Taro Okamoto

Effects of Sodium Chloride and Ethanol on Stomach Tumorigenesis in ACI Rats Treated with N‐Methyl‐N′‐nitro‐N‐nitrosoguanidine: A Quantitative Morphometric Approach

Effects of sodium chloride (NaCl) and ethanol on gastric tumor development in rats after treatment with N‐methyl‐N′‐nitro‐N‐nitrosoguanidine (MNNG) were studied. MNNG, dissolved in distilled water (5 g/liter), was administered orally once fay gastric tube at a dose of 0.25 ml/10 g body weight to 4‐week‐old ACI rats. After this carcinogen initiation, animals were fed on a diet containing 10% NaCl (Group 2) or normal diet with 10% ethanol in the drinking water (Group 4). MNNG alone (Group 1), NaCl alone (Group 3), ethanol alone (Group 5), and control (Group 6) animals were also maintained. All survivors were killed one year after the MNNG application. Incidences of tumors in the forestomach and glandular stomach were significantly increased in Group 2 as compared to Group 1 (P<0.05). The height of the pyloric mucosa was significantly greater in Group 2 than in Groups 4, 5 or 6 (P<0.05). In the fundic area, the mucosal height was significantly decreased in Group 4 as compared to Group 6 (P< 0.05). The present results demonstrate that whereas tumors in the glandular stomach and forestomach are both promoted by NaCl, ethanol is without influence. Furthermore, NaCl, a promoter of glandular stomach tumorigenesis also increases cell proliferation.

Influence of Gastric pH Modifiers on Development of Intestinal Metaplasia Induced by X‐Irradiation in Rats

The influence of gastric pH on intestinal metaplasia was examined in male Crj:CD(SD) rats. At the age of 5 weeks, animals were irradiated with two 10 Gy doses of X‐rays to the gastric region at a 3‐day interval (total 20 Gy), and 6 months after irradiation, received either secretin or histamine in silicon tubes for 2 months or had their bilateral submandibular salivary glands removed. The incidences of intestinal metaplasia in the fundus of animals after administration of secretin or histamine, or removal of the salivary glands were reduced, along with the pH values, as compared with values for rats given X‐rays alone. In both the pyloric and the fundic gland mucosae, the numbers of alkaline phosphatase (ALP)‐positive foci and type B metaplasias (intestinal crypts without Paneth cells) were also significantly decreased (P<0.01). In a second experiment, started six months after irradiation, rats were kept on 1% sodium chloride (NaCl) diet for 6 months. Subsequent removal of salivary glands along with histamine treatment brought about a marked drop in pH and in numbers of ALP‐positive foci after three and five days. The present results thus indicated that development and maintenance of intestinal metaplasia can be influenced by a decrease of pH value.

The Effects of Sodium Chloride, Miso or Ethanol on Development of Intestinal Metaplasia after X‐Irradiation of the Rat Glandular Stomach

The influence of sodium chloride (NaCl), miso (Japanese soybean paste) and ethanol on development of intestinal metaplasia was examined. Five‐week‐old male CD(SD): Crj rats were treated with two 10 Gy doses of X‐rays to the gastric region at a 3‐day interval (total 20 Gy). After irradiation, the rats received supplementation with NaCl (1% or 10% in diet), miso (10% in diet) or ethanol (10% in drinking water) for 12 months. The number of alkaline phosphatase‐positive foci of intestinal metaplasia in rats given 1% NaCl diet (Group 3) after X‐rays was significantly elevated as compared to that in rats given X‐rays alone (Group 1) (P < 0.01) or X‐rays with 10% NaCl (Group 2) (P < 0.01). In the pyloric gland mucosae, the total numbers of metaplastic foci in rats of Group 3 were much higher than in Group 2, or after miso diet (Group 4) or ethanol supplementation (Group 5) (P < 0.01), but no difference was found between Group 2, 4 or 5 and Group 1. Atypical hyperplasia only appeared at incidences of less than 6% in Groups 1–3 and no promoting effect on gastric tumorigenesis was evident in Group 2. The present results thus showed that the occurrence of intestinal metaplasia induced by X‐irradiation can be significantly increased by administration of 1% NaCl and decreased by 10% NaCl and ethanol, but this is not associated with any influence on gastric neoplasia.

