Mitsuru Matsuda

Immunohistochemical study of p53, c-erbB-2, and PCNA in Barrett's esophagus with dysplasia and adenocarcinoma arising from experimental acid or alkaline reflux model

Purpose. An immunohistochemical study of p53, c-erbB-2, and proliferating cell nuclear antigen (PCNA) in Barretts esophagus with dysplasia and adenocarcinoma, arising from experimental acid or alkaline reflux, was performed in dogs. Methods. Cardiectomy was performed in group A (n = 26) as an acid reflux model, and total gastrectomy was performed in group B (n = 24) as an alkaline reflux model. After surgery, the esophageal mucosa was observed and biopsied endoscopically every 3 months over a period of 6 years. Immunohistochemical staining of p53, c-erbB-2, and PCNA was performed, using biopsied specimens. Results. In group A, Barretts esophagus developed in 14 of the 26 dogs. Low-grade dysplasia occurred in 5 of the 26 dogs, and in 1 of these 5 dogs, it developed into high-grade dysplasia. In this animal, adenocarcinoma arose 63 months after the operation. In group B, Barretts esophagus developed in 10 of the 24 dogs. Low-grade dysplasia was observed in 4 of the 24 dogs. In 1 of these 4 dogs, the dysplasia became high-grade and adenocarcinoma occurred 66 months after the operation. In group A, PCNA was positive in adenocarcinoma; the PCNA labeling index (LI) was 58. c-erbB-2 and p53 were negative in all animals in group A. In group B, PCNA was positive in Barretts esophagus with high-grade dysplasia and adenocarcinoma; the PCNA LI was 77. p53 was positive in adenocarcinoma. c-erbB-2 was negative in adenocarcinoma. Conclusions. The results of this study provided evidence of the dysplasia-carcinoma sequence arising from alkaline reflux, as well as from acid reflux. To the best of our knowledge, this is the first report of the use of an alkaline reflux model and a 6-year study using dogs to observe the course of Barretts esophagus.

Interferon-|[gamma]|-mediated hepatocarcinogenesis in mice treated with diethylnitrosamine

Hepatocarcinogenesis is a complex multifactorial process in which continuous intrahepatic inflammation plays a major role. Although inflammatory cell infiltration is observed in the process of chemical-induced hepatocarcinogenesis, the pathophysiological role of the inflammatory response is not well defined. To approach this question, molecular and cellular responses were monitored during the development of liver tumors in mice exposed to a chemical hepatocarcinogen, diethylnitrosamine (DEN), in drinking water (50 μg/l). Intrahepatic type I and type II interferon (IFN-β and IFN-γ, respectively) mRNA expression was found to be induced 2 months before the appearance of hepatocellular carcinomas. The pathogenetic importance of IFNs was determined by monitoring tumor development in mice genetically deficient in the IFN-α/β receptor (IFN-α/βR KO) or the IFN-γ receptor (IFN-γR KO). IFN-γR KO mice developed fewer tumors than IFN-α/βR KO and wild-type (wt) mice, although the tumor diameters did not differ significantly among the three lineages. Interestingly, immunohistochemical studies demonstrated that the percentage of monocytes/macrophages in infiltrating mononuclear cells was reduced greatly in the livers of IFN-γR KO mice, which is consistent with the facts that intrahepatic cytokine expression was diminished and oxidative DNA damage was induced to a lesser extent. In conclusion, type II IFN, but not type I IFNs, may be involved critically in the initiation stage, but not the promotion stage, of DEN-induced hepatocarcinogenesis by enhancing monocytes/macrophages activation and eventual hepatocyte DNA damage.

Gastrointestinal amyloidosis secondary to hypersensitivity vasculitis presenting with intestinal pseudoobstruction

Hypersensitivity vasculitis is characterized byinflammation and necrosis of small blood vesselssecondary to allergic or hypersensitivity mechanisms (1,2). Gastrointestinal involvement with edema and bleeding also has been reported (3-5).Long-standing inflammation, such as rheumatic disease,infectious disease, inflammatory bowel disease, familialMediterranean fever, and malignancy, may lead tosystemic amyloidosis (6). Gastrointestinal involvementmay induce anorexia, nausea and vomiting, diarrhea,constipation, bleeding, malabsorption, andpseudoobstruction (6, 10-12). In this report we discussa patient with hypersensitivity vasculitis with severeintestinal bleeding who developed systemic amyloidosiswith intestinal pseudoobstruction 29 months after onset.Secondary amyloidosis due to hypersensitivity vasculitis has not been previously reported,and the causal relationship is discussed in thisreport.

Utility and limitations of a method for detecting Helicobacter pylori-specific antigens in the stool

Background: Recently, a method for detecting Helicobacter pylori-specific antigens in the stool (HpSA) has been proposed to be useful clinically. The aim of this study was to determine the accuracy of HpSA for the diagnosis of H. pylori infection, including early assessment after eradication treatment, and the potential for quantitative evaluation of H. pylori in the stomach. Methods: The subjects were 85 patients with gastroduodenal disorders who underwent endoscopic examination. Of these, 36 were treated for eradication of H. pylori infection and reassessed 4–8 weeks after treatment. HpSA was tested by enzyme immunoassay. For the definitive diagnosis of H. pylori infection, biopsy specimens were taken endoscopically and examined by quantitative culture, rapid urease test, and immunohistostaining. In addition, serum antibody against H. pylori was tested before the eradication treatment and a 13C-urea breath test was conducted after treatment. The results of these reference tests were compared with those obtained by HpSA. Results: The sensitivity and specificity of HpSA were 90.4% and 100% before eradication treatment and 57.1% and 100% after the treatment. There was a positive correlation between the optical density of HpSA and the number of H. pylori bacilli evaluated by quantitative culture. Conclusions: The HpSA test is considered to be an accurate method for the diagnosis of H. pylori infection, with high specificity. However, there may be problems of false negativity if HpSA is used for the early assessment of treatment efficacy. Furthermore, HpSA is suggested to have potential for the quantitative evaluation of H. pylori status in the stomach.

