Search

Background: The standard range of D-dimer level associated with each type of gynecologic surgery is required to note the occurrence of bleeding or thromboembolism. Methods: Plasma levels of D-dimer of patients who underwent different types of gynecologic surgery were measured on the Day of Preoperative Examination (DPE) and the first postoperative day (POD-1). Patients were classified by surgery type: hysterectomy for benign diseases or cervical intraepithelial neoplasia; hysterectomy for uterine cancer; surgery for ovarian cancer; laparoscopic surgery for a benign adnexal mass; laparotomy for a benign adnexal mass; laparotomic myomectomy; cervical conization; transcervical resection of an intrauterine mass; vaginal surgery for prolapse of a pelvic organ. Results: In each type of gynecologic surgery, plasma levels of D-dimer on POD-1 were higher than those on the DPE. Prophylactic subcutaneous injection of heparin calcium for patients who underwent surgery for endometrial cancer showed no significant difference in the plasma level of D-dimer on the sixth postoperative day (POD-6) and the plasma level of D-dimer on POD-6 was in the same level as those on POD-1. Conclusions: Plasma levels of D-dimer on POD-1 were higher than those on the DPE in each type of gynecologic surgery. The D-dimer level remained high even on POD-6, and not changed by prophylactic subcutaneous injection of heparin calcium.

Background: RNA-binding motif protein 10 (RBM10), originally identified as S1-1 protein, is a nuclear protein with likely functions in transcription and RNA splicing. The RBM10 gene maps to the X chromosome and, in female cells, is inactivated in one of the two X chromosomes near the boundary with genes escaping inactivation. This study investigated the occurrence of the RBM10 gene product in complete hydatidiform mole, which is composed of cells with paternal diploid chromosomes (46, XX). Methods: Deparaffinized normal chorion or complete hydatidiform mole tissues were hybridized with a fluorescein-conjugated RBM10 gene probe in fluorescent in situ hybridization (FISH) analysis. Immunohistochemistry and immunoelectron microscopy of the tissues were performed using an anti-RBM10 antiserum. Proteins from complete hydatidiform mole tissues and those separated by anti-RBM10-linked affinity chromatography were also examined by western blotting. Results: As expected, the RBM10 gene was detected by FISH as double spots in the nuclei of complete hydatidiform mole cells. Immunohistochemistry revealed a nuclear presence of RBM10 in normal chorion and complete hydatidiform moles, and a notable cytoplasmic presence in complete hydatidiform moles. Western blotting and immunoaffinity chromatography revealed that a 50 kDa protein was predominantly found in the cytosolic fraction of complete hydatidiform moles. Conclusions: A 50 kDa protein with common antigenicity to RBM10 was found in the cytoplasm of complete hydatidiform mole cells, and could represent one of the characteristics of the disease.

Existence of lymph node metastasis is a risk factor in the prognosis of patients with cervical cancer. But the mechanism of lymph node metastasis and its control factor are not clear. This study was implemented to elucidate this mechanism based on animal experiments. Mouse hepatoma cell (MH 134) was used as the material for Tumor Extract (TE), which was prepared by ultrasonication. After pretreatment with TE at various concentrations and various durations on the left footpads of mice, inoculation of tumor cells was performed at the same site. Regional lymph nodes from this site were obtained after various durations and the rate of lymph node metastasis was histologically observed. Immunocapacity of lymph node cells due to various mitogens were also measured after pretreatment with TE. As a result, pretreatment with TE effected a decrease in immunocapacity of the lymph node cells, especially the T-cells. On the other hand, pretreatment with TE also brought about an increase in the rate of lymph node metastasis. In conclusion it can be said that the soluble substance derived from the cancer mass decreased the immunocapacity of regional lymph nodes. Therefore, lymph node metastasis was considered to have been effected.

In this work, we studied the monocyte function as accessory cells to T-cells during and after pregnancy. The function tended to decrease in the 1st trimester, but showed a significant increase in the 3rd trimester (p

Clinical practice guidelines for gynecologic cancers have been published by the National Comprehensive Cancer Network and the National Cancer Institute. Whereas these guidelines form the basis for the standard of care for gynecologic malignancies in the United States, it has proven difficult to institute them in Japan due to differences in patient characteristics, health-care delivery systems, and insurance programs. Therefore, evidence-based guidelines for treating cervical cancer specifically in Japan have been under development. The Guidelines Formulation Committee and Evaluation Committee were independently established within the Committee for Treatment Guidelines for Cervical Cancer. Opinions from within and outside the Japan Society of Gynecologic Oncology (JSGO) were incorporated into the final draft, and the guidelines were published after approval by the JSGO. These guidelines are composed of ten chapters and comprise three algorithms. Each chapter consists of a clinical question, recommendations, background, objectives, explanations, and references. The objective of these guidelines is to clearly delineate the standard of care for cervical cancer treatment in Japan in order to ensure equitable care for all Japanese women diagnosed with cervical cancer.

Objective To investigate the possible involvement of collagen in the characteristic structure and function of human corpora lutea (CL), type V collagen expression was determined in the CL tissues during the menstrual cycle and early pregnancy. Design In vitro experiment. Setting Department of Obstetrics and Gynecology, Wakayama Medical University, Wakayama, Japan. Patient(s) Regulatory cycling women and pregnant women with ovarian tumor and ectopic pregnancy who underwent adnexectomy. Intervention(s) Composition of the various types of collagen in human CL was analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Main Outcome Measure(s) Expression of type V collagen. Result(s) The ratios of type III to type I collagen and the ratios of type V to type I collagen in the CL tissues were significantly increased in early pregnancy compared with those in the menstrual cycle. Conclusion(s) These results suggest that alterations in composition of collagen might play an important role in determining the physiology and structure of the CL during the menstrual cycle and early pregnancy.

