- [Show abstract] [Hide abstract] ABSTRACT: STUDY QUESTION Is the micro-RNA (miRNA) miR-503, downregulated in endometriotic cyst stromal cells (ECSCs) and does this affect the cell cycle, cell proliferation, angiogenesis and contractility of these cells? SUMMARY ANSWER miR-503 expression is downregulated in ECSCs by DNA hypermethylation and this contributes to their proliferation, resistance to apoptosis, extracellular matrix (ECM) contractility and angiogenesis through effects on cyclin D1, B-cell lymphoma/leukemia (Bcl)-2, Ras homology A and vascular endothelial growth factor A (VEGF-A). WHAT IS KNOWN ALREADY A variety of miRNAs are demonstrated to involve in the pathogenesis of endometriosis. miR-503 is a miRNA with tumor-suppressor functions, whose expression is suppressed in ECSCs. STUDY DESIGN, SIZE, DURATION We isolated ECSCs and normal endometrial stromal cells (NESCs) from ovarian endometriotic tissues (n = 32) and eutopic endometrial tissues without endometriosis (n = 8), respectively. PARTICIPANTS/MATERIALS, SETTING, METHODS We investigated the functions of miR-503 by using miR-503-transfected ECSCs and the DNA methylation status of miR-503 gene in ECSCs and NESCs by combined bisulfite restriction analysis. MAIN RESULTS AND THE ROLE OF CHANCE In ECSCs, miR-503 is downregulated by the DNA hypermethylation of its gene. The transfection of miR-503 into ECSCs resulted in the inhibition of cell proliferation and induction of cell-cycle arrest at G0/G1 phase through the suppression of cyclin D1, the induction of apoptosis through Bcl-2 suppression, the inhibition of VEGF-A production and the attenuation of ECM contractility via the suppression of Rho/Rho-associated coiled-coil-forming protein kinase-pathways. LARGE SCALE DATA NA. LIMITATIONS, REASONS FOR CAUTION The present experiments were carried out only with the stromal component of endometriosis and eutopic endometrium. The experiments with the eutopic endometrial stromal cells from women with endometriosis are not performed. WIDER IMPLICATIONS OF THE FINDINGS Our findings indicate that epigenetically repressed miR-503 in ECSCs is involved in the acquisition of endometriosis-specific cellular functions. STUDY FUNDING/COMPETING INTEREST(S) This work was supported in part by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (no. 13237327 to K.N., no. 26861335 to K.K. and no. 23592407 to H.N.) and the Kanzawa Medical Research Foundation (to K.K.). There are no conflicts of interest to declare.
- [Show abstract] [Hide abstract] ABSTRACT: Intravenous leiomyomatosis (IVL), a rare disease that is histologically benign but clinically aggressive, is characterized by the intraluminal growth of benign leiomyoma in the intrauterine and systemic veins. Preoperative diagnosis of IVL is difficult, because the symptoms of early stage IVL are similar to those of uterine leiomyoma. The efficacy of adjuvant hormone therapy after surgical resection of IVL remains unclear. Herein is described a case of IVL that was diagnosed preoperatively, in which successful total resection of the tumor was achieved by radical hysterectomy. The patient, a 50-year-old premenopausal Japanese woman, also underwent aromatase inhibitor treatment and was free of disease at 36 months after surgery. Contrast-enhanced computed tomography is suggested as the best assessment for identifying and diagnosing IVL. Radical hysterectomy can be considered a successful therapy for total resection. Aromatase inhibitor treatment may be effective, especially when the patient has not yet entered menopause.
- [Show abstract] [Hide abstract] ABSTRACT: Decidualization of the endometrium and endometriosis involves the morphological and biochemical reprogramming of the estrogen-primed proliferative stromal compartment under the continuing influence of progesterone. Here, we evaluated the involvement of microRNA in the decidualization processes of normal endometrial stromal cells (NESCs) and endometriotic cyst stromal cells (ECSCs). In vitro decidualization of NESCs and ECSCs was induced by long-term culture with a combination of 0.5 mmol/L of dibutyryl cyclic adenosine monophosphate and 100 nmol/L of dienogest. We investigated the effect of in vitro decidualization on the microRNA and messenger RNA (mRNA) expression profiles of the NESCs and ECSCs using global microarray techniques and an Ingenuity Pathways Analysis. Decidualization differentially enhanced the miR-30a-5p expression in the NESCs and the miR-210 expression in the ECSCs. The enhanced miR-30a-5p expression in the NESCs correlated with the increased mRNA expression of Krüppel-like factor 9 and period circadian clock 3 as well as the decreased mRNA expression of tolloid-like 1, tolloid-like 2, and paired-like homeodomain 1. The enhanced expression of miR-210 in the ECSCs correlated with the decreased mRNA expression of growth hormone receptor and thymidine kinase 1. Although there is no direct evidence, we speculate that the loss of miR-30a-5p-mediated mechanisms of decidualization and the acquisition of miR-210-mediated mechanisms of decidualization may be involved in the progesterone resistance in endometriosis. Further investigations are necessary to test this speculation.
