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Background: It is still difficult to detect and diagnose early adenocarcinoma of the esophagogastric junction (EGJ) using conventional endoscopy or image-enhanced endoscopy. A glutamylprolyl hydroxymethyl rhodamine green (EP-HMRG) fluorescent probe that can be enzymatically activated to become fluorescent after the cleavage of a dipeptidyl peptidase (DPP)-IV-specific sequence has been developed and is reported to be useful for the detection of squamous cell carcinoma of the head and neck, and esophagus; however, there is a lack of studies that focuses on detecting EGJ adenocarcinoma by fluorescence molecular imaging. Therefore, we investigated the visualization of early EGJ adenocarcinoma by applying EP-HMRG and using clinical samples resected by endoscopic submucosal dissection (ESD)., Methods: Fluorescence imaging with EP-HMRG was performed in 21 clinical samples resected by ESD, and the fluorescence intensity of the tumor and non-tumor regions of interest was prospectively measured. Immunohistochemistry was also performed to determine the expression of DPP-IV., Results: Fluorescence imaging of the clinical samples showed that the tumor lesions were visualized within a few minutes after the application of EP-HMRG, with a sensitivity, specificity, and accuracy of 85.7, 85.7, and 85.7%, respectively. However, tumors with a background of intestinal metaplasia did not have a sufficient contrast-to-background ratio since complete intestinal metaplasia also expresses DPP-IV. Immunohistochemistry measurements revealed that all fluorescent tumor lesions expressed DPP-IV., Conclusions: Fluorescence imaging with EP-HMRG could be useful for the detection of early EGJ adenocarcinoma lesions that do not have a background of intestinal metaplasia.

Background and study aim  Magnifying narrow-band imaging (M-NBI) is useful for the accurate diagnosis of early gastric cancer (EGC). However, acquiring skill at M-NBI diagnosis takes substantial effort. An Internet-based e-learning system to teach endoscopic diagnosis of EGC using M-NBI has been developed. This study evaluated its effectiveness. Participants and methods  This study was designed as a multicenter randomized controlled trial. We recruited endoscopists as participants from all over Japan. After completing Test 1, which consisted of M-NBI images of 40 gastric lesions, participants were randomly assigned to the e-learning or non-e-learning groups. Only the e-learning group was allowed to access the e-learning system. After the e-learning period, both groups received Test 2. The analysis set was participants who scored < 80 % accuracy on Test 1. The primary end point was the difference in accuracy between Test 1 and Test 2 for the two groups. Results  A total of 395 participants from 77 institutions completed Test 1 (198 in the e-learning group and 197 in the non-e-learning group). After the e-learning period, all 395 completed Test 2. The analysis sets were e-learning group: n = 184; and non-e-learning group: n = 184. The mean Test 1 score was 59.9 % for the e-learning group and 61.7 % for the non-e-learning group. The change in accuracy in Test 2 was significantly higher in the e-learning group than in the non-e-learning group (7.4 points vs. 0.14 points, respectively; P  < 0.001). Conclusion This study clearly demonstrated the efficacy of the e-learning system in improving practitioners' capabilities to diagnose EGC using M-NBI.Trial registered at University Hospital Medical Information Network Clinical Trials Registry (UMIN000008569)., Competing Interests: Competing interests: None, (© Georg Thieme Verlag KG Stuttgart · New York.)

Background: Little is known about the specific risks of metastasis in esophageal adenocarcinoma in relation to invasion depth or other pathologic factors., Methods: We conducted a multicenter retrospective study in 13 high-volume centers in Japan from January 2000 to October 2014 to elucidate the risk of metastasis of esophageal adenocarcinoma. A total of 458 patients (217 surgically resected and 241 endoscopically resected) with esophageal adenocarcinoma or esophagogastric adenocarcinoma involving the esophagus were included. Metastasis was considered positive if there was histologically confirmed metastasis in the surgical specimen or clinically confirmed metastasis during follow-up. Metastasis was considered negative if no metastasis was identified in resected specimens and during follow-up in patients treated surgically or no metastasis during follow-up for >5 years in patients treated by endoscopic resection., Results: Metastasis was identified in 72 patients. Multivariate analysis confirmed lymphovascular involvement [odds ratio (OR) 6.20; 95 % confidence interval (CI) 3.12-12.32; p < 0.001], a poorly differentiated component (OR 3.69; 95 % CI 1.92-7.10; p < 0.001), and lesion size >30 mm (OR 3.12; 95 % CI 1.63-5.97; p = 0.001) as independent risk factors for metastasis. No metastasis was detected in patients with mucosal cancer without lymphovascular involvement and a poorly differentiated component (0/186 lesions) or in patients with cancer invading the submucosa (1-500 µm) without lymphovascular involvement, a poorly differentiated component, and ≤30 mm (0/32 lesions)., Conclusions: Mucosal and submucosal cancers (1-500 µm invasion) without risk factors have a low incidence of metastasis and may thus be good candidates for endoscopic resection.