Tail DNA genotyping of fetal and neonatal mice from C/EBPbeta heterozygous parents was performed to determine whether the decreased number of surviving C/EBPbeta mutants was caused by prenatal or postnatal death. Eighty-four 3-week-old mice born of heterozygous parents had significantly lower numbers of C/EBPbeta-deficient offspring than the expected Mendelian ratio (29.8%+/+, 65.5%+/-, 4.76%-/-, P0.05). The genotypes of 72 fetal mice from intercrossed heterozygotes showed approximately the expected 1:2:1 Mendelian ratio (18.1% +/+, 52.8% +/-, 29.2% -/-, P0.05). No difference in the proportions by sex could be detected in these perinates. This data indicates that C/EBPbeta-deficient mice have unknown lethal problems between the embryonic stage and weaning.

Objectives The efficacy and toxicity of combined therapy with irinotecan (CPT-11) plus mitomycin-C (MMC) were evaluated in patients with advanced or recurrent squamous cell carcinoma (SCC) of the uterine cervix. Methods CPT-11 (100 mg/m 2 ) was administered on days 1, 8, and 15 by intravenous (iv) infusion over 90 min, while MMC (10 mg/m 2 iv) was given on day 1. This regimen was repeated every 28 days and at least two courses were given. Results Among 51 eligible patients (median age: 52 years; range: 25–72 years), 2 showed complete response (CR) and 24 showed PR, for an overall response rate (ORR) of 51.0% (95% confidence interval: 36.6–65.3%). In patients without prior chemotherapy, the ORR was 54.8% (38.7–70.2%). Twenty-five patients (Ib2:3, IIb:17, and IIIb:5) received this regimen as neoadjuvant chemotherapy and their ORR was 76% (54.9–90.6%). Twenty-two patients were able to undergo radical surgery after NAC. The major toxicity was neutropenia, which was grade 3–4 in 59% of the patients. Grade 3–4 thrombocytopenia and anemia were also seen in 26% of the patients each. The most common nonhematologic toxicity was diarrhea (grade 3–4 in 12%). Conclusion CPT-11 combined with MMC can be effective against advanced or recurrent SCC of the uterine cervix.

Mesothelin is a glycosylphosphatidylinositol-linked cell surface molecule expressed in the mesothelial lining of the body cavities and in many tumor cells. Based on the finding that a soluble form of mesothelin specifically binds to ovarian carcinoma cell line OVCAR-3, we isolated cDNAs encoding a mesothelin-binding protein by expression cloning. The polypeptides encoded by the two cloned cDNA fragments matched to portions of CA125, an ovarian cancer antigen and a giant mucin-like glycoprotein present at the surface of tumor cells. By flow cytometric analysis and immunoprecipitation, we demonstrate that CA125 binds to mesothelin in a specific manner. Binding of CA125 to membrane-bound mesothelin mediates heterotypic cell adhesion as anti-mesothelin antibody blocks binding of OVCAR-3 cells expressing CA125 to an endothelial-like cell line expressing mesothelin. Finally, we show that CA125 and mesothelin are co-expressed in advanced grade ovarian adenocarcinoma. Taken together, our data indicate that mesothelin is a novel CA125-binding protein and that CA125 might contribute to the metastasis of ovarian cancer to the peritoneum by initiating cell attachment to the mesothelial epithelium via binding to mesothelin.

To provide some insight into the mechanism of cervical ripening, the expression of type I collagen was investigated in human uterine cervical tissues obtained from the first (n = 4) and third (n = 3) trimesters of normal pregnancy. Indirect immunofluorescent staining was performed for type I collagen, and Northern blot analysis was done to assess expression of mRNA for the alpha1(I) chain. Collagens were also extracted from the human cervical tissues in the first and third trimesters of pregnancy. Immunohistochemical analysis revealed loose distribution of type I collagen in the uterine cervix of the first trimester compared with the third trimester of pregnancy. The relative levels of various collagens were evaluated by SDS-PAGE. The ratios of the intensity of the band of alpha1(I) to that of total collagen alpha1 chain in cervical tissues of the third trimester were significantly lower than those in cervical tissues of the first trimester of pregnancy (P0.05). In contrast, the ratios of the intensity of the band of alpha1(III) to that of total collagen alpha1 chain in cervical tissues of the third trimester were significantly higher than those in cervical tissues of the first trimester of pregnancy (P0.05). Northern blot analysis revealed that the cervical expression of mRNA for the alpha1(I) chain was significantly reduced in the third trimester compared with the first trimester of pregnancy (P0.01). These results suggest that type I collagen might play an important role in the maintenance of pregnancy and that decreased expression of this collagen could be associated with the process of uterine cervical ripening.

Objectives. To examine the possible localization and production of activin A in human normal endometrium, endometrial hyperplasia, and adenocarcinoma tissues. Methods. Human endometrial tissues were collected from 45 patients who were undergoing abdominal hysterectomy. Tissue sections were stained with monoclonal antibodies against the inhibin/activin α- and βA-subunits and activin A using an avidin-biotin-peroxidase complex technique. Concentrations of activin A and inhibin A in tissue extracts of the endometrial tissues were measured using enzyme-linked immunosorbent assays (ELISAs). The expressions of the inhibin α-subunit and activin βA-subunit messenger RNA (mRNA) in the endometrial tissues were demonstrated by reverse transcription–polymerase chain reaction (RT-PCR) analysis. Results. No immunostaining with an antibody against the inhibin α-subunit was observed in human normal endometrium, endometrial hyperplasia, and adenocarcinoma. By contrast, immunostaining for the activin βA-subunit and activin A was observed in the cytoplasm of glandular cells in normal endometrium, endometrial hyperplasia, and tumor cells of endometrial adenocarcinoma. The percentages of stained cells in endometrial adenocarcinoma were higher than those in normal endometrium. Also, the percentages of stained tumor cells with poor differentiation were higher than those with good and moderate differentiation of the endometrium. The stromal cells in normal endometrium, endometrial hyperplasia, and adenocarcinoma were weakly immunoreactive with antibodies against the βA-subunit and activin A. Immunoreactivity of activin A in tissue extracts from normal endometrium and endometrial adenocarcinoma was detected by the two-site ELISA. Immunoreactivity of activin A was significantly higher in adenocarcinoma than in normal endometrium. On the other hand, the immunoreactive inhibin A was not detected. The expression of the α-subunit mRNA in endometrial tissues was demonstrated as the RT-PCR products migrated at 905 bp and the PCR products of the βA-subunit showed a band at 366 bp. Conclusions. It is suggested that activin A, but not inhibins, are produced by endometrial tissues. The amounts of produced activin A were higher in adenocarcinoma tissues than in normal endometrium. Activin A might be involved in human endometrial tumorigenesis.

