diagnosis of an elevated-type early gastric cancer is often difficult. The optimal band imaging (OBI) system can reconstruct the best spectral images decomposed from ordinary endoscopic images with free selection of 3 wavelengths and provide unmagnified images with high light intensity as well as magnified images. OBJECTIVE: To evaluate whether the OBI system facilitates detection of the demarcation lines between an elevated-type early gastric cancer and surrounding tissue and thus is more helpful for performing endoscopic therapy. DESIGN: A prospective study. SETTING: Jichi Medical University, Japan. PATIENTS: Seventy-five patients, 81 lesions with an elevated-type early gastric cancer. MAIN OUTCOME MEASUREMENTS: A comparison between OBI images and conventional endoscopic images in the identification of the demarcation lines of an elevated-type early gastric cancer without magnification and the rate of success in identifying the abnormal surface structure of cancer by using low-magnified OBI images. RESULTS: Demarcation lines were easily identified in OBI images, even without magnification, because such cancers could be clearly distinguished from the surrounding whitish atrophic mucosa. Inexperienced endoscopists could determine demarcation lines with significantly greater accuracy with unmagnified OBI images than with conventional images. With 40-fold magnification, irregular microstructural or nonstructural patterns were also found within cancer lesions in all cases studied but in none of the cases in the surrounding noncancerous mucosa. CONCLUSIONS: The new contrast images obtained with the OBI system enable better determination of the demarcation lines of elevated-type early gastric cancers, and this system may be useful for performing endoscopic therapy of this type of cancer as a new endoscopic modality.

Squamous intraepithelial neoplasia of the esophagus: past, present, and future.

With regard to the esophagus, the term "squamous dysplasia" has been used in European countries, the United States, and China, while its use is controversial in Japan. Recently, "low-grade intraepithelial neoplasia" and "high-grade intraepithelial neoplasia" have been used as inclusive terms for dysplasia and carcinoma in situ in the World Health Organization classification. Endoscopically, it is often difficult to identify squamous intraepithelial neoplasia by conventional endoscopy, but application of iodine is useful for the diagnosis of such a lesion. In addition, new types of endoscopic techniques, including magnifying endoscopy, narrow-band imaging (NBI), and endocytoscopy are helpful to detect squamous intraepithelial neoplasia. NBI is very useful for identifying the intrapapillary capillary loop pattern. Regarding the pathological criteria of squamous dysplasia and squamous cell carcinoma, the views of Japanese and Western pathologists have differed significantly. Before the term "intraepithelial neoplasia" was introduced, severe dysplasia as diagnosed by Western pathologists was in fact the same as squamous cell carcinoma in situ or noninvasive carcinoma as diagnosed by Japanese pathologists. This problem has been solved by the introduction of the Vienna classification; however, there are still some issues that need to be resolved. One of them is the presence of basal layer type squamous cell carcinoma in situ, which is often underdiagnosed as lowgrade intraepithelial neoplasia by Western pathologists. Endoscopic treatments such as endoscopic mucosal resection and endoscopic submucosal dissection have recently become possible choices for squamous intraepithelial neoplasia; however, these techniques are not in widespread use in the West. We believe that a consensus meeting between Japanese and Western pathologists as well as endoscopists should be held promptly to reach a common ground for the nomenclature.

[A case of gastric xanthogranuloma associated with early gastric cancer].

A 67-year-old man complaining of epigastric pain was referred for evaluation. Upper gastrointestinal endoscopy and CT revealed two extraluminal tumors in the posterior wall of the gastric body. Both of the lesions were remarkably reduced two months after the evaluation, but early gastric cancer was diagnosed on the mucosal side of the gastric body at that time. The patient underwent a distal gastrectomy, with resection of both of the extraluminal tumors. The posterior wall of the stomach was thickened and had a yellowish tumor which was diagnosed as xanthogranuloma. We report this very rare case of synchronous xanthogranuloma and gastric carcinoma.

Indian hedgehog promotes the migration of rat activated pancreatic stellate cells by increasing membrane type-1 matrix metalloproteinase on the plasma membrane.

