Kazuo Takei

APC, K-ras codon 12 mutations and p53 gene expression in carcinoma and adenoma of the gall-bladder suggest two genetic pathways in gall-bladder carcinogenesis

Currant histopathoiogical evidence suggests that gall‐bladder cancer has two main morphological pathways for Its development: de novo (ab Inltlo) origin and adenoma‐carcinoma sequence. In order to investigate the genetic difference between them, APC mutations were examined by RNase protection analysis, K‐ras mutations by nested porymerase chain reaction‐restriction fragment length polymorphism analysis, and p53 gene overexpression by immunoriisto‐chemical analysis in both tumors and benign lesions of the gall‐bladder. Overexpression of the p53 gene was detected in 105 of 164 (64%) de novo carcinomas regardless of size and depth of Invasion, but not in 16 tumors of carcinoma‐ln‐pyloric‐gland‐type adenoma, or In 51 adenomas (47 pyloric gland‐type and 4 Intestinal‐type). K‐ras codon 12 mutation was detected in 4 of 40 (10%) de novo carcinomas, ail four being associated with p53 gene overexpression, but not in 12 tumors of carcinoma in adenoma or 16 adenomas (14 pyloric gland‐type and 2 intestinal‐type). APC mutation was not found in 16 de novo carcinomas or the one pyloric gland‐type adenoma examined. These results suggest that there are two distinct genetic pathways in gall‐bladder carcinogenesis; that is, de novo carcinoma develops from a predominant p53 alteration with low K‐ras mutation, and carclnoma‐in‐pylortc‐gland‐type adenoma develops from p53‐, K‐ras‐, and APC‐gene‐unrelated, as yet unknown, alteration.

Nuclear cyclin D1 overexpression is a critical event associated with cell proliferation and invasive growth in gallbladder carcinogenesis.

Abstract: Cyclin D1 overexpression is remarkably frequent in several human carcinomas and is believed to be a critical event in oncogenesis. We examined cyclin D1 expression, p53 expression, and the Ki-67 labeling index by immunostaining in human gallbladder mucosa in conditions varying from normal to malignant tissue. We also examined K-ras codon 12 mutations in these tissues with a two-step polymerase chain reaction. Nuclear cyclin D1 overexpression was observed in 48% of carcinomas occurring independently of adenoma, but not in adenomas, carcinomas arising in adenomas, or nonneoplastic lesions. Cytoplasmic cyclin D1 overexpression was observed in about 15% of abnormal specimens, irrespective of the type of epithelial abnormality. Carcinomas showing nuclear cyclin D1 overexpression had significantly higher Ki-67 labeling indexes than those with no overexpression. Moderately to poorly differentiated adenocarcinomas showed a higher incidence of nuclear cyclin D1 overexpression than papillary to well differentiated carcinomas. Specimens with cyclin D1 overexpression showed a high incidence of lymph permeation, venous permeation, and lymph node metastasis. We conclude that nuclear cyclin D1 overexpression is a critical event importantly associated with cell proliferation and invasive growth in gallbladder carcinogenesis, and that cyclin D1 immunostaining may become a useful marker for evaluating gallbladder carcinomas.

IMPROVEMENT OF CHOLEDOCHOSCOPY: CHROMOENDOCHOLEDOCHOSCOPY, AUTOFLUORESCENCE IMAGING, OR NARROW‐BAND IMAGING

Past and present results concerning assessment of choledochoscopy using chromoendoscopy, autofluorescence imaging (AFI), or narrow‐band imaging (NBI) are summarized herein. On chromoendocholedochoscopy using methylene blue, cancer was stained dark blue. Interestingly, normal bile duct had dimple signs that are a significant feature of non‐neoplastic mucosa. First‐generation AFI (laser‐induced fluorescence endoscopy–gastrointestine system) and system of autofluorescence endoscopy made it possible to detect neoplastic lesions as dark green–black lesions, although the image was insufficient. The sensitivity, specificity and diagnostic accuracy of white light illumination and AFI were 88.0%, 87.5%, 87.7%, and 100%, 52.5%, 70.8%, respectively. In contrast, the recently developed NBI system made it possible to emphasize the imaging of certain features such as mucosal structures and mucosal microvessels. NBI showed not only clear neoplastic findings such as irregular mucosa or tortuous tumor vessel, but also non‐neoplastic findings such as smooth surface mucosa or dimple sign. In conclusion, the diagnostic power of chromoendoscopy and AFI were low, but NBI is expected to become the new‐generation diagnostic tool for biliary tract diseases.