Background: Parameters reported in pathologic reviews have been failing to assess exactly the malignant potential of gastrointestinal cancers. We hypothesized that malignant potential could be defined by common latent variables (hypothesis I), but there are substantial differences in the associations between malignant potential and pathologic parameters according to the origin of gastrointestinal cancers (hypothesis II). We shed light on these issues by structural equation modeling., Materials and Methods: We conducted a cross-sectional survey of 217 esophageal, 192 gastric, and 175 colorectal cancer patients who consecutively underwent curative surgery for their pathologic stage I cancers at Keiyukai Sapporo Hospital. Latent variables identified by factor analysis and seven conventional pathologic parameters were introduced in the structural equation modeling analysis., Results: Because latent variables were disparate except for their number, 'three' in the examined gastrointestinal cancers, the first hypothesis was rejected. Because configural invariance across gastrointestinal cancers was not approved, the second hypothesis was verified. We could trace the three significant paths on the causal graph from latent variables to lymph node metastasis, which were mediated through depth, lymphatic invasion, and matrilysin expression in esophageal cancer, whereas only one significant path could be traced in both gastric and colorectal cancer. Two of the three latent variables were exogenous in esophageal cancer, whereas one factor was exogenous in the other gastrointestinal cancers. Cancer stemness promoted viability in esophageal cancer, but it was suppressed in others., Conclusion: These results reflect the malignant potential of esophageal cancer is higher than that of the other gastrointestinal cancers. Such information might contribute to refining clinical treatments for gastrointestinal cancers.

Background: Esophageal stenosis following endoscopic submucosal dissection (ESD) is a serious adverse event that makes subsequent management more difficult., Methods: This parallel, randomized, controlled, open-label study was designed to examine whether local steroid injection is an effective prophylactic treatment for esophageal stenoses following extensive ESD. This single center trial was conducted at the Keiyukai Hospital, a tertiary care center for gastrointestinal disease in Japan [University Hospital Medical Network Clinical Trial Registry (UMIN-CTR) on 15 September 2011 (UMIN000006327)]. Thirty-two patients with mucosal defects involving ≥75% of the esophageal circumference were randomized to receive a single dose of triamcinolone acetonide injections (n = 16) or be treated conventionally (n = 16). The primary outcome was the frequency of stricture requiring endoscopic dilatation; the surrogate primary endpoint was the number of dilatation sessions needed. Secondary outcomes included adverse event rates, the minimum diameter of the stenotic area and the duration of the course of dilatation treatments., Results: The frequency of stricture was not significantly different between the groups because of insufficient statistical power, but the number of dilatation sessions required was significantly less in the steroid group (6.1 sessions [95% confidence interval, CI 2.8-9.4] versus 12.5 [95% CI 7.1-17.9] sessions in the control group; P = 0.04). The perforation rate was similar in both groups. The minimum diameter of stenotic lumens was significantly greater in the treatment group than controls (11.0 mm versus 7.1 mm, respectively; P = 0.01). The perforation rate was not significantly different between the groups (1.0% versus 0.5% in the treatment and control group, respectively). Steroid injection was effective in cases of mucosal defects encompassing the entire esophageal circumference., Conclusions: Prophylactic endoscopic steroid injection appears to be a safe means of relieving the severity of esophageal stenoses following extensive ESD.

Background: Endoscopic submucosal dissection (ESD) was originally developed in Japan for en bloc resection of gastric neoplasms., Objective: To clarify whether the novel ESD procedure is feasible and gives results that justify the pursuit of integrated minimally invasive procedures aimed at curing early squamous cell carcinoma of the esophagus (SCCE)., Design: Retrospective cohort study., Setting: A single-institution trial by experienced endoscopists., Patients: This study involved 300 consecutively enrolled patients with SCCE (Tumor, Nodes, Metastasis classification T1, N0) who underwent either EMR (n = 184) or ESD (n = 116) from March 1994 to July 2007., Intervention: The patients underwent endoscopic resection and then were followed by periodic endoscopy for 8 to 174 months (mean 65 months)., Main Outcome Measurements: Resectability, cure rates, complications, disease-free survival of the two groups, and risk factors for local recurrence were explored., Results: En bloc resection and the local recurrence rate were significantly better in the ESD group (P = .0009 and .065, respectively). The frequency of perforation was not significantly different between the two groups (P = .68). Four independent risk factors for local recurrence were identified by the Cox regression model: EMR, deep cancer invasion, upper esophagus location, and family history of esophageal cancer. Radical cure is mostly obtained by successful endoscopic retreatment of local recurrence after previous endoscopic resection. Disease-free survival was significantly better with ESD., Limitations: The study's retrospective nature prevents definitive conclusions., Conclusions: We provide evidence that ESD gives a higher cure rate and is safer than conventional endoscopic resection when applied to early SCCE. ESD warrants prospective comparative studies with conventional endoscopic resection., (Copyright 2010 American Society for Gastrointestinal Endoscopy. Published by Mosby, Inc. All rights reserved.)

