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To clarify the pathogenesis of cervical adenocarcinoma, we studied the biological properties of glandular dysplasia (GD). The coexistence of squamous neoplasia with cervical adenocarcinoma has been demonstrated. We analyzed the incidence of the coexistence of GD with squamous neoplasia in this study. Materials were surgically removed uterine cervix specimens (n = 142), 52 benign disease cases, 19 squamous dysplasias of the uterine cervix, 66 squamous cell carcinomas of the uterine cervix and 5 cervical adenocarcinomas. Diagnosis of GD was based on the general rules for clinical and pathological management of uterine cervical cancer and Ng's criteria (1983). We divided GD into two types: I: endocervical type, and II: endometrioid type. These fell into subtypes, a (mild) and b (severe) based on the observed degrees of cell atypia. 1. GD coexisted in 17.3% of benign disease cases, 15.8% of squamous dysplasias, 24.2% of squamous cell carcinomas and 100% of cervical adenocarcinomas. 2. GD Ib and IIb were not found in any of the benign disease cases, but were present in 15.8% of squamous dysplasias, 13.6% of squamous cell carcinomas and 100% of cervical adenocarcinomas. If GD was defined as only Ib and IIb, GD coexisted with squamous neoplasia in this study. Our results support the theory that both cervical squamous atypia and cervical glandular atypia are derived from reserve cells.

We examined the starting age for measuring bone mineral density (BMD) in premenopausal women to detect osteopenia as soon as possible. BMD of the second to fourth lumbar spine vertebrae was measured by dual-energy X-ray absorptiometry to determine normal values for 500 healthy premenopausal women (aged from 17 to 55). We found the rate for low BMD premenopausal women, whose BMD was under the peak bone mass-2SD. And we compared normal BMD women with low BMD women with reference to menstrual history, obstetrical history, and life style, by means of a questionnaire. The peak bone mass of premenopausal women was reached between 35 and 39 years of age (1.059 +/- 0.097g/cm2). The low BMD rate was 7% in all premenopausal women, and increased to 13.5% at from 45 to 49 years. On the other hand, it was only from 5.7 to 7.4% even at from 20 to 29 years. There was the positive correlation between BMD and the body mass index (BMI). There was no statistically significant difference between the low BMD women and the normal BMD women in menstrual history, obstetrical history or life style (parity was 1.7 +/- 1.6 and 1.1 +/- 1.2, respectively, p < 0.05). We concluded that premenopausal women should have their BMD measured after aged 45, and be measured once from 20 to 40 years of age if possible.

We assessed the relationship between bone mineral density (BMD) and hormonal cytology in 181 postmenopausal women. BMD was measured by dual energy X-ray absorptiometry (DXA). Age, height, weight, body mass index (BMI), age at menopause, hormonal cytology (eosinophilic index (EI), karyopyknotic index (KPI) and maturation value (MV)) and estradiol were investigated. A positive correlation was found between BMD and hormonal cytology (EI r = 0.17 p < 0.05, KPI r = 0.19 p < 0.05 and MV r = 0.37 p < 0.005). The low BMD group (BMD < 0.8g/cm2 n = 87) had significantly lower hormonal cytology than the normal BMD group (BMD > or = 0.8g/cm2 n = 94). The receiver operating characteristic curve analysis showed MV at 30 was available for the cutoff point in predicting osteopenia. MV < 30 detected osteopenia (BMD < 0.8g/cm2) as 0.76 in sensitivity and 0.65 in specificity. These findings suggest that hormonal cytology is useful for screening osteopenia in post-menopausal women.

Premature ovarian failure (POF) and Turner's syndrome patients who are also hypoestrogenomic, like postmenopausal women, are considered to be a high risk group for hyperlipemia. Our long-term study was conducted to evaluate the effect of hormone replacement therapy (HRT) on lipid metabolism in 16 POF and 10 Turner's syndrome women. 1. The initial average total cholesterol (TC) of the untreated and treated POF patients (209, 196mg/dl) and that of untreated and treated Turner's syndrome patients (213, 240mg/dl) were significantly higher than those in the control group (175mg/dl) except treated POF patients. LDL cholesterol (LDL-C) of the untreated and treated POF patients (135, 113mg/dl) and that of untreated and treated Turner's syndrome patients (142, 144mg/dl) were significantly higher than those in the control group (108mg/dl) except treated POF patients. In comparison to healthy women of a similar age, POF and Turner's syndrome patients were at high risk of hyperlipemia because of higher serum TC and LDL-C levels. 2. After HRT for 2 years, LDL-C decreased by 18% and 13%, and HDL cholesterol increased by 38% and 41% in POF and Turner's syndrome patients, respectively. Hence AI decreased by 40% and 50% respectively. The younger the hyperlipemic patients are, the higher the relative risk for atherosclerosis is. The results of this study suggest that, because of the beneficial effects of HRT on serum lipid metabolism, it can help to prevent the development of coronary heart disease.

