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In a survey of patients with vulvar cancer registered during the period from 1968 through 1970, a total of 319 cases were registered at 82 medical institutions in Japan, and the data from these cases were statistically analyzed to find the current status of onset and treatment of this malignancy in Japan. The results of vulvar cancer treatment in terms of 3-year and 5-year survival rates in this country proved similar to those recently attained in other countries. It was learned that the use of bleomycin for treatment of this malignancy was widespread, and analysis of its therapeutic effects revealed that both the primary effects and long-term effects were rather satisfactory.

A placenta of a twin pregnancy with a retained dead fetus (RDFt) was studied im-munohistochemically by comparison with controls consisting of 9 other placentae with a retained dead fetus (RDF) and 20 placentae without an intrauterine fetal death (IUFD) (control placentae without IUFD). By immunohistochemical examination, immunoglobulins were found in villous syncytiotrophoblasts and villous endothelial cells. The positive reactions were, furthermore, diminished by pretreatment with ammonium thiocyanate by immunoelectron microscopy, so that the immunoglobulin binding to chorionic villi were regarded as one of nonspecific bindings. However, a strongly positive immunoreaction for IgG remained in the specimens from the placenta of RDFt after pretreatment with ammonium thiocyanate. The findings indicate that an immunological injury of a placenta is provoked in RDFt.

Irinotecan (CPT-11) and cisplatin are singly active against cervical cancer. We evaluated the efficacy and toxicity of CPT-11 plus cisplatin as first-line chemotherapy in patients with advanced or recurrent cervical cancer. Twenty-nine chemotherapy-naive patients with advanced or recurrent cervical cancer were treated with CPT-11 (60 mg/m2) on days 1, 8, and 15 by intravenous infusion over 90 min, followed by cisplatin (60 mg/m2 i.v.) on day 1 over 90 min. The patients’ median age was 57 years (range 35–75). Nineteen patients (66%) had advanced primary disease. Six patients with recurrent disease (21%) had been treated with prior radiotherapy. The remaining 4 patients (14%) had residual or recurrent disease after radical surgery. The histologic diagnoses were squamous cell carcinoma in 25 patients (87%), adenocarcinoma in 3, and adenosquamous cell carcinoma in 1. All eligible patients were included in the toxicity and response analysis based on the intent to treat. Two patients (7%) achieved a complete response and 15 (52%) a partial response (overall response rate: 59%, 95% confidence interval; 41–74%). Stable disease was recorded in 6 patients (21%) and progressive disease in 3 patients (10%). In 3 patients, image-guided evaluation of response was judged to be unfeasible at the time of independent extramural review (10%). The median time to response was 32 days (range 16–62 days). The median survival was 27.7+ months (range, 6.4–52.8+ months). Two dose-limiting side effects were observed: grade 3 (28%) or 4 (45%) neutropenia and grade 3 (7%) or 4 (7%) diarrhea. Other severe toxicities included anemia (45%), thrombocytopenia (3%), nausea/vomiting (31%), and alopecia (7%). The combination of CPT-11 with cisplatin is an active regimen for treatment of advanced or recurrent cervical cancer albeit with a significant degree of myelosuppression.

Lipopolysaccharide from Pantoea Agglomerans (LPSp) has a remarkably high antitumor activity even against poorly immunogeneic tumors when given by intradermal injection combined with cyclophosphamide (CY). We have extended this study to gain an insight into the mechanism of this antitumor effect, and especially into the induction of cell mediated immunity. In immunohistological studies, extensive necrosis and marked infiltration of the inflammatory cells at the tumor were observed after intradermal injection of LPSp combined with CY, but not after CY alone or after no treatment. The cells around the tumors were mostly neutrophils and macro phages (Mac 1+); T cells (CD4+, CD8+) were also present. The serum levels of cytokines, induced after intradermal injection of LPSp, were determined and compared with intravenous administration of LPSp or recombinant TNF-SAM2. TNF-alpha, IL-1, IL-6 and GM-CSF were measured by ELISA as a marker of cytokine induction. The peak level of TNF-alpha induced by intradermal injection of LPSp was about 5000 pg ml-1, which was considered relatively small since this level was observed even in clinical trial. There seems to be a longer period of release of TNF-alpha after an intradermal injection than after an intravenous injection. This may produce the remarkably high antitumor effect of the intradermal injection. The antitumor effect of intradermal administration combined with CY was evaluated in nude mice to clarify the role of T cells in high antitumor activity. In this experiment, antitumor activity was found to be much less in BALB/c nu/nu mice without regression, while complete regression was frequently observed in syngeneic mice, showing the crucial role of T cells in this treatment. These observations suggest that intradermal administration of LPSp in combination with CY continuously releases and induces not only extensive necrosis of the tumor but also cell mediated antitumor immunity, which may be indispensable for complete regression of the tumor. Clinical application of this treatment for advanced cancer patients is in progress.