- [Show abstract] [Hide abstract] ABSTRACT: Primary large-cell neuroendocrine carcinoma of the endometrium is extremely rare and has a poor prognosis. This report describes a case of combined large-cell neuroendocrine carcinoma and endometrioid adenocarcinoma of the endometrium diagnosed as stage IIIA. The patient underwent surgery and chemotherapy and has been well with no evidence of disease for 20 months. The optimal treatment for this rare tumor has not been established. Considering its rarity and variability, it is difficult to establish an evidence-based therapeutic regimen.
- [Show abstract] [Hide abstract] ABSTRACT: Background. Although radiation exposure is of great concern to expecting patients, little information is available on the fetal radiation dose associated with prophylactic internal iliac artery balloon occlusion (IIABO). Here we estimated the fetal radiation dose associated with prophylactic IIABO in Caesarean section (CS). Cases. We report our experience with the IIABO procedure in three consecutive patients with suspected placenta previa/accreta. Fetal radiation dose measurements were conducted prior to each CS by using an anthropomorphic phantom. Based on the simulated value, we calculated the fetal radiation dose as the absorbed dose. We found that the fetal radiation doses ranged from 12.88 to 31.6 mGy. The fetal radiation dose during the prophylactic IIABOs did not exceed 50 mGy. Conclusion. The IIABO procedure could result in a very small increase in the risk of harmful effects to the fetus.
- [Show abstract] [Hide abstract] ABSTRACT: Olanzapine is effective in chemotherapy-induced nausea and vomiting (CINV). In patients receiving highly emetogenic chemotherapy (HEC), its efficacy was reported as rescue therapy for breakthrough emesis refractory to triplet therapy (palonosetron, aprepitant, and dexamethasone). However, its preventive effects with triplet therapy for CINV are unknown. This study aimed to investigate efficacy and safety of preventive use of olanzapine with triplet therapy for CINV of HEC. This study is a prospective multicenter study conducted by Kansai Clinical Oncology Group. Forty chemo-naïve gynecological cancer patients receiving HEC with cisplatin (≥50 mg/m(2)) were enrolled. Oral olanzapine (5 mg) was administered with triplet therapy a day prior to cisplatin administration and on days 1-5. The primary endpoint was complete response (no vomiting and no rescue) rate for the overall phase (0-120 h post-chemotherapy). Secondary endpoints were complete response rate for acute phase (0-24 h post-chemotherapy) and delayed phase (24-120 h post-chemotherapy) and complete control (no vomiting, no rescue, and no significant nausea) rate and total control (no vomiting, no rescue, and no nausea) rate for each phase. These endpoints were evaluated during the first cycle of chemotherapy. Complete response rates for acute, delayed, and overall phases were 97.5, 95.0, and 92.5 %, respectively. Complete control rates were 92.5, 87.5, and 82.5 %, respectively. Total control rates were 87.5, 67.5, and 67.5 %, respectively. There were no grade 3 or 4 adverse events. Preventive use of olanzapine combined with triplet therapy gives better results than those from previously reported studies of triplet therapy.
- [Show abstract] [Hide abstract] ABSTRACT: Lymphoepithelioma-like carcinoma occurring in the reproductive organs is a rare variant of squamous cell carcinoma, and this tumor of the uterine cervix accounts for 0.7% of all primary cervical uterine neoplasms. Associations with Epstein-Barr virus (EBV) and human papilloma virus (HPV) have been demonstrated in some studies. Some investigators suggested that EBV has an important role in the initiation of lymphoepitheliomalike carcinoma in Asian women. Here we report the case of a 45-year-old Japanese woman, gravida 2 and parity 2. She was admitted due to severe atypical genital bleeding caused by uterine cervical cancer. A >60-mm tumor was detected at the uterine cervix, and no distal metastasis or swallowing of lymph nodes was revealed by magnetic resonance imaging and a computed tomography scan. The cervical cancer stage FIGO Ib2 was diagnosed, and a radical hysterectomy was performed for this malignant tumor. The in situ hybridization for EBV was negative. HVP infection was strongly suspected because the squamous cell carcinoma was observed macroscopically in the uterine cervix. The prognosis of uterine lymphoepithelioma-like carcinoma is thought to be better than those of other cervical cancer types, but careful follow-up at fixed intervals is recommended. The patient has been followed up for 4 months since her surgery, and no evidence of recurrence has been detected.