We assessed bone mineral density (BMD) in the local population by means of a portable dual energy X-ray absorptiometry (DXA) unit. BMD was measured by DXA in 197 women (62 premenopausal and 135 postmenopausal) in Shiunji town. Age, height, weight, body mass index (BMI), menstrual history, obstetric history, habits, symptoms and hormonal cytology (eosinophilic index (EI), karyopyknotic index (KPI) and maturation value (MV)) were investigated. A negative correlation (r = -0.645, p < 0.01) was found between BMD and age. Low BMD (BMD < 0.8g/cm2) was found at a rate of 3.2% in premenopausal women and 51.1% in postmenopausal women. The low BMD group of postmenopausal women had significantly lower BMI and higher age at first delivery than the normal BMD group (BMD > or = 0.8g/cm2). There were no differences between the 2 groups in other factors. We found a positive correlation between BMD and hormonal cytology (KPI and MV). These findings suggest that the rate of osteopenia in postmenopausal women is high than expectation and it is difficult to predict bone loss by symptoms, history and habits. The portable DXA unit is useful for screening osteopenia in local populations.

We studied bone metabolism in hyperprolactinemia in 21 hyperprolactinemic women, and compared it with 57 normal subjects. Second to fourth lumbar bone mineral density (BMD) was measured by dual energy X-ray absorptiometry (DXA). The mean BMD (g/cm2) in hyperprolactinemic women was 9% less than in normal subjects (0.940 +/- 0.115 (SD) vs. 1.030 +/- 0.106, p < 0.05). A negative correlation was found between BMD and the duration of hyperprolactinemia. The analysis of bone metabolic parameters, bone turnover, bone formation and bone absorption showed that they increase in the hyperprolactinemic state. The main mechanism of BMD loss in hyperprolactinemia is probably due to hypoestrogenemia, but a direct effect of prolactin cannot be excluded.

A synthetic peptide containing the RGD (Arg-Gly-Asp) sequence is known to inhibit the attachment between cells and the extracellular matrix (ECM) in vitro, and also inhibit experimental pulmonary metastasis of murine melanoma cells in vivo. Prevention of peritoneal seeding by RGD-containing peptides has never previously been discussed. In this study, the inhibition of peritoneal seeding by RGD-containing peptides is examined, using the in vivo experimental peritoneal seeding model with human ovarian cancer cells (JHOC-1). Intraperitoneal (i.p.) inoculation of nude mice with JHOC-1 cells soon resulted in peritoneal seeding in all of the mice. Most of them expired within 4 to 80 weeks, and none survived for as long as 10 weeks. GRGDS (Gly-Arg-Gly-Asp-Ser) sequenced synthetic peptides were administered by i.p. injection after tumor cell inoculation following some regimens, and the changes in body weight and the periods of survival of the peptides-treated and untreated mice were observed. Intraperitoneal administration of 2mg/mouse of GRGDS peptides (every 8 hours, for 4 days, beginning just after tumor cell inoculation) significantly prolonged the survival periods of the tumor implanted mice. In this study, RGD-containing peptides were found to be able to prevent in vivo experimental peritoneal seeding by continual i.p. administration. This might indicate that RGD and integrins plays a critical role in peritoneal seeding as well as in hematogeneous metastasis.

