[Clinical evaluation of granisetron hydrochloride against nausea and vomiting induced by anticancer drugs for gynecological malignant tumors].

We, in the Department of Obstetrics and Gynecology, Kansai Medical College, conducted an evaluation of the usefulness and safety of granisetron hydrochloride used for nausea and vomiting due to chemotherapy in patients with gynecological malignant tumors, with an additional study of the efficacy of different regimens. The subjects were 9 patients in whom 16 courses of CAP therapy were given (group A) and 13 patients in whom 24 courses of CAP therapy were given (group B). Granisetron hydrochloride 3 mg/body was administered by intravenous drip in the two groups before chemotherapy. Clinical symptoms of nausea, vomiting, and anorexia were observed for 2 days after anticancer drugs were administered in order to evaluate its efficacy. The percentage of patients who responded as "effective" or better was 90.0%. In different regimens, the efficacy was 93.8% in group A and 87.5% in group B. These results indicated clinically high usefulness in both groups. No side effects related to granisetron hydrochloride were found in this study.

[Expression of Le(y) antigen in adenocarcinoma and its related lesions of the human uterine cervix].

The natural history and biological behavior of adenocarcinoma and related lesion of the uterine cervix remain controversial issues, but the dynamic alterations in glycosylation in the cancer cells are well known. Recently, it was recently documented that the Ley antigen might be correlated with apoptosis. Over the past eight years, we have encountered 12 cases of invasive adenocarcinoma (AD), 11 cases of early adenocarcinoma (early AD) including 6 adenocarcinoma in situ and 5 microinvasive adenocarcinoma, 16 cases of endocervical glandular dysplasia (EGD) and 10 patients with normal endocervix (control) among 2,165 postoperative cases. Immunohistochemical localizations of Le(y), sialyl Le(x) and epidermal growth factor receptor (EGFR) antigens were examined in serial sections. The localization of Le(y) antigen was predominant in the subcolumnar reserve cells in controls. The localization of sialyl Le(x) was predominant in the perinuclear portion of cells in cases of EGD. The localization of EGFR was presented in cases of tubal metaplasia, tubal type EGD, early AD and AD. These antigens were present in cases of EGD, early AD and AD, with AD cases showing the highest concentrations. To conclude, the presence of the Le(y) antigen might be correlated with differentiation, development and oncogenesis rather than with apoptosis in these lesions, EGD might indicate a precancerous lesion, and localization of the EGFR antigen indicates that tubal metaplasia, tubal type EGD, early AD and AD may have a common origin.

Influence of a cigarette smoke extract on the hormonal regulation of platelet-activating factor acetylhydrolase in rats.

We evaluated the effects of estrogen, progestin, and cigarette smoke extract (CSE) on plasma platelet-activating factor (PAF) acetylhydrolase (AH; PAF-AH) activity in rats. The effects on rat tissues of an i.v. injection of PAF were studied as part of our investigation of the mechanisms involved in thrombotic episodes. Plasma PAF-AH activity in adult female rats (14 wk of age) treated with 17 alpha-ethynylestradiol (100 micrograms/kg, 5 days) was decreased by 70%. Medroxyprogesterone (50 mg/kg, 5 days) increased PAF-AH activity by 50%. CSE (0.5 cigarette/kg, 5 days) did not alter PAF-AH activity during the treatment. However, a combination of CSE and 17 alpha-ethynylestradiol decreased plasma PAF-AH activity by 90%. The decrease in PAF-AH activity was age-dependent. The effect of medroxyprogesterone on plasma PAF-AH activity was not influenced by CSE. When PAF (5-40 nmol/kg) was injected i.v. into untreated adult female rats, 9 of 16 animals died after a 20-nmol/kg dose of PAF. Macroscopic findings included hemorrhage, hyperemia, and congestion in the lungs and heart, and necrosis-like changes in the gastrointestinal tract. Microscopically, thrombi were observed in the lungs and heart. When PAF was administered to adult female rats pretreated with sex steroid hormones, the mortality of rats with low plasma PAF-AH activity caused by 17 alpha-ethynylestradiol was increased but that of rats with high PAF-AH activity caused by medroxyprogesterone was decreased. Thus, PAF and PAF-AH may play important roles in the thrombotic episodes known to occur in female smokers who use oral contraceptives.

