Teruo Kouzu

Protective immunity is induced in murine colon carcinoma cells by the expression of interleukin-12 or interleukin-18, which activate type 1 helper T cells

We investigated the antitumor effects induced by the production of interleukin-12 (IL-12) or IL-18, which influence the function of T helper type 1 cells, in murine colon carcinoma cells (Colon 26). Retrovirally transduced cells with IL-12 genes that encoded both p35 and p40 (Colon 26/IL-12) lost their tumorigenicity when inoculated subcutaneously or intraperitoneally into syngeneic immunocompetent mice. Moreover, the mice that had rejected the Colon 26/IL-12 cells generated protective immunity to wild-type (wt) cells when subsequently challenged. Colon 26 cells transduced with the IL-18 gene (Colon 26/IL-18) could not form subcutaneous tumors in immunocompetent mice, and the mice became resistant to inoculated wt cells. Immunohistochemical analysis revealed that the numbers of blood vessels in Colon 26/IL-12 or Colon 26/IL-18 tumors were markedly reduced, and that the expression of adhesion molecules such as intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 increased on the endothelium in the stroma of Colon 26/IL-12 tumors. The loss of tumorigenicity of Colon 26/IL-12 or Colon 26/IL-18 cells was not observed in immunocompromised mice. However, the survival days of the immunocompromised mice inoculated with Colon 26/IL-12 but not Colon 26/IL-18 cells were significantly longer than those inoculated with wt cells. The secretion of cytokines that stimulate T helper type 1 cells from tumor cells can thereby induce an antitumor response. However, the effector cells involved in these antitumor effects could differentially migrate to the tumors, and the inhibition of angiogenesis may partially contribute to the antitumor responses observed.

Nationwide epidemiological study on gastroesophageal reflux disease and sleep disorders in the Japanese population

BackgroundTo elucidate the relationship between gastroesophageal reflux disease and sleep disorders in the Japanese population, we conducted a nationwide survey on the prevalence of heartburn, the cardinal symptom of the disease, and sleep disorders.MethodsQuestionnaires regarding the frequency of heartburn and sleep disorders were distributed and endoscopic findings were assessed among patients who visited 35 participating institutions from March through September 2005, with a target sample size of 100 consecutive endoscopy patients per institution.ResultsA total of 2426 patients were included in the analysis population. The prevalence of gastroesophageal reflux disease in patients was 26.5% (n = 644). Mean sleeping time was 6.5 ± 1.2 h, and 48.3% (n = 1172) of all patients reported experiencing sleep disorders. Sleep disorders were significantly more prevalent among patients with heartburn, at 56.3% (615/1093 patients, P < 0.0001), with the number of sleep disorder events increasing with the frequency of heartburn. Conversely, those with sleep disorders reported experiencing heartburn at a significantly higher rate (approximately 75%). However, sleep disorders occurred in only 51.6% (197/382) of patients with reflux esophagitis, showing no significant difference compared with those without reflux esophagitis. No definite tendency was seen in relation to the severity of reflux esophagitis.ConclusionsIn Japanese people, patients with heartburn had a significantly higher prevalence of sleep disorders than those without heartburn.

Endoscopic Clipping with a New Rotatable Clip-Device and a Long Clip

Abstract: We developed a rotatable, highly durable clipping device (rotatable clip‐device) and a long clip which can be used to effectively grasp a large bite of tissue. However, application of the long clip required a special reinforced clipping device. The new rotatable clip‐device can be appropriately used in combination with the long clip because of its improved strength and rotatability. The rotatable clip‐device was used for endoscopic treatment of 133 patients, including 43 requiring hemostasis of gastrointestinal bleeding, 43 with prophylactic clipping following polypectomy, 39 with mucosal closure following endoscopic mucosal resection (EMR), and 10 undergoing prophylactic ligation of esophageal varices. The long clips were used mainly for mucosal closure after EMR. The rotatable clip‐device was found to be especially useful for hemostasis of soft bleeding lesions. Prophylactic clipping following polypectomy prevented complications in 40 out of 41 patients. Mucosal closure by means of clipping following EMR prevented complications in all 39 patients, and the rotatability of the rotatable clip‐device and the large bite capacity of the long clip greatly facilitated closing mucosal defects, especially large defects. In the 10 patients who underwent prophylactic clipping of esophageal varices, the rotatable clip‐device allowed the varices to be grasped securely and ligated effectively. During endoscopic treatment, three of the four clip‐devices functioned normally despite frequent auto‐claving and clipping procedures.

