Biomedical subjects

Tomoharu Miyashita

Publications and source records attributed to Tomoharu Miyashita.

9 recordsLinked to original sources

PubMed2006

Selective decrease in the DNA base excision repair pathway in squamous cell cancer of the esophagus.

OBJECTIVES: Oxidative damage can lead to a highly mutagenic 8-oxoguanine lesion, which mispairs with adenosine residues, leading to G:C-->T:A transversions. In mammalian cells 8-oxoguanine glycosylase initiates the DNA base excision repair pathway to repair the 8-oxoguanine lesion. To date, there is no information regarding oxidative DNA damage and repair pathways in esophageal cancer. Therefore we designed the current study to demonstrate the DNA damage and repair pathways in esophageal cancer by expression of 8-oxoguanine glycosylase in reflux-induced and mutagen (methyl-n-amyl nitrosamine)-induced DNA damage and apoptosis in esophageal tumors. METHODS: Gastroduodenal reflux was surgically created in male Sprague Dawley rats (n = 120). Half of the animals received methyl-n-amyl nitrosamine. Animals not undergoing operations served as control animals (n = 10). The experiment concluded 30 weeks postoperatively. Immunohistochemistry for 8-oxoguanine and 8-oxoguanine glycosylase was assessed by 2 independent observers. Protein expression was assessed by using the Western blot method. RESULTS: There was significantly more DNA damage in both adenocarcinoma (n = 15) and squamous cell carcinoma (n = 19), as exemplified by positive 8-oxoguanine expression compared with that seen in control animals (P < .05). 8-Oxoguanine glycosylase was several folds upregulated in adenocarcinoma (P < .05), but there was significantly decreased expression in squamous cell carcinoma (P < .01). The apoptosis was assessed as caspase-dependent and caspase-independent pathways, and both were active and correlated well with 8-oxoguanine expression. CONCLUSION: These results demonstrate the selective decrease in the DNA base excision repair pathway in combined reflux and methyl-n-amyl nitrosamine-induced squamous cell cancer of the esophagus.

Adenocarcinoma↗

PubMed2006

Role of cyclooxygenase-2 in the carcinogenesis of gastrointestinal tract cancers: a review and report of personal experience.

Selective cyclooxygenase (COX)-2 inhibitors (coxibs) were developed as one of the anti-inflammatory drugs to avoid the various side effects of non-steroidal anti-inflammatory drugs (NSAIDs). However,coxibs also have an ability to inhibit tumor development of various kinds the same way that NSAIDs do. Many experimental studies using cell lines and animal models demonstrated an ability to prevent tumor proliferation of COX-2 inhibitors. After performing a randomized study for polyp chemoprevention study in patients with familial adenomatous polyposis (FAP),which showed that the treatment with celecoxib, one of the coxibs, significantly reduced the number of colorectal polyps in 2000, the U.S. Food and Drug Administration (FDA) immediately approved the clinical use of celecoxib for FAP patients. However, some coxibs were recently reported to increase the risk of serious cardiovascular events including heart attack and stroke. In this article we review a role of COX-2 in carcinogenesis of gastrointestinal tract, such as the esophagus, stomach and colorectum,and also analyze the prospect of coxibs for chemoprevention of gastrointestinal tract tumors.

Adenomatous Polyposis Coli↗

PubMed2006

Duodenal juice stimulates oesophageal stem cells to induce Barrett's oesophagus and oesophageal adenocarcinoma in rats.