While the treatment of ovarian cancer has made remarkable progress in recent years, the chemotherapy of ovarian germ cell tumor has not as yet been fully established and remains to be improved. We investigated the effectiveness of a single-agent therapy with Vincristine (VCR), Actinomycin D (ACD), and Cyclophosphamide (CPM) against a human undifferentiated dysgerminoma's cell line (JOHYL-1) with the following results. The ratio of the number of viable cells to the total cell population treated for JOHYL-1 cells of ascitic type was 70% with VCR, 58% with CPM and 25% with ACD; hence the efficacy on this malignant cell line was the greatest with ACD followed by VCR and CPM in that descending order. Notably with CPM, a striking antitumor effect was observed from 48 to 24 hours after treatment. The L.I. attained a peak at 24, 18 and 30 hours, respectively, after treatment with VCR, ACD and CPM. The M.I. was as high as a little more than 6% at 36 hours after treatment with VCR. There also was noted a shift in the cell cycle with any of the test drugs. Morphological changes observed in the cell were most obvious with ACD followed in order by VCR and CPM. LDH & isozyme pattern: In these respects there were no striking differences among the three drugs, even though the total enzyme activity was somewhat higher with VCR.(ABSTRACT TRUNCATED AT 250 WORDS)

Most malignant ovarian tumors metastasize by peritoneal dissemination and have a poor prognosis. Few studies have been made to determine how free ovarian tumor cells act on the peritoneum and become lodged and proliferate therein and much still remains to be clarified concerning this issue. In the present study, we transplanted 2 X 10(6) cells of JOHYL-1 strain established from an atypical dysgerminoma into the peritoneal cavity of nude mice observed serially morphological changes in the peritoneum resulting from tumor cell dissemination both by light microscopy and SEM. The findings thus obtained may be summarized as follows: From 5 to 7 days after intraperitoneal transplantation of tumor cells, mesothelial cells of the peritoneum began to swell, with the intercellular boundaries becoming distinct. Microvilli of the mesothelial cells increased in number, forming a mesh-like structure, and in some places were found to be in direct contact with a tumor cell. From 10 days after tumor cell transplantation onwards the mesothelium showed enlarged intercellular spaces in some places, and at these sites tumor cells were seen to have adhered. On other sites mesothelial cells were being partially lost. From 11 days after being transplanted, the tumor cells started proliferating and infiltrating in the muscle layer. Concerning the site of tumor cell implantation, evidence was obtained showing that tumor cells adhered to intercellular spaces of mesothelial cells, and/or in defects formed on connective tissue by a loss of mesothelial cells. The study thus demonstrated a salient usefulness of the JOHYL-1 ascites type cell line, with a reliably great capacity for growth in vivo, as an experimental model for the study of peritoneal dissemination of tumor cells.

The dose limiting factors of cisplatinum are nephrotoxicity and emesis. Nephrotoxicity has been reduced by hydration but nausea and vomiting caused by cisplatinum have led to refusal of potentially curative therapy by a number of patients. The prevention of nausea and vomiting by a combination of antiemetic drugs administered to ovarian patients receiving chemotherapy inducing (cisplatinum 50mg/m2, adriamycin 300 mg/m2, cyclophosphamide 300 mg/m2 and 5FU 350 mg/m2) was studied. the combination antiemetic drugs were metoclopramide (1mg/kg), dexamethasone (10mg/m2), droperidol (1mg/m2) and diphenhydramine (20mg/body). These drugs without diphenhydramine were administered intravenously 30 minutes before and 2.5 hours, 5 hours and 7.5 hours after chemotherapy. Diphenhydramine was administered intramuscularly 30 minutes before and 5 hours after chemotherapy. No vomiting was noted in 82.6% (19/23) of cases, and no patient vomited more than four times. This combination regimen provided very good protection against cisplatinum induced emesis.

Early diagnosis is difficult in ovarian cancer and the prognosis is unfavorable even in stage I case. A total of 131 cases with stage I ovarian carcinoma were treated at our institution, 73 were stage Ia, 13 were stage Ib, 45 were stage Ic and 39 were LPM. To define the criteria for selection of therapy, we retrospectively reviewed the stage I ovarian cancer. The results were as follows: The best survival rate was demonstrated in 96% of LPM cases followed by 73% of endometrioid adeno-carcinoma. Cases with rupture of capsule and with ascites at surgery influenced the 5 year survival rate. We observed no difference in survival rate between the conservative operation (unilateral salpingo-oophorectomy) group and the complete operation (bilateral salpingo-oophorectomy and total hysterectomy) group. Those who had received postoperative chemotherapy showed the longest survival rate of 86%. Evaluation of deaths; 9 of 21 with stage Ic died within 12 months after surgery, and 4 of 7 with stage Iai between 1 and 3 years. The analysis has shown the importance of adequate postoperative treatment and of strict follow-up to guard against recurrence of malignancy in patients with ruptured tumor capsules as well as in those with ascites.