The effect of TNF-SAM2 on cytotoxic activity of tumor-infiltrating lymphocytes (TIL) was investigated. TIL were prepared from 11 human cancer patients. They were propagated by double in vitro stimulation with anti-CD3 monoclonal antibody and interleukin-2, and cultured for 3 weeks. The cytotoxic activity of TIL was tested with standard 4h 51Cr-release assays in the presence or the absence of TNF-SAM2. In the presence of TNF-SAM2 (500U/ml), the mean cytotoxic activity against autologous tumor cells was significantly augmented compared to that in its absence. However, the fact that cytotoxic activity against K562 and Daudi showed no difference whether substance was present or not, indicates that LAK and NK activity were not affected by TNF-SAM2. Direct cytotoxicity by exogenously added TNF-SAM2 to tumor cells was measured in 9 out of 11 cases and this revealed that cytotoxicity solely by TNF-SAM2 was seen in 3 tumors. However, there was no correlation between the augmentation of cytotoxicity by TIL in the presence of TNF-SAM2 and the cytotoxicity shown by TNF-SAM2 alone. These results suggested that TIL therapy combined with administration of exogenous TNF may exert a synergistically stronger therapeutic effect on cancer.

Background. The failure rate with radiation therapy alone for Stage III cervical cancer is quite high, and therefore other modalities are being pursued as adjuvants to radiation therapy in hopes of improving the results. Methods. A randomized, controlled, comparative study on the efficacy and safety of radiation therapy combined with LC9018 (a biologic response modifier prepared from heat-killed Lactobacillus casei YIT9018) was conducted using 228 patients with Stage IIIB cervical cancer. Results. LC9018 enhanced tumor regression (P < 0.1) by radiation after both 30 Gy of external radiation and at the completion of radiation therapy. The combination therapy also prolonged survival and the relapse-free interval (P < 0.05) compared to radiation alone. Analysis of survival using the Cox proportional hazard model indicated that use of LC9018 was a significant factor related to survival duration. Major side effects of combined LC9018 included fever and skin lesions at the injection site, but no severe symptoms were noted. Radiation-induced leukopenia was significantly less severe (P < 0.05) in the LC9018-combined group than in the radiation-alone group, suggesting that this agent might help to prevent leukopenia during radiation therapy. Conclusions. LC9018 was shown to be an effective agent for adjuvant immunotherapy when combined with radiation therapy.

The authors studied data of combination assays of tumor markers, because simultaneous elevation of different types of tumor markers in the serum was puzzling. They interpreted such phenomena regarding cancer antigen 125, carcinoembryonic antigen, and carbohydrate determinant 19-9 in ovarian tumors. The tissue expression of the antigens was compared with preoperative serum levels. Several different factors were found to cause the simultaneous elevation of two or three of these markers in the serum. Furthermore, even when the levels of some of the tumor markers were raised in the serum, the ovarian tumor did not always produce the marker by itself. This study indicates that immunohistochemical identification of a marker in tumor tissue is prerequisite to the use of that marker in the serum to monitor disease status.

Objective: To evaluate the efficacy and toxicity of a combination of irinotecan (CPT-11) and cisplatin as first-line chemotherapy in advanced ovarian cancer. Methods: Twenty-six patients with previously untreated advanced epithelial ovarian cancer were enrolled in this study. CPT-11 60 mg/m2 was administered intravenously on days 1, 8, and 15 in combination with cisplatin 60 mg/m2 on day 1. Cycles were repeated every 28 days for at least two cycles. The median patient age was 55 years (range, 37–75), and the median performance status was 1. Results: Objective responses were recorded in 19 of 25 eligible patients (76%; 95% confidence interval, 55–91%). Complete responses were obtained in 2 patients (8%), and partial response in 17 patients (68%). Stable disease was recorded in 2 patients (8%) and progressive disease in 2 (8%). The median time to response was 62 days (range, 28–234 days). The median survival time for all 25 patients was 30.9+ months (range, 4.1–60.0+ months). The major toxic effects were leukopenia, neutropenia, and diarrhea. Grade 3 or 4 leukopenia, neutropenia, and diarrhea occurred in 17 (68%), 20 (83.3%), and 5 patients (20%), respectively. Thrombocytopenia was less common. No treatment-related deaths occurred. Conclusion: The combination of CPT-11 and cisplatin showed significant activity in chemotherapy-naive patients with advanced ovarian cancer. Neutropenia was the dose-limiting adverse effect, whereas diarrhea was mainly mild to moderate.

The effect of LPSw, a lipopolysaccharide from a water extract of wheat flour, on pain response was investigated using an acetic acid-induced writhing test in mice. LPSw inhibited writhing dose-dependently in the range of 10 ng-10 micrograms/mouse i.v. This effect reached its maximum 1.5-3 h after the LPSw inoculation and was detectable even after 8 h. The analgesic effect of LPSw was inhibited by i.v. injection of naloxone and also beta-endorphin was detected in serum and brain tissue following injection of LPSw. Preliminary clinical trials were done in which LPSw was administered percutaneously to relieve the pain of patients with herpes. The results showed that pain was relieved by this application. LPSw may be the best analgesic drug so far known, since it induces the endogenous mediator of analgesia, beta-endorphin.

