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. AIM: To assess the early effects of both drugs on gastric pH using a wireless pH monitoring system. METHODS: The test was conducted by a cross-over test: 10 healthy male volunteers were administered famotidine 20 mg twice a day and lansoprazole 30 mg once a day. Monitoring of gastric pH over four consecutive days was performed using a unique method we have developed that is an elaboration of the Bravo system. RESULTS: The time to reach a pH level of 3 or more with famotidine was significantly shorter than that for lansoprazole. The pH3 holding time ratio of famotidine during the first 4 h of administration was significantly higher than that of lansoprazole. The pH3 holding time ratio on each day from day 1 to day 3 was significantly higher following lansoprazole administration compared with famotidine administration. CONCLUSIONS: Famotidine was shown to act quickly in elevating gastric pH; however, lansoprazole was superior to famotidine in terms of its ability to elevate gastric pH for a long duration.

Multiple granular cell tumor of the esophagus treated endoscopically.

Granular cell tumor (GCT) of esophagus is a rare lesion, usually found incidentally during upper gastrointestinal endoscopic examination undertaken for another reasons. The origin of this neoplasm is still unclear but no organ seems to be immune to this neoplasm. Although most of the lesions are benign, few reports of malignant GCT, synchronous as well as metachronous, are also reported. It can occur at any age, but are most commonly observed in fourth and fifth decade of life. We herein report a case of multiple GCT treated by endoscopic mucosal resection and review the relevant literatures.

What are the findings of esophageal cancer to be treated endoscopically?

In Japan, the results of histopathologic analyses on esophageal carcinomas have shown that almost all of them are squamous epithelial cancers. The abnormal epithelium that is difficult to differentiate by endoscopy can be easily visualized by chromoendoscopy with the use of iodine staining. Since the establishment of endoscopic mucosal resection (EMR), it has been used increasingly to treat mucosal cancers. It is necessary to diagnose accurately the depth of invasion of mucosal cancer when it is to be treated by EMR. In this article, we explain our routine techniques to visualize and interpret the lesions that are candidates for EMR. It is of great benefit to detect lesions at their early stage, which leads to the most desirable endoscopic treatment.

[Treatment of gastric MALT lymphoma by H. pylori eradication].

Strong evidence exists for the efficacy of H. pylori eradication in achieving gastric low-grade MALT lymphoma (L-MALT) regression when the bacteria present. Besides histological evaluation, the appearance of endoscopic finding such as 'discolored mucosa-like atrophy' after treatment may be useful for the prediction of its outcome (endoscopic evaluation). However, a reliable marker for molecular evaluation is not obtained so far. On the other hand, long-term control of L-MALT with H. pylori eradication therapy is uncertain and there still remains a subset of patients with no evidence of H. pylori or who fail H. pylori eradication therapy. Therefore, the optimal non antibiotic therapy for these patients has been studied. According to the recent report, radiation therapy appears to be well tolerated and effective for patients with gastric L-MALT.

[X-ray and endoscopic diagnosis of esophageal achalasia].

We evaluated diagnostic X-ray and endoscopic examination findings in 486 patients with esophageal achalasia. Concerning the association between the duration of disease and the X-ray dilatation type, the duration was 1-4 years in more than 50% of patients with the Sp type, a mean of 8.5 years in those with the F type, and frequently more than 10 years in those with the S type. Endoscopy is generally used to determine the presence or absence of abnormal movement. In achalasia, the endoscope can be inserted into the stomach despite resistance at the stenotic site, and the mucosal surface is normal. Squamous cell carcinoma as a complication was observed in 21 patients (4.3%). The carcinoma complication rate was higher with a longer duration of disease and a longer observation period. The mean total course including the postoperative course was 27 years. Long-term and periodic X-ray and endoscopic observation of the disease course is important, and iodine staining is indispensable for early detection of esophageal cancer.

[Improved gastric patch method for esophagocardioplasty in esophageal achalasia].

We performed esophagocardioplasty with the gastric patch (original GP) as the treatment of first choice in patients with esophageal achalasia. However, postoperative reflux esophagitis occurred in many due to secretory dysfunction of the gastric mucosa implanted in the mediastinum. We therefore developed two modifications of the gastric patch technique (GP II and GP III) which do not involve implantation of the gastric mucosa in the esophagus. Twenty-three patients have undergone the modified GP II procedure in our institution. Postoperative changes in the esophagus were examined fluoroscopically, and it was found that esophageal diameter increased from an average 2.9 +/- 0.6 cm to 5.2 +/- 1.0 cm at an average follow-up of 7.1 months (p < 0.01). All 23 patients experienced amelioration of symptoms, even though some reddening was still present in the lower esophagus, with a maximum follow-up of 8 years. Based on these results, the modified GP procedures are an acceptable open surgery modality for esophagocardioplasty in esophageal achalasia.