Lack of Any Positive Effect of Intestinal Metaplasia on Induction of Gastric Tumors in Wistar Rats Treated with N‐Methyl‐N‐nitrosourea in Their Drinking Water

The influence of intestinal metaplasia on gastric cancer induction was examined in five‐week‐old male Wistan:Crj rats. The animals were first treated with two 10 Gy doses of X‐rays to the gastric region at a 3‐day interval (total 20 Gy) and then, starting two months after the irradiation, received 100 ppm N‐methyl‐N‐nitrosourea (MNU) in their drinking water for 15 weeks. Thereafter they were maintained for 37 weeks with or without a dietary 1% sodium chloride (NaCl) supplement. The incidences of gastric adenocarcinomas in the MNU or MNU plus NaCl groups were significantly higher than in animals receiving X‐rays plus MNU with or without NaCl. Intestinal metaplasias and the numbers of alkaline phosphatase(ALP)‐positive foci were significantly increased in the X‐ray irradiation groups but the numbers of ALP‐positive foci were not increased with or without 1% NaCl. An inverse relationship between incidences of gastric tumors and intestinal metaplasias was apparent. The present experiment thus showed that the presence of intestinal metaplasia does not exert a positive influence on induction of gastric neoplasia by MNU in the rat.

Significance of strain and sex differences in the development of 252Cf neutron-induced liver tumors in mice.

Mouse liver tumors occurring in C3H/HeN, C57BL/6N and C3B6F1 hybrid (C3H × C57BL) were studied following 252Cf fission neutron irradiation. Three strains of mice of both sexes (about 30 mice/group) were irradiated once with 252Cf at doses of 0,12.5, 50 and 200 cGy. The groups were observed for 13 months after irradiation. The incidence of liver tumors in the non‐irradiated controls was 0% in both sexes of CS7BL/6N, 11.7% in males and 0% in females of C3B6F1 and 39.5% in males and 11.4% in females of C3H/HeN mice. In the four strains of mice thus far studied, including B6C3F1 hybrid (CS7BL × C3H) which was previously studied, 252Cf irradiation has increased the tumor incidence dose‐dependently in males and in females, but less effectively in females. The mean number and size of liver tumors were clearly correlated with tumor incidence. The incidence was always highest in C3H/HeN mice of both sexes, followed by B6C3F1, C3B6F1 and C57BL/6N mice. The influence of sex hormones was studied in B6C3F1 mice of both sexes after 200 cGy of 252Cf irradiation. In males, the incidence of liver tumors was significantly decreased from 55.2% to 23.3% and 25.9% after orchidectomy, and in females it was slightly decreased from 27.6% to 14.8% and 18.8% after ovariectomy. Supplementation of testosterone in orchidectomized mice did not restore the occurrence of liver tumors.

Inhibition of Mammary Tumors by Pretreatment with 17β‐Estradiol in F344 Rats Induced with N‐Methyl‐N‐nitrosourea

The influence of 17β‐estradiol (E2) and prolactin was studied on N‐methyl‐N‐nitrosourea (MNU)‐induced mammary carcinomas (MCAs) in rats. MNU was intravenously injected once into seven‐week‐old female F344 rats at a dose of 50 mg/kg body weight. Groups of rats also received either 2.5 mg of E2 or a continuous supply of prolactin and/or growth hormone via transplanted MtT/F84 (mammo‐somatotropic pituitary tumor). Rats were observed for up to 36 weeks after MNU administration. Although simultaneous administration of MNU and E2 did not much affect the occurrence of MCAs as compared to administration of MNU alone, rats treated with 2.5 mg of E2 for two weeks before MNU administration had significantly reduced occurrence of MCAs compared to those given MNU alone. In contrast, rats with MNU plus MtT/F84 showed high incidence and shortened latency of MCAs and they also had a high incidence of clitorial gland hyperplasias. Average pituitary weights and serum prolactin levels in E2‐treated rats were greatly increased compared to those of MNU‐alone rats. Average serum E2 levels were about 100 ng/ml in E2‐treated rats and 0.05 ng/ml in rats without E2 treatment. Serum prolactin levels were greatly increased in rats with MtT/F84. The results indicated that pretreatment with E2 before MNU administration was inhibitory while increased prolactin caused by grafting MtT/F84 after MNU injection was promotive for the occurrence of MCAs in female F344 rats.

