[Study on the intensity of MMC and UFT in postoperative adjuvant chemotherapy for gastric cancer--study report of JFMTC Study No. 10].

The purpose of this study was to investigate the correlation between efficacy and dose intensity of postoperative adjuvant chemotherapy with MMC and UFT. A total of 1,410 patients from 180 institutions were allocated into a low-dose group and a high-dose group. The patients in the low-dose group received MMC at 8 mg/m2 on the day of surgery and 3 capsules of UFT (300 mg in tegafur) daily for 6 months. The patients in the high-dose group received MMC at 8 mg/m2 on the day of surgery, and in weeks 4, 10, 16, and 22 after surgery and 6 capsules of UFT (600 mg in tegafur) daily for 6 months. The patients in the high-dose group tended to exhibit higher survival rates than those in the low-dose group, although the difference was not significant. For the n(+)ps(-) patients, however, the survival rates were significantly higher in the high-dose group (p = 0.043). The recurrence-free rates showed a similar tendency. The incidence rates of adverse events were significantly higher in the high-dose group than in the low-dose group. Compliance was poorer in the high-dose group. Although the number of adverse events increases, a better prognosis can be expected with a high dose. These results confirmed a dose-dependency in adjuvant chemotherapy with MMC and UFT.

Immunostained cathepsins B and L correlate with depth of invasion and different metastatic pathways in early stage gastric carcinoma.

BACKGROUND: With the recent development of minimal treatment for early stage gastric carcinoma, identifying specific indicators of the metastatic potential of primary tumors has become more important. Cathepsin B and cathepsin L, both lysosomal cysteine proteases, degrade the extracellular matrix during tumor progression. Although many studies have shown their relation to human cancer progression, little is known about their roles in the early stage. The clinicopathologic significance of cathepsins was therefore studied in early stage gastric carcinoma. METHODS: Expression of both cathepsins was studied immunohistochemically in 51 tissue specimens from gastric carcinomas that invaded the submucosal layer or muscularis propria. The relation between their expression and clinicopathologic factors was analyzed. RESULTS: Both cathepsins were expressed at higher levels in tumors that invaded the muscularis propria than in those within the submucosa (P < 0.05). In addition, tumors with lymphatic invasion showed higher cathepsin B expression than those without it (P < 0.05), whereas tumors with venous invasion showed higher cathepsin L expression than those without it (P < 0.05). No other clinicopathologic factors correlated with expression of either cathepsin. CONCLUSIONS: Tumors with overexpression of cathepsins have powerful potential for invasiveness in the early stage of gastric carcinoma. Moreover, the authors hypothesize that cathepsins may be one of the determinants of the metastatic route. To the authors' knowledge, this is the first report on specific proteases concerning the mode of metastasis, and the results of this study suggest that therapeutic strategies for early stage gastric carcinoma might need to be changed according to the status of cathepsins.

[Comparison of crossing-over between 30-minute drip infusion vs 30-second injection of granisetron for nausea and vomitting with cisplatin].

Recently, Granisetron (KYT) was proved to have a strong effect for cisplatin (CDDP)-induced emesis. We compared the effect of KYT for CDDP-induced emesis between two different administration schedules. Forty micrograms/kg of KYT was administered either by 30-minute drip infusion with 100 ml of saline (Group A) or 30-second injection with 10 ml of saline (Group B). We investigated the therapeutic effect of KYT in both group A and Group B by the crossing-over method. After the patients who had a malignant tumor and were going to receive CDDP (over 50 mg/m2) in two courses were selected, KYT was administered by the method of Group A or Group B in a double-blind comparison. The clinical efficacy was at least "effective" in 70% (7/10) of Group A and Group B. The study treatment was considered "useful" in 80% (8/10) of Group A, 90% (9/10) of Group B, and "safe" in 100% of Group A and B. There was no difference between two groups in this respect. The results showed that the slow intravenous injection of KYT also has an excellent antiemetic effect on CDDP-induced emesis and a high degree of safety.

Lymphatic endothelium expresses PECAM-1.

The expression of adhesion molecules on the lymphatic endothelium of human small intestine and submandibular lymph node was studied immunohistochemically with the antibodies for selectin family and Ig superfamily members. In both small intestine and submandibular lymph node, lymphatic endothelium did not express intercellular adhesion molecule-1 and endothelial cell-selectin but expressed platelet-endothelial cell adhesion molecule-1 (PECAM-1). Though lymphatic vessels may not have a positive function in leukocyte rolling and adhesion, lymphatic endothelium may interact with leukocytes, with PECAM-1 playing a role.