Lipopolysaccharide (LPS) has been recognized as a potent antitumor agent in animal tumor models; however, its use in human cancer therapy has been limited to only one trial, in which LPS from Salmonella was given intravenously. It was not very successful because of poor tumor response and was also toxic. We originally developed LPS prepared from Pantoea agglomerans (LPSp), and this was a well-purified, small-molecular-mass (5 kDa) agent. We chose intradermal rather than intravenous administration in the hope that the former would release LPS slowly into the bloodstream, and thus be less toxic while preserving antitumor activity. In our animal tumor models, intradermal administration was indeed less toxic and more beneficial for tumor regression than intravenous administration. We made a pilot study with intradermal administration of LPSp on the treatment of ten advanced cancer patients. Five of them had evaluable tumor, which had failed earlier to respond to conventional chemotherapy. Cyclophosphamide was also administered in this trial, in anticipation of its synergistic effect with LPSp. In this study LPSp was injected intradermally into each patient twice a week, starting with an initial dose of 0.4 ng/kg, and raising it to 600 or 1800 ng/kg. A 400-mg/m2 dose of cyclophosphamide was given intravenously every 2 weeks. After completion of the dose escalation, the treatment was continued for at least 4 months, and it was found that 1800 ng/kg LPSp was well tolerated. A significant level of cytokines was observed in the sera for at least 8 h. These results indicate higher tolerable doses and remarkably more continuous induction of the cytokines than were reported in a previous study by others using intravenous administration. Three of the five evaluable tumors showed a significant response to our combined therapy. Intradermally administered, LPS was less toxic and elicited a tumor response in combination with cyclophosphamide; it can thus can be applied to cancer treatment even in humans.

The natural outcomes of successive new pregnancies of 66 recurrent aborters were analysed in relation to their immunological profiles. The data demonstrated that the presence of anti-phospholipid antibodies (success rate 6.7%), positive anti-paternal cytotoxicity (8.7%) and a negative mixed lymphocyte reaction (MLR)-blocking effect (33.3%) in the patients' sera were factors associated with a poor prognosis. By the combined evaluation of these testings, a rational scheme of clinical management for recurrent aborters was established.

Thirty-nine unexplained recurrent aborters underwent vaccination using husband's lymphocytes according to the previously reported protocol. No mixed lymphocyte culture reaction-blocking antibodies (MLR-BAbs) were observed in these patients prior to vaccination. Of 35 newly pregnant patients after vaccination(s), pregnancy successfully continued in 28 (80.0%) and have already been terminated with a liveborn offspring. Pregnancy outcome was also analyzed in unexplained recurrent aborters who revealed positive MLR-BAbs without immunotherapy. In this group, out of eight pregnancies in seven patients, five (62.5%) continued beyond their critical period of 14 wks of gestation. Three infants born from these pregnancies, however, presented severe abnormalities. Furthermore, outcome of 14 pregnancies in 12 unexplained recurrent aborters with negative MLR-BAbs was analyzed since they had become pregnant without immunotherapy; pregnancy was successfully continued in only four cases (28.6%). Thus, vaccination using husband's lymphocytes on unexplained recurrent aborters with negative MLR-BAbs is suggested to be effective. In addition, it is suggested that immunotherapy for patients with positive MLR-BAbs should be carefully followed.

Purpose: The presence of immunological dysfunction has not been well demonstrated in cancer patients. Recent studies have revealed that the immune response can be classified into types 1 and 2, and in the present work the immunological function of patients was studied from the perspective of these two types of response. Methods: Types 1 and 2 immune response were evaluated by monitoring the production of various cytokines by peripheral blood mononuclear cells from 38 patients with advanced cancer of various organs and 20 healthy subjects. The usual immunological parameters, differential cell leukocyte counts, the level of T cell subsets (CD4 and CD8) and natural killer activity were also examined. Results: The production of interleukin-2 (IL-2), interferon γ, IL-10, IL-12 and tumor necrosis factor α was found to be significantly lower in the patients (75 ± 57, 171 ± 205, 40 ± 34, 8 ± 8, 1450 ± 1010 pg/ml) than in healthy subjects (143 ± 99, 422 ± 296, 64 ± 34, 16 ± 10, 2550 ± 950 pg/ml); however, the mean level of IL-4 in the patients seemed to be higher. The correlations between different cytokine levels suggested that they were produced differently. Lymphocyte counts were significantly lower in patients, but there was no difference in the other usual immunological parameters. Conclusions: Patients with advanced cancer are deficient in monocytes and the type 1 immune response. The measurement of various cytokines reported in this study provides a more sensitive and valuable tool for evaluating the function of cell-mediated immunity in cancer patients than do the usual tests.

To elucidate the nature of trophoblastic disease, trophoblastic tissue was transplanted into nu/nu mice and immunosuppressed Syrian hamsters. All tissue was successfully transplanted, with no tumorigenicity shown in either the 21 cases of hydatidiform mole (HM) or the 10 cases of invasive mole (IM). However, in seven of the nine cases of choriocarcinoma (CC), tumorigenicity was demonstrated by successful serial transplantation. Thus, the conclusion was that CC was clearly a malignant neoplasm, whereas IM and HM should be considered to be benign disease because of their cellular behavior, which was clearly distinct from that of CC in this series.

Frequency of prenatal X-ray examination in 1, 701 parturient women was surveyed in 19 Japanese hospitals in 1974. Of 1, 701 women, 470 or 27.6% have received maternal X-ray examination during the pregnant period. There is no significant difference in frequency of prenatal X-rays between in the primipara and multipara. Chest examination was frequent in the 3rd to 6th month of gestation, while a pelvimetric study was performed mainly after the 10th month. About 82% of the fetal dose was contributed from a prenatal pelvimetric study. The fetus receives averagedly 202 mrad of radiation from the prenatal X-ray examinations. It is calculated that about 6.3 leukemias may be induced yearly by maternal X-ray. This corresponds to about 1% of leukemias in the same generation.