We performed genome-wide linkage analysis in 58 patients and nine unaffected members among 28 families with no mutation in BRCA1 or BRCA2, employing a set of 410 microsatellite markers. We initially screened the whole genome, including the X chromosome, by a non-parametric method using the GENEHUNTER program. As a result, chromosome 3p22-p25 showed a suggestive score for linkage [LOD = 3.49 and non-parametric LOD (NPL) = 2.77 at D3S3611] based on a multipoint analysis. Additionally, based on a two-point analysis using dense markers, this 3p22-p25 region showed a P-value0.05 at 10 markers and there is suggestive evidence for linkage at two markers within approximately 19 cM (NPL = 2.60 and 2.49 at D3S1597 and D3S3611, respectively). To explore whether the candidate gene in this 3p22-p25 region contributed to carcinogenesis of familial ovarian cancer in a similar fashion to the tumor suppressor gene, we performed loss of heterozygosity (LOH) analysis. It was observed that the frequency of LOH at four markers in this region was50% only in tumor tissues from patients with no mutation in BRCA1 or BRCA2, not in those with a BRCA1 mutation.

Objective. The effectiveness of positron emission tomography with 18 F-fluorodeoxyglucose (FDG-PET) for diagnosis of uterine sarcoma was evaluated in comparison to the effectiveness of magnetic resonance (MR) imaging and power Doppler imaging. Method. The cases of five Osaka City University Hospital patients diagnosed with uterine sarcoma based on histopathological examination, in whom FDG-PET, MR imaging, and power Doppler imaging studies had been performed preoperatively, were reviewed. A comparative study of the usefulness of these three imaging modalities for diagnosis of sarcoma was conducted. Tumors comprised three leiomyosarcomas, one endometrial stromal sarcoma, and one carcinosarcoma. Results. FDG-PET examinations were 100% positive for the five sarcomas; MR imagings were 80% positive (four of five cases), and US was 40% positive (two of five cases). The mean strandardized uptake value of the sarcomas was 4.5 ± 1.3. Conclusion. The sarcoma lesions were clearly imaged by FDG-PET. FDG-PET may be a most useful diagnostic method for uterine sarcoma.

Decidualized human endometrial stromal cells and human decidual CD56+ cells are reported to produce macrophage colony-stimulating factor (M-CSF), although its physiological roles remain unclear. In this study, the effects of M-CSF on cell viability and 8-Br-cAMP-stimulated decidualization of normal human endometrial stromal cells are examined by using an in vitro decidualization activity assay system. M-CSF alone affected neither the viable cell numbers nor PRL release of nonstimulated stromal cells, while high concentrations of M-CSF strongly suppressed the viable cell numbers and PRL secretion of stromal cells costimulated with 8-Br-cAMP and M-CSF. However, M-CSF did not suppress the viable cell numbers and PRL secretion of 8-Br-cAMP-induced decidualized cells. These results indicate that high concentrations of M-CSF can suppress the cell viability of stromal cells in the decidualization process, and inhibit decidualization of endometrial stromal cells. Thus, nonpregnant decidual M-CSF may autoregulate decidualization and the viable cell numbers of endometrial stromal cells in a paracrine manner.

High expression of interleukin-11 (IL-11) and the IL-11 receptor alpha chain in developing decidual cells in mice has been reported, and mice lacking IL-11 receptor expression have been reported to show impaired implantation owing to defective decidualization. However, the direct effect of IL-11 on endometrial stromal cells has not been studied. In this study, we examined the direct effects of IL-11 on normal human endometrial stromal cells using an in vitro decidualization assay system. IL-11 enhanced cell viability and prolactin secretion of 8-Br-cAMP-induced decidualized cells but not of non-stimulated stromal cells. IL-11 dose-dependently enhanced the viability of stromal cells co-stimulated with 8-Br-cAMP and IL-11 without any significant effect on prolactin secretion from the cells. The extracellular matrix did not affect the effect of IL-11 on the viability of 8-Br-cAMP-stimulated stromal cells. These results indicate that IL-11 enhances the viability of 8-Br-cAMP-stimulated stromal cells and of decidualized stromal cells, and that the cell survival signals generated by IL-11 are independent of those generated by the extracellular matrix. IL-11 produced locally in decidual tissues may enhance the viability of decidualized stromal cells and possibly protect against cell damage during embryo implantation and trophoblastic invasion.

Umesaki N, Tanaka T, Miyama M, Ogita S, Ochi H. Combined diagnostic imaging of uterine carcinosarcoma. A case report. The diagnostic imaging characteristics of uterine carcinosarcoma have not been established because the tumor is very rare. We studied magnetic resonance (MR) imaging, power Doppler ultrasonography, and positron emission tomography (PET) in one such carcinosarcoma to define its imaging characteristics. On T1-weighted MR images, the tumor mass in the uterus was low-signal intensity and had a slight inhomogeneous appearance. On T2-weighted images, it had a heterogeneous appearance and was of medium- or high-signal intensity; marked flow void was apparent from the myometrium to the tumor mass. The MR flow void was also detected by power Doppler ultrasonography. Increased glucose metabolism was detected on PET images, suggesting a malignant tumor in the endometrial cavity. Combined diagnostic images with MR, power Doppler ultrasonography, and PET is recommended as the diagnostic method for uterine carcinosarcoma.

