Takeshi Oohara

Flat early cancers of the large intestine

From January 1976 to December 1987, 37 early colorectal cancers of the flat type were treated. Thirty‐four of them (91.9%) were not accompanied by adenoma, and were thought to have arisen de novo. There is indeed a de novo route of cancer development in the human large intestine, and cancers de novo merely show polypoid growth. Flat type cancers arising de novo tend to reach deeper layers at an earlier stage than polypoid‐type carcinomas in adenoma. Of those with a diameter of less than 10 mm, only 40% stayed in the mucosa. Consequently, advanced cancers cannot be prevented by snare polypectomy alone. More attention should be directed to the discovery of small, flat, nonpolypoid cancers.

Minute cancers arising de novo in the human large intestine

In order to search for the histogenesis and progression of colorectal cancer, the background mucosas of 18 patients with a single colorectal cancer, apart from familial adenomatosis coli, were studied by a step sectioning method. Three early minute cancers (3‐5 mm in diameter) were detected in the apparently normal mucosa, and two cancers in the adenoma (focal cancer in adenomatous polyp). The three early cancers had no evidence of preexisting adenoma, so they were considered to be de novo cancers. In form they were depressed, flat, and slightly elevated. In humans, de novo cancer has an important significance in histogenesis and treatment of colorectal cancer. Clinically, it is also important to recognize the early phase of colorectal cancer in flat type as well as polypoid type.

Induction of Glandular Stomach Cancers in Helicobacter pylori-sensitive Mongolian Gerbils Treated with N-Methyl-N-nitrosourea and N-Methyl-N′-nitro-N-nitrosoguanidine in Drinking Water

An animal model of stomach carcinogenesis was established using Mongolian gerbils with N‐methyl‐N‐nitrosourea (MNU) and N‐methyl‐N′‐nitro‐N‐nitrosoguanidine (MNNG) as the carcinogens. In addition, the sensitivity of these gerbils to Helicobacter pylori (H. pylori) was confirmed. One hundred and sixty specific pathogen‐free male MGS/Sea animals, 7 weeks old, were treated with MNU in the drinking water (30 ppm for alternate weeks to give 10 weeks exposure, or 10 ppm or 3 ppm for 20 weeks continuous exposure), or given MNNG in the drinking water at 400 ppm or 200 ppm for 20 weeks, or orally inoculated with ATCC43504 H. pylori (1.7×1088 CFUs/animal). Adenocarcinomas in the glandular stomach were found in 2 out of 12 effective animals (2/12) treated with 30 ppm MNU at week 20, although all were dead or moribund by week 30 due to MNU toxicity. At week 50, the incidences of gastric adenocarcinomas in groups treated with 10 ppm MNU, 3 ppm MNU, 400 ppm MNNG, and 200 ppm MNNG were 2/21 (9.5%), 1/23 (4.3%), 7/11 (63.6%), and 1/10 (10.0%). The lesions were generally well differentiated, although poorly differentiated adenocarcinoma was also found in a single gerbil in each of the 10 ppm MNU and 400 ppm MNNG groups. In control animals no tumors were found. In the infection study, the animals were killed at week 20, and H. pylori was detected in all cases, causing multiple erosions with marked inflammatory cell infiltration in the lamina propria and submucosa, and frequent formation of lymphoid follicles. Thus, MNU and MNNG in the drinking water induced neoplastic lesions in the glandular stomach epithelium of H. pylori‐sensitive gerbils.

Mutations of the Ki‐ras, p53 and APC genes in adenocarcinomas of the human small intestine

In contrast to the origins of colorectal carcinomas, the mechanisms of carcinogenesis in the small intestine remain unclear. We therefore analyzed the mutational status of the Ki‐ras, p53, and adenomatous polyposis coli (APC) genes in primary carcinomas of the small intestine and compared the mutation patterns with those established for colorectal cancers. DNA was extracted from 15 formalin‐fixed, paraffin‐embedded lesions. Codons 12, 13 and 61 of the Ki‐ras gene, exons 5–8 of the p53 gene, and codons 1268–1569, which contain the mutation cluster region (MCR) of the APC gene, were amplified by means of PCR, subcloned and sequenced. Mutations of the Ki‐ras and p53 genes were observed in 8 (53.3%) and 4 lesions (26.7%), respectively. The mutational frequency of the Ki‐ras gene in the present series of small intestinal carcinomas was similar, while that of the p53 gene was slightly lower than the reported frequencies for colorectal carcinomas. Only one case showed a mutation of the APC gene, involving an insertional mutation of an adenine at codons 1554–1556 with formation of a stop codon immediately downstream. Since the occurrence of an APC mutation is considered an early event in colorectal carcinogenesis, our findings indicating an extremely low frequency of such changes in and around the MCR suggest that carcinomas of the small intestine arise via a genetic pathway distinct from that involved in the development of carcinomas of the colorectum. Int. J. Cancer, 70:390–395, 1997.

