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To evaluate the short-term effect of leuprorelin acetate microspheres in preventing recurrence of ovarian endometrioma after conservative surgery.From January 2011 to September 2011, 190 ovarian endometrioma patients undergoing conservative laparoscopic surgery at Affiliated Obstetrics and Gynecology Hospital Affiliated to Fudan University were enrolled in this retrospective study. Among 184 patients were followed up, the range of following up were 12 to 21 months. 116 cases presented dysmenorrheal. Based on postoperative treatment, they were classified into 124 cases treated by domestic gonadotropin releasing hormone agonist(GnRH-a) post-operatively for 3-6 months and 60 cases without postoperative treatment. Among all, 63 patients were treated with, that was leuprorelin acetate microspheres for injection (Beiyi, 3.75 mg, q28 d), 61 patients were treated with imported GnRH-a post-operatively for 3-6 months, that were either Zoladex(3.6 mg, q28 d), Dophereline(3.75 mg, q28 d) or Enatone (3.75 mg, q28 d). The recurrence and pain improvement were compared among those groups.(1) The total rate of cyst recurrence was 12.5% (23/184) while the average recurrent time was (13.7 ± 2.6) months (2-21 months). The cyst recurrence rate was significantly lower in patients treated with GnRH-a post-operatively than those who didn't take medications [21.7% (13/60) versus 8.1% (10/24), P0.05]. However, there was no significant difference between domestic GnRH-a group and the imported one [7.9% (5/63) versus 8.2% (5/61), P0.05]. (2) After conservative surgery, symptoms were found to be relieved in 87.1% (101/116) patients among 116 patients complaining of dysmenorrheal pre-operatively and the pain recurrence rate was 12.9% (13/101). However, there was no significant difference in either symptom relief rate or pain recurrence rate among different groups. The symptom relief rate were 87% (33/38), 86% (37/43) and 89% (31/35) while the pain recurrence rate were 12% (4/33), 14% (5/37) and 13% (4/31) respectively in none, imported GnRH-a group and domestic GnRH-a group.Leuprorelin acetate microspheres could be effective in preventing recurrence of ovarian endometrioma, but not in symptom relieving after conservative surgery in short term. The effect of domestic and imported GnRH-a was similar.

To investigate clinicopathological features of abdominal wall endometriosis (AWE).A retrospective study was conducted on 151 consecutive AWE patients undergoing treatment in Affiliated Obstetrics and Gynecology Hospital, Fudan University from January 2003 to December 2010. The period of following up was at range of 16 to 97 months.(1) The incidence of AWE was 1.96% (166/8469). All 151 AWE cases followed up had previous cesarean sections. The period between the previous cesarean section (CS) and the onset of symptoms of AWE was 24 months (3 - 192 months). However, the latency was not associated with the age at CS, incision site, gestational week at CS, duration of lactation, postpartum menstruation recovery, the choice of contraceptives and size of AWE (P0.05). The duration of disease, defined to be the time interval between the onset of symptoms and surgery, was 26 months (2 - 168 months), which was negatively correlated with the latent period (r = -0.267, P0.05) and was positively with size of AWE (patients with large-scar endometrioma with diameter of lesions ≥ 3 cm had longer disease duration than those with small-scar endometriomas3 cm, r = 0.326, P0.05). (2) The rate of pre-operational ultrasonography detection was 97.4% (147/151). The lesion size detected by pre-operative ultrasonography was significantly smaller than that measured intraoperatively by palpation (20 mm versus 35 mm, P0.05). Moreover, only 26.5% (40/151) of AWE patients were found to have deep infiltration by pre-operative ultrasonography. (3) All patients were managed by surgical treatment to completely excise lesions on the abdominal wall. Of all 34 patients (22.5%, 34/151) took medicine pre-operatively while 57 patients (37.7%, 57/151) taking medicine post-operatively. The rate of recurrence was 3.1% (3/96) of cases with lesions ≥ 3 cm, which was significantly lower than 17.8% (8/45) in cases with lesion3 cm (P0.05). (4) After surgery, the symptoms were found to be relieved in 93.4% (141/151) of patients. The recurrence rate was 7.8% (11/141) while the average recurrent time was (20 ± 16) months.Surgery is the main management on AWE. The risk factors associated with recurrence were size of lesion and postoperative medication.