Allogenic leukocyte immunization is one of several treatments tried for unexplained recurrent aborters, and is reported to have few maternal and neonatal side effects after the immunotherapy having been reported to date. In the present study, we report a rare case of neonatal thrombocytopenia (41 000 cells/μl) observed in a female infant delivered by an unexplained habitual aborter. The mother was immunized with her husband’s leukocytes once before pregnancy and twice at the 5th and 6th week of her successful pregnancy. Serological studies using mixed passive hemagglutination assays (MPHA) showed that maternal serum did not contain any antibodies which were reactive to 11 platelet-specific antigens, or to granulocyte antigens extracted from 9 persons. Lymphocyte cytotoxity tests, however, showed that maternal serum but not infant serum had anti-HLA antibodies against both paternal and infant lymphocytes. Moreover, the maternal serum was found to have anti-HLA IgGs against platelet antigens extracted from the father and the infant. It is highly likely that this case of neonatal thrombocytopenia was caused by transplacental perfusion of maternal anti-HLA antibodies whose production was induced or enhanced by the allogenic leukocytes immunizations.

The effects of epidermal growth factor (EGF) on human endometrial stromal cells have not been characterized well, although production of EGF in endometrial epithelial and stromal cells and expression of EGF receptors in endometrial stromal cells have been reported. We investigated the effects of EGF on endometrial cell viability, 8-Br-cAMP-induced stromal decidualization, and prolactin secretion from decidualized endometrial stromal cells using an in vitro decidualization activity assay of human endometrial stromal cells. EGF did not show any significant effects on viable cell numbers of nondecidualized and 8-Br-cAMP-induced decidualized cells. Prolactin release from the 8-Br-cAMP-induced decidualized cells was not affected by EGF. However, EGF dose-dependently inhibited prolactin release from the stromal cells that were in the process of decidualization by co-stimulation with 8-Br-cAMP and EGF, though there was no significant change in viable cell numbers of the 8-Br-cAMP-stimulated decidualizing cells. Flow cytometric analysis revealed that 8-Br-cAMP enhanced EGF receptor expression on the endometrial stromal cells. These results indicate that endometrial EGF inhibits decidualization through autocrine/paracrine mechanisms.

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.

Effects of granulocyte colony-stimulating factor (G-CSF) on proliferation and differentiation of normal human endometrial stromal cells were investigated in an in vitro decidualization culture of stromal cells. Unstimulated stromal cells secreted little prolactin and G-CSF, whereas 8-Br-cAMP-stimulated stromal cells secreted higher levels. There was no relationship, however, between the levels of prolactin and G-CSF secreted from the stimulated cells. Detectable levels of prolactin secretion were not found in two of six stromal cell cultures stimulated with 8-Br-cAMP; however, these two culture supernatants contained high concentrations of G-CSF. Co-stimulation of the stromal cells with 8-Br-cAMP and G-CSF enhanced prolactin secretion from the stimulated cells in a G-CSF concentration-dependent manner without any change in viable cell numbers. However, G-CSF did not affect prolactin secretion or viable cell numbers of 8-Br-cAMP-stimulated decidualized cells. These results indicate that G-CSF enhances cAMP-mediated decidualization of human endometrial stromal cells in an autocrine or paracrine fashion.

We have re-evaluated the effects of bestatin, an aminopeptidase-N (CD13) inhibitor, on in vitro decidualization of normal human endometrial stromal cells by using an in vitro decidualization activity assay. Bestatin did not show any effects on the viability of both the decidualizing stromal cells co-stimulated with 8-Br-cAMP and bestatin and the 8-Br-cAMP-induced decidualized stromal cells, or on prolactin release from the decidualized stromal cells. However, bestatin dose-dependently enhanced prolactin release from the decidualizing stromal cells co-stimulated with 8-Br-cAMP and bestatin. These results indicate that bestatin enhances cAMP-mediated decidualization of human endometrial stromal cells and suggests that membrane aminopeptidase-N in the human endometrium is involved in the regulation of endometrial differentiation by inhibiting cAMP-mediated decidualization signals in endometrial stromal cells.

Intermittent cisplatin (CDDP) administration as consolidation therapy for stage-III ovarian cancer was studied. No patients with residual disease at surgery or at second-look operation or patients with 2 for 5 days was administered every 3–4 months for 5 years. A significant increase in 5-year survival rate was found in the intermittent chemotherapy group when compared with the control group. Side effects from the intermittent chemotherapy were controllable. Intermittent CDDP therapy seems to be an effective consolidation therapy for stage-III ovarian cancer patients.

Summary G-CSF is a hematopoietic factor, which induces differentiation and proliferation of immature granulocytes. During pregnancy, decidual tissue produces G-CSF and the receptor for G-CSF is expressed on chorionic villous tissues. This study attempted to determine the cell population responsible for G-CSF production in decidual tissue and the influence of G-CSF on trophoblast cells. Immunostaining and in situ hybridization showed that both the decidual cells and macrophages in the decidual tissue were sources of G-CSF. With 50 ng of G-CSF the [ 3 H] thymidine uptake was 11,100±2,200 DPM and the control uptake was 7,970±1,820 DPM. G-CSF induced an increase of [ 3 H] thymidine uptake of cytotrophoblast cells 1.4 times than that of control. It is concluded that the decidual cells and macrophages were sources of G-CSF in the decidual tissue, and G-CSF might induce decidualization and promote trophoblast cell proliferation.