Indian hedgehog (Ihh) is a member of hedgehog peptides family that exerts diverse effects on multiple cellular functions. Since Ihh expression is elevated in the pancreas of chronic pancreatitis patients, Ihh has been assumed to participate in the chronic pancreatic injury, especially in pancreatic fibrosis. However, its function in pancreatic fibrosis is still unknown. We thus examined Ihh effects on rat activated pancreatic stellate cells (PSCs) that play a central role in pancreatic fibrosis. Activated PSCs express both patched-1 and smoothened that are essential components of hedgehog receptor system. Ihh did not alter the PSC expression of collagen-1 or alpha-smooth muscle actin, a parameter of PSC transformation, or did not change PSC proliferation. However, Ihh enhanced PSC migration in both chemotactic and chemokinetic manners. Furthermore, Ihh increased the amount of membrane-type 1 matrix metalloproteinase (MT1-MMP) and altered its localization on the plasma membrane, which plays a stimulatory role in cellular migration. In addition, tissue inhibitor of metalloproteinase-2 (TIMP-2) attenuated Ihh-stimulated PSC migration. Since most hedgehog intracellular signals are mediated by Gli-1 transcription factor, we investigated its contribution to Ihh-enhancement of PSC migration. Ihh induced Gli-1 nuclear accumulation in PSCs, indicating that Ihh stimulates Gli-1-dependent signaling pathway in PSCs. Unexpectedly, however, adenovirus-mediated Gli-1 overexpression blocked the Ihh enhancement of both MT1-MMP localization on the plasma membrane and PSC migration. Furthermore, reduction of Gli-1 expression with RNA interference augmented Ihh-stimulated PSC migration. These data indicate that Ihh promotes PSC migration by enhancing MT1-MMP localization on the plasma membrane but is negatively regulated by Gli-1.

Endoscopic observation of Meckel's diverticulum by double balloon endoscopy: report of five cases.

BACKGROUND AND AIM: Most cases of Meckel's diverticula are asymptomatic, however, some cases presented with gastrointestinal (GI) bleeding. It is often difficult to determine whether Meckel's diverticulum is a source of obscure GI bleeding. Double balloon endoscopy allows endoscopic access to the entire small intestine. The aim of this study was to compare endoscopic findings of three hemorrhagic and two non-hemorrhagic Meckel's diverticula in patients with obscure GI bleeding using this novel technique. METHODS: Between September 2000 and April 2005, 354 enteroscopies, including 162 anterograde and 192 retrograde procedures, were performed on 217 patients at the Jichi Medical University Hospital, Japan, using the double balloon endoscopy system. Five consecutive patients where Meckel's diverticulum was endoscopically observed were selected and analyzed. RESULTS: Double balloon endoscopy enabled direct observation of Meckel's diverticula in all five patients. Surgical procedures were indicated for three patients where double balloon endoscopy discovered ulcers. By contrast, double balloon endoscopy detected other sources of bleeding in the remaining two patients where no ulcers were found in the Meckel's diverticula. CONCLUSION: Endoscopic observation of the ulcers in Meckel's diverticula was important evidence of bleeding in patients with obscure GI bleeding. Other sources of bleeding should be considered when no ulcers are found in the Meckel's diverticula.

Difference between the Upper and the Lower Gastrointestinal Bleeding in Patients Taking Nonvitamin K Oral Anticoagulants.

Nonvitamin K oral anticoagulants (NOACs) sometimes cause hemorrhage, and the gastrointestinal tract is a common site of involvement. However, clinical characteristics of gastrointestinal bleeding (GIB) during NOAC therapy have not been fully elucidated. We studied 658 patients who were prescribed dabigatran, rivaroxaban, or apixaban between April 2011 and November 2015. Medical charts were reviewed to examine whether clinically relevant bleeding (Bleeding Academic Research Consortium criteria type 2 or greater) developed. The incidence of GIB was 2.0%/year, and one-third was from the upper GI. Among all hemorrhagic events, GIB was the most common cause. The extent of bleeding from the GI tract, particularly the upper GI tract, was more serious than bleeding from the other site. Multiple regression analysis showed that both past digestive ulcer and absence of concomitant proton pump inhibitors were significantly associated with the incidence of upper GIB, while concomitant nonsteroidal anti-inflammatory drugs, dual antiplatelets, and past GIB were significant factors regarding lower GIB. GIB was common and serious in patients taking NOACs. Upper GIB tended to become more serious than lower GIB. Proton pump inhibitors seem to be key drugs for preventing upper GIB during NOAC therapy.