Background and Aim: According to a few recent reports on the long-term clinical outcome of gastric marginal zone B-cell mucosa associated lymphoid tissue lymphoma (MALT lymphoma); localized gastric MALT lymphoma generally has a favorable prognosis. However, the risk of metachronous gastric cancer has not been evaluated. In this study, we analyzed long-term outcomes of localized gastric MALT lymphoma including the incidence of metachronous gastric cancer., Methods: Between April 1996 and May 2008, 60 patients (31 men and 29 women; mean age 58.1 years) with localized gastric MALT lymphoma (stage I and II(1) according to Lugano classification) were analyzed retrospectively., Results: Forty-eight patients (82.6%) achieved complete remission by eradication therapy. Radiation therapy was conducted on eight patients as second-line treatment, and all of them achieved remission. The median follow-up period was 76 months (range, 12-157 months). One patient had local relapse after remission for 5 years and three patients developed early gastric cancer without recurrence of lymphoma (5%). All of the three gastric cancers appeared in the same areas where MALT lymphoma had been eradicated., Conclusion: Eradication therapy and radiation therapy for localized gastric MALT lymphoma have a favorable long-term outcome, though regular follow-up endoscopy should be performed for detecting metachronous early gastric cancer.

Introduction: More effective regimens are urgently needed for squamous cell carcinoma of esophagus (SCCE), therefore, we conducted a phase I/II trial of a combination of docetaxel, platinum, and fluorouracil (TPF) for treating metastatic SCCE., Methods: This phase I/II trial (n = 12/39) was conducted in our institute from April 2005 to June 2008. Progression-free survival (PFS) and overall survival were analyzed by the Kaplan-Meier method., Results: The recommended dose of docetaxel was determined to be 50 mg/m in phase I. In phase II with a mean follow-up period of 13.3 months, the objective response rate was 66.6%, a median survival period of 13 months and PFS of 7 months was achieved, and the 1-year survival and PFS rates were 52.9% and 19.6%, respectively. Grade 3/4 toxicities of leukopenia, neutropenia, and anorexia were observed in 53.8%, 43.6%, and 25.6%, respectively., Conclusions: A TPF regimen against metastatic SCCE was well tolerated and achieved a favorable objective response rate and survival benefit compared with other recently reported regimens. Randomized phase III trials of the TPF regimen are warranted and urgently required.

Gastric MALT lymphoma shows unique features including regression by Helicobacter pylori eradication and API2-MALT1 fusion. We performed a molecular and clinicopathologic study for 115 cases. All eradication-responsive cases were devoid of API2-MALT1 fusion. All tumors positive for the fusion and all negative for H. pylori infection were nonresponsive to the eradication. Consequently, gastric MALT lymphomas were divided into three groups: Eradication-responsive and fusion-negative (group A, n = 72), eradication-nonresponsive and fusion-negative (group B, n = 22), and eradication-nonresponsive and fusion-positive (group C, n = 21). Group A tumors were characterized by low clinical stage and superficial gastric wall involvement, and group C tumors by low H. pylori infection rate, advanced clinical stage, and nuclear BCL10 expression. All group C tumors showed exclusively low-grade histology. Group B tumors, which have not been well recognized, frequently showed nodal involvement, deep gastric wall involvement, and advanced clinical stage, and sometimes an increased large cell component. A multivariate discriminant analysis revealed that responsiveness to the eradication could be predicted accurately by negative API2-MALT1 fusion, positive H. pylori infection, low clinical stage, and superficial gastric wall invasion, the former being the most important factor for the prediction. This 3-group categorization may be helpful for a comprehensive understanding of gastric MALT lymphoma.