Neonatal thymectomy in mice at 3 days of age (Tx-3) can induce autoimmune oophoritis and results in complete loss of oocyte at young adult age. We examined endocrinological and immunological abnormalities in Tx-3 (C3H/He X A/J)F1 female mice to find some similarities to premature ovarian failure (POF) in humans. The majority of the Tx-3 mice showed irregular estrous cycles during 7 to 9 weeks of age then fell into continuous diestrous. Endocrinological analysis of Tx and sham-Tx mice revealed that serum gonadotropin levels (LH and FSH) of Tx-3 mice rapidly increased from 8 weeks of age and serum estradiol levels significantly decreased from 10 weeks of age (P less than 0.05). In contrast with estradiol, serum androstenedione levels significantly increased from 10 weeks of age (P less than 0.01). In the mice with oophoritis, circulating autoantibodies against ooplasm and/or zona pellucida determined by immunoperoxidase method could be detected from 6 weeks of age, became high titer from one or two weeks later, but resulted in low titer or negative test from about 4 months of age. Acute loss of oocyte with massive mononuclear cell infiltration coincident with the appearance of these autoantibodies were progressed, and then atrophic ovaries with complete destruction of follicles were seen at 3 months of age. This experimental model of autoimmune oophoritis abounds in suggestion for the understanding of one of the possible etiology of POF in women.

To evaluate the clinical effects of the anti-tumor polysaccharide Schizophyllan (SPG), a randomized study was done on 220 patients with Stage II or Stage III cervical cancer who had been given irradiation, concomitantly. The tumor-reducing effect of SPG was significant in patients in either stage. The time to recurrence was longer in SPG-dosed patients with Stage II cancer, compared with findings in the control group. There was no significant difference in the time to recurrence in patients with Stage III cancer between the SPG and control groups. When comparing the 48-month survival curve, the survival time of patients with Stage II cancer in the SPG group was significantly longer than in the control group. However, there was no significant difference in the survival rate of patients with Stage III cancer between the SPG- dosed and control groups.

Tumor-infiltrating lymphocytes (TIL) from six gynecologic malignant tumors (two uterine cervical cancers, two ovarian serous cystadenocarcinomas, and two uterine corpus cancers), cultured in the presence of recombinant interleukin 2, were assayed for their cytotoxic activities against various fresh tumor cells including autologous tumors. A clear correlation between phenotype and cytotoxic activity of TIL was observed. Four of six TIL preparations exhibited strong cytotoxic activity against autologous fresh tumor target cells, and were all CD8+. In contrast, cytotoxic activity was not detected in any of the CD4+ TIL preparations. The cytotoxic activities of the CD8+ TIL preparations were highly specific; only autologous fresh tumor cells were lysed. This result is consistent with the notion that TIL are of a different cell lineage from lymphokine-activated killer cells which are antigen-nonspecific and CD8-. Instead, TIL appear to be of cytotoxic T cell lineage that is highly antigen-specific and CD8+. To explore the potential for clinical use, we have attempted to augment the cytotoxic activities of these CD8+ TIL by treatment of the target tumor cells with gamma interferon (IFN) in vitro, hoping that elevated expression of MHC class I gene products on the cell surface would enhance their recognition. It was observed that brief treatment of freshly prepared tumor cells in vitro with gamma-IFN resulted in augmentation of the expression of MHC class I gene products, and the treated tumor cells were more susceptible to lysis by TIL than untreated cells.

Immunohistochemical localization of HLA antigens and placental proteins (alpha hCG, beta hCG CTP, hPL and SP1) in villous and extravillous trophoblast at various stages of normal human gestation were studied, using hysterectomy specimens. In the chorionic villi, the capacity for synthesizing placental proteins seemed to develop in parallel with the morphological change from mononuclear cells to multinucleated syncytiotrophoblast and no villous trophoblast expressed HLA antigens. In contrast, extravillous trophoblast, including the multinucleated trophoblastic cells at the deciduomuscular junction, expressed HLA-A, -B, and -C, and their capacity for synthesizing placental proteins did not seem to correspond with the degree of morphological change: the location of alpha hCG, beta hCG CTP and SP1 was restricted to mononuclear trophoblast in the superficial decidua, while hPL was present extensively in extravillous trophoblast. These findings strongly suggest that extravillous trophoblast possesses many distinctive biological features and differentiates in an independent manner. Mononuclear trophoblast forming the cell columns was also positive for HLA-A, -B, and -C, and no placental protein was demonstrated in these cells; this, together with previous morphological observations, may indicate the germinative nature of these cells.

In normal and molar pregnancy, a morphological discrimination between nonvillous trophoblasts which lie scattered in the placental bed and surrounding maternal cells is considered to be difficult. We examined the reactivity of two monoclonal antibodies (Troma 1 and CAM 5.2) against cytokeratin by an immunoperoxidase technique and analyzed their usefulness as a histological trophoblast marker. Materials were taken from 42 uteri with normal pregnancy, 7 uteri with hydatidiform mole, 2 uteri with gestational choriocarcinoma, 1 fallopian tube with nongestational choriocarcinoma, 5 delivered term placentae of normal pregnancy, and 5 nongestational uteri. The reactivities of Troma 1 on frozen sections and those of CAM 5.2 on paraffin sections were identical. They reacted with surface epithelium and gland epithelium in the nongestational uterine corpus. In the implantation site of normal and molar pregnancy, they reacted with villous and nonvillous trophoblasts as well as endometrial gland epithelium. In gestational and nongestational choriocarcinoma, they reacted with carcinoma cells specifically. Since the histological detection of gland epithelium may not be difficult, it was concluded that the two antibodies were very beneficial as a histological marker for trophoblasts in normal pregnancy and trophoblastic disease.