To evaluate the response rate and toxicity of the combination of irinotecan (CPT-11) and cisplatin in a neoadjuvant setting, a phase II study was conducted regarding the regimen of this combination in patients with locally advanced cervical cancer. Eligibility included patients with previously untreated stage Ib2, IIb, or IIIb squamous cell carcinoma with good performance status. CPT-11 (60 mg m−2) was administered intravenously on days 1, 8 and 15, followed by cisplatin (60 mg m−2) given intravenously on day 1. Treatment was repeated every 4 weeks for a total of two or three cycles. Among 23 eligible patients (median age: 59 years), three showed complete response (13%), 15 showed partial response (65%), for an overall response rate of 78% (95% confidence interval 58–90%). Stable disease was observed in four cases (17%) and progressive disease in one (4%). The median time to failure and median survival time have not yet been reached. Of the 52 treatment cycles administered, diarrhoea and grade 3 or 4 neutropenia were observed in 10% and 75% respectively. There were no therapy-related deaths. The combination of CPT-11 with cisplatin is a promising regimen for neoadjuvant chemotherapy in locally advanced cervical cancer. The toxicities of this regimen are well tolerated. © 1999 Cancer Research Campaign

Objective: To examine the relationship between estrogen receptor (ER) and progesterone receptor (PR) content in needle biopsy specimens and the growth of uterine leiomyomata after biopsy. Design: Prospective clinical study. Setting: University teaching hospital. Patient(s): Thirty-one women with uterine leiomyomata and a normal menstrual cycle. Intervention(s): Transcervical needle biopsy of uterine leiomyomata. Main Outcome Measure(s): The relationships between histologic features (smooth muscle content, immunohistochemical expression of ER and PR) and the percent increase over a 12-month observation period in the volume of the largest myoma nodule measured by magnetic resonance imaging were analyzed. Result(s): Both the density and intensity of immunohistochemical staining of PRs in uterine leiomyoma tissue showed significant positive correlation with leiomyoma growth. Conclusion(s): The growth of uterine leiomyomata can be determined by histologic and immunohistochemical analysis of needle biopsy specimens from uterine leiomyomata.

Interleukin-1 (IL-1) is considered to be an essential cytokine for embryonic implantation. Expression of the IL-1 receptor in endometrial luminal epithelium increases maximally in the peri-implantation period, and embryonic implantation in mice is blocked by the IL-1 receptor antagonist. However, the function of IL-1 alone in implantation is still unclear. It has been reported that endometrial epithelial cells undergo apoptosis at the implantation site. In this study we have investigated the regulatory function of IL-1 in endometrial epithelial apoptosis, using the human endometrial epithelial cell line HHUA, which is susceptible to Fas-mediated apoptosis. The enhancement of endometrial apoptosis by IL-1 beta was not accompanied by any increase in cell-surface expression of Fas, which suggested that IL-1 beta enhanced the postreceptor apoptotic signals in the activated cells. IL-1 may be a regulator of apoptotic susceptibility in endometrial epithelium in the peri-implantation period.

Adenoma malignum (minimum deviation adenocarcinoma) is a rare neoplasma of the uterine cervix, the diagnosis of wich cannot be determined by cervical smear. Recently, magnetic resonance imaging (MRI) was reported as useful for its diagnosis, but differentiation of adenoma malignum from deep-seated nabothian cysts remains problematic. We report here a case of adenoma malignum of the uterine cervix, for which MRI findings could not neglect deep-seated nabothian cysts. However, transvaginal power Doppler ultrasonography clearly showed richness of small vessels, whose arterial flow had higher velocity in the diastolic phase, around the cystic lesion of the uterine cervix. These findings indicate that, at least in the case reported here, transvaginal power and pulsed Doppler ultrasonography is a useful tool for the diagnosis of adenoma malignum of the uterine cervix.

We compared transvaginal ultrasonography (TVS) and endometrial cytology by the Endocyte method for endometrial cancer screening. A total of 600 postmenopausal women who hoped for endometrial cancer screening (mean age, 61.1 +/- 8.8 years; range, 44-87 years) underwent TVS, endometrial cytology (Endocyte method), and endometrial histology. The endometrial borders could be visualized by TVS in all women studied. However, cytology could not be performed in 59 women (9.8%) due to cervical stenosis. These 59 women were excluded from further study. Of the 541 remaining women, 38 had pathologic conditions (16 had endometrial cancer and 22 had endometrial hyperplasia). One (6.3%) of the 16 endometrial cancer patients and 10 (45.5%) of the 22 hyperplasia patients were asymptomatic. One hundred thirty-nine (83.7%) of the 166 women with postmenopausal bleeding had no pathological condition. When the cutoff value of endometrial thickness was set at 4 mm for women5 years since menopause and 3 mm for thoseor =5 years since menopause, TVS showed a 97.4% sensitivity, 75.7% specificity, 23.8% positive predictive value, and 99.7% negative predictive value. Thirty-seven of the 38 patients with endometrial disease were detected by TVS. Eight patients with a benign Endocyte examination were found to have endometrial hyperplasia. However, all endometrial cancers were detected by cytological examination. The Endocyte method exhibited 78.9% sensitivity, 95.4% specificity, 56.6% positive predictive value, and an 88.5% negative predictive value. In conclusion, TVS is thought to be useful for identification of patients who required further diagnostic investigation including endometrial histology.

SummarySummaryWe treated eight ovarian cancer patients, who had malignant ascites refractory to standard therapy and a poor performance status (≥ 3), by intraperitoneal administration of recombinant interleukin-:! plus in vitro sensitised cells or OK432. Ascitic fluid disappeared completely in three patients and decreased in three patients. The CA125 level decreased in four cases. However, the amount of residual disease did not change, and the survival period after therapy was generally short, reflecting the poor performance status. Intraperitoneal immunotherapy using recombinant interleukin-2 may be effective as a palliative therapy for malignant ascites in ovarian cancer patients.

A rarely reported case of cystic teratoma with floating globules or fat balls is presented. Comparative imaging investigations of the floating globules in an ovarian cystic teratoma were performed using magnetic resonance and two- and three-dimensional ultrasound. Ultrasound imaging easily detected the floating globules, especially the 3-dimensional features showed almost the same findings that were observed macroscopically after surgery. Magnetic resonance thus clearly revealed the character of floating globules.