An MRI analysis of brain-stem and cerebellar lesions and olivary hypertrophy.

We describe the relations between primary brain stem or cerebellar infarct or haemorrhage and secondary inferior olivary pseudo-hypertrophy (OPH). We identified 17 patients (43.6%) among 39 with brain stem or cerebellar vascular disease who had MRI follow-up more than 3 months after their ictus, with OPH. The primary lesions in the 22 cases without OPH were 11 haemorrhages, including 8 medial cerebellar and 3 brain stem lesions, and 11 infarcts: 4 brain stem lesions without accompanying cerebellar involvement, 2 cerebellar infarcts with brain stem extension, and 5 cerebellar lesions without a brain stem infarct. The causative lesion in the 17 patients with OPH included 5 brain stem and 7 cerebellar haemorrhages and 5 brain stem infarcts; no cerebellar infarcts without brain stem involvement were found to cause OPH. Primary involvement of the tegmentum of the brain stem was closely related to secondary OPH, but we could not characterise MRI differences in the cerebellar lesions between the patients with or without OPH.

[Randomized controlled study on adjuvant immunochemotherapy with carmofur (HCFU) for noncuratively resected and unresected gastric cancer].

To evaluate the efficacy of adjuvant immunochemotherapy, especially the long-term administration of HCFU to patients with noncuratively resected and unresected gastric cancer, a randomized controlled study was conducted by 16 institutions in Hokkaido. After surgery, 185 patients were divided into two groups using the envelope method; group A (84 patients) treated by MMC (4 mg, twice a week, total 1 mg/kg)+OK-432 (or PSK): group B (101 patients) treated with MMC+OK-432+HCFU (600 mg, per day). The 5- and 10-year survival rates were 9.8 and 3.1% in group A, and 11.1 and 11.1% in group B (p=0.062). Better survival rates were obtained in those cases with unresected, S3, or peritoneal dissemination in group B. These results suggested the long-term administration of HCFU was effective for noncuratively resected and unresected gastric cancer.

[The study of chemotherapy via the reservoir to colo-rectal cancer patients with liver metastases].

From January 1986 to December 1994, we administered intra-arterial chemotherapy via the reservoir to 26 colo-rectal cancer patients with liver metastases. The protocol of this chemotherapy was administration of ADM 30 mg/body/4 wks, MMC 10 mg/body/2 wks and 5-FU 500 mg/body/2 wks. Responses to this chemotherapy were PR in 8 cases, NC 3 cases, PD 14 cases and unknown 1 case. The rate of response was 32.0%. Side effects were shown in 12 cases (46.2%), and trouble with the reservoir in 5 cases (20.8%). Survival times of patients were from 5 months to 42 months (average 13.6). We think that this intra-arterial chemotherapy via the reservoir was effective for patients with liver metastases from colo-rectal cancer.

Streamline phenomena in liver metastasis of gastrointestinal tumors - a clinical-study based upon 172 patients.

Location and number of liver metastasis of gastrointestinal tumors were detected preoperatively and intraoperatively. The distribution of the liver segment(s) occupied by metastatic tumors varied significantly (p<0.05). Significantly more frequent distributions were demonstrated in the lateral segment with gastric cancer (p<0.05), in the posterior segment with left colic cancer (p<0.001), in the medial segment with rectal cancer (p<0.01), in the anterior segment with bile duct cancer (p<0.05) and the whole of the liver with pancreatic cancer (p<0.05). Significantly less frequent distribution was demonstrated in the posterior segment with gastric cancer (p<0.01). When the liver was divided into the right and the left halves, the distribution of each half of the liver occupied by metastatic tumors varied significantly (p<0.05). Liver metastases of whole colic cancer were significantly more frequent in the right half of the liver (p<0.05). The results suggest that the tumor distribution in liver metastases of gastrointestinal tumors differ depending upon the primary tumors, basically in accordance with the 'streamline' phenomena.

The inhibitory effects of cephalosporin and dipeptide on ceftibuten uptake by human and rat intestinal brush-border membrane vesicles.

