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The effect of trisodium nitrilotriacetate monohydrate [N,N-bis(carboxymethyl)glycine trisodium salt] (Na3NTA X H2O) on development of renal tubular cell tumors induced with N-ethyl-N-hydroxyethylnitrosamine [CAS:13147-25-6; 2-(ethylnitrosamino)-ethanol] (EHEN) was studied. Six-week-old male inbred W rats were given a diet containing 1,000 ppm of EHEN for 2 weeks and then a diet containing a high (10,000 ppm) or low (500 ppm) concentration of Na3NTA X H2O for 30 weeks. The rats were killed during week 32. The higher concentration of Na3NTA X H2O enhanced the development of renal tubular cell tumors and increased the number and size of tumors in rats treated with EHEN, but the lower concentration of Na3NTA X H2O did not. The incidence of renal tubular cell tumors in week 32 was 33% in rats treated with 1,000 ppm EHEN for 2 weeks, 100% in rats treated with 1,000 ppm EHEN for 2 weeks plus high Na3NTA X H2O diet for 30 weeks, and 39% in rats treated with 1,000 ppm EHEN for 2 weeks and then given low Na3NTA X H2O diet for 30 weeks. Numbers of atypical cell foci per kidney area (No./cm2) were 17.0 +/- 7.6 in rats treated with EHEN and high Na3NTA X H2O, 7.3 +/- 2.2 in rats treated with EHEN and low Na3NTA X H2O, 3.7 +/- 1.4 in rats treated with EHEN alone, and 1.0 +/- 2.4 in rats treated with high Na3NTA X H2O diet alone. Atypical cell foci retained a tubular pattern and consisted of basophilic cells with a large nucleus or clear cells with a small nucleus.

Fifteen of 152 pediatric patients with spinal cord insults (10%) developed heterotopic ossification (HO) at 19 locations. The average age of the patient was eight and one-half years. The spinal cord levels were 13 thoracic and two cervical. The average time to detection of the HO from spinal insult was six and one-half years. The hip was involved in 15 of 19 HO lesions. Decreased range of motion of the affected extremity was the most common sign of occurrence. Alkaline phosphatase was elevated in five of eight patients at the time of detection. Three patients had some resorption of the HO, and one had nearly complete resorption. Five patients (3.3%) with HO had no other etiologic agent other than the neurologic insult, and their average age at time of injury was 13 and one-half years. The hip was involved in six of seven instances. The average time to diagnose this HO was 14 months after injury. Ten patients had late concurrent etiologic factors such as surgery, decubitus ulcers, late neurogenic hip dislocation, and late acute local trauma influencing HO formation. Pediatric patients who developed HO appeared to have a lower incidence, delayed onset, and fewer associated signs and symptoms compared with their adult counterparts with spinal cord injury. Patterns of ossification about the hip differ from adults. The HO lesion has the potential to resorb. HO may be initiated years after the spinal injury by an incidental insult.

Studies were made on the dose and sex dependence of thyroid tumor development in rats pretreated with N-bis(2-hydroxypropyl)nitrosamine (DHPN) followed by exposure to various doses of phenobarbital (PB). A direct dose-response relationship in induction of thyroid tumors was found in both male and female rats. Upon feeding the DHPN-treated rats with basal diet containing 20, 100, 500, and 2500 ppm of PB, the incidences of follicular adenoma were, respectively, 8, 45, 70, and 66% in male rats and 12, 17, 50, and 58% in female rats. Development of papillary adenomas in male rats was observed only at the higher doses of PB, at incidences of 12 and 20% for doses of 500 and 2500 ppm. Follicular carcinoma was also seen at higher doses of PB, at 16 and 12%, respectively, for the 500- and 2500-ppm groups. Neither follicular nor papillary carcinomas were induced in female rats; only a low incidence of papillary adenoma (4%) was observed with a PB concentration as high as 2500 ppm. A single injection of DHPN resulted in production of approximately 1 tumor/female rat and 2.5 tumors/male rat. DHPN combined with posttreatment with PB at doses up to 500 ppm did not increase tumor yield in female rats, whereas a 3-fold increase was observed in male rats for the 500-ppm-treated groups. When PB was increased to 2500 ppm a marked increase (8-fold) in tumor yield in male rats was observed, in contrast to a less than 3-fold increase in similarly treated female rats.