To profile methylation alterations of cytosine-phosphate-guanosine islands (CGI) in epithelial ovarian cancer and investigate its applications for finding new candidate tumor markers.Cancer cells were obtained by laser microdissection from 20 tissues of frozen-preserved epithelial ovarian tumors. Primary cultured epithelial cells were isolated from 5 tissues of normal ovaries. Differential methylation hybridization (DMH) based on microarray assay was conducted using DNA to construct the aberrant DNA methylation pattern of epithelial ovarian cancer. MethyLight was conducted to verify the methylation status of 7 hypomethylated promoter CGI detected by DMH in tumor tissues of 87 patients with epithelial ovarian cancer and 42 patients with benign ovarian diseases.The aberrant DNA methylation pattern of epithelial ovarian cancer were included 182 hypermethylated loci and 64 hypomethylated loci, of which the positive loci located more than 25% arrays were 18 and 31, respectively. The methylation ratio of gene LSM2, EGFLAM and CDKN2A in tissue DNA of patients with epithelial ovarian cancer and benign ovarian diseases was 11% (10/87) versus 33% (14/42), 8% (7/87) versus 21% (9/42), 9% (8/87) versus 31% (13/42), respectively, which was significantly decreased in tissues DNA of ovarian cancer than that from benign ovarian diseases (P0.05).The aberrant DNA methylation pattern of epithelial ovarian cancer is important for finding new cancer related genes. The promoter CGI of gene LSM2, EGFLAM and CDKN2A may be novel candidate for ovarian cancer-specific hypomethylated tumor markers.

To investigate clinicopathological features of endometriosis-associated epithelial ovarian carcinoma.Retrospective follow-up study, clinicopathological data from patients with ovarian epithelial carcinoma were retrieved, analyzed and compared. Among the 727 cases, 34 were found to originate from endometriosis (group A), 33 were found to have co-existing ovarian endometriosis (group B), and the remaining 660 had no ovarian endometriosis at all (group C).Seven hundred and twenty-seven epithelial ovarian carcinoma patients were identified and their clinicopathological data retrieved. Sixty-seven (9.2%) of these cases were found to have coexisting endometriosis. The frequency of malignant tumors arising from ovarian endometriosis in this case series was estimated to be 0.87% (34/3890). The mean (standard deviation) age in groups A, B, and C were (47.2 +/- 1.3), (47.8 +/- 1.2), (51.2 +/- 0.4) years, respectively, with patients in group C being significantly older (P = 0.013). Patients with coexisting ovarian endometriosis were mostly diagnosed at stage I (P = 0.000) and having subtype of clear-cell (P = 0.000), while other patients were mostly diagnosed at stage III (P = 0.001), and having subtype of serous carcinoma (P = 0.000). The estrogen receptor (ER) positivity was significantly lower in groups A and B than that in group C (22.2%, 31.6% vs 43.9%; P = 0.018), but the difference in positivity of progestogen receptor among the three groups did not reach statistical significance (22.2%, 15.8% vs 35.5%; P = 0.082). While the five-year overall survival rate for all patients was 55.6%, significant difference in overall survival among the three groups was found 78.9%, 92.8%, 51.9%, respectively, for groups A, B and C (P = 0.000).Patients of endometriosis-associated epithelial ovarian carcinoma, especially patients with tumors arising from endometriosis, were found to be younger, having a significant lower stage and a better survival, and were mostly diagnosed with the subtype of clear-cell.

To evaluate the correlation of the expression of homeodomain-interacting protein kinase 2 (HIPK2) with human papillomavirus (HPV) infection and apoptosis in cervical cancer.Formalin-fixed, paraffin embedded tissue samples from 50 cervical cancers and 15 normal uterine cervix cases were obtained. Apoptosis was quantified by TdT-mediated dUTP nick end labeling (TUNEL) assay and the expression of HIPK2 as well as HPV by immunohistochemical staining.HIPK2 protein expression was detected in 88.0% (44/50) of cervical cancers and 6.7% (1/15) of normal cervical tissues. HPV was found in 78.0% (39/50) of cervical cancers and 20.0% (3/15) of normal cervical tissue samples. The expression of HIPK2 protein was significantly and positively correlated with HPV presence (r=0.467, P0.01), but negatively with apoptotic index (r=-0.370, P0.05).HIPK2 protein expression is positively correlated with HPV infection, but negatively with apoptotic index in cervical cancers. Therefore, HIPK2 may be involved in the mechanism of apoptosis in cervical cancer and may play an important role in cervical carcinogenesis.