[Positive and negative effects of progestins on platelet-activating factor acetylhydrolase activity in rat plasma].

Platelet-activating factor acetylhydrolase (PAF-AH), the enzyme that inactivates PAF, is regulated by steroid hormones including progestin. It has been reported that 17 alpha-ethynylestradiol decreases plasma PAF-AH activity and medroxyprogesterone increases the enzyme activity. In this study, we elucidated the effects of various progestins on plasma PAF-AH activity and lipoprotein cholesterol levels. Plasma PAF-AH activity in female adult rats treated with either progesterone or 17 alpha-hydroxyprogesterone (50mg/kg, 3 days) did not change significantly. Both medroxyprogesterone and megestrol acetate (50mg/kg, 3 days) significantly increased plasma PAF-AH activity, but both norethindrone acetate and norethynodrel (50mg/kg, 3 days) significantly decreased the enzyme activity. In addition, not only did medroxyprogesterone increase plasma PAF-AH activity but plasma lipoprotein cholesterol and norethindrone acetate decreased both of them. A significant correlation between plasma PAF-AH activity and the lipoprotein level was found (r = 0.974, p < 0.01). When PAF (10nmol/kg) was administered to female adult rats pretreated with progestins, the mortality of the rats that had low plasma PAF-AH activity due to norethindrone acetate was increased in the same manner as observed in the 17 alpha-ethynylestradiol-pretreated group. These findings indicate that progestins have various effects on plasma PAF-AH activity and the lipoprotein level. In addition, some progestins, which have an estrogenic effect on enzyme activity, may be related to the thrombotic episodes observed in oral contraceptive users.

[Effects of estrogen and progestin on platelet-activating factor acetylhydrolase].

Platelet-activating factor (PAF) is one of the potent proinflammatory agents and is associated with a number of human diseases, including asthma, endotoxin shock and cardiovascular diseases. Additionally, plasma PAF acetylhydrolase (PAF-AH) activity to inactivate PAF is regulated by hormones. In this study, we elucidated the effects of estrogen and progestin on plasma PAF-AH and also the effects of PAF on rat tissues to investigate the mechanisms involved in the thrombotic episode. Plasma PAF-AH activity in female adult rats treated with 17 alpha-ethynylestradiol (50 micrograms/kg, 5 days) was decreased by 50%. However, medroxyprogesterone (50 mg/kg, 5 days) increased the enzyme activity by 50%. When PAF (5 to 60 nmol/kg) was injected intravenously into non-treated female adult rats, 80% of the animals died at 20 nmol/kg of PAF. Macroscopic findings showed hemorrhage, hyperemia and congestion in the lungs and heart, and necrosis-like change in the gastrointestines. Microscopically, thrombus was observed in the lungs and heart. When PAF was administered to female adult rats pretreated with sex steroid hormones, the mortality of the rats with low plasma PAF-AH activity caused by estrogen was increased, but decreased in the animals with high enzyme activity caused by progestin. These findings suggest that the imbalance between PAF and plasma PAF-AH is one of the mechanisms involved in the thrombotic episode, and estrogen and progestin are related to the event by regulating the plasma PAF-AH activity.

Measurement of erythrocyte Na,K-ATPase activity in normal pregnant women.