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.

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.

[Barrett's esophagus].

Barrett's esophagus (BE) has recently gained the interest of Japanese physicians. In BE, the squamous epithelium of the distal esophagus is replaced by metaplastic columnar epithelium. This intestinal metaplasia usually occurs as a complication of severe reflux esophagitis and its association with adenocarcinoma of the esophagus is well established. In 1950 Norman Barrett described a tubular, intrathoracic structure that appeared to be the esophagus, except that the distal portion was lined with columnar epithelium. Although he believed that the distal portion was not the esophagus, the condition in which the distal esophagus is lined with columnar epithelium became known as BE. From animal and clinical studies, the intestinal metaplasia is generally believed to arise from multipotential stem cells located in the basal layer of the squamous epithelium and at the base of the glandular epithelium. Evidence for a genetic basis underlying the dysplasia-adenocarcinoma sequence is now being accumulated. It is known that gastric acid reflux as well as bile reflux can cause distal esophagitis. Therefore, treatment with a proton pump inhibitor alone may not be sufficient therapy for all patients. Antireflux surgery can cause regression of BE in up to 50% of patients. Overall 1-, 2-, and 5-year survival rates for patients with adenocarcinoma arising from BE after surgical resection is reported to be 63%, 41%, and 32%, respectively. Therefore, endoscopic surveillance of patients with BE is suggested.

[Feature of screening-detected cancer and progress of treatment--esophageal cancer].

The recent increase in the detection of esophageal mucosal cancer has been changing the direction of treatment. The rate of esophageal cancer detection in mass screening by X-ray is 0.008%, which is 1/13 that of gastric cancer. Moreover, the rate by endoscopy is higher; the former is 0.1% and the later is 0.6%. Further, endoscopic screening using iodine staining for a high risk group like alcoholism has 3.6% detectability on esophageal cancer and 1.7% on gastric cancer. The rate of cancer-detection of upper intestinal organs comes to 5.35% in all. Most of the esophageal cancer detected by endoscopy is mucosal cancer, which is treatable by endoscopic mucosal resection (EMR). The result of the treatment is 100% 5 year-survival in cases of m1 and 2 esophageal cancer. EMR of esophagus-preserving treatment is truly effective for patients. Endoscopic examination using iodine staining for the high risk group is excellent for mass screening of esophageal cancer.

Induction of T cell dependent acquired immunity in syngeneic mice by the combined expression of interleukin-4 and granulocyte macrophage-colony stimulating factor gene in murine colon carcinoma cells.

The inoculation of cytokine-producing tumor cells into syngeneic animals can produce antitumor effects. We previously reported that injection of a mixed population of murine colon carcinoma (Colon 26) cells transduced with interleukin-4 (IL-4) gene with granulocyte macrophage-colony stimulating factor (GM-CSF) gene developed subcutaneous tumors in syngeneic mice, but these tumors thereafter regressed spontaneously (Oncology 1997;54:69-73). In this study, we found the generation of tumor-specific acquired immunity in the mice which had rejected the tumors of a mixed population of IL-4 and GM-CSF producer cells, and that the immunity was mediated by mature T cells. Moreover, local secretion of both IL-4 and GM-CSF in the vicinity of tumors was found to be crucial for this rejection. These data suggest that enhanced host defense brought about by the combined expression of IL-4 and GM-CSF genes in tumor cells is a potential therapeutic strategy.

Inhibition of experimental lung metastasis of murine colon carcinoma cells depends on the amount of interleukin-2 secreted from the transduced cells.