To study the anti-tumor immunotherapeutic effect induced by the suicidalcancer vaccine FC/TK, and to evaluate the safety of this vaccine.The suicidal cancer vaccine, named FC/TK, was prepared by fusion of suicide gene (HSVI,-TK gene) -modified ovarian carcinoma NuTu-19 cells with rat bone marrow-derived dendritic cells (DCs). The morphology of FC/TK was evaluated by scanning electron microscopy. The stimulatory effect of FC/TK on T cells was determined by T cell proliferation assay. In immunotherapeutic studies in vivo, Fischer344 rats were injected subcutaneously with NuTu-19 cells, followed by treatment of FC/TK on days 7 and 14, compared to controls treated with irradiated FC/TK, FC or PBS, respectively. Tumor incidence and volume were measured in 90 days after challenge. To determine the killing effect of FC/TK in vivo, TUNEL assays were applied to detect apoptotic cell death in spleen of vaccinated rats with prodrug ganciclovir administration.FC/TK cells were of irregular shape with surface membrane processes. Compared to the control groups, FC/TK significantly promoted T cell proliferation (P0.01). The rats vaccinated with FC/TK and FC significantly inhibited the tumor growth compared to rats vaccinated with irradiated FC/TK (P0.05) or with PBS ( P0.01). The immunotherapeutic effect induced by FC/TK was similar to that using FC. Fluorescence microscopy showed that fluorescein-stained FC/TK cells migrated into spleen also showed to be TUNEL-positive, suggesting that the FC/TK cells were killed by ganciclovir in vivo.Our data indicate that suicidal cancer vaccine is an effective and safe therapy for ovarian carcinoma and may serve as a broadly applicable approach for other cancer vaccines in the future.

Progesterone plays an important role in the regulation of normal endometrium function by binding to progesterone receptor (PR). In endometrial cancer, however, PR is always down-regulated. Previous reports showed that methylation in the promoter region of the PR gene may be responsible for PRB isoform repression. However, the CpG islands in the exon region of the PR gene are much richer and longer than in the promoter region. We hypothesize that methylation in the exon region may also take part in the down-regulation of the PR gene. The methylation status of the first exon of the PR gene in endometrial cell cultures was investigated. Aberrant methylation patterns were observed in the first exon of PR gene, and the methylation density is correlated with the differentiation of different types of endometrial cancer cells. DNA methyltransferase (DNMT) and histone deacetylase inhibitor 5-aza-2'-deoxycytidine (ADC), as well as trichostatin A (TSA), which reverses PR gene expression, were also studied. A combination of ADC and TSA resulted in synergistic effects in inducing PR expression, down-regulation of DNMT1 and DNMT3A, and could also have antigrowth effect on endometrial cancer cells by inducing apoptosis.

This study investigated the prognostic significance of age at diagnosis, stage, tumor subtype, pelvic lymph node metastasis (PLNM), lymph-vascular space involvement (LVSI), presence or absence of deep cervical stromal invasion (DCSI) in stage IB-IIA cervical cancer patients. It also investigated the inter-relationship among these factors.152 patients treated with radical hysterectomy plus pelvic lymphadenectomy were followed up for a median of 49 months and were evaluated retrospectively.The 5-year overall survival rate was 84.8%. The distribution of age at diagnosis is of bimodal shape, peaking at 42 and 68 years, respectively. Tumor subtype, PLNM, DCSI, and LVSI were found to be significant prognostic factors individually. After multivariate analysis, only tumor subtype and PLNM were found to be independent, significant prognostic factors for survival. The prognostic importance of LVSI appeared to be eclipsed by the presence of PLNM. DCSI was statistically related with FIGO stage, LVSI and PLNM.Tumor subtype and PLNM are the two most important independent prognostic factors for stages IB-IIA cervical cancer. Some prognostic factors are inter-related and may reflect different facets of tumor progression.