To investigate the peripheral metabolic status during normal pregnancy, we measured the number of erythrocyte Na,K-ATPase units as well as the cation transport activity of the pump from 32 normal pregnant women and 12 normal controls. The number of pump units determined by maximal ouabain binding to erythrocyte in normal pregnancy was significantly higher than that in normal controls (mean +/- SEM: 0.52 +/- 0.03 vs. 0.39 +/- 0.04 pmol/10(9)RBC, P < 0.05). The total cation transport activity of the pump measured by 86Rb uptake also significantly increased during pregnancy (98.9 +/- 6.4 vs. 73.1 +/- 5.4 nmol/10(9) RBC, P < 0.01). However, the mean cation transport activity per pump unit, which was presumed to be an indicator of the peripheral metabolic status, was unchanged in any of three trimesters when compared with that in normal controls. Serum FT4 levels measured by two different methods were significantly lower in the third trimester than in the first trimester (P < 0.01). In conclusion, erythrocyte Na, K-ATPase activity per pump unit is normal in pregnant women, suggesting that the peripheral metabolic status in pregnancy seems to be normal. Increases in both the number and function of the pump may be influenced by factors other than thyroid function.

Plasma immunoreactive endothelin-1 concentration in human fetal blood: its relation to asphyxia.

To elucidate the effects of birth stress on immunoreactive endothelin-1 (irET-1) concentrations in fetal blood, we determined irET-1 levels in cord plasma in different modes of delivery associated with or without complications such as asphyxia. The irET-1 concentrations in both the umbilical artery and vein were significantly higher than those found in maternal venous blood at delivery, although there was no significant difference between preterm and full-term infants. When plasma irET-1 concentrations of healthy infants born by vaginal delivery and by cesarean section without labor were compared, the former had significantly (p less than 0.05) higher levels than the latter (15.4 +/- 4.9 pg/mL versus 11.1 +/- 3.1 pg/mL). Furthermore, umbilical venous plasma obtained from vaginally delivered infants complicated by asphyxia showed significantly (p less than 0.001) higher irET-1 levels (28.2 +/- 9.4 pg/mL) than those of nonasphyxiated infants (14.2 +/- 4.5 pg/m). These data suggest that birth stress, especially asphyxia, may contribute to the increase in fetal circulating irET-1 levels.

Physiologic and anatomic assessment of patients with rectocele.

Clinical, physiologic, and anatomic assessments were carried out in 22 female patients with symptomatic rectocele (Group A), 15 patients with asymptomatic rectocele (Group B), and 14 subjects having no rectocele (Group C). Resting and pressure, rectal pressure, rectal compliance, anorectal inhibitory reflex, and rectal sensation did not differ among the groups. Proctography revealed that the lengths of the rectocele during attempted defecation in groups A (1.6 [1.0-3.5] cm) (median and range) and B (1.6 [1.0-3.0] cm) were significantly greater than that in Group C (0.4 [0.1-0.9] cm) (P less than 0.001 in both groups). Median pelvic floor descent at rest in Groups A (4.3 [1.6-7.5] cm) (median and range) and B (4.3 [1.3-6.9] cm) were significantly greater than that in Group C (2.5 [1.2-5.0] cm) (P less than 0.001 and P less than 0.02, respectively). These results indicate that rectocele is not associated with any physiologic change apart from a significant increase of pelvic floor descent.

Mechanism of thyroid stimulation by human chorionic gonadotropin in sera of normal pregnant women.

To elucidate the mechanism of thyrotropic activity of human chorionic gonadotropin in sera of normal pregnant women, we examined the effect of blockade of the TSH receptor on the serum-induced cAMP accumulation and the effect of hCG on the TSH binding to FRTL-5 cells. In the presence of crude immunoglobulin fractions in sera from patients with primary hypothyroidism, cAMP accumulation induced by both crude and purified hCG, and normal pregnant women serum were significantly inhibited compared with that in the presence of normal IgGs. The mode of inhibition of these IgGs on the cAMP accumulation was similar for TSH and hCG when analysed by Lineweaver-Burk plots. Moreover, binding of [125I]bTSH to the TSH receptor in porcine thyroid cell membrane was apparently inhibited by adding 4 x 10(6) IU/l of purified hCG. Binding studies of TSH in FRTL-5 cells also indicated the dose-dependent displacements of [125I]TSH by hCG. Although half-maximal inhibitory concentration of hCG was about 20 times as high as that of TSH on a molar basis, displacement of [125I]TSH was observed at a concentration of hCG of 10(5)IU/l or more, which could be a physiological concentration of hCG in sera of normal pregnant women. These results suggest that thyrotropic activity of hCG in sera of normal pregnant women is, at least in a part, mediated by TSH receptors.