We investigated the effect of local injections of danazol suspension (DZS) into the uterine cervix. In the cervix, danazol (DZ) reached high concentrations 1 and 4–6 h after injection; then it decreased. In the endometrium, the DZ level reached a peak 1 h after injection, and then declined. On the other hand, the DZ concentration tended to increase with time after injection in ovarian tissue and it remained at a relatively constant level for more than 2 days. During treatment with DZS, various subjective symptoms and clinical findings gradually improved from the 4th week after the start of injection onward. Moreover, an improvement of subjective symptoms was observed in all the patients by the 24th week.

We examined the activity of natural killer (NK) cells and suppressor cells and the population of peripheral blood lymphocytes before and after cis-diamminedichloroplatinum (CDDP) treatment using therapeutic doses in 15 ovarian cancer patients. CDDP did not decrease NK cell activity but selectively abrogated suppressor cell activity up to 7 days after treatment (P < 0.05). The CD56+CD16+ cell and CD8+CD11+ T cell populations significantly decreased; however, the CD4+2H4+ T cells, showed a significant increase after treatment (P < 0.05). We conclude that CDDP treatment using therapeutic doses could selectively abrogate suppressor cell activity.

We evaluated the usefulness of transabdominal ultrasonography (TAS) for endometrial abnormalities in postmenopausal women. A total of 232 postmenopausal women were examined by TAS and endometrial sampling. Abnormal findings, including endometrial hyperplasia, atypical hyperplasia and endometrial cancer, were noted in 0.7% ( 1 141 ) of sonographically measured endometrium 14 91 ) of measurements ≥ 2 mm. Endometrial cancer was found in 5.9% in the postmenopausal bleeding group (n = 85) and in 1.4% in the symptom-free group (n = 147). With one exception, all endometrial abnormalities were in endometrial thickness ≥ 2 mm. We conclude that TAS has limitations as a technique but is useful in deciding which postmenopausal women require endometrial biopsy.

We report two cases in which we describe the impact of sonography (US) in the management of vasa previa. In the first case, with two-dimensional US, the diagnosis of vasa previa was made at 21 weeks gestation. In the second case, using three-dimensional US, the diagnosis of vasa previa was made at 19 weeks gestation. An elective Cesarean section was carried out at 34 weeks in both cases. Diagnosis of vasa previa is critical when low-lying placenta or velamentous insertion of the umbilical cord is detected during the pregnancy. © 2010 Wiley Periodicals, Inc. J Clin Ultrasound 38:389-392, 2010

Patients with unresectable advanced uterine leiomyosarcoma have a very poor prognosis because no effective chemotherapeutic protocols exist. There are currently few established primary human uterine leiomyosarcoma cell lines that can be used to investigate effective therapies. To overcome this problem, we carried out long-term in vitro cell culture and/or nude mouse transplantation and successfully established novel human uterine leiomyosarcoma cell lines from extrauterine and intrauterine tumors that were surgically excised from a single patient. The established cells were characterized by flow cytometry, anticancer drug-sensitivity assays and karyotyping analyses. All the established cell lines showed unstable multiple chromosome abnormalities. Since the cells can proliferate in vitro and in vivo, they will be useful for developing new therapeutic strategies for advanced uterine leiomyosarcoma patients.

We evaluated the use of 18 F-fluorodeoxyglucose positron emission tomography (FDG-PET) for the diagnosis of uterine sarcomas. FDG-PET combined with serum lactate dehydrogenase (LDH) levels were compared with FDG-PET alone for the diagnosis of leiomyosarcomas (LMS), which are the most difficult uterine sarcomas to diagnose. FDG-PET imaging of endometrial cancer (EC) was used as a reference. Immunoreactivity for glucose transporter-1 (GLUT-I) correlated with FDG uptake was evaluated in sarcomas and leiomyomas (LM), including cases not examined by FDG-PET. FDG was injected after at least 5 h fasting and standardized uptake values (SUVs) were analyzed quantitatively 50-70 min after injection. Immunohistochemical expression of GLUT-1 was studied in paraffin sections of tumors using anti-GLUT-1 antibodies and GLUT-1 expression scores were derived based on staining intensities. FDG-PET was performed preoperatively in a total of 53 patients including 10 with sarcomas, 19 with EC and 24 with LM. Immunohistochemical examination was performed in 17 sarcomas, 6 EC and 9 LM [6 usual LM, 1 uterine smooth muscle tumor of uncertain malignant potential (UMP), and 2 bizarre LM (BLM)]. SUVs for uterine sarcomas and EC were significantly higher (p=0.0001) than those for LMs. There were no significant differences in SUVs among ECs, carcino-sarcomas (CS) and LMS. Significant differences in SUVs existed between LM and LMS (p=0.003). However, the diagnostic accuracy for LMS was only 73%. The diagnostic accuracy of FDG-PET combined with serum LDH was 100%. GLUT-1 expression scores were significantly higher in sarcomas and EC than in LM (p

In vitro sensitization (IVS)を用い自己癌細胞に対し強い細胞障害性を持つcytotoxic T lymphocytes (CTL)を大量に誘導し得る条件につき検討するとともに,婦人科癌患者4例に対しその臨床応用を試みた. CTL誘導は婦人科癌患者8例を対象とし,患者単核球とMMC処理癌細胞との前培養後rIL 2を添加して行った.その際(1)培養時のrIL 2濃度の検討では0.02, 0.2, 2.0U/mlまでは細胞障害性,細胞増殖率は上昇傾向を示したが,それ以上の濃度では変化がなかった. (2)CTL感作時の癌細胞濃度は上昇させるに従い,増殖率,細胞障害性は上昇した.以上CTLの誘導条件として培養時のrIL 2濃度は2U/ml, CTL感作時の単核球:癌細胞は10:1が良好な結果となった.また臨床応用の検討では癌性腹膜炎症例に対しては腹水消失,腹水細胞診陰性化,腹水減少等,全例である程度の効果が認められたが,固形腫瘍の縮小には至らなかった.