Preoperative biliary drainage using a fully covered self-expandable metallic stent for pancreatic head cancer: A prospective feasibility study.

Background/Aims: The role of endoscopic preoperative biliary drainage (PBD) for pancreatic head cancer is controversial because of the high incidence of stent occlusion before surgery. This study was performed to evaluate the feasibility and safety of PBD using a fully covered self-expandable metallic stent (FCSEMS). Patients and Methods: This multicenter prospective study involved 26 patients treated for pancreatic head cancer with distal bile duct obstruction from April 2011 to March 2013. An FCSEMS was endoscopically placed in 24 patients. Among these, 7 patients were diagnosed with unresectable cancer, and 17 underwent surgery at a median of 18 days after FCSEMS placement. The main outcome measure was preoperative and postoperative adverse events. Results: Two adverse events (cholecystitis and insufficient resolution of jaundice) occurred between FCSEMS placement and surgery (12%). Postoperative adverse events occurred in eight patients (47%). The cumulative incidence of stent-related adverse events 4 and 8 weeks after FCSEMS placement among the 24 patients who underwent this procedure were 19%. Conclusions: PBD using an FCSEMS is feasible in patients with resectable pancreatic head cancer. Placement of an FCSEMS can be an alternative PBD technique when surgery without delay is impossible. A larger randomized controlled trial is warranted.

Quantitative and functional analysis of PDC-E2-specific autoreactive cytotoxic T lymphocytes in primary biliary cirrhosis.

While the pathologic mechanisms responsible for organ-specific tissue damage in primary biliary cirrhosis (PBC) remain an enigma, it has been suggested that the pathology is mediated by autoreactive T cells infiltrating the intrahepatic bile ducts. Previously, we have documented that there is 100-fold enrichment in the frequency of CD4(+) autoreactive T cells in the liver that are specific for peptides encoded by the E2 components of the pyruvate dehydrogenase complexes (PDC-E2). We have also recently characterized the first MHC class I-restricted epitope for PDC-E2, namely amino acid 159-167, a region very similar to the epitope recognized by MHC class II-restricted CD4(+) cells and by autoantibodies. The effector functions of these PDC-E2(159-167)-specific CD8(+) cytotoxic T lymphocytes (CTLs) are not well understood. We have taken advantage of tetramer technology and report herein that there is tenfold increase in the frequency of PDC-E2(159-167)-specific CTLs in the liver as compared with the blood in PBC. In addition, the precursor frequency of the CTLs in blood was significantly higher in early-stage PBC. Of interest was the fact that, upon stimulation with the peptide, the response of PDC-E2(159-167) tetramer-positive cells is heterogeneous with respect to IFN-gamma synthesis. These data, we believe for the first time, document the enrichment of autoantigen-specific CD8(+) T cells in the PBC liver, suggesting that CD8(+) T cells play a significant role in the immunopathogenesis of PBC.

Autoreactive CD8-specific T-cell response in primary biliary cirrhosis.

Primary biliary cirrhosis (PBC) is an autoimmune liver disease of unknown etiology. Autoimmune attack in PBC is predominantly organ-specific, despite the presence of mitochondrial autoantigens, the major targets of autoimmunity in PBC, in all nucleated cells. Cytotoxic T lymphocytes are thought to be directly involved in the tissue injury in PBC. The major histocompatibility complex (MHC) class I-restricted epitope for E2 components of pyruvate dehydrogenase complexes, namely amino acid 159-167, a region very close to the epitoperecognized by MHC class II-restricted CD4 cells and by antibody, has been characterized. In addition, there was a 10-fold increase in the frequency of autoreactive cytotoxic T lymphocytes in the liver as compared to the blood in PBC patients using tetramer technology.