Thyroid-stimulating activity of human chorionic gonadotropin in sera of normal pregnant women.

To ascertain the thyrotropic activity of human chorionic gonadotropin in sera of normal pregnant women, we examined the adenylate cyclase activation in the cultured FRTL-5 cells by extracted hCG from 7 normal pregnant women. hCG was extracted from the sera using anti-hCG-beta subunit monoclonal antibody-coated microwells, eluted with 2 mol/l guanidine-HCl, and reconstituted with hypotonic Hanks' solution. FRTL-5 cells were precultured in 5H medium, incubated for 2 h with the serum extracts, and the cAMP released into the medium was measured. hCG levels in serum extracts ranged from 1100 to 6800 IU/l; values corresponded to 1.4-19.8% compared with those in the original serum samples. Addition of the extracts to FRTL-5 cells resulted in significant increases in the cAMP accumulation, ranging from 9.8 to 59.0 nmol/l. cAMP levels were also increased in a dose-dependent manner by adding purified hCG as well as crude hCG and hTSH to FRTL-5 cells. These findings suggest that the thyroid gland of normal pregnant women may actually be stimulated by hCG itself.

[Epidemiology of malignant tumors of the female genital organs].

Incidence, risk factors, prognosis and 5-year survival of the malignant tumors in the female genital organs, except the trophoblastic diseases, were described. The uterine cervical cancer is the most in Japan, but is already one the controlling cancer, though prognosis of the cervical adenocarcinoma is still poor. Incidence of the endometrial cancer is increasing. Ovarian malignant tumor is one of silent diseases and their 5-year survival rate is very low. Significant of the annual population screening against them was emphasized.

Immunotherapy using the streptococcal preparation OK-432 for the treatment of uterine cervical cancer. Cervical Cancer Immunotherapy Study Group.

The efficacy of immunotherapy using a streptococcal preparation, OK-432, was evaluated in each clinical stage of uterine cervical cancer. The 382 eligible patients were stratified by clinical stage and presence/absence of surgery. Within each stratum, patient's were randomly allocated to OK-432 treatment or to control treatment. OK-432 significantly inhibited recurrence in patients with stage II cervical cancer; the recurrence-free interval and survival time were remarkably prolonged in patients with stage II disease who underwent surgery. However, OK-432 did not significantly prolong these parameters in patients with stage III disease. Retrospective analyses revealed that in patients with or without lymph node metastases who underwent surgery, the recurrence-free interval and survival time were significantly prolonged by OK-432 treatment. These results indicate that OK-432 is an effective and useful postoperative immunotherapeutic agent for uterine cervical cancer.

Thyroid-stimulating activity in sera of normal pregnant women.

To evaluate the effect of a thyroid stimulator on thyroid function in the sera of normal pregnant women, we measured thyroid-stimulating activity (TSA) using a highly sensitive bioassay based on cAMP accumulation in cultured rat FRTL-5 thyroid cells. Serum was pretreated with 10% polyethylene glycol (PEG), and the supernatant (PEG-pretreated serum) was then used in the following studies. FRTL-5 cells were preincubated in 5H medium and incubated for 2 h with PEG pretreated serum, and cAMP was measured. All 11 patients with untreated hyperthyroid Graves' disease with strongly positive thyroid-stimulating antibody activity had normal TSA, because only 5.6% of their immunoglobulin G was recovered in the PEG-pretreated serum. In 32 normal pregnant women, 29 (91%) had positive TSA. Their TSA showed statistically significant positive correlations with serum hCG and free T4 levels, and a negative correlation with serum TSH levels. Moreover, when hCG was absorbed from sera by incubation with the solid phase anti-HCG monoclonal antibody, a significant positive correlation was observed between the rate of decrease in hCG and that in TSA. In conclusion, 1) TSA exists in the sera of normal pregnant women, which reflects hCG itself; and 2) thyroid glands of normal pregnant women may be stimulated by TSA to induce a slight suppression of TSH but not sufficient to induce overt hyperthyroidism.