the present study was performed to examine the sequential process of the development of Barrett's oesophagus (BE) and oesophageal adenocarcinoma (ADC) induced by duodeno-oesophageal reflux (DER) in rats. Total gastrectomy was performed in male Wistar rats weighing approximately 250 g followed by reconstruction with oesophago-jejunostomy, which causes unavoidable DER without exposure to exogenous carcinogens. Animals were selected at random and sacrificed every 10 weeks after surgery until 50 weeks. Severe squamous oesophagitis with erosion, regenerative thickening (RT), and basal cell hyperplasia (BCH) were observed on the 10th week after surgery. On the 20th week, glandular structures that stained positively with Galactose oxidase-Schiff (foveolar metaplasia) were observed in the basal layer of the oesophageal squamous epithelium. On the 30th week, the glands developed and formed cysts that stained positively with concanavalin A (pyloric glandular metaplasia) and/or high-iron diamine and Alcian blue (intestinal metaplasia). From the 40th week after surgery, ADC cells surrounded by columnar-lined epithelium were found. Persistent stimulation with DER can alter the stem cells in the squamous epithelial basal layer leading to the formation of columnar-lined cells and subsequent ADC. Foveolar metaplasia was observed as part of the sequence of events leading to the development of columnar-lined epithelium (CLE), followed by the appearance of pyloric glandular metaplasia and intestinal metaplasia, completing the histogenesis of BE.

Adenocarcinoma↗

PubMed2005

[Limited surgery for early gastric cancer using lymphatic basin dissection--a sure method of sentinel node biopsy for gastric cancer].

The results of our sentinel node biopsy for early-stage gastric cancer had a high predictive value for nodal metastasis, with a sensitivity of 85% (34/40) and an accuracy of 98% (259/265). Therefore, sentinel node biopsy is expected to be decided as an adaptation of limited surgery for early gastric cancer. However, there were two serious problems in sentinel node biopsy for gastric cancer; one was the great difficulty of sentinel node detection and biopsy in the operative field, and the other was the possibility of false negative cases in the frozen section diagnosis. To solve these problems, we developed lymphatic basin dissection, a new technique suitable for sentinel node biopsy of gastric cancer. The lymphatic basin is an own lymphatic components dyed in blue in the dye method. In the lymphatic basin dissection method, sentinel nodes are detected and harvested at the back table after en bloc dissection of the lymphatic basins. Lymphatic basin dissection is an excellent method because of the certainty in sentinel node biopsy, and the sure back-up dissection. Lymphatic basin dissection and following limited surgery was performed on 143 patients for early-stage gastric cancer in our hospital. No patient had a recurrence of gastric cancer; 9 patients died of other diseases, and the other 134 survived.

Gastrectomy↗

PubMed2004

A COX-2 inhibitor prevents the esophageal inflammation-metaplasia-adenocarcinoma sequence in rats.

Barrett's esophagus (BE) and esophageal adenocarcinoma (ADC) is associated with reflux of duodenal contents. Cyclooxygenase (COX)-2 is over-expressed in BE and ADC, and supposedly contributes to esophageal carcinogenesis. The aim of this study is to investigate what effect a COX-2 inhibitor has on esophageal adenocarcinogenesis in rats. A series of 90 rats underwent a duodenoesophageal reflux procedure and were divided into 2 groups. One group was given commercial chow (control group), and the other was given experimental chow containing celecoxib (celecoxib group). The animals were sacrificed sequentially, at the 10th, 20th, 30th and, finally, 40th week after surgery, and their esophagi were examined. In the control group, esophagitis, columnar-lined epithelium (CLE) and ADC were first observed at the 10th week, 20th week and 30th week, respectively. Their incidences sequentially increased and at the 40th week reached 100, 89 and 47%, respectively. In the celecoxib group, the esophagitis was mild and the incidence of CLE was significantly lower at each week (P < 0.001), compared with the control group, and ADC was not observed throughout the experiment (P < 0.05). COX-2 expression was observed predominantly in the stroma of inflamed esophageal epithelia, and up-regulated at the 10th and 20th week (P < 0.05, respectively). PGE2 level and proliferative activity were also up-regulated in both groups, but they were lower in the celecoxib group than in the control group (P < 0.05). Apoptosis was observed to increase with celecoxib treatment (P < 0.05). Celecoxib is effective in preventing CLE and ADC by suppressing esophagitis in rats.