A drug delivery catheter system with subcutaneously implantable port, PORT-A-CATH, was applied for intra-arterial, intravenous and intraperitoneal chemotherapy and hyperalimentation in treating 99 cancer patients. The average implantation period was 135.1 days and this system was applied for more than one year in 5 cases. Any troubles due to port or catheter materials were not observed during the study. Catheter occlusion occurred in 11 cases infection in 7 (catheter-related infection 4, pocket infection 3), and skin necrosis in 4. This system was proved useful to reduce the risk of infection and enabled easy and safe long-term repeated administration, compared to the catheters with external end. Intra-arterial chemotherapy became possible to the outpatients with the use of this system, which seemed to contribute for the improvement of quality of life of the patients.

In order to elucidate the factors responsible for evaluation of various tumor markers (CEA, CA-19-9, TPA, Ferritin) in colorectal cancer, correlation between portal blood values of these markers and microangiography of the tumor was examined. 1) Mean values of these markers in portal blood were higher than those in peripheral blood. 2) Microangiography of tumor coincided well with cancer infiltration. A significant extramural vascular change was found in ulcerative cancers which showed a vertical invasion for colonic wall than in those with horizontal invasion or protuberant cancers. 3) The elevated portal CEA was noted in ulcerative cancers with vertical invasion extending through muscular vessels and/or in tumors with vascular disarray and histological necrotic foci. 4) Elevated portal TPA relationship between portal TPA levels and vascular patterns of tumor. 5) Portal CA19-9 levels changed within normal value in correlation with the degree of vascular change. Portal ferritin values showed wide variations as well as peripheral ones. The present study indicates that the extra or intramural vascular change and vascular pattern of tumor may be a major contributing factor to transfer these markers from tumor into blood circulation.

A 39-year-old woman was admitted to our hospital complaining of hemosputum and right neck swelling. Pharyngography, neck CT scan and laryngoscopy revealed moderately differentiated squamous cell carcinoma of the right pyriform sinus. After series of examinations, it was found that she had pancytopenia, hypoplastic bone marrow, hyperpigmentation of the skin, cardiac anomaly, small stature, hypogonadism, chromosomal aberrations and consanguinity in her parents. These findings suggested that she was the congenital aplastic anemia, that is Fanconi's anemia, variant form. Although pepleomycin and corticosteroids were administrated for the treatment of squamous cell carcinoma and aplastic anemia, she died of cardiovascular shock due to massive hemorrhage. Flow cytometric analysis of squamous cell carcinoma showed an unusual aneuploidy DNA histogram. This is the first report on Fanconi's anemia with squamous cell carcinoma in Japan. It is said that chromosomal aberrations and impairment of DNA cross-links repair may play an important role developing of malignancy in Fanconi's anemia.

The effect of 5 beta-chol-3-en-24-oic acid (delta 3) on N-methyl-N-nitrosourea (MNU)-induced colonic tumorigenesis was studied by intrarectal injection of these compounds in rats. Female Fischer rats received 0.5 ml of distilled water (DW) alone or DW containing 2.5 mg of MNU twice in one week followed by 0.5 ml of peanut oil (PO) alone or PO containing 1 mg of delta 3, or 1 mg of lithocholic acid (LC) thrice weekly for 48 weeks. Thus, 6 groups were employed as follows: group I, DW + PO (n = 12); group II, DW + delta 3 (n = 30); group III, DW + LC (n = 30); group IV, MNU + PO (n = 30); group V, MNU + delta 3 (n = 30) and group VI, MNU + LC (n = 37). Fecal bile acid profiles were analyzed before and during the treatment. Numbers of rats bearing colonic tumor were none in the groups without MNU, but 5 (17%) in group IV, 15 (50%) in group V and 12 (32%) in group VI (corrected X2 = 6.07, P less than 0.025 for group IV vs V, and 1.42, P less than 0.3 for group IV vs VI). Total numbers of tumors were 7, 17 and 15 in group IV, V and VI, respectively, and they were mostly adenomas and adenocarcinomas. A breast fibroadenoma in one rat of group VI was the sole extracolonic neoplasm in these rats. Total fecal bile acids ranged from 7.7 to 10.5 mumol/g dry feces during the study without any significant quantitative or qualitative difference with respect to with or without bile acids and MNU treatment. These results indicated that delta 3 promoted MNU-induced colonic tumorigenesis in rats without alteration in bile acid metabolism.