The types of inhibitory effects caused by compound V (an analogue of ceftibuten) and alanylproline (dipeptide) on the uptake of ceftibuten by brush-border membrane vesicles (BBMV) prepared from human and rat small intestine were analysed. In the presence of an inward H(+)-gradient, the initial uptake rate of ceftibuten by both human and rat intestinal BBMV was concentration-dependent with apparent Km and Vmax values of 0.35 mM and 2.052 nmol (mg protein)-1 min-1 for human BBMV, and 0.50 mM and 3.056 nmol (mg protein)-1 min-1 for rat BBMV, respectively. For both human and rat BBMV, kinetic analysis by Dixon and Lineweaver-Burk plots demonstrated that the uptake of ceftibuten was competitively inhibited by compound V, whereas inhibition by alanylproline was noncompetitive or partially competitive. These results suggest that there is a stereospecific transport system which is common to ceftibuten and compound V, and that this system is not identical to the carrier system for the dipeptide, alanylproline.

Streamline phenomena in liver metastasis of gastrointestinal tumor - an experimental-study using rats.

The establishment of liver metastasis from gastrointestinal tumor is mainly considered to be via the portal vein, but its precise mechanism is still unknown. The purpose of this study is to evaluate the significance-of 'streamline' phenomena in liver metastasis of gastrointestinal tumor by means of an experimental model. An animal model for the metastatic liver tumor was made in the Donryu rat. Five million cells of AH-66 strain, alpha-fetoprotein (AFP) producing hepatoma cells maintained as an ascites type strain, were administered via portal vein. The superior mesenteric vein (group A), the inferior mesenteric vein (group B) and the splenic vein (group C) were used as the sites of injection. In every group, serum AFP levels were elevated after administration of AH-66 cells and no significant differences were revealed between each group. In the pathological specimens of the liver taken after 7 days, many tumorous lesions were seen microscopically with islet formations, but no definitive difference was seen in each lobe. The serum AFP concentration in group A was significantly higher than that in group C. The tissue AFP concentrations of the right lobe were significantly higher than those of the left in groups A and B, but significantly lower than those of the left lobe in group C. The results indicate that the distribution and proliferation of tumor cells administered via portal vein differed depending upon the site of tumor injection in accordance with the 'streamline' phenomena.

Transport characteristics of cephalosporin antibiotics across intestinal brush-border membrane in man, rat and rabbit.

The uptake of orally active cephalosporins, ceftibuten and cephradine, by intestinal brush-border membrane vesicles isolated from man, rat and rabbit was studied. In the presence of an inward H+ gradient, ceftibuten but not cephradine was taken up into intestinal brush-border membrane vesicles of man and rat against the concentration gradient (overshoot phenomenon). In rabbit jejunal brush-border membrane vesicles, the uptake of both cephalosporins in the presence of an inward H+ gradient exhibited the overshoot phenomenon. In human and rat vesicles, the initial uptake of ceftibuten was strongly inhibited by compound V, an analogue of ceftibuten, but the uptake of cephradine was not affected by any of the cephalosporins tested, whereas in the rabbit brush-border membrane vesicles, initial uptake of both ceftibuten and cephradine were markedly inhibited by all cephalosporins and dipeptides used. These results suggest that the transport characteristics of human and rat intestinal brush-border membrane for cephalosporins are comparable, and that rabbit is an inadequate animal for investigating the transport characteristics of beta-lactam antibiotics.

[A study of urinary tegafur, 5-fluorouracil (5-FU) and uracil concentrations in the cases of gastric carcinoma for the confirmation of drug-taking compliance after UFT oral administration].

We have measured urinary tegafur (FT), 5-FU and uracil concentrations after UFT oral administration (300 mg daily for 7 days) to confirm drug-taking compliance in the 17 cases undergone gastrectomy. Urinary FT and 5-FU concentrations reached to the plateau 2 and 3 days after administration, respectively, and were maintained until the day after termination of administration. Subsequently, FT and 5-FU concentrations also decreased about 50% at 2 day, 20% at 3 day, 10% of the plateau values at 4 day after termination, respectively. The mean plateau value of urinary FT was 12.9 +/- 6.8 micrograms/dl, and that of urinary 5-FU was 0.67 +/- 0.50 microgram/dl. On the other hand, uracil concentration, was not different before and after administration because of the uracil being present endogenously. Therefore, it was suggested that measurement of urinary FT and 5-FU concentrations is useful for confirmation of UFT-taking compliance.

A study on conformationally restricted sangivamycins and their inhibitory abilities of protein kinases.