- [Show abstract] [Hide abstract] ABSTRACT: Objective: To assess the involvement of phosphatidylinositol-3 kinase (PI3K)-Akt-mammalian target of rapamycin (mTOR) on the extracellular matrix contractility of endometriotic cells. Materials and methods: The effects of wortmannin, LY294002, Akt inhibitor IV, and Ku-0063794 on the contractility of endometriotic cyst stromal cells (ECSCs) were investigated using collagen gel contraction assay. Results: All four inhibitors of PI3K-Akt-mTOR evaluated in the current study significantly inhibited the contractility of ECSCs. Conclusion: The current findings suggest that the PI3K-Akt-mTOR signaling pathway is involved in the development of endometriosis-associated fibrosis. The PI3K-Akt-mTOR signaling pathway is a promising target for the treatment of endometriosis.
- [Show abstract] [Hide abstract] ABSTRACT: What are the roles of the microRNA miR-210-an miRNA that is up-regulated in endometriotic cyst stromal cells (ECSCs)-in the pathogenesis of endometriosis? Up-regulated miR-210 expression in ECSCs is involved in their proliferation, resistance to apoptosis and angiogenesis through signal transducer and activator of transcription (STAT) 3. In the pathogenesis of endometriosis, a number of roles for microRNAs (miRNAs) are becoming apparent. ECSCs and normal endometrial stromal cells (NESCs) were isolated from ovarian endometriotic tissues (patients aged 24-40 years undergoing salpingo-oophorectomy or evisceration for the treatment of ovarian endometriotic cysts, n = 10) and the eutopic endometrial tissues without endometriosis (premenopausal patients aged 35-45 years undergoing hysterectomies for subserousal leiomyoma, n = 13), respectively. We used a global gene expression microarray technique to identify downstream targets of miR-210, and we assessed the functions of miR-210 in the pathogenesis of endometriosis by using the miR-210-transfected NESCs. Gene expression microarray analysis revealed that one of the key target molecules of miR-210 is STAT3. In the NESCs, in comparison to the control, miR-210 transfection resulted in the induction of cell proliferation (P < 0.0005), the production of vascular endothelial cell growth factor (VEGF) (P < 0.0005) and the inhibition of apoptosis (P < 0.05) through STAT3 activation [increased levels of mRNA (P < 0.0005), and protein (P < 0.005)]. In the ECSCs, inhibitors of STAT3 inhibited the cell proliferation and VEGF production (P < 0.05), and induced the apoptosis of these cells (P < 0.05). The roles of aberrant miR-210 expression were investigated only in the stromal component of ectopic and eutopic endometrium. Control endometrial tissues were obtained from premenopausal patients who had subserosal leiomyoma and NESC gene expression patterns may be altered in these women. Furthermore, the effects of STAT3 inhibitors were evaluated only in ECSCs and not in NESCs. The present findings indicate that miR-210 induces NESCs to differentiate into the endometriotic phenotype and we speculate that up-regulated miR-210 expression in ECSCs is involved in the creation of the endometriosis-specific cellular dysfunctions through epigenetic mechanisms. The data indicate that STAT3 inhibitors may be promising candidates for the treatment of endometriosis. This work was supported in part by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (no. 13237327 to K.N., no. 25861500 to Y.K. and no. 23592407 to H.N.). There are no conflicts of interest to declare. © The Author 2014. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: firstname.lastname@example.org.
- [Show abstract] [Hide abstract] ABSTRACT: Background Glycosylation is one of the most common post-translational modifications of eukaryotic proteins and is known to undergo dynamic changes in a wide range of biological processes. To date, however, the glycan expression profiles in endometriosis are largely unknown. The objective of the study was to identify the panel of glycans that were aberrantly expressed in endometriosis, a hormone-dependent disease. Methods The glycan expression profiles in primary cultured human endometriotic cyst stromal cells (ECSCs) and normal endometrial stromal cells (NESCs) were determined by lectin microarray analysis. Distribution of Wisteria floribunda agglutinin (WFA)-binding glycans in ovarian endometriotic cysts and eutopic proliferative phase endometrium were assessed by lectin histochemistry. The expressions of N-acetylgalactosaminyl transferases that synthesize WFA-binding glycans were evaluated in ECSCs and NESCs. Results We found that the levels of WFA-binding glycans were decreased in ECSCs. Lectin histochemistry revealed that WFA-binding glycans were decreased only in the stromal components of the ovarian endometriotic cysts, but not in the epithelial components, compared to the eutopic proliferative phase endometrium. The expressions of N-acetylgalactosaminyl transferases that synthesize WFA-binding glycans were downregulated in ECSCs. Conclusions Utilizing lectin microarray analysis and lectin histochemistry, we found that WFA-binding glycans were decreased in endometriosis. The synthetic enzymes of WFA-binding glycans were significantly downregulated in ECSCs. It is suggested that reduced expression of N-glycans with WFA-binding properties on ECSCs is a novel characteristics of endometriosis.