We examined the antitumor effect of low and high interleukin-2 (IL-2) producers of murine colon carcinoma cells (Colon 26) which were generated by transduction with IL-2 gene in an experimental lung metastasis model using syngeneic mice. Intravenous injection of the low IL-2 producer cells formed multiple lung metastatic foci and the survival of the mice was not different from that of the mice injected with wild-type cells. However, the mice administrated with the high producer cells survived significantly longer. Subcutaneous inoculation of the low producers, although it caused the development of local tumors at the inoculation sites in some of the mice tested, inhibited lung metastasis of wild-type cells subsequently inoculated and prolonged the survival of the mice rechallenged with Meth A cells, syngeneic fibrosarcoma cells. In contrast, inoculation of the high producers did not cause the development of subcutaneous tumors and inhibited the experimental metastasis of parental but not Meth A cells inoculated thereafter. Thus, the amount of secreted IL-2 from tumor cells differentially influences antitumor effects by inducing tumor specific and nonspecific immunity.

Discordant production of released exogenous protein and infectious virions from retrovirus-packaging cells used for gene transduction.

We examined the correlation between the amount of exogenous protein secreted and that of its viral transcript from PA317 packaging cells transduced with a cytokine gene. Amphotropic packaging cells for the retrovirus expressing murine interleukin-15 (IL-15) gene were cloned, and we examined 22 clones for both the amount of IL-15 secreted with enzyme-linked immunosorbent assay and the IL-15 transcript released as infectious virions by slot blot-hybridization analysis. The study revealed that there was no statistical correlation between them, and suggests that the integrated transcript is used discordantly. Thus, the examination of secreted protein from packaging cells cannot be substituted for laborious assays to determine the amount of virion transcripts when isolating high titer packaging cells.

Endoscopic ultrasound-guided pancreatography: a case report.

Endoscopic ultrasound-guided pancreatography was performed on a 48-year-old man with a diagnosis of pancreatic stone. A pylorus-preserving pancreaticoduodenectomy had been performed previously on this patient, approximately two years earlier, following the diagnosis of a tumor-forming pancreatitis. Endoscopic retrograde pancreatography and conventional ultrasound-guided percutaneous pancreatography had failed to yield a diagnosis. However, endoscopic ultrasound-guided pancreatography was performed successfully, delineating the pancreatic duct and a filling defect caused by intraductal calculi. Endoscopic ultrasound-guided pancreatography will be a potential alternative in cases when endoscopic retrograde pancreatography has failed or proved non-diagnostic.

[Anatomical analysis of small bronchial arteries in front of the trachea by 3D-CT and digital subtraction angiography: implications for esophageal cancer surgery].

To preserve blood supply to the trachea and bronchus in the surgical procedure for esophageal cancer, anatomical characteristics of small bronchial arteries which course in front of the trachea were analysed by three-dimensional computed tomography (3D-CT) and digital subtraction angiography (DSA). In the 3D-CT study using five mediastina, three dimensional images of the bronchial arteries were reconstructed after the injection of contrast medium into the intercostobronchial arteries. Thus the detailed vascular network of the course of the small bronchial arteries in front of the trachea could be delineated. In the DSA study using seven mediastina, through this network of bronchial arteries, the branches originating from the aorta and the arteries supplying the cranial portion of the trachea could be viewed. These results indicate that the bronchial arteries are connected by a vascular network in front of the trachea. Based on these detailed findings, it is considered critical to avoid damage to the intercostobronchial artery and also the network of bronchial arteries in order to preserve blood supply to the trachea and bronchus.

[Anatomical study on the right bronchial artery for operation of esophageal cancer through right thoracotomy with special reference to the intercostobronchial arteries].

In view of the operative field of esophageal cancer, anatomical findings of the right bronchial arteries were studied in specimens of 71 cadavers. Intercostobronchial arteries were absent only in 3 cadavers (4.2%; group A). As 22.6% of the cadavers had only one intercostobronchial artery supplied as the right bronchial artery (group B), it was considered to be important to preserve this artery. Cadavers both with the intercostobronchial artery and with the other right bronchial-arteries were observed in 70.4% (group C). Right bronchial arteries deriving from the aorta to course similarly to intercostobronchial arteries were present in small number (group D). Further, right bronchial arteries were classified into three types according to the deriving arteries as follows: (I) intercostobronchial arteries, (II) bronchial arteries deriving from the aorta, (III) other right bronchial arteries deriving from right subclavian artery, right inferior thyroid artery or right interthoracic artery. Considering difficulty of the approach from the operative field with right thoracotomy and the anatomical relationship with neighboring organs, it was thought that preserving the type (I) arteries is easy, the type (III) has a possibility to be preserved, and (II) is hard to be preserved. We concluded that preserving intercostobronchial arteries is important in esophageal cancer surgery approached through right thoracotomy because of small number of cadavers without these arteries and ease of preservation.