Seventy-six patients with invasive hydatidiform mole (HM) were reviewed as to clinical course, particularly treatment and outcome, in relation to their age. The results were as follows: (i) metastatic cases showed approximately a twofold increase in patients over 40 compared with younger patients, (ii) more courses of chemotherapy were required to achieve a cure in patients over 40 than in younger patients and (iii) 4 of 19 patients (21.1%) over 40 developed choriocarcinoma, whereas none of younger patients did.

Tumor-specific antibodies reacted with an isografted ascitic form of mouse mammary tumor, MM2, with a higher sensitivity in an immune adherence test than in an immune cytotoxicity test. Immune adherence and immune adherence inhibition tests were applied for the detection of surface antigens of MM2 tumor reacting with tumor-specific antibodies. After treatment with ether, ethanol, methanol, ethanol-ether mixture, acetone, chloroform-methanol mixture, deoxycholate, triton × 100, snake venoms, phospholipase A, or heating at 100° C for 15 minutes, the MM2 cells did not react with syngeneic antibodies in immune adherence. The reactivity of the cells was not suppressed by heating at 62° C for 15 minutes after treatment with deoxyribonuclease, ribonuclease, proteinases, neuraminidase, ultraviolet irradiation or freezing and thawing. In the immune adherence inhibition test, deoxycholate extract or triton × 100 extract of MM2 cells inhibited the immune adherence reactivity of syngeneic antibodies with MM2 cells, while the organic solvent extracts did not. This indicates that antigenic material was extractable in deoxycholate or triton × 100. After removal of surface antigens with 0.1% deoxycholate, fractions were prepared from treated MM2 cells. Fractions precipitated at 105,000 × g (microsomal fractions) as well as fractions precipitated at 11,000 × g (mitochondrial fractions) inhibited the immune adherence reactivity of tumor-specific antibodies with MM2, indicating that antigens were also present in these fractions.

Oncofetal antigen-I (OFA-I) is a membrane antigen of human cancer cells that cross-reacts with human fetal brain tissues. The antibody profile against this antigen was analyzed in relation to the course of disease. Fifteen out of 22 patients had persistently stable antibody levels and antibody titer in three of them increased by more than 4-fold. These patients did not show either recurrence or death, but had a good prognosis. In four patients, antibody levels dropped by more than 4-fold and was followed by clinical recurrence and death. These studies show that persistently stable antibody titers are predictive of non-recurrence, and decreasing titers predictive of recurrence.

To determine the clinical significance of conservative surgical therapy, namely focal excision of myometrial molar deposits, 22 patients with invasive hydatidiform mole (HM) who had received the therapy were analysed for their postoperative clinical course and reproductive performance. They were operated on because of their prolonged HCG regression curve and the presence of abnormal shadows in the uterine wall revealed by pelvic angiography, ultrasonography and computerized tomography after evacuation of intra-uterine molar tissue. A definitive diagnosis of invasive HM was established histopathologically in all of the extirpated materials. Seven of the patients were given postsurgical chemotherapy because of prolongation of their HCG decrease after the operation. The following items were emphasized as necessary criteria when selecting patients for surgery consisting in complete resection of the myometrial lesion: (1) urinary HCG titers below 10,000 IU/day; (2) no evidence of pulmonary metastatic involvement; or (3) metastases in the lungs, controlled with chemotherapy prior to the operation. Their reproductive performance was almost the same as that of comparable patients who were treated by chemotherapy alone.

This presentation deals with the large-scale statistics of 19 951 patients of trophoblastic diseases (TDs). The information was obtained by regional registration of 16 prefectures in Japan since 1974, and based on a definite classification of TDs given by the Japanese Society of Obstetrics and Gynaecology. The population of these prefectures comprises approximately 40% of that in all Japan. The number of registrations accumulated in this series was estimated to be greater than 90% of all affected patients in all regions, indicating a high degree of reliability of these statistics. The overall incidence of hydatidiform mole (HM) including invasive mole (IM) in 16 regions between 1974 and 1983 was one HM per 306 live births or 482 pregnancies. The incidence of HM with or without IM per 100,000 women showed a tendency to decrease in parallel with the reduction in birth rate during this period, thus indicating no significant change in the incidence of HM per 1000 live births. In this series the number of cases 'undetermined' because of a lack of appropriate histology was 943 (or approximately 5% of all cases). These may potentially be categorized as either IM or choriocarcinoma. Also, criteria for the distinction between a partial and a complete mole could not be defined satisfactorily.