The histopathological discrimination between malignant trophoblastic diseases and benign trophoblastic diseases depends on the presence or absence of a villous structure. However, molar extravillous trophoblasts and cells in some placental site trophoblastic tumors (PSTT) of a benign nature, lack a villous structure. We therefore observed the morphology of trophoblastic cells which do not constitute a villous structure, including choriocarcinoma cells, and analyzed the location of placental proteins in these cells immunohistochemically. The results were as follows: 1. Molar extravillous trophoblasts were composed of large mononuclear cells and multinuclear cells. Most of them were positive for hPL and negative for hCG and SP1. 2. Choriocarcinoma consisted of cytotrophoblast-like cells, syncytiotrophoblast-like cells, large mononuclear cells and multinuclear cells resembling large mononuclear cells. HCG was noted in syncytiotrophoblast-like cells and large mononuclear cells, while hPL and SP1 were found only in syncytiotrophoblast-like cells. 3. PSTT was made up of large mononuclear cells and multinuclear cells which contained abundant hPL and very little hCG and SP1 or none at all. Molar extravillous trophoblasts were clearly distinguishable from choriocarcinoma cells in terms of their morphology and the location of placental proteins. In contrast, it seemed difficult to distinguish cells of PSTT from molar extravillous trophoblasts on a cell level.

Trophoblasts of normal human pregnancy are classified into syncytiotrophoblasts (STs), cytotrophoblasts (CTs) and intermediate trophoblasts (ITs) which exist in cell columns and so forth. We analyzed the trophoblast subpopulations which appear on touch smears of chorionic villi morphologically and immunohistochemically, using the uterine contents of 37 cases of induced abortion. Troma 1, a rat monoclonal antibody, was utilized as a trophoblast marker and a mouse monoclonal antibody to HLA-A,B,C was employed to discriminate ITs from CTs. The results were as follows: 1. Two sorts of cells were positive for Troma 1 and therefore were considered to be trophoblastic: Multinuclear cells of various sizes and relatively large mononuclear cells. 2. Multinuclear trophoblasts were thought to be STs because of their characteristic cytomorphology and negative reaction for HLA-A,B,C. 3. The lower the gestational age was, the more ITs were observed. 4. The cellular and nuclear size of ITs varied and their chromatin was coarsely granular with aggregates. In addition one or more marked nucleoli were noted. Consequently it would be important to take care not to misdiagnose ITs as trophoblasts of a malignant nature.

A blocking antibody in pregnant sera seems essential in understanding why a fetus can survive as a semi-allograft in an immunologically competent mother. It has been demonstrated that blocking antibody is closely related to the paternal HLA-DR antigens. However, we previously reported that HLA-DR is not expressed on any trophoblast constituting the fetal frontier at the feto-maternal interface. The present study was then undertaken to clarify whether or not trophoblasts of normal pregnancy and trophoblastic diseases express HLA-DP or HLA-DQ antigens which are closely linked to HLA-DR as a haplotype. Materials were taken from ten pregnant uteri, ranging from 8 to 22 weeks of gestation, two uteri containing complete mole and two uteri each containing gestational choriocarcinoma. Curettage specimens obtained from three cases of complete mole and two cases of partial mole were also employed. Antigen expression was examined by an indirect immunoperoxidase technique using various monoclonal antibodies. From this immunohistochemical study, neither HLA-DP nor HLA-DQ seemed to be expressed on any trophoblast of normal pregnancy and trophoblastic diseases, which, together with the negative findings of HLA-DR on trophoblasts, may suggest that blocking antibody is not generated against HLA-D locus antigens on trophoblasts.