The effects of 20 mg of famotidine or placebo on secretion of gastric juice and gastric acid were studied in ten healthy subjects in a randomized, crossover study. Gastric juice was aspirated and collected at hourly intervals for 24 hours after oral administration, and acid output was calculated based on gastric juice output and acid concentration. Secretion of gastric juice and acid output were lower after famotidine was administered than after placebo; over the 12-hour post-administration period, the hourly acid concentrations were significantly lower after famotidine than after placebo. During the 12 hours after famotidine or placebo, gastric juice output was 180.7 +/- 32.1 ml (mean +/- SE) in the placebo group and 64.7 +/- 9.1 ml in the famotidine group (P less than 0.01); acid concentrations were 49.3 +/- 3.8 mmol/L in the placebo group and 9.6 +/- 3.1 mmol/L in the famotidine group (P less than 0.01); acid output was 8.89 +/- 1.59 mmol in the placebo group and 0.55 +/- 0.17 mmol in the famotidine group (P less than 0.01). These results support the effectiveness of a 12 hour or possibly a 24-hour dosing interval for famotidine.

SM-4300, a newly developed human immunoglobulin preparation, has been studied for the safety and effectiveness/efficacy in the 16 patients with severe bacterial and/or fungal infections which are resistant to antibiotic therapy. Clinical effect of 16 cases were excellent 1 case, good 4, fair 4, poor 4 and unknown 3. The efficacy rate was 38.5% and the efficacy rate including fair was 69.2%. No remarkable adverse reaction due to administration of SM-4300 were observed.

Bile acids have been implicated in carcinogenesis of the large bowel, and since epidemiological, clinical and histopathological studies suggest a link between adenomatous polyps and cancer of the large bowel, fecal bile acid profiles were studied in 33 patients with adenomatous polyps of the large bowel and these data were analyzed with particular reference to the distribution, multiplicity, size and degree of dysplasia of the polyps. The more polyps and the greater the severity of dysplasia, the higher was the excretion of total bile acids (mean mumol/day: single vs multiple polyps, 344.8 vs 369.1; mild vs moderate vs severe dysplasia, 347.5 vs 370.0 vs 399.3). However, in patients with larger polyps, total fecal bile acid excretion tended to be lower (mean mumol/day: large vs small polyps, 267.7 vs 389.5). These differences were not statistically significant. When fecal bile acid profiles were analyzed with respect to the extent of bacterial metabolism determined from the degree of dehydroxylation and oxidoreduction, there was a large variation with no consistency in relation to the factors studied among the polyp patients. Deconjugation of bile acids in feces was almost complete without difference among the patients. These results seem to indicate that the significance of bile acid in the development of adenomatous polyps in Japanese subjects is likely to be small.

A phase I trial of a new anthracycline derivative, idarubicin, was conducted in 16 patients with various advanced solid tumors. Doses administered were 20, 30 and 40 mg/m2 with single oral doses. Dose-limiting factors were both leukopenia and thrombocytopenia reaching a nadir about 2 weeks after the start of treatment and requiring 7 to 10 days for recovery. Other toxicities were anorexia, nausea and vomiting, but alopecia did not occur. The maximum tolerated dose was judged to be 40 mg/m2 and the recommended dose for phase II trials was determined to be 30-35 mg/m2.

The concentration of Tegafur, 5-FU and Uracil in tumor and normal tissue were measured in 47 colorectal cancer patients who had been administered UFT (400/mg) for seven days before operation. The concentration of Tegafur, 5-FU and Uracil in tumor was higher than in normal tissue (p less than 0.01), and the concentration of 5-FU was correlative to the concentration of Tegafur and Uracil in both tissues. The Dukes group and histological type were not related to the concentration of Tegafur, 5-FU and Uracil in either tissue. The uptake of each drug was good and high in tumor tissue.