Massive ovarian edema (MOE) is a rare disease. Therefore, preoperative diagnostic method of massive ovarian edema (MOE) has not been established. We have succeeded in making a preoperative diagnosis of MOE aided by ultrasonogram and magnetic resonance imaging (MRI) and the patient's ovaries were preserved. Characteristics and proposed diagnostic imaging criteria for MOE are discussed.

We previously reported that activin A, not inhibin, was localized to endometrial tissues, and that the endometrium might be a major source of activin A during the menstrual cycle, using an immunohistochemical method. However, there are few detailed reports concerning the expression of inhibin subunits, activin receptors and Smad proteins in the ectopic endometrial tissues of endometriosis. In this study, our purpose was to evaluate the immunohistochemical localization of inhibin alpha-, betaA-subunits, activin A, activin receptor, and Smad proteins in ovarian endometriosis. Tissue samples from ovarian endometriosis were obtained from 13 women. Normal endometrial tissues were obtained during the proliferative phase from 5 premenopausal women without endometriosis who were undergoing a hysterectomy for the treatment of uterine cervical intraepithelial neoplasia 3. We examined the immunohistochemical localization of inhibin/activin alpha-, betaA-subunit, activin A, activin receptors types IA, IB, IIA, IIB, Smad2, Smad3 and Smad4 using an avidin-biotin-peroxidase complex technique. No immunostaining for the alpha-subunit of inhibin was observed in ovarian endometriosis and the normal endometrium. Positive immunostaining for the betaA-subunit of inhibin, activin A, activin receptors types IA, IB, IIA, IIB, Smad2, Smad3 and Smad4 was observed in ovarian endometriosis and the normal endometrium. In conclusion, these results suggest that activin A, but not inhibins, is produced by ovarian endometriosis and the normal endometrium, and that the activin signal transduction system exists in both ovarian endometriosis and the normal endometrium.

Although death-associated protein kinase (DAPK) is a Ca 2+ /calmodulin-regulated serine/threonine kinase that plays important roles in various types of apoptotic cell death, there have been no reports of its tissue distributions and functions in female reproductive organs. By comparing C57BL/6 wild-type mice with DAPK-mutant mice lacking the 74-amino acid catalytic kinase domain of DAPK, the cellular distributions and biological functions of DAPK in murine ovaries were investigated. In situ hybridization analyses with sense and antisense riboprobes revealed that DAPK mRNA was selectively and highly expressed in granulosa cells in the ovaries of both types of mice. There were no significant differences in the body weights, ovarian weights and unstimulated ovarian follicular numbers between the wild-type and DAPK-mutant mice. Intraperitoneal injection of CPT-11, an anticancer topoisomerase I inhibitor that causes granulosa cell-specific apoptosis partly through Fas-Fas ligand (FasL) interactions in MCH mice, induced follicular apoptosis in both the wild-type and DAPK-mutant mice. However, the numbers of apoptotic follicles were significantly reduced in the DAPK-mutant mice. The Fas and FasL expression levels in the CPT-11-injected mice did not differ significantly between the wild-type and DAPK-mutant mice. These results indicate that DAPK positively regulates intracellular signaling pathways for CPT-11-induced granulosa cell apoptosis.

The aim of this study (JGOG1063) was to determine the recommended dose (RD) for combination chemotherapy with irinotecan hydrochloride (CPT-11) and nedaplatin (NDP) for advanced cervical squamous cell carcinoma. CPT-11 was given intravenously in fixed doses of 60 mg/m 2 on days 1 and 8 and NDP, in escalating doses, on day 1, every 4 weeks. A total of 15 patients were enrolled in the study. At level 1 (NDP: 50 mg/m 2 ), one of the 3 patients developed grade 3 diarrhea, so 3 additional patients were enrolled at this level. As none of the 3 additional patients exhibited dose-limiting toxicity, level 1 was elevated to level 2 (NDP: 60 mg/m 2 ). The maximum tolerated dose was not reached, even at the highest dose level (level 4; NDP: 80 mg/m 2 ). No further dose escalation was carried out, and level 4 (CPT-11: 60 mg/m 2 , NDP: 80 mg/m 2 ) was determined as the RD.

This study aimed to clarify the mechanism by which apoptosis and Fas ligand (FasL) expression are induced in the ovarian granulosa cells of mice injected with irinotecan HCl (CPT-11). To this end, the direct effects of CPT-11 and its active metabolite, SN38, on granulosa cells were investigated. Normal ovarian tissue fragments obtained from 8-week-old female MCH mice were cultured in vitro with CPT-11 or SN38 and paraffin-embedded. After sectioning, the ovarian fragments were analyzed by TUNEL staining to detect apoptotic cells and by immunohistochemistry with an anti-FasL antibody to detect FasL expression. The results revealed no increase in TUNEL-positive granulosa cells in the ovarian tissue fragments cultured with CPT-11 or SN38. Furthermore, CPT-11 and SN38 did not induce FasL expression in the ovarian fragments. In conclusion, apoptosis and FasL expression induced in the ovarian granulosa cells of mice injected with CPT-11 is not caused by direct stimulation with CPT-11 or SN38. Therefore, systemic CPT-11 administration appears to induce apoptosis and FasL expression in granulosa cells via currently unknown endogenous FasL-inducing factors or by active metabolites of CPT-11 other than SN38.