Adenocarcinoma↗

PubMed2004

Impact of the biliary diversion procedure on carcinogenesis in Barrett's esophagus surgically induced by duodenoesophageal reflux in rats.

OBJECTIVE: To determine whether the elimination of bile reflux in the established esophagojejunostomy model of Barrett's esophagus (BE) will reduce or eliminate the risk of developing esophageal adenocarcinoma. SUMMARY BACKGROUND DATA: Reflux of duodenal juice as well as gastric acid plays an important role in the pathogenesis of BE and adenocarcinoma. Duodenoesophageal reflux (DER) per se induces these diseases without carcinogen. However, it is unclear whether antireflux surgery induces regression of BE and prevents adenocarcinoma. METHODS: Two hundred F344 male rats underwent one of following 3 operations: (1) total gastrectomy and esophagojejunostomy to induce DER, followed by killing after 20 (n = 13), 30 (n = 12), and 50 weeks (n = 30); (2) biliary diversion procedure, converted to Roux-en-Y method, to avoid bile regurgitation into the esophagus at 20 (n = 29) and 30 weeks (n = 32) after the operation to induce DER, followed by killing 50 weeks after initial operation; or (3) total gastrectomy and Roux-en-Y esophagojejunostomy followed by killing after 50 weeks served as controls (n = 28). RESULTS: BE developed in more than half of the animals exposed to DER for 20 weeks, in more than 90% of rats with DER for 30 weeks, and in 100% of animals exposed to DER for 50 weeks. In the incidence and the length of BE, there is no difference between the animals that underwent biliary diversion at 20 (62%) and 30 weeks (94%) and those that had DER for 20 (54%) and 30 weeks (92%), respectively. Incidence of adenocarcinoma was significantly lower in the rats that underwent the biliary diversion procedure after 30 (19%) and 20 weeks (3%) than in the rats that had DER for 50 weeks (60%) (P < 0.005). None of the control animals that underwent Roux-en-Y esophagojejunostomy developed BE and carcinoma. CONCLUSIONS: It is likely that the converting procedure from the esophagojejunostomy to induce DER to biliary diversion does not lead to regression of BE but prevents the development of esophageal adenocarcinoma in the rats.

Adenocarcinoma↗

PubMed2004

[Reflux of duodenal or gastroduodenal contents induces esophageal carcinoma in rats].

We observed the sequential development of columnar lined epithelium associated with adenocarcinoma, squamous dysplasia related with squamous cell carcinoma and adenosquamous carcinoma which were induced by duodeno-esophageal or gastro-duodeno-esophageal reflux in rats. Wistar male rats, weighing approximately 250 g were employed. Animals received total gastrectomy and were reconstructed with esophago-jejunostomy, which causes unavoidable duodeno-esophageal reflux. The animals were sacrificed every 10 weeks after surgery until 50 weeks. Erosions and basal cell hyperplasia were observed in the lower esophageal squamous epithelium at 10 weeks after surgery. At 20 weeks, glandular structures featured with galactose oxidase-Schiff-positive staining (foveolar metaplasia) appeared in the basal layer of esophageal squamous epithelium. At 30 weeks, the glands developed and formed cysts which were stained with concanavalin A (pyloric glandular metaplasia) or/and high iron diamine and alcian blue (intestinal metaplasia). Since 40 weeks after surgery, esophageal carcinomas were found. As adenocarcinomas were surrounded by the columnar-lined epithelium, squamous cell carcinoma and adenosquamous carcinoma were accompanied by squamous dysplasia. Persistent duodeno-esophageal reflux can change the stem cells of squamous epithelium to make columnar-lined cells. As part of the sequence of events leading to the development of columnar-lined epithelium, foveolar metaplasia was observed followed by the appearance of pyloric glandular metaplasia and intestinal metaplasia. Chronic duodenal reflux induces the development of esophageal carcinoma not only adenocarcinoma also squamous cell carcinoma and adenosquamous carcinoma. These pathways of carcinogenesis were different dual patterns.