HLA expression by the trophoblast in invasive hydatidiform mole was analysed by immunoperoxidase staining. In the invading villi of an invasive mole, villous trophoblast, both syncytiotrophoblast and cytotrophoblast, failed to show a positive reaction for HLA-A, -B and -C and HLA-DR. By contrast, extravillous trophoblast showed an intense reaction for HLA-A, -B and -C. The distribution of HLA antigens in the invading villi was the same as in the non-invading villi, and the antigens were also indistinguishable- from those noted in non-invasive hydatidiform moles. The histopathology of invasive mole may suggest that it is a malignant neoplasm. This immunohistochemical study, however, lends support to the current view that invasive mole is a variant of a benign hydatidiform mole rather than a form of malignant trophoblastic disease.

Oncofetal Antigen-I (OFA-I) is a membrane antigen of human cancer cells that cross-reacts with human fetal brain tissues. The presence of this antigen was examined in a variety of histological types of gynecologic tumors, trophoblasts and normal tissues. A total of 22 tumors, 13 trophoblasts and 48 normal tissues were tested by IA absorption using patient's sera containing functionally mono-specific anti-OFA-I. Ovarian carcinoma had the highest percentage of reactivity to OFA-I (78%) followed by cervical carcinoma (40%). Conversely, this antigen was not detected in endometrial carcinoma (0%), normal trophoblast tissue (0%) or hydatidiform mole (0%) or in normal tissues from non-cancer patients. These studies show that OFA-I is frequently detected in ovarian carcinomas.

Physical development and tests of immunologic function are reported from the first year of life for 13 infants born to mothers who were habitual aborters and who had undergone subcutaneous vaccination with their husband's lymphocytes. The mean weight of the infants at birth was 2,975 ± 540 g, including one infant who was small for dates. Physical development parameters for the first year were all within normal range. Immunologic studies were performed at ages 0, 1, 3, 6, 9, and 12 months. The studies included the following: (1) serum levels of immunoglobulins and complement components; (2) the number of peripheral blood lymphocytes (PBL) and their subpopulations; and (3) proliferative responses by PBL against unrelated lymphocytes and some mitogens (pokeweed, phytohemagglutinin, and concanavalin A). All were normal when compared with studies of infants of nonimmunized mothers. These observations suggested that subcutaneous vaccination of women with their husband's lymphocytes did not result in any adverse effects on their infants' physical or immunologic development.

Following a previous report [1] we ascertained the effectiveness of sizofiran (Schizophyllan:SPG) to prolong the survival and time to recurrence of the patients with Stage II or III cervical cancer, as evaluated in a 5-year randomized controlled study conducted in 19 institutions in Japan. Of the overall patients with Stage II or III cancer, time to recurrence and survival rate in the group on SPG were significantly longer than in the control group. In the Stage II patients, there was significant difference in time to recurrence, and survival of SPG group tended to be longer than that of the control group. However, in the Stage III patients, there was no significant difference in either time to recurrence or survival rate.

Twelve out of 13 infants born from mothers having both HBsAg and HBeAg developed HBV carrier state within 4 months after birth. On the other hand, no babies from mothers having HBsAg and anti-HBe developed HBV carrier state. In order to prevent perinatal transmission of HBV, HBIG was administered into 14 babies born from mothers with positive HBeAg three or four times during 6 months after birth. During 12 months or more of observation period 5 out of 14 infants who received HBIG acquired active anti-HBs response after discontinuation of HBIG (passive-active immunization). However, 3 out of 14 infants unfortunately developed persistently positive HBsAg antigenemia at 12th, 14th and 14th month respectively after birth. Remaining 6 babies still have no virus markers, indicating not infected. These results indicates that HBIG administration was extremely effective for prevention of perinatal transmission of HBV. However, additional preventive measures with active immunization (HBV vaccine) seems to be necessary to prevent completely the perinatal transmission of HBV.

Our study of the sequence of morphological events leading to the formation of hydatidiform mole (HM) led us to this study. Our object in this paper is to present evidence supporting our 1971 hypothesis with results obtained by various immunological methods in our laboratory, and to propose the importance of an immunoregulatory mechanism by blocking antibody (BA). Our hypothesis is that the conceptus, after the early demise of the embryo, may be dropped out in most cases as spontaneous abortion (SpA), and the trophoblast in the remaining cases continues to grow, developing into HM by an “immune selection” mechanism. Our conclusion is that the trophoblast will be damaged by immune cytotoxic mechanism through a decrease of BA in SpA, and continue to grow in HM through continuous production of BA after the demise of the embryo.

A high incidence of autoimmune oophoritis can be induced in (C57BL/6Cr x A/J)F1 mice that were thymectomized at 3 days of age. The vaginal opening day was significantly delayed (thymectomized mice [n = 35], 38.1 +/- 5.8 days [mean +/- SD] versus sham thymectomized mice [n = 26], 34.0 +/- 5.2 days; p less than 0.02). Most of the thymectomized mice showed irregular estrous cycles during the first several weeks and then fell into continuous diestrus. Local infiltration of mononuclear and plasma cells inside and around growing follicles was a prominent feature in the early stage of oophoritis. This abnormal feature was first noticed at 24 days of age and progressed in the follicular units. Acute loss of oocytes, especially of growing follicles, with massive mononuclear cell infiltration rapidly progressed after puberty, and atrophic ovaries with complete destruction of both primordial and growing follicles were then seen for 1 to 2 months after puberty. In mice with oophoritis, circulating autoantibodies against, ooplasm, zona pellucida, or steroid-producing cells were constantly detected by immunohistochemical assay. Autoimmune thyroiditis and gastritis accompanied by specific circulating antibodies were also detected in mice thymectomized at 3 days of age. This experimental model may serve as a tool for studying premature ovarian failure in humans.