EFFECTS OF SEX HORMONES ON INDUCTION OF INTESTINAL METAPLASIA BY X-IRRADIATION IN RATS

The influence of sex hormones on induction of intestinal rnetaplasia was examined in 5 week old Crj: CD (SD) rats of both sexes. At the age of 4 weeks, the animals were gonadectornized and given testosterone or dimethyl estradiol (DES). One week after operation, they were irradiated with two 10 Gy doses of X‐rays to the gastric region at a 3 day interval for a total of 20 Gy. At the termination of the experiment, 6 months after the X‐irradiation, the incidence of intestinal metaplasia with alkaline phosphatase (ALP) positive foci in males was significantly higher than in females, in orchidectomized males or orchidectomized plus DES treated rats (P <0.01). On the other hand, the incidence of intestinal metaplasia with ALPpositive foci in normal females appeared lower than in ovariectomized females (P < 0.01), and was increased in rats by treatment with testosterone or decreased by DES. Numbers of foci of intestinal metaplasias with Paneth cells and total numbers appeared to increase in males treated with DES. The results suggested a promoting role for testosterone in the development of ALP positive lesions and indicated considerable heterogeneity between intestinal metaplasia subtypes.

Significance of Mass Screening for Simultaneous Thyroid Disease and Breast Cancer

乳癌集団検診における甲状腺同時検診の意義について, 当教室の甲状腺疾患合併乳癌症例を併せて検討した。広島県集団検診では, 1985年より1991年の間にのべ約27万人の30歳以上の女性を対象として, 乳癌146人と甲状腺癌56人を発見した。その発見率はそれぞれ0.05%, 0.02%であった。発見乳癌および甲状腺症例の平均年齢はいずれも約50歳で, 年齢別発生率にも差を認めなかった。一方, 広島大学第2外科において1965年から1991年末までに加療した原発性女性乳癌506症例中, 確診の得られた甲状腺疾患合併症例は32例, 6.3%であった。そのうち特に甲状腺癌および甲状腺機能亢進症がそれぞれ10例と多く見られた。また甲状腺疾患合併群には比較的早期の乳癌が多く, 逆に進行例が少ない傾向が見られ, したがってその生存率も非合併群に比して比較的良好であった。甲状腺疾患と乳癌発生のリスクに関しては依然として未解明な点も多く, また今回, 甲状腺機能検査値からは明らかな相違を見出せなかった。しかし乳腺疾患と同様, 甲状腺疾患も女性に多い疾病の1つとしてまったく無関係とは言い難く, また重複癌例では乳癌家系や両側乳癌例, 被爆例が多いなど両者の発生要因として, 共通の内分泌あるいは遺伝・環境因子の関与が示唆された。したがって乳癌検診時に同時に甲状腺の視・触診を行うこと, また甲状腺疾患の既往などを十分聴取することの意義は大いにあるものと考えられた。

Tow cases of primary small intestinal cancer.

原発性小腸癌は, 比較的まれな疾患であるが, われわれは最近2手術症例を経験したので報告する.症例1は59歳男性, イレウス症状で発症, CAI9-9の高値および, 小腸造影でTreitz靱帯より10cm肛側で全周性の狭窄を認めた.腫瘍は同部の空腸にあり, 空腸および回腸の腸間膜付着部側に動脈血行性転移と思われる小病巣を多発性に認めた.原発巣を含む空腸部分切除を行いえた.術後1年5か月で死亡した.症例2は53歳女性.約6か月間心窩部痛, 悪心, 嘔気が続き, イレウス症状が出現, 小腸造影で空腸末端付近での閉塞を認めた.腫瘍はTreitz靱帯より130cm肛側の空腸にあり, napkinringconstrictionを認め, 腹膜播種もあった.空腸部分切除を行った.術後1年11か月で死亡した.