Adenocarcinoma↗

PubMed2003

A new scoring system for peritoneal metastasis in gastric cancer.

BACKGROUND: The degree of peritoneal metastasis (PM) of gastric cancer has been classified into four grades (P0, P1, P2, and P3) in the Japanese Classification of Gastric Carcinoma, First English Edition. However, the PM category in this version was so ambiguous in terms of volumetry that it was unlikely to estimate PM status correctly. We have developed a new volume scoring system for PM, modifying Sugarbaker's classification. METHODS: Eighty-five patients with gastric cancer with PM underwent surgery and/or laparoscopy at our hospital at Kanazawa University between January 1990 and December 2000. The grading (Gr) by the volume scoring system was decided according to the sum of scores for nine (in male) or ten (in female) abdominopelvic regions. These regions included left subphrenics, right subphrenics, left flank, right flank, pelvis, omenta, mesentery, small and large bowels, ovaries (only for females), and other intraabdominal organs. Volumetry for each region was carried out using the following categories: VS0, indicating the absence of cancer in a particular abdominopelvic region; VS1, indicating that tumor nodules are less than 10 mm in diameter; VS2, indicating tumors between 1 and 5 cm in diameter; and VS3, indicating that tumor is more than 5 cm in diameter or that an organ is coated by a mat of tumor (confluent disease). The scores for VS0, VS1, VS2, and VS3 were 0, 1, 2, and 3 points, respectively. Total scores of 1 to 3 were the equivalent of Gr I, total scores of 4 to 6 were equivalent to Gr II, total scores of 7 to 9 were equivalent to Gr III, and total scores of more than 9 were equivalent to Gr IV. RESULTS: There was no significant difference between P1 and P2, or between P1 and P3 in survival curves. But the 50% survival times of Gr I, Gr II, Gr III, and Gr IV were 1.23, 0.66, 0.67, and 0.32 years, respectively. The prognosis of Gr I was significantly better than that of any other grades. Eight of the 28 patients (29%) assessed as Gr I survived more than 2 years, whereas only 2 of the 57 (4%) assessed as Gr II, Gr III, or Gr IV did so. Multivariate analysis by Cox's proportional hazard model revealed that the volume scoring, resection of primary tumor, and resection of peritoneal tumor were independent factors to predict prognosis. CONCLUSION: These results showed that the volume scoring system was strongly related to the prognosis, and the patients assessed as Gr I had a great probability of cure by surgery.

Adolescent↗

PubMed2003

[Sentinel node navigation surgery in early-stage gastric carcinoma: a limited gastric resection with lymphatic basin dissection in sentinel node-negative patients].

The high accuracy of sentinel node biopsy in clinical T1 gastric cancer leads to the idea of excluding conventional D2 from node-negative patients. The question now arises of what to do when sentinel nodes are missed during surgery and micrometastases are over looked in frozen tissue sections. To avoid and correct a mistaken diagnosis, surgeons should remove the lymphatic basin even in the case of negative sentinel nodes, because the basin is exclusively associated with the involved nodes. We call this procedure "lymphatic basin dissection." Gastric lymphatic basins were divided into five compartments corresponding to the feeding artery, and clinical T1 gastric cancer involved a single basin in 42% of patients, two in 47% and three in 12%. Patients with one or two basins can be treated with limited gastric resection, because the devascularization does not cause insufficient blood supply to the remnant stomach. Since 1995, 123 patients have undergone lymphatic basin dissection and limited gastric resection (segmental resection, local resection, proximal gastrectomy, and limited distal gastrectomy) in our institution. There was no recurrence in the limited surgery patients with a median follow-up period of 3.8 years. The overall survival curve after surgery in the limited group is almost the same as that in the conventional group. Quality of life was significantly higher in the limited group than in the conventional group.

Gastrectomy↗