Sialylated Lewis(x) and sialylated Lewis(a) antigens, which are structural isomer each other, were serologically tested to determine the clinicopathological differences and correlation between two antigens, and were also compared with those of serum CEA in 141 patients with gastric cancer. Percent positives in sialylated Lewis(a), CEA and sialylated Lewis(x) showed 26.9%, 21.8% and 17.0% respectively. Percent positive of sialylated Lewis(x) correlated with degree of liver metastasis and peritoneal dissemination. Therefore, it is emphasized that the role of sialylated Lewis(x) is characteristics of detecting a presence of liver metastasis and/or peritoneal dissemination. On the other hand, sialylated Lewis(a) showed high percent positive in cases which had lymph nodes metastasis and mucinous or papillary adenocarcinomas. These two carbohydrate antigens indicated no correlation (r = 0.062) in the spectrum of sera. It is suggested that combination assay of sialylated Lewis(x) and sialylated Lewis(a) is useful in detecting many gastric cancer patients including CEA-negative one.

The effect of castration on the development of thyroid tumors was studied histologically and biochemically in Wistar rats given a single ip injection of 210 mg of N-bis (2-hydroxypropyl)-nitrosamine (DHPN) followed by phenobarbital (Pb). Castration was performed one week after, or one week before the injection of DHPN. The injection of DHPN was given at the end of the first week, and the rats were fed 500 ppm Pb in the basal diet for 38 weeks from week 3 to week 40. The incidence of thyroid adenomas and cancers was 20% (4/20) and 10% (2/20) in rats treated with DHPN alone. It was 75% (15/20) and 40% (8/20) in rats treated with DHPN and Pb; 30% (6/20) and 15% (3/20) in rats treated with DHPN and Pb, and castrated after DHPN; 20% (4/20) and 0% in rats treated with DHPN and Pb, and castrated before DHPN and Pb; and 0% and 0% in rats castrated either before or after receiving DHPN. Castration thus inhibited the development of thyroid tumor in rats treated with DHPN. The inhibition of tumor development in rats treated with DHPN and Pb, and castrated before receiving DHPN, was greater than in the rats castrated after receiving DHPN. Castration inhibited the secretion of TSH in rats treated with DHPN and Pb.

Protein and RNA content in accumulated G1 cells was measured with B16 melanoma cells by flow cytometer to study the mechanism of antineoplastic action of delta 12PGJ2. DNA histogram showed that, after a 6 hr exposure to delta 12PGJ2, the percentage of tumor cells in G2M phase increased, and G1 accumulation with depletion of cell population in S phase was seen after 12-24 hr exposure to 2.0 micrograms/ml of delta 12 PGJ2. Protein content in accumulated G1 cells increased at 6 hr after exposure, and subsequently decreased. However, the protein content treated with delta 12PGJ2 was higher than that of the control. A reduction of RNA content in G1 cells was seen after delta 12PGJ2 exposure. As the result, it was found that delta 12PGJ2 made cell progression ceased in G1 phase of cell cycle, and where protein and RNA content was higher than that of control. It is suggested that some hyper-metabolite state was caused by delta 12 PGJ2 in cultured B16 melanoma cells.

In order to elucidate the effect of supplying vessels on 5-FU distribution within a tumor, the correlation between 5-FU tissue concentration and tumor microangiography was examined in 31 patients with colorectal cancer after administration of 5-FU (500 mg/day for 3 days). The 5-FU concentration at the tumor margin was significantly higher than that in the other two tissue areas (p less than 0.05). A low 5-FU concentration was noted in the central region of ulcerative cancer showing vertical invasion with vascular disarray and/or histological necrotic foci. This type of tumor also showed a low RNA index by flow cytometry. The present study indicates that the vascular change and vascular pattern of a tumor may be a major contributing factor to 5-FU transfer from the blood circulation into a tumor.

Carcinoembryonic antigen (CEA) titer (Dinabot-Kit) were determined in proven 177 patients with colorectal carcinoma preoperatively, and at routine intervals following operation. The assay was positive in 39.1% with stage I, II, 65.9% with III, 65.9% with IV and 85.7% with V. Elevated CEA levels were noted in those who had infiltration of cancer cells extending through the proper muscle layer. In 79.2% of curative resections CEA levels returned to normal within one month, but the titers remained elevated in 73.3% of palliative resections. Among 26 patients with recurrent disease, 16 had a hepatic metastasis showing a previous or simultaneous CEA rise, whereas 10 had a local recurrence with a slow rise or normal. In addition, a quantitative study of CEA in extracts of 87 tumors was made in order to examine the factors affecting the level of circulating CEA. There was no significant difference between the CEA contents of the tumor and its level of circulating CEA. The level of circulating CEA might be influenced by the spread cancer cells, rather than the tumor contained CEA.