Conformational restrictions of sangivamycin, a rather selective inhibitor of PKC, could be achieved by the use of the steric effect and the gauche effect of the substituents on the ribofuranose moiety. The conformational deviations obtained by these methods were found to nicely correlate with the inhibitory ability of PKC.

Transport characteristics of ceftibuten, cefixime and cephalexin across human jejunal brush-border membrane.

The transport characteristics of orally active cephalosporins, ceftibuten, cefixime and cephalexin have been examined using brush border membrane vesicles isolated from human jejunum. In the initial uptake of ceftibuten, the stimulation and overshoot phenomena were observed in the presence of an inward H+ gradient. Effects of H+ gradient on the uptake of cefixime and cephalexin were low and no overshoot was observed. These transport characteristics, especially uphill transport phenomena, were in agreement with previous results obtained from rat intestinal brush-border membrane vesicles and suggest that these beta-lactam antibiotics are absorbed by different transport systems, despite their similar molecular structures.

[A case of chemotherapy by the transarterial catheter with reservoir against malignant lymphoma of the colon].

We had a case of malignant lymphoma of the colon with two lesions, one in the transverse colon and the other in the ascending colon. The tumor of the transverse colon was resected, but that of the ascending colon was unresectable. Chemotherapy was performed through the catheter with reservoir via the iliac artery into the right colic artery. Three months later, the tumor disappeared completely, and the ascending colon was resected. On histopathological examination, there was no lymphoma cell in the ascending colon. Chemotherapy by a transarterial catheter with reservoir is a new method of treatment against malignant lymphoma.

[Clinical evaluation of CA-50 in cases with colorectal cancer].

Serum CA-50 has been evaluated in 67 healthy donors and in 46 patients with a colorectal cancer by an enzyme immunoassay (EIA Kit, Mitsui pharmaceuticals, Inc.). The mean value of the healthy donors (n = 67) was 10.6 +/- 6.1 U/ml and for patients with a colorectal cancer 31.7 +/- 55.2 U/ml. Both in healthy donors and in patients, the mean value was found to be higher in females than males. The overall sensitivity in the colorectal cancer patients was 26.1 percent, the percentages for those in stage I, 20, II, 9.1, III, 40, IV, 20, and V, 50% respectively. In a correlation between serum CA-50 and CA 19-9, the correlation coefficient was 0.82 (p less than 0.01), and in between CA-50 and CEA, 0.51 (p less than 0.01). Thus a combination assay among CA-50, CA 19-9, and CEA has proved to be of significant value in cases of a colorectal cancer.

[Clinical evaluation of a combination assay of CEA, CA-19-9 and TPA in patients with colorectal cancer].

The effectiveness of serum CEA (56 cases), CA-19-9 (53 cases) and TPA (48 cases) in patients with colorectal cancer has been evaluated. The preoperative sensitivity and specificity of CEA and CA 19-9 were found to be almost the same in level but the level of TPA was low. In 20 cases recurrent, the sensitivity of the marker was 66.7% in the liver, 60% in the lung, and 66.7% in the local recurrence of primary foci. In these recurrent cases, serum CEA in initially elevated to 65%, CA 19-9 to 25%, and TPA to only 10%. In diagnostic rate imaging or in our clinical findings, however, the frequency was almost the same as tumor markers.

Normotensive primary aldosteronism.

A very unusual case of normotensive primary aldosteronism is described. A 25 year old woman first noticed numbness of both hands followed by a typical tetany attack. The blood pressure was within normal ranges. The results of other physical examinations were negative except for the findings of Trousseau's sign. Hypokalemi, increased potassium clearance, disturbed urine concentration and increased circulating plasma volume were noticeable. Diagnosis was established by (1) increased levels of plasma aldosterone, (2) low plasma renin activity, (3) normal adrenocortical function and (4) typical aldosterone-producing adenoma. After removal of the adenoma, the abnormalities subsided. The lack of hypertension in primary aldosteronism is a rare condition. Several possible causes of normotension must be considered, such as the early phase of primary aldosteronism, essential hypotension associated with primary aldosteronism and lack of concomitant secretion of other mineralocorticoids from the adenoma, but these were all negligible. As blood pressure response to the administration of angiotensin II was lower than is typical for primary aldosteronism, and the patient transiently suffered from frequent attacks of blackouts soon after the operation, the cause of normotension was thought to be due to the existence of a hypotensive mechanism which counteracts the increase in blood pressure in primary aldosteronism.