母体にとってSemiallograftである胎児を維持する免疫学的機序を知るべく,脱落膜組織に浸潤している単核球(MNC)を取り出し,その細胞膜表面の性格をモノクローナル抗体を用い検討するとともに,それらの細胞の存在部位を免疫組織学的に検討した.さらにその機能についても検討した. MNCは初期妊娠中絶により得られた脱落膜組織より得た.細胞膜表面の性格の検討では末梢血MNC (P-MNC)に比し, CD 8+細胞が多く, CD 4+/CD 8+ ratioが著明に低下していた.またこのCD 8+細胞はCD11b-細胞でcytotoxic T-cellと判断された.これらの細胞の占拠部位は脱落膜緻密層にはマクロファージ(Mφ)のみ存在し,リンパ球はみられなかった.一方,脱落膜海綿層ではリンパ球およびMφがみられ,その他NK細胞も少数ながらみられた.これらの多くの細胞は, HLA-DR+細胞であった.しかしIL-2 receptor陽性細胞はみられなかった.またCD 8+細胞はCD 8+, CD11b-のcytotoxic T-cellであった.そこで次にこれらの細胞の機能をP-MNCと比較検討した.PHA反応性は低値を示した.しかしIL-2に対する反応性は高値を示した.またNK活性も認められず,逆にsuppressor活性が高かった.以上,脱落膜組織のT-cellは膜表面の性格はcytotoxic T-cellで,また活性化されているが,膜表面にIL-2 receptorをもたず,また全体の細胞の機能として抑制機能が有意で,妊娠維持に好環境が形成されているものと判断された.

The biological roles of laminin and type IV collagen in human endometrial stromal tissues were investigated by the evaluation of the expression levels in human endometrial tissues using immunohistochemistry. In addition, normal human endometrial stromal cells were cultured in vitro on laminin- or type IV collagen-coated plates and subjected to cytological analyses. Cyclic production of laminin and type IV collagen were detected and the two productions were significantly increased in late proliferative and late secretory endometrial stromal cells. Unstimulated endometrial stromal cells proliferated with specific growth structures that varied depending on the extracellular matrix component coated on the culture plates. The expression levels of integrin subunits on endometrial stromal cells were sufficiently enhanced by 8Br-cAMP treatment to mask any differences in the growth structures induced by the extracellular matrix components. 8Br-cAMP-stimulating stromal cells exhibited significant survival on laminin-coated plates, while 8Br-cAMP-deprived stromal cells, after 8Br-cAMP stimulation, showed significant survival on type IV collagen-coated plates. In conclusion, human endometrial stromal cells produce laminin and type IV collagen, and these productions are possibly regulated by ovarian estrogen and progesterone. Human endometrial stromal cells specifically bind to laminin and type IV collagen via integrins, and regulate endometrial stromal cell structures, viability and differentiation. Thus, laminin and type IV collagen may autoregulate human endometrial stromal remodeling during the menstrual cycle in an autocrine and paracrine fashion.

Minimal optimal surgery without chemotherapy is often performed for patients with ovarian immature teratoma, which frequently occurs in young women who hope for future pregnancies. If tumors recur after the operation, anticancer drug chemotherapy is often administered, although few studies have highlighted differences between the recurrent and the primary tumor cells. Therefore, we have established experimental animal models of recurrent ovarian immature teratoma cells after optimal surgery and characterized the anticancer drug sensitivity and antigenicity of the recurrent tumors. Surgically-excised tumor cells of a grade II ovarian immature teratoma were cultured in vitro and transplanted into nude mice to establish stable cell lines. Differential drug sensitivity and antigenicity of the tumor cells were compared between the primary and the nude mouse tumors. Nude mouse tumor cells showed a normal 46XX karyotype. Cultured primary cells showed a remarkably high sensitivity to paclitaxel, docetaxel, adriamycin and pirarubicin, compared to peritoneal cancer cells obtained from a patient with ovarian adenocarcinomatous peritonitis. The drug sensitivity of teratoma cells to 5-fluorouracil, bleomycin or peplomycin was also significantly higher. However, there was no significant difference in sensitivity to platinum drugs between the primary teratoma and the peritoneal adenocarcinoma cells. As for nude mouse tumor cells, sensitivity to 12 anticancer drugs was significantly lower than that of the primary tumor cells, while there was little difference in sensitivity to carboplatin or peplomycin between the primary and nude mouse tumor cells. Flow cytometry showed that the expression of smooth muscle actin (SMA) significantly decreased in nude mouse tumor cells when compared to cultured primary cells. In conclusion, ovarian immature teratomas with normal karyotypes have a malignant potential to recur after minimal surgery. During nude mouse transplantation, SMA-overexpressing cells appeared to be selectively excluded and nude mouse tumor cells were less sensitive to the majority of anticancer drugs than the primary tumor cells. These results indicate that after optimal surgery for ovarian immature teratoma, recurrent cells can be more resistant to anticancer drugs than the primary tumors. Therefore, it is likely that adjuvant chemotherapy lowers the risk of ovarian immature teratomas recurring after optimal surgery. BEP and PBV regimens are frequently given to teratoma patients. However, paclitaxel/carboplatin or docetaxel/carboplatin, which are the most effective chemotherapy treatments for epithelial ovarian cancer patients, are considered to be an alternative regimen, especially in the prevention of reproductive toxicity.

To better understand the molecular mechanisms of carcinogenesis induced in uterine endometrium by therapeutic anti-estrogenic Tamoxifen (TAM) exposure, 27 uterine tumors (4 benign endometrial polyps and 23 carcinomas) associated with TAM exposure were analyzed for the presence and spectrum of p53 and K-ras mutations. Although there was no significant difference between TAM-associated endometrial carcinomas and sporadic endometrial tumors in the frequency of these mutations, the spectrum of p53 mutations was characteristically unique to the TAM-associated tumors. The median duration of TAM exposure was significantly longer in patients with p53 mutations than those without p53 mutations (62 vs. 30 months, p=0.028). Our observation suggests that prolonged TAM exposure may directly inactivate the p53 gene by acting as a mutagen in a significant fraction of TAM-associated endometrial carcinomas.