Synergistic antitumor effect of antiangiogenic factor genes on colon 26 produced by low-voltage electroporation.

Antiangiogenic factors are potent endothelial cell growth inhibitors that have been shown to inhibit angiogenesis in vitro and tumor growth in mice. We have demonstrated the synergistic antitumor effect of antiangiogenic genes (mouse angiostatin: pBLAST-mAngio; and mouse endostatin: p-BLAST42-mEndo XV) delivered to tumors by low-voltage electroporation in mouse colon 26 models. A synergistic antitumor effect was strongly suggested by in vivo tumor growth kinetics, as well as in survival studies with the mice. RT-PCR confirmed that the fragments of each gene were transferred by low-voltage electroporation in the tumor. Decreased microvessel density measurements in tumors also confirmed the efficacy of the synergistic antitumor effect of both genes. Significant growth inhibition was observed in mice treated with a 1:1 proportion of angiostatin and endostatin genes, and the order of the both genes transferred (first the endostatin gene, followed 1 week later by the angiostatin gene) had a profound inhibitory effect on tumor growth. These data suggest that in vivo delivery of antiangiogenic genes with low-voltage electroporation could be a possible therapeutic strategy for established solid tumors when both genes were applied in combination.

Possible involvement of antitumor immunity in the eradication of colon 26 induced by low-voltage electrochemotherapy with bleomycin.

Abstract.Purpose: The antitumor efficiency of electrochemotherapy using chemotherapeutic agents and high-voltage electric pulse has been reported. This study was done to define the precise nature of the involvement of antitumor immunity in the regression of tumor nodules in electrochemotherapy, and to evaluate the effectiveness of using low-voltage electroporation. Methods: Balb/c mice and Balb/c nu/nu nude mice were inoculated subcutaneously with Colon 26 cells or Meth A cells. Electrochemotherapy using bleomycin and low-voltage electroporation (CUY21) was performed as a treatment against tumor nodules. Results: Colon 26 tumors were eradicated in the mice given an intratumor (i.t.) injection of 500 μg bleomycin followed by treatment with electric fields ranging from 50 to 150 V/cm, with complete response rates ranging from 80% to 100%. The mice rejected inoculations of rechallenged Colon 26 cells, but not Meth A cells. In the Balb/c nu/nu nude mice, complete regression of the tumor was not seen after electrochemotherapy under the same therapeutic conditions that resulted in almost complete cure in the Balb/c mice. Conclusion: Our results suggest that the generation of T-cell-dependent, tumor-specific protective immunity might be involved in the process of tumor nodule regression in low-voltage electrochemotherapy.

Survey on the prevalence of GERD and FD based on the Montreal definition and the Rome III criteria among patients presenting with epigastric symptoms in Japan.

BackgroundThe present survey aimed to clarify the prevalence of gastroesophageal reflux disease (GERD) and functional dyspepsia (FD) in patients presenting with epigastric symptoms in Japan based on the Montreal definition and the Rome III criteria, respectively, and to determine the degree of overlap between the two disease entities and the validity of using these Western-developed diagnostic criteria in Japan.MethodsPatients presenting with epigastric symptoms for whom the first upper gastrointestinal endoscopy was scheduled from April through August 2007 at 55 institutions were asked to complete a questionnaire to ascertain the type, frequency, and severity of epigastric symptoms. The prevalence of esophageal mucosal damage was also determined from endoscopic findings.ResultsA total of 1,076 patients were included in the analysis population. There was a high degree of coincidence for all symptoms, with the mean number of symptoms per patient of 2.8. With strict application of the Montreal and Rome III definitions, symptomatic GERD accounted for 15.6% (168 patients), whereas FD accounted for 10.3% (111 patients), and the overlap between GERD and FD symptoms was less than 10%. However, when frequency and severity alone were considered in more broadly defined criteria, the overlap between GERD and FD symptoms was 30–40%.ConclusionA highly specific disease classification is possible when the Montreal definition and the Rome III criteria are strictly applied. On the other hand, the present survey highlighted a problem with the criteria whereby a definitive diagnosis could not be made in a substantial number of patients. This problem will require further research.