Correlation of serum pepsinogen with histological atrophy following successful Helicobacter pylori eradication: PEPSINOGEN AND HISTOLOGICAL FINDINGS AFTER H. PYLORI ERADICATION

Levels of pepsinogen have been reported to correlate with the degree of gastric atrophy in Helicobacter pylori‐infected gastric mucosa.

Correlation between serum pepsinogen levels and gastric mucosal histological findings before and after Helicobacter pylori eradication therapy

Background:  Helicobacter pylori causes chronic gastritis and is also associated with many other gastrointestinal diseases. The incidence of gastric cancer is thought to vary according to the degree and topography of chronic gastritis. Histological findings of specimens obtained at endoscopy are therefore important. In the present study, we investigated the correlation between these histological findings and serum pepsinogen (PG) levels.

A Case of Hemophilia B with Esophageal Varices Treated by Sclerotherapy with Factor‐IX Complex

A 64‐year‐old man with hemophilia B and HCV‐positive chronic hepatitis who had been followed at our hospital presented with hematemesis. Gastrointestinal fiber‐scopy (GIF) demonstrated a small active gastric ulcer (Az stage) at the pyloric ring and esophageal varices (F1 Lm Cw RC(+)). He was admitted and the esophageal varices were safely and successfully treated by sclerotheapy. Sclerotherapy was performed by in‐traluminal injection of 4 mL 5% ethanolamine oleate with sufficient supplementation of factor‐lX complex (PPSB ‐HT) for four days to a total amount of 24,000 U. The patient was followed with GIF and endoscopic ultrasonography. Sclerotherapy proved effective after six months. We report a rare case of hemophilia B with esophageal varices successfully treated by sclerotherapy.

Experience with Percutaneous Electronic Choledochoscopy

Experience with percutaneous choledochoscopy using a prototype electronic choledochoscope (Pentax ECN‐1530) is presented herein. This electronic endoscope is 5.3 mm in outside diameter at the tip and has a forceps channel 2.0 mm in diameter. The outside diameter is 0.4 mm larger, while the forceps channel diameter is 0.2 mm smaller, than that of the conventional fiberoptic choledochoscope (FCN‐15X) produced by the same company. Although the new electronic choledochoscope could be inserted through a 16 Fr in size fistula, we considered an 18 Fr fistula to be preferable for insertion without resistance. Various types of accessory equipment for endoscopic treatment, such as an electrohydraulic Shockwave lithotriptor (EHL) and an Nd‐YAG laser, could be used without difficulty. The electronic choledochoscope was useful for examining bile duct carcinoma invasion to the hepatic side and evaluating the efficacy of various multi‐modal treatments, as it provided observation of the bile duct mucosa in great detail due to a very clear dynamic image. Moreover, endoscopic treatment was also greatly facilitated because it provided a clear view on a large, bright monitor screen for the surgeons. We therefore believe that this new electronic choledochoscope is very useful for the accurate diagnosis and treatment of biliary diseases.

Prophylactic Effect of Famotidine on Acute Gastric Ulcers due to Ranger Training

Abstract: Since 1978, we performed endoscopic examinations of the upper gastrointestinal tract in trainees before and after ranger training to study the relationship between the training program and the occurrence of acute gastrointestinal disease. Since 1987, the H2 blocker famotidine has been administered to all ranger trainees as a prophylaxis against stress ulceration. In the 617 subjects studied, the following conditions were detected following the completion of the training: gastric ulcers occurred in 42 subjects (6.8%), duodenal ulcers occurred in 27 subjects (4.4%), and gastroduodenal ulcers occurred in six subjects (1%). Ulcers occurred in 41 out of 421 trainees (9. 7%) during the nine years between 1978 and 1986. Since 1987, however, ulcers have occurred in only seven out of 196 trainees (3.6%).