In view of the protective and enhancing effect of blocking antibodies (BA) on the survival of trophoblastic cells, the presence or absence of individually specific BA against paternal HLA antigens in trophoblast-bound immunoglobulin G (IgG) of molar as well as normal term placentas were investigated using a mixed lymphocyte culture reaction (MLR) blocking assay and complement-dependent lymphocytotoxicity test. It was found in this study that IgG could be eluted from molar trophoblasts. Further, it was strongly suggested that each molar and normal placental eluate-IgG had individual, specific cytotoxic and blocking effects against paternal lymphocytes and on MLR between spouses, respectively. In conclusion, in molar as well as in normal term placenta-bound IgG, BA that are heterogeneous and partly contain IgG specific to the paternal HLA antigens, including HLA-D/DR antigens, are likely to exist. BA may also have a protective and enhancing effect on the survival of trophoblastic cells by binding with these cells.

The mixed lymphocyte reaction (MLR)-blocking activity of sera was examined in patients with gestational choriocarcinoma. The frequencies of human leukocyte antigens (HLAs) in seven choriocarcinoma patients and their husbands were not different from those in the normal Japanese population. In patients who were successfully treated, many mismatches were found between the woman's HLA-A, B, C antigens and those of her spouse. Sera from three patients showed cytotoxic activity against their husbands' T lymphocytes. Similar results were obtained with sera absorbed with platelets to test for cytotoxic activity against the husbands' B lymphocytes. Cytotoxic activity sometimes disappeared at the recovery stage of the disease. Significant MLR-blocking activity was found in sera of patients in a tumor-bearing stage, but was absent 3-4 months after serum human chorionic gonadotrophin levels dropped into the normal range. It reappeared when patients relapsed, showing that MLR-blocking activity reflected tumor burden. The MLR-blocking factors in patients' sera may not be identical to the so-called serum nonspecific immune inhibitor factors, but was specific to, or dependent on, the use of the husbands' lymphocytes as stimulator cells and was mediated by immunoglobulin (antibodies) reactive with antigens expressed on the husbands' B lymphocytes, e.g. the MHC class II antigens.

A newly synthesized 16, 16-dimethyl trans delta 2 PGE1 methyl ester (ONO 802) was clinically applied in the form of a vaginal suppository for therapeutic abortion of second trimester pregnancies. Its effects were studied in a double-blind test comparing it with an inactive placebo suppository. The study was conducted at 12 Japanese university hospitals. The number of patients was 125 in total, i.e. 63 receiving ONO 802 vaginal suppository (containing 1.0 mg ONO 802) and 62 receiving inactive placebo suppository. ONO 802 was more effective than placebo with a success rate of 87% (complete (71%) and incomplete (16%) abortions). The onset of uterine contractions was observed in 154.3+/-18.1 min. and the onset of uterine bleeding in 323.6+/-41.0 min. The expulsion of the fetus and placenta was observed in 955.4+/-97.0 and 961.6+/-97.0 min., respectively. The cervix dilating effect of ONO 802 was observed in 63.5% of the patients at 3 hours after the start of administration. Nausea, vomiting, abdominal cramps, diarrhea and pyrexia were noticed. However, all these side effects were transient and mild, requiring no treatment. No abnormality was observed in the puerperal course, duration of uterine bleeding or onset of subsequent menstruation following the therapeutic abortion. Therefore, the present study demonstrated that ONO 802 vaginal suppository was an effective and valuable drug for therapeutic abortion of second trimester pregnancies.

Summary We compared here the correlation between the colorimetric method and some other precise testing methods. The results are summarized as follows. 1 A good correlation was observed between the colorimetric method and the LAIR (Neoest, New Estrotec) and HAIR (Estrotec) methods estimating E3 in the urine. The calculated correlation coefficients between the E3 kit and the Neoest, New Estrotec and Estrotec kits were 0.865, 0.729 and 0.788, respectively. Compared to the E3 kit, the LAIR methods tended to give somewhat lower E3 levels. 2 Among 15 samples with below 10μg/ml E3 in the urine by the E3 kit, 13 samples(86.7%) also showed coincident results by the LAIR method (Neoest). 3 A good correlation between serum E3 level and urine E3 level was observed at the low levels. Eight patients with a low serum E3 level of below 10ng/ml revealed low urine E3 levels of below 5μg/ml. Among 14 patients with low serum E3 levels of below 20ng/ml, 12 showed E3 levels in the urine of 5μg/ml, and the other 2 had urine levels below 10μg/ml. 4 It is concluded that the LAIR methods are useful in the mass screening of dysfunction of the feto-placental unit in pregnancy in their rapidity and simplicity, although the E3 levels so obtained tend to be somewhat lower than those obtained by the colorimetric method.

In early pregnancy, a variety of pathology of trophoblastic cells is observed in trophoblastic disease and in spontaneous abortion. Trophoblastic disease includes hydatidiform mole, metastatic and/or invasive mole, and choriocarcinoma. Therefore, for better understanding of trophoblastic disease and spontaneous abortion, an exact knowledge of the morbid anatomy of trophoblasts is required. Especially needed is profound insight into regulatory mechanisms of in vivo trophoblastic growth which may undergo either damage or proliferation and survival. But the regulatory mechanisms are not clear because of their complexity, involving cellular factors such as benign or malignant neoplastic cellular changes, and/or environmental factors such as nutritional, endocrinological, and immunological factors.