- [Show abstract] [Hide abstract] ABSTRACT: Mayer-Rokitanski-Kuster-Hauser (MRKH) syndrome is a rare disease. A 27-year-old woman was admitted for primary amenorrhea and cyclic pelvic pain. Magnetic resonance imaging (MRI) revealed bilateral Müllerian remnants with functioning endometrium and a pelvic mass considered to be an endometriotic cyst. Bilateral Müllerian remnants were removed, and right ovarian cystectomy was performed at laparoscopic surgery. Accurate evaluation before the operation and informed consent are necessary to treat patients with MRKH syndrome.
- [Show abstract] [Hide abstract] ABSTRACT: While mature cystic teratoma of the ovary is the most common ovarian tumor in young women, immature teratoma is a very rare tumor, representing only 1% of all ovarian cancers. In the three cases presented here, young women who were suspected to have mature cystic teratoma, based on CT scan and MRI, were ultimately diagnosed with immature teratoma Ic (b) G1 after laparoscopic operation. They underwent salpingo-oophorectomy of the affected side only and have shown no sign of recurrence during follow-up. We sometimes encounter patients with immature teratoma who have no findings pointing to malignancy on CT or MRI. Generally, if the components of immature nerve cells that represent immature teratoma are very few, it is difficult to diagnose the entity as immature teratoma with imaging evaluations such as CT or MRI. In many hospitals, laparoscopic surgery is selected for patients with ovarian mature teratoma. Therefore, it is essential to attempt as much as possible not to disseminate the fluid content of the tumor into the intra-abdominal space during laparoscopic operation, because in rare cases the tumor turns out not to be benign mature teratoma.
- [Show abstract] [Hide abstract] ABSTRACT: A 33-year-old woman with type 2 diabetes mellitus (DM) was suspected of being primarily infected with Toxoplasma gondii at 12 weeks of gestation (GW). Although acetylspiramycin was started at 17 GW, the T. gondii DNA gene was detected in the amniotic fluid at 18 GW. Chemotherapy was changed to pyrimethamine plus sulfadiazine from 20 GW, but was changed back to acetylspiramycin after 2 weeks because of vomiting. Acetylspiramycin was continued until her delivery. DM was controlled well during the pregnancy. An asymptomatic male baby was born by cesarean section at 37 GW, and was treated with acetylspiramycin for 4 weeks because the polymerase chain reaction results of umbilical cord blood were positive. He has developed normally until the present, that is, 6 months of age. Herein, we describe a case report in which symptomatic congenital toxoplasmosis was avoided in a pregnant woman with an immunosuppressive risk due to prompt chemotherapy.
- [Show abstract] [Hide abstract] ABSTRACT: Purpose: Gastrointestinal involvement of endometriosis may exist in up to 37% of women suffering from endometriosis, but malignant transformation of intestinal endometriosis is extremely rare. In this case report, we present a case of endometrioid adenocarcinoma arising from 2 different large bowel endometriotic sites, with a review of the reported cases of epithelial malignancies developed in gastrointestinal endometriosis. Case: A 33-year-old nulligravid Japanese woman was admitted for the evaluation of massive ascites. The patient had undergone a laparoscopic bilateral cystectomy for bilateral endometriomas 8 years before. At laparotomy, we found massive serous ascites, diffuse peritoneal endometriotic lesions, edematous gastrointestinal tract with small surface nodules, stenosis of the sigmoid colon and firm and thick peritoneum. No endometriotic or tumorous lesions were found in the genital tract. The patient underwent a resection of the sigmoid colon, partial resection of the transverse colon, partial omentectomy and multiple biopsies of the peritoneum and ovaries. On the histologic examination, benign endometriosis, atypical hyperplasia and grade 1 endometrioid adenocarcinoma were found to be present in the transverse and sigmoid colon. Subsequently, the patient was treated with chemotherapy consisting of paclitaxel and carboplatin under a diagnosis of endometrioid adenocarcinoma arising in the intestinal endometriosis. The patient is well without evidence of disease 26 months following the surgery. Conclusions: The tumors arising from intestinal endometriosis can clinically and pathologically mimic primary neoplasms of the gastrointestinal tract. Recognition of these lesions is important because primary gastrointestinal neoplasms are managed differently from those arising in endometriosis, and these differences may have significant clinical implications.
Ōita, Ōita, Japan
- Department of Obstetrics and Gynecology