To evaluate the frequency of MSI in epithelial ovarian tumors and its relationship with clinicopathologic features.Ninety fresh specimens of epithelial ovarian tumors, including 74 primary and 16 secondary tumors, were collected. Microsatellite analysis was carried out using 5 mono-and dinucleotide markers from the National Cancer Institute Consensus Panel by fluorescence-labeled polymerase chain reaction.Of 90 epithelial ovarian tumors analyzed, 18 demonstrated a high level of microsatellite instability (MSI-H), 30 demonstrated a low level of microsatellite instability (MSI-L), and the remaining 42 exhibited microsatellite stability (MSS). Frequency of microsatellite instability (MSI) at loci BAT-25 was higher than that at any other loci. No correlation was found between MSI level and patient age, tumor type, tumor differentiation (P0.05). But the microsatellite instability-high phenotype correlates with clinical stage. It tended to occur more frequently in early-stage tumors (P=0.03).The frequent MSI in epithelial ovarian tumors suggests that it is an early event to involve in the development of epithelial ovarian tumors.

To investigate the efficiency of antitumor immune responses induced by a controlled live dendritic cell (DC) vaccine.DC precursors were isolated from Fischer 344 rat bone marrow and cultured with granulocyte-macrophage colony-stimulating factor and interleukin-4. The rat ovarian tumor cell line NuTu-19 was genetically modified by retroviral-mediated suicide gene (HSV(1)-TK), and the positive clones were selected using G418. Live DC vaccine was then fused with DC and NuTu-19/TK cell by polyethylene glycol. The characteristics of live DC vaccine were assayed with flow cytometry and confocal laser scanning microscopy. The specific expression of HSV(1)-TK gene in live DC vaccine was evaluated by RT-PCR and western blot. The sensitivity of live DC vaccine to ganciclovir (GCV) was evaluated by methylthiazoletetrazolium assay. In vivo, rats vaccinated twice with live DC vaccine were compared to those vaccinated with killed DC vaccine, unfused DC and NuTu-19/TK cell or phosphate buffered saline. Seven days following the last immunization, the rats were sacrificed to test the specific cytotoxic T lymphocyte (CTL) activity by lactate dehydrogenase release assay, or challenged with NuTu-19 and tumor incidence was observed.The fusion efficiency was approximately (23 +/- 14). Live DC vaccine displayed an up-regulated expression of major histocompatibility complex (MHC)-IIOX6 (87.6 +/- 3.4)%, costimulatory molecule B(1 - 2) (71.1 +/- 9.3)%, integrin OX 62 (68.0 +/- 7.4)%, and adhesion ICAM-1 (77.1 +/- 2.0)%, and specifically expressed HSV(1)-TK gene. Our data showed that spleen T lymphocytes from rats vaccinated with live vaccine displayed enhanced CTL activity (61.8 +/- 8.3)% contrast to that of rats vaccinated with killed vaccines (26.0 +/- 3.8)% (P0.05). Compared to the control groups, rats immunized with live DC vaccine demonstrated a significant delay in tumor development [(39 +/- 8) d vs (70 +/- 16) d], reduced tumor incidence (100% vs 80%) and decreased tumor volume [(806 +/- 553) mm(3) vs (89 +/- 53) mm(3), P0.05]. Seventy-three percent of TK-transduced live DC vaccine was killed after 7 of GCV treatment by a functional assay.The results demonstrate that DC live vaccine modified by HSV(1)-TK gene can induce efficient protective immunity and be killed by GCV.

Live tumor vaccines could achieve better immunotherapeutic effects than irradiated tumor vaccines; however, the tumorigenicity is the crucial drawback incurred by the current procedures for vaccine preparation. This study was to explore the application of herpes simplex virus type 1 thymidine kinase/ganciclovir (HSV1-TK/GCV) system as "in vivo death switch" to control the survival status of cancer vaccines under certain circumstances.Suicide gene HSV(1)-TK was transferred into ovarian cancer cell line NuTu-19 with a retrovirus vector, followed by G418 selection to obtain HSV(1)-TK-transfected NuTu-19 cells (NuTu-19/TK). Dendritic cells (DCs) derived from Fischer344 rat bone marrow were fused with NuTu-19/TK cells to construct live tumor vaccine FC/TK. The expression of HSV(1)-TK in FC/TK cells was determined by reverse transcription-polymerase chain reaction (RT-PCR) and Western blot. The cytotoxic efficacy of GCV on FC/TK cells was evaluated by XTT assay. The apoptosis of FC/TK cells was analyzed by flow cytometry and Hoechst33258 staining after GCV treatment. Rats were vaccinated with FC/TK cells and divided into 2 groups: GCV group (5 rats) were intraperitoneally treated with GCV for 7 days, control group (5 rats) were treated with normal saline. The tumorigenesis and tumor metastasis in the rats were observed 90 days after inoculation.HSV1-TK was specifically expressed in FC/TK cells. GCV showed in vitro cytotoxicity to FC/TK cells in a dose-dependent manner, and 86.25% of the FC/TK cells were killed by GCV at a concentration of 100 microg/ml; the apoptosis rate of FC/TK cells was over 80%, and apoptotic morphology, including cell shrinkage, chromatin condensation, was observed. In the rat models, the tumor was developed at the injection site in 3 rats of control group, while no tumor was observed in the rats of GCV group.HSV(1)-TK/GCV could act as the "death switch" of tumor vaccines by triggering apoptosis of tumor vaccines both in vitro and in vivo.