A concentration in sera of a new antigen CA125 related to cancer of the ovary was measured by radioimmunoassay which used a monoclonal antibody, and its usefulness as a tumor marker in the diagnosis of cancer of the ovary was investigated. The mean values for CA125 in sera of healthy controls (80 females) were 14.2 +/- 12.2 U/ml. Mean values for CA125 in sera of various patients were 29.0 +/- 39.6 for myoma uteri (30 cases), 26.7 +/- 30.1 for benign ovarian tumors (10 cases), 64.4 +/- 146.2 for cervical carcinoma (14 cases), and 31.5 +/- 19.8 for endometrial carcinoma (6 cases), whereas the mean values for ovarian cancers (23 cases) were as high as 311.3 +/- 250.4. On the other hand, positive rates for CA125, when the cut-off value was set to 65 U/ml, were 1.3% for healthy controls (1 out of 80 cases), 10.0% for myoma uteri (3 out of 30 cases), 10.0% for benign ovarian tumors (1 out of 10 cases), 14.3% for cervical carcinoma (2 out of 14 cases), and 16.7% for endometrial carcinoma (1 out of 6 cases), whereas the positive rate for ovarian cancers was 78.3% (18 out of 23 cases). Especially for serous cystadenocarcinoma, the positive rate was 100% (10 out of 10 cases). From the above, the measurement of CA125 in sera was considered to be significant in the diagnosis of ovarian cancer.

This study was provided biochemical findings on ascitic fluid following the treatment of patients with ovarian tumors. The results were as follows: LDH and LDH isozyme. The ascitic fluid from patients with germ cell tumors showed an LDH1 value of 38.8% with an H/M ratio of 2.82, which were significantly higher than those found in the benign tumor group (LDH1, 15.2%: H/M ratio, 1.05). In cases of adenocarcinomas, the LDH5 value was 27.2%, compared to 15.7% in cases of benign tumors. Of 28 patients with adenocarcinoma, 15 patients (53.6%) were positive for this elevation. The decline in total LDH activity and elevation of H/M ratio were observed as a general tendency in patients satisfactorily responding to treatment. ALP and ALP isozyme. The malignant tumor group displayed higher values for both total ALP activity and HSAP in ascitic fluid, as compared with the benign tumor group. In the malignant tumor group, alpha 2 and alpha 2-beta regions were prominent in the isozyme pattern and the isozymes of the same regions remained even after inactivation by heat. The total activity decreased significantly in the responders to treatment. TP, alpha 1-AT, alpha 1-AG, alpha 2-M and IgG. The ascitic fluid levels of alpha 1-AT, alpha 2-M and IgG did not significantly differ among the group of patients with germ cell tumors, the group of patients with ovarian gonadal stroma and the group of patients with benign tumors. In the adenocarcinoma group the alpha 1-AT and alpha 2-M levels were higher than those in the benign tumor group. The ascitic fluid alpha 1-AG level and alpha 1-AG/TP ratio were elevated in tumors of germ cell origin and in adenocarcinomas; they tended to correlate with the degree of malignancy of the tumor. The results of the present study suggest that simultaneous measurement of the ascitic fluid levels of LDH isozymes, ALP isozymes, alpha 1-AG, alpha 1-AT, alpha 2-M and IgG may play a potential adjunctive role in providing information for diagnostic differentiation between benign and malignancy, estimation of the histologic type and extent of neoplastic growth, evaluation of the therapeutic response and prediction of the clinical progress.

The malignant ovarian cancer cells removed on operation were cultured and exposed to the anticancer drug (either 5-fluorouracil or mitomycin C) for 30 minutes or 24 hours respectively. The activity of the LDH and LDH isozyme in the culture medium was measured. Also the activity of the LDH and its isozyme was determined in the patients undergoing chemotherapy with either 5-fluorouracil or mitomycin C. The results are summarized as follows: 1) The LDH isozyme pattern of the culture medium prior to exposure of malignant cells to the anticancer drugs was classified into 2 types i.e., M type which is characterized by a predominance of LDH4,5 (referred hereinafter to as group M) and H type with a predominance of LDH1,2 (referred to as group H). 2) Of 11 cases studied, 7 were classified as group M and 4 were categorized as group H. there was no distinct relationship between histological type and LDH isozyme pattern. 3) In the group with exposure to anticancer drugs the total LDH activity in both group H and group M was lower than in the control group. Control specimens in group H showed increased total LDH activity. 4) The H/M ratio based on subunits of LDH isozyme was virtually unchanged by exposure to anticancer drugs in group M, while rapidly lowered by the same treatment in group H. 5) The death rate of malignant cells as estimated by dye exclusion methods was higher with exposure to anticancer drugs than without it. 6) The serum LDH was more markedly lowered after treatment in group H than in group M. However, there was no substantial difference between the two groups in M/H ratio before and after treatment.