Gastric adenocarcinoma of fundic gland type: Five cases treated with endoscopic resection

Recently, a new disease entity termed gastric adenocarcinoma of fundic gland type (GA-FG) was proposed. We treated five cases of GA-FG with endoscopic submucosal dissection. All tumors were small and located in the upper third of the stomach. Four tumors were macroscopically identified as 0-IIa and one was identified as 0-IIb. Narrow-band imaging with magnifying endoscopy showed an irregular microvascular pattern in 2 cases and a regular microvascular pattern in the remainder. All tumors arose from the deep layer of the lamina propria mucosae and showed submucosal invasion. Lymphatic invasion was seen only in one case, while no venous invasion was recognized. All tumors were positive for pepsinogen-I  and MUC6 by immunohistochemistry. None showed p53 overexpression, and the labeling index of Ki-67 was low in all cases. All cases have been free from recurrence or metastasis. Herein, we discussed the clinicopathological features of GA-FG in comparison with past reports.

Novel diagnostic method of testing for Helicobacter pylori infection using the rapid leukocyte strip test, Leukostix

Background and Aim:  A characteristic of gastric mucosa infected with Helicobacter pylori is infiltration of inflammatory cells, mainly consisting of neutrophils. The present study aimed to detect neutrophils in homogenates of biopsied gastric mucosa semiquantitatively using the rapid leukocyte strip test, Leukostix. The authors then investigated the association of these results with H. pylori status.

Gastric adenocarcinoma of the fundic gland (chief cell-predominant type): A review of endoscopic and clinicopathological features

Gastric adenocarcinoma of the fundic gland (chief cell-predominant type, GA-FG-CCP) is a rare variant of well-differentiated adenocarcinoma, and has been proposed to be a novel disease entity. GA-FG-CCP originates from the gastric mucosa of the fundic gland region without chronic gastritis or intestinal metaplasia. The majority of GA-FG-CCPs exhibit either a submucosal tumor-like superficial elevated shape or a flat shape on macroscopic examination. Narrow-band imaging with endoscopic magnification may reveal a regular or an irregular microvascular pattern, depending on the degree of tumor exposure to the mucosal surface. Pathological analysis of GA-FG-CCPs is characterized by a high frequency of submucosal invasion, rare occurrences of lymphatic and venous invasion, and low-grade malignancy. Detection of diffuse positivity for pepsinogen-I by immunohistochemistry is specific for GA-FG-CCP. Careful endoscopic examination and detailed pathological evaluation are essential for early and accurate diagnosis of GA-FG-CCP. Nearly all GA-FG-CCPs are treated by endoscopic resection due to their small tumor size and low risk of recurrence or metastasis.

Short-term outcomes of multicenter prospective cohort study of gastric endoscopic resection: ‘Real-world evidence’ in Japan

A Japanese multicenter prospective cohort study examining endoscopic resection (ER) for early gastric cancer (EGC) has been conducted using a Web registry developed to determine the short‐term and long‐term outcomes based on absolute and expanded indications. We hereby present the short‐term outcomes of this study.

The Role of an Undifferentiated Component in Submucosal Invasion and Submucosal Invasion Depth After Endoscopic Submucosal Dissection for Early Gastric Cancer

Background/Aims: The role of an undifferentiated component in submucosal invasion and submucosal invasion depth (SID) for lymph node metastasis (LNM) of early gastric cancer (EGC) with deep submucosal invasion (SID ≥500 μm from the muscularis mucosa) after endoscopic submucosal dissection (ESD) has not been fully understood. This study aimed to clarify the risk factors (RFs), including these factors, for LNM in such patients. Methods: We enrolled 513 patients who underwent radical surgery after ESD for EGC with deep submucosal invasion. We evaluated RFs for LNM, including an undifferentiated component in submucosal invasion and the SID, which was subdivided into 500–999, 1,000–1,499, 1,500–1,999, and ≥2,000 µm. Results: LNM was detected in 7.6% of patients. Multivariate analysis revealed that an undifferentiated component in submucosal invasion (OR 2.22), in addition to tumor size >30 mm (OR 2.51) and lymphatic invasion (OR 3.07), were the independent RFs for LNM. However, the SID was not significantly associated with LNM. Conclusion: An undifferentiated component in submucosal invasion was one of the RFs for LNM, in contrast to SID, in patients who underwent ESD for EGC with deep submucosal invasion. This insight would be helpful in managing such patients.

A unique case of massive gastrointestinal bleeding

Objectives: Lipomas are the second most common benign tumors of the small bowel, and most lipomas are asymptomatic. However, lipomas with diameters of >20 mm tend to be symptomatic, for example, to cause bleeding, obstructive jaundice, abdominal pain, intestinal obstruction, intussusception, and/or perforation. Methods/Results: We report a case of massive gastrointestinal bleeding from a jejunal lipoma combined with intussusception. A preoperative diagnosis of gastrointestinal bleeding derived from a jejunal lipoma combined with intussusception was made based on double-balloon enteroscopy and contrast-enhanced computed tomography, and partial resection of the small intestine was performed. After surgery, there was no additional gastrointestinal bleeding. Conclusion: There have only been a few reports about cases of jejunal lipoma involving simultaneous bleeding and intussusception. Double-balloon enteroscopy is useful for preoperatively diagnosing bleeding from a lipoma. Our case highlights that jejunal lipoma can cause massive unexplained gastrointestinal bleeding.