Depressed adenoma in the large intestine

To clarify the presence of depressed adenomas in the human large intestine, a prospective study was performed from January 1986 to December 1987. During these two years, 997 colonoscopies were conducted in patients, bdexcluding cases of familial adenomatosis coli. Of 32 small, depressed lesions biopsied, seven were depressed adenomas, demonstrating that depressed adenomas do exist in the colon and rectum, and can be detected endoscopically. Resembling a sucker, they are easily detected through inflation and deflation.

Altered expression of extracellular matrix molecules and their receptors in chronic pancreatitis and pancreatic adenocarcinoma in comparison with normal pancreas

SummaryThe aim of this study was to elucidate the expression and distribution patterns of both integrins and extracellular matrix (ECM) molecules in chronic pancreatitis (CP) and pancreatic adenocarcinoma (PC) compared with normal pancreas (NP). Expression of nine α-subunits (α2-α6, αv, αl, αm, and αx), four β-subunits (β1, β3-β5), and four ECM molecules (type IV collagen, laminin, fibronectin, and vitronectin) was investigated immunohistochemically. In CP, all integrins except αv showed nearly the same staining patterns compared with NP. Some acinar cells in CP expressed αv. Whereas α2, α3, and α6 expression was stronger and diffuse, no α5 expression was seen in PC. Basement membrane (BM) showed continuous staining in CP, whereas it showed discontinuous/absent staining in PC with antitype IV collagen, laminin, and vitronectin antibodies. Some carcinoma cells showed reverse correlation between α2, α3, and α6 expression and type IV collagen and laminin expression. Fibronectin showed diffuse stromal expression in CP and PC. Some acinar cells or duct cells in CP carcinoma cells in PC showed intracellular VN expression. These results suggest that these integrins and ECM molecules are involved in inflammatory and malignant processes in pancreas.

Endoscopic classification of chronic gastritis based on a pilot study by the research society for gastritis

Background: Various types of classification of gastritis have been proposed, but no plausible classification has been available until now. The Research Society for Gastritis performed a pilot study to establish an endoscopic classification, taking into consideration the following: (i) ease of use; (ii) permitting everyone the common image; and (iii) presence of histopathological evidence.

Minute gastric cancers less than 5 mm in diameter

Minute gastric cancers with maximum dimensions of less than 5 mm were studied clinicopathologically. There were 49 intramucosal cancers among 46 patients and nine submucosal cancers among nine patients. No lymph node metastasis was found. Macroscopically, eight (13.8%) were elevated, 12 (20.7%) were flat, and 38 (65.5%) were depressed. Most submucosal cancers were of the depressed type (8/9, 88.9%). Classification of cancers according to association with other large cancers into single group (22 cases) and multiple group (33 cases) revealed that (1) the majority of the minute gastric cancers (20/22, 90.9%) in the single group were the depressed type and (2) submucosal cancers in the single group were 8/22, accounting for 36.4%, a much higher incidence as compared with 1/36 (2.9%) in the multiple group. These facts indicate that gastric cancers should be detected when they are about 5 mm in maximum dimension and before they invade beyond the submucosal layer, especially in single and depressed type.

Different carcinogenesis in the gastric remnant after gastrectomy for gastric cancer

The incidence of gastric remnant cancer after surgery for gastric malignancies has been increasing. The interval between previous operations and the diagnosis of gastric remnant cancer, location of cancer development, and histologic type were different from those after surgery for benign diseases. However, very little is known about the reasons for these differences. Patients with gastric cancer already have cancer‐related gastric mucosal changes at gastrectomy, and they undergo a wide range of dissection of nerve distribution to the stomach due to lymph node dissection. Therefore, the effects of preliminary administration of a carcinogenic agent and denervation of the gastric mucosa on tumorigenesis in the gastric remnant were investigated.

Overexpression of intercellular adhesion molecule-1 (ICAM-1) in pancreatic adenocarcinoma in comparison with normal pancreas

To elucidate the role of intercellular adhesion molecules (ICAMs), which has not been well understood in pancreas, we investigated the localization and expression of ICAM-1 by immunohistochemistry and in situ hybridization (ISH) in pancreatic adenocarcinoma and in normal pancreas. The localizations of ICAM-2 and ICAM-3 were also investigated by immunohistochemistry. In normal pancreas, acinar cells, duct epithelial cells, and Langerhans islet cells failed to stain with anti-ICAM-1, anti-ICAM-2, and anti-ICAM-3 antibodies. These cells showed no expression of ICAM-1 mRNA. On the other hand, various percentages of carcinoma cells were stained with anti-ICAM-1 antibody, while no carcinoma cells were stained with anti-ICAM-2 and anti-ICAM-3 antibodies. ICAM-1 mRNA expression was also observed in carcinoma cells, and ICAM-1 mRNA expression was associated with localization of the ICAM-1 protein. These results suggest that ICAM-1 expression is up-regulated in pancreatic adenocarcinoma cells and that ICAM-1 is involved in malignant processes in pancreas.