[The influence of radiotherapy on T lymphocyte subpopulations analyzed by monoclonal antibodies].

The effect of therapeutic irradiation upon the lymphocyte subpopulation has been investigated in patients with cervical uterine cancer. The influence of radiotherapy was studied on lymphocyte subpopulations analyzed by monoclonal antibodies such as anti-Leu 2a, anti-Leu 3a, anti-Leu 4, anti-Leu 12, and anti-Leu 11a by a FACS analyzer, and by the PHA (phytohemagglutinin) response in 29 patients with cervical uterine cancer. The absolute counts of the various lymphocyte subpopulations were seen to remarkably decrease during radiation therapy, however, their percentages remained unchanged. As for 17 patients with cervical uterine cancer who each received a radical operation, the Th/Ts (T helper T/suppressor) ratio was seen to slightly decrease during radiation therapy. In contrast, in the remaining 12 patients with cervical uterine cancer who each received radiotherapy alone, the Th/Ts ratio was found to be higher than the former cases. This suggests that this phenomenon might be caused by the presence or absence of a tumor.

Immunocytochemical presentation of alpha-fetoprotein-producing gastric cancer in ascitic fluid: a case study.

A case of primary gastric cancer without hepatic metastasis showing extremely high alpha-fetoprotein (AFP) levels is reported. This case illustrates the application of the immuno-peroxidase technique to ascitic fluid cytology. Papanicolaou-stained smears of the ascites permitted the diagnosis of a metastatic carcinoma. A positive reaction to AFP was demonstrated in the tumor cells in the ascitic fluid cellular samples as well as in the paraffin-embedded tissue section of the primary gastric carcinoma. Rising AFP levels were also detected in ascitic fluid. AFP fractionation using lectin-affinity-crossed-line immunoelectrophoresis showed the hepatic rather than yolk sac type. Reports of such occurrences are few; no study, to the best of our knowledge, has previously documented cytological and immunocytochemical diagnosis in ascitic fluid. AFP-producing gastric cancer should be considered in the differential diagnosis.

Immunocytochemical demonstration of Chlamydia infection in the urogenital tracts.

The peroxidase-antiperoxidase (PAP) technique was applied in cellular samples for the detection of chlamydial infection. Urethral scrapings were obtained from 316 males with clinically suspected urethritis. Positive PAP staining was detected in 118 (37%) of 316 tested. Cellular samples from the endocervix of 25 (54%) of 46 female contacts of males with positive Chlamydia-infected cells had positive Chlamydia-PAP staining. Chlamydia was also found in 12 (25%) of 48 male with gonorrhea. Serum IgG antibodies against Chlamydia trachomatis were evaluated using an enzyme-linked immunosorbent assay. A total of 29 out of 73 patients had positive Chlamydia serology; of these, 21 were positive for PAP staining, and eight were negative. The determination of Chlamydia antigen by means of the PAP technique appears to be a satisfactory method for detecting Chlamydia in male and female genital specimens; also, the procedure can be done readily in most laboratory settings.

Application of immunoperoxidase staining in the cytodiagnosis of herpes simplex keratitis.

In corneal scraping smears from 13 patients with clinically suspected herpes simplex keratitis (HSK), HSK is demonstrated by means of peroxidase-antiperoxidase (PAP) technique with antisera to herpes simplex virus (HSV) in Papanicolaou-destained cellular samples. The staining for HSV antigen was present in seven cases of corneal scraping smears with superficial keratitis (dendritic and geographic ulcers) while six cases of stromal keratitis (deep keratitis) failed to show HSV antigen except in one case. Specific antigen for HSV was predominantly present in the cytoplasm rather than in the nucleus. Immunoreactions were negative with HSV antisera in patients with other infections and in those in a normal control group. Using the PAP technique, detection of HSV antigen in corneal scraping smears was of great value in the diagnosis of HSK, especially in cases of superficial keratitis.