Transduction of murine colon carcinoma cells with interleukin-15 gene induces antitumor effects in immunocompetent and immunocompromised hosts

We examined the antitumor effects caused by murine colon carcinoma cells (Colon 26) transduced with interleukin-15 (IL-15) gene. Although the in vitro proliferation rate of IL-15-secreting Colon 26 (Colon 26/IL-15) cells was not different from that of wild-type (wt) cells, small subcutaneous tumors of Colon 26/IL-15 cells that developed in syngeneic immunocompetent mice regressed spontaneously in contrast to tumors of wt cells. The mice that had eliminated tumors of Colon 26/IL-15 cells rejected wt cells when subsequently challenged. The survival of the mice that had been inoculated intraperitoneally with Colon 26/IL-15 cells was significantly prolonged compared with that of the mice injected with wt cells. However, in an experimental lung metastasis model, the survival of the mice inoculated with Colon 26/IL-15 cells remained the same as that of the mice inoculated with wt cells. The inoculation of Colon 26/IL-15 cells into immunocompromised nude or severe combined immunodeficient mice produced tumors, but the survival of the immunocompromised mice was significantly longer than that of the mice inoculated with wt cells. The nude mice inoculated with Colon 26/IL-15 cells also survived longer than the severe combined immunodeficient mice with Colon 26/IL-15 cells. Depletion of natural killer cells in nude mice with anti-asialo GM1 antibody did not influence the survival of the mice injected with Colon 26/IL-15 cells. Immunohistological examination revealed that CD31+ cells migrated into tumors of Colon 26/IL-15 cells that developed in immunocompetent and immunocompromised mice. Taken together, our results indicate that an inoculation of IL-15-producing tumor cells can produce antitumor effects that are mediated by a variety of immunocompetent cells.

Four‐day continuous gastric pH monitoring following anti‐acid secretory drug administration: cross‐over test to assess the early effects

Background  There have been few reports that compare the effect of histamine H2‐receptor antagonists (H2RAs) and proton pump inhibitors (PPIs) using continuous gastric pH monitoring for a long duration.

Fine-needle Aspiration Biopsy of a Submucosal Tumor of the Stomach Using Endoscopic Ultrasonography

Abstract: We report here on the use of the new fine‐needle aspiration biopsy under endoscopic ultrasonography (EUS), developed in the course of our research into an EUS‐guided puncture. From a specimen obtained using this method, a submucosal tumor of the stomach was identified as a leiomyosarcoma by histologic examination. As our equipment for aspiration biopsy was confirmed to be useful, we hope to establish a new system of EUS diagnosis by collecting more clinical data and improving the technique and instruments further.

Primary malignant melanoma of the esophagus treated with heavy-ion radiotherapy.

Primary malignant melanoma of the esophagus (PMME) is an uncommon but aggressive tumor with very poor prognosis. There is no established treatment plan for the disease, which may be attributed to its rarity and aggressiveness. Surgery is the choice of treatment in early cases. Radiotherapy follows surgery, and chemotherapy has an insignificant role in its treatment. Radiation with heavy ion beams is showing promising results in cancer therapy. Compared to conventional radiation, it permits selective irradiation with minimal injury to the surrounding normal tissue, and treatment with a low dose within a short interval of time is possible. We herein report a case of PMME treated with heavy ion radiation, the first case to be reported so far, and review the relevant literature.