Analyzing the protein expression of biomarkers CK7, Vim, and P53 to investigate their possible pathogenic roles in the development of variant subtypes of endometrial carcinoma.Biomarkers CK7, Vim, and P53 were immunohistochemistry-stained among 131 endometrial carcinoma specimens including 93 endometroid, 8 adenoacanthoma, and 32 rare subtypes of adenosquamas carcinoma, clean cell carcinoma, and papillary carcinoma, which had been confirmed clinically and pathologically, and studied statistically with Fisher test and Cochran-Mantel-Haenszel (CMH) Test.Positive correlation was demonstrated among CK7, Vim, and P53 expression levels. The CK7 protein expression is increased, while the Vim and P53 are decreased in the subtype of endometrioid carcinoma. The clinical staging of endometriroid carcinoma is positively correlated with the expression of Vim. The positive rate of Vim and P53 is correlated with cytological differentiation of the carcinoma cells.Biomarkers CK7, Vim, and P53 are playing pathogenic roles, assuming as a mutual transcriptional modulator, and Vim but not P53 is likely the favorable prognostic factor, in the development of variant subtypes of endometrial carcinoma in addition to a evaluating the treatment.

The association of pseudo-Meigs' syndrome, elevation of CA 125 to the struma ovarii is a rare condition. So far only nine cases have been reported in English literature through MEDLINE search. Here we report a 46-year-old case of the struma ovarii, presented with ascites, hydrothorax, right ovarian mass and elevated serum CA 125 level. These findings were misdiagnosed for an ovarian malignancy at the first impression. Immediate resolution of the ascites, hydrothorax and normalization of the serum CA 125 level were followed by ovarian mass removal. Struma ovarii could be a rare cause of ascites, hydrothorax, ovarian mass and elevated CA 125. This rare condition should be considered in the differential diagnosis in patents with ascites and pleural effusions but with negative cytology.

Similar to estrogens, bone morphogenetic protein 4 (BMP4) promotes the accumulation of more metabolically active subcutaneous fat and reduction of visceral fat. However, whether there is a cross-talk between BMP4 and estrogen signaling remained unknown. Herein, we found that BMP4 deficiency in white adipose tissue (WAT) increased the estrogen receptor α (ERα) level and its signaling, which prevented adult female mice from developing high fat diet (HFD)-induced obesity and insulin resistance; estrogens depletion up regulated BMP4 expression to overcome overt adiposity and impaired insulin sensitivity with aging, and failure of BMP4 regulation due to genetic knockout led to more fat gain in aged female mice. This mutual regulation between BMP4 and estrogen/ERα signaling may also happen in adipose tissue of women, since the BMP4 level significantly increased after menopause, and was inversely correlated with body mass index (BMI). These findings suggest a counterbalance between BMP4 and estrogen/ERα signaling in the regulation of adiposity and relative metabolism in females., Highlights • BMP4 knockout improves ERα stability and its signaling in WAT of female mice. • BMP4 knockout female mice get higher energy expenditure. • Depletion of estrogens up regulates BMP4 level in adipose tissue. • Failure of BMP4 regulation leads to obesity and insulin resistance in aged females. Estrogens play a beneficial role in regulating adiposity and glucose metabolism, however not all women with low estrogen levels become obese and develop insulin resistance. Such variation may be related to other factors involved. In the present study, we revealed a reciprocal interaction between bone morphogenetic protein 4 (BMP4) and estrogen/ERα signaling in regulating fat accumulation and insulin sensitivity. Our findings may explain why cycling females are less prone to gain weight and less susceptible to glucose dysmetabolism than menopausal females and males. The regulation of BMP4 may offer a new opportunity of intervention in the control of excessive obesity.