The clinical usefulness as a tumor-associated antigen of the new monoclonal antibody CSLEX1, which reacts with the sialylated LewisX antigen, has been evaluated serologically in 141 patients with a gastric cancer. The serum sialylated LewisX was measured by fluorescent EIA. The percent positive figure of these gastric cancer patients was 17.0% (24/141), which indicates a significant increase when compared with that of the controls. The percent-positive values, according to the clinical stage, were 9.2%, 9.1%, 15.6%, and 36.4% for stages I, II, III, and IV, respectively. The degree of liver metastasis and peritoneal dissemination of the cancer correlated with the percent-positive values of the antigen. This suggests that sialylated LewisX is useful as a tumor-associated antigen.

The fatty acid composition of cholesterol (cholesteryl) ester, triglyceride, and lecithin has been investigated in whole plasma and individual lipoproteins of healthy control subjects, of patients with malabsorption, and also of patients without malabsorption. The results show a decreased proportion of the essential fatty acid linoleic acid in all three lipid classes in both groups of patients as compared with the healthy controls. This abnormality was more marked in the malabsorbers, especially those with steatorrhoea secondary to intestinal resection. Unequivocal biochemical evidence of essential fatty acid deficiency, as indicated by the appearance of 5, 8, 11 eicosatrienoic acid in plasma lecithin, was observed in two patients, both of whom had undergone major intestinal resections. The results suggest that intestinal resection predisposes to the development of essential fatty acid deficiency.

We investigated the effect of nutritional therapy with an elemental diet (ED) for active Crohn's disease. One hundred and thirty-nine patients with Crohn's disease were enrolled in this study. Remission was judged to be present when the International Organization of Inflammatory Bowel Disease score wasor = 1 and the CRP and ESR values were within the respective normal ranges. An amount of 30kcal per 1kg of ideal body weight (IBW) per day was administered enterally, and the effect on the induction of remission in relation to various patient background factors, such as disease type, history of bowel resection, and the presence/absence of complications, was determined. An excellent remission rate was achieved in those patients to whom an adequate amount of ED could be administered. Remission rates were lower in the patient groups with any of the following complications: stenotic bowel lesions, abdominal masses, fistulas, and anal lesions. Even in those groups in which stenotic lesions or abdominal masses were present, when adequate amounts of ED could be administered, the remission rate did not differ from that in the groups without these complications. The remission rates in the groups with and without fistulas at any site, including fistulas in the anal region, were 40.0% and 82.5%, respectively, with remission being considerably easier to achieve in the patients without fistulas. Similarly, remission was difficult to achieve when anal lesions were present. These results suggest that, for active Crohn's disease, nutritional therapy with ED (or = 35kcal/kg IBW) should be enthusiastically administered, and in patients in whom the presence of complications necessitates therapy for 3 months or more, this point be considered to indicate a possible surgical approach.

Atrophic gastritis caused by Helicobacter pylori is the precursor lesion in the development of intestinal-type gastric adenocarcinoma. In animal models, atrophic gastritis induced by Helicobacter felis has been shown to be host dependent, developing in some mouse strains and not in others. The lipopolysaccharide (LPS) of H. pylori has been suggested to play a role in the induction of gastritis. The goal of this study was to compare the inflammation induced by long-term infection of the C3H/He and the C3H/HeJ strains of mice with H. felis. C3H/HeJ mice are unresponsive to LPS. Six months after infection, severe atrophic gastritis had developed in the body mucosae of all infected C3H/He mice, with replacement of parietal and chief cells. Atrophy was associated with a loss of the H. felis from the antral mucosa. In contrast, no atrophy was seen in the infected C3H/HeJ non-LPS responder animals, and heavy colonization of the antrum remained. There were no significant differences between both the quantitative and qualitative serum immunoglobulin G (IgG) and salivary IgA levels in both strains of mice. The main difference between the two strains of long-term-infected mice was a lack of macrophage infiltration in the lamina propria. Immunization induced good protective immunity to challenge with viable H. felis. Helicobacter-induced, host-dependent gastritis is likely to be cell mediated. The C3H/He and C3H/HeJ mouse model provides an excellent opportunity to investigate the cellular basis of atrophic gastritis.