Background: The purpose of this study was to determine the usefulness of magnifying endoscopy for the diagnosis of Helicobacter pylori-induced histopathologic gastritis., Methods: A total of 92 patients scheduled to undergo routine endoscopic examination were enrolled. After routine endoscopic examination, 3 sites in the stomach were studied by magnified observation. Visualized collecting venulae were classified into the following 3 patterns: regular, irregular, and obscured. The sites observed by magnifying endoscopy were assessed histopathologically with an Updated Sydney System; 4 morphologic parameters (activity, inflammation, atrophy, metaplasia) were assessed and graded from 0 to 3., Results: The regular pattern cases were negative for H pylori infection at all sites observed by magnifying endoscopy (antrum greater curve, 0/11; body greater curve, 0/24; body lesser curve, 0/23). The scores for all 4 morphologic parameters were significantly lower in the regular pattern group than the irregular and obscured groups (p < 0.01). The value of the atrophy parameter in the irregular group was significantly higher than that in the obscured group (p < 0.05 for a single test of hypothesis; correction for multiple testing of data removed significance)., Conclusion: Visibility of collecting venulae in the gastric mucosa is influenced by H pylori-induced histopathologic gastritis. Magnifying endoscopy is useful for the diagnosis of histopathologic gastritis.

Background: Primary and acquired resistance to the antimicrobial agents is a primary reason for the failure of Helicobacter pylori eradication therapies. We assessed the primary antibiotic resistance rates of H. pylori to three different antibiotics and its relationship due to the annual antibiotic consumption in Japan during the period prior to approval of anti-H. pylori therapy in Japan., Materials and Methods: Antibiotic susceptibility was tested using the agar dilution method for clarithromycin, amoxicillin and metronidazole. Isolates were considered resistant when the MIC value was > 8 mg/l for metronidazole, > 1 mg/l for clarithromycin and < 0.5 mg/l for amoxicillin., Results: Helicobacter pylori isolates were obtained from 593 Japanese patients from 1995 to 2000. Primary resistance of H. pylori to clarithromycin, metronidazole and amoxicillin was found in 11%, 9% and 0.3% strains, respectively. The proportion with clarithromycin resistance significantly increased from 7% in 1997-98 to 15.2% in 1999-2000 (p =.003). During the same period the metronidazole resistance rate also increased from 6.6% in 1997-98 to 12% in 1999-2000 (p =.02). The prevalence of clarithromycin and metronidazole was related to the annual consumption of these antimicrobial agents., Conclusion: Resistance rates for both clarithromycin and metronidazole appear to reflect the annual consumption of these agents. The high rate of clarithromycin resistance in Japan suggests that the effectiveness of clarithromycin-based therapies may be compromised in the near future.

We present a case of protein-losing cytomegalovirus gastritis in a previously immunocompetent 14-year-old Japanese girl that occurred during treatment of drug (zonisamide)-induced Stevens-Johnson syndrome with hepatic failure. Her hepatic failure and symptoms of Stevens-Johnson syndrome were successfully treated with intravenous prednisolone and infusion of fresh-frozen plasma or albumin, as the occasion demanded. However, during the course of treatment, she complained of severe epigastralgia together with hypoproteinemia, and cytomegalovirus gastritis was found by endoscopic and histological examinations. The possible mechanism by which cytomegalovirus gastritis occurred in the present case and effective diagnostic procedures are discussed., (Copyright 2002 S. Karger AG, Basel)

The prognosis of immunoblastic lymphadenopathy (IBL)-like T-cell lymphoma is grave, and its effective treatments have not been established. We applied oral cyclosporin A (CsA) treatment to two cases of IBL-like T-cell lymphoma, and succeeded in achieving complete remissions. CsA is known to have a suppressive effect on the immune system, most notably T-cells, but it also has a direct cytotoxic/apoptosis-inducing effect on lymphocytes. Its combined effects on neoplastic T-cells might have played an important role in achieving remission. In both cases, serum levels of interleukin-12 (IL-12) and tumor necrosis factor-alpha (TNF-alpha) were elevated and decreased or returned to normal after achieving remissions. Considering that both cytokines represent monokines, it seems that a macrophage system is also involved in the pathogenesis of this disorder. Our two cases indicate that administration of CsA may be an effective therapy for IBL-like T-cell lymphoma.

Immunoblastic lymphadenopathy (IBL)-like T-cell lymphoma is considered to belong to peripheral T-cell lymphoma. Its prognosis is grave and effective treatments have not been established. Recently, we gave oral cyclosporin A (CsA) to a patient with IBL-like T-cell lymphoma, and succeeded in achieving dramatic remission. In this case, serum levels of interleukin-12 (IL-12) and tumor necrosis factor-alpha (TNF alpha) were elevated and decreased or returned to normal after achieving remission. Since CsA is a potent suppressor of the immune system and most notably T-cells, the immunosuppression of T-cell function might have played an important role in achieving remission in this case, although the precise mechanism still remains to be elucidated. The present case indicates that administration of CsA may be a very effective and safe selection of therapy for IBL-like T-cell lymphoma, as well as analogous disorders such as IBL and angioimmunoblastic lymphadenopathy with dysproteinemia (AILD), thereby will contribute to improving the prognosis of patients with these diseases.