The purpose of this study is to clarify the problem regarding individual specificity of maternal serum immunoglobulin G (IgG) and placental eluate IgG that block the unidirectional mixed lymphocyte reaction (MLR) in which maternal and cord blood lymphocytes (lys) were used as responder and stimulator, respectively. Both maternal serum IgG and placental eluate IgG were found to include blocking antibodies (BA) which showed similar blocking effect on MLR. But, in the case of serum IgG, individual specificity of BA on MLR was observed to be less great in MLR done using whole lys or T-enriched lys of the cord blood as stimulator, whereas it became greatly significant when MLR was done using B-enriched lys of the cord blood as stimulator. This was the case even in MLR done by using unrelated maternal lys as responder. On the other hand, when in the case of placental eluate, it was found to be greater when compared to serum IgG even where MLR was done using not only B lys but also T lys as stimulator. It is thus strongly suggested that BA include individual specific antibodies against fetal B lys having HLA-D/DR locus determinants in addition to individually nonspecific antibodies common to pregnancy which may be produced to a "yet unknown fetal antigen."

The survival of the fetoplacental unit to term in a potentially hostile environment remains an immunological enigma. The development of trophoblast-reactive monocional antibodies (mAbs) has allowed in situ characterization of phenotypically distinct villous and extravillous fetal trophoblast populations in normal human pregnancy (Bulmer and Johnson, 1985). Maternal decidual leucocytes have also been defined by the same approach: macrophages are common throughout gestation, often closely associated with extravillous trophoblast (Bulmer and Johnson, 1984; Smith, Bulmer and Wells, 1986), whereas granulated lymphocytes expressing certain T-cell differentiation antigens are prominent only in early pregnancy tissues (Bulmer and Sunderland, I&; Bulmer, Johnson and Buimer, 1987). The immunobiological importance of both fetal trophoblast surface antigens and the local maternal leucocytic response in successful implantation and placentation are of current interest. The response of gestational choriocarcinoma to chemotherapy has highlighted the interrelationship between this tumour and the maternal host. It is often associated with a local host mononuclear cell response (Elston, 1978) and high serum levels of anti-paternal lymphocytotoxic antibodies (Shaw et al, 1979). In Caucasian populations, approximately equal numbers of cases of choriocarcinoma follow normal term delivery, molar pregnancy and non-molar abortion, although the proportion following hydatidiform mole is higher in Japan (World Health Organization, 1983). The risk of choriocarcinoma following a molar pregnancy is around one thousand times greater than after normal term delivery (Bagshawe et al, 1973). but it is likely that choriocarcinoma ensues in no more than 5 per cent of hydatidiform moles (World Health Organization, 1983). Complete hydatidiform moles are diploid and of androgenetic origin (Kajii and Ohama, 1977) and hence are fully allogeneic with the maternal host. Most are homozygous 46XX and may arise by fertilization of an empty egg by a haploid sperm which dupli

In this study, the reactivity of mixed lymphocyte reaction-blocking antibodies toward trophoblasts was investigated. Nineteen sera that had a significant level of MLR-blocking effect were obtained from normal pregnant women and from primary habitual aborters after immunotherapy. The blocking effects of these sera were studied before and after absorption with syncytiotrophoblast plasma membrane (STPM) from the respective mothers' placenta (autologous) as an experimental group and from unrelated mothers' placenta (allogeneic) as a control. The HLA types of cord blood lymphocytes corresponding to ten of these STPM were then determined. In the study with the 11 normal pregnancy sera, the blocking effect of every serum was partially removed by autologous STPM absorption. This revealed a significant difference between the preabsorption and postabsorption MLR-blocking effect. Nevertheless, absorption by the allogeneic STPM either partially removed or did not remove the blocking effect. Furthermore, there was a statistically significant difference in the elimination of the MLR-blocking effect between the autologous STPM and the allogeneic STPM. Studies with the sera from the immunized aborters revealed similar results. There was no statistically significant difference in the elimination of the antibodies between absorption with autologous and with allogeneic STPM. In these habitual aborters' sera, comparison of paternal stimulator and cord blood lymphocytes HLA types showed that the positive allogeneic STPM absorptions could not be explained sufficiently by coincidence of HLA types. Further studies are needed to determine whether the alloantigens are HLA-linked or not.

Twenty-one placentae were examined by light microscopic immunohistochemistry, scanning electron microscopy, transmission electron microscopy, and immunoelectron microscopy for the histogenesis of intervillous thrombus formation. Two possible mechanisms were investigated to explain the structural initiation of intervillous thrombus formation. Either the thrombus occurs precisely on the intravillous stromal fibril or the basal lamina, directly facing the intervillous space, and is derived from the degenerated trophoblastic epithelium in a similar fashion to conventional intravascular thrombus formation, or the thrombus is formed on the degenerated trophoblastic epithelium without any trophoblastic epithelial defects. The villous trophoblastic epithelium is, furthermore, thought to behave in the process of thrombus formation as the endothe-lium in conventional intravascular thrombosis because the villous trophoblastic epithelium had the same stainability as the endothelium in ultrastructural localization of Factor VIII.