Hypoxia Promotes Extravillous Trophoblast Cell Invasion through the Hypoxia-Inducible Factor Urokinase-Type Plasminogen Activator Receptor Pathway.

OBJECTIVES: Hypoxia is a common feature of extravillous trophoblast (EVT) cells that promote invasion during the early stages of human placentation. This study aimed to examine whether hypoxia-induced an invasive phenotype in EVT cells in vitro and explore the underlying molecular mechanisms. DESIGN: The invasiveness of primary EVT cells isolated from the first trimester placental tissues during weeks 5-8 of gestation was examined under hypoxic (5% O2) and normoxic (20% O2) conditions. METHODS: Invasiveness was determined by transwell and wound-healing invasion assays using the IncuCyte ZOOM™ Live-Cell Imaging System. Protein expression of the urokinase plasminogen activator (uPA), uPA receptor (uPAR), and plasminogen activator inhibitor of hypoxia or normoxia-treated cells was measured using Western blot analysis. Knockdown of hypoxia-inducible factor-1 alpha (HIF-1α) was assessed using small interfering RNA (siRNA). RESULTS: Hypoxia enhanced EVT cell invasion but did not affect apoptosis. The stimulatory effect of hypoxia on EVT cell invasiveness was associated with induction of the uPA-uPAR pathway. The synthetic inhibitor of uPAR significantly inhibited hypoxia-induced EVT cell invasion. Silencing of HIF-1α by siRNA abolished the stimulatory effect of hypoxia and inhibited the upregulation of uPAR expression, suggesting that the HIF-1α-uPAR signal is the key mediator for hypoxia-induced EVT cell invasion. Further experiments need to be performed to elucidate the HIF-1α-uPAR signal pathways. CONCLUSIONS: The low oxygen-regulated early events of EVT invasion may be mediated by the HIF-1α-uPAR pathway.

Involvement of Visceral Adipose Tissue in Immunological Modulation of Inflammatory Cascade in Preeclampsia.

OBJECTIVES: The pathophysiology of preeclampsia is characterized by abnormal placentation, an exaggerated inflammatory response, and generalized dysfunction of the maternal endothelium. We investigated the effects of preeclampsia serum on the expression of inflammation-related genes by adipose tissue. MATERIALS AND METHODS: Visceral adipose tissue was obtained from the omentum of patients with early ovarian cancer without metastasis. Adipose tissue was incubated with sera obtained from either five women affected with severe preeclampsia or five women from control pregnant women at 37°C in a humidified incubator at 5% CO2 for 24 hours. 370 genes in total mRNA were analyzed with quantitative RT-PCR (Inflammatory Response & Autoimmunity gene set). RESULTS: Gene expression analysis revealed changes in the expression levels of 30 genes in adipose tissue treated with preeclampsia sera. Some genes are related to immune response, oxidative stress, insulin resistance, and adipogenesis, which plays a central role in excessive systemic inflammatory response of preeclampsia. In contrast, other genes have shown beneficial effects in the regulation of Th2 predominance, antioxidative stress, and insulin sensitivity. CONCLUSION: In conclusion, visceral adipose tissue offers protection against inflammation, oxidative insults, and other forms of cellular stress that are central to the pathogenesis of preeclampsia.

Mechanism of pain generation for endometriosis-associated pelvic pain.

PURPOSE: Endometriosis-associated pelvic pain appears due to persistent nociceptive stimulation, but the precise mechanisms remain poorly understood. METHODS: A search was conducted to screen and select articles from PubMed. MAIN RESULTS: Neurotrophins (NTs), a family of neuronal growth factors, are overexpressed in endometriosis and encompass NGF, BDNF and NT-3 and NT-4/5. NT receptors, TrkA and p75NTR, and NT receptor-interacting proteins, MAGE and NDN, were also expressed. NTs and their receptors play a role in the development and maintenance of neural tissues in non-neuronal cell types such as endometriosis. Nerve fibers contain unmyelinated sensory C, myelinated sensory Adelta and adrenergic nerve fibers that innervate abnormal cell growths. An increased release of proinflammatory cytokines from endometriotic lesions is responsible for the excessive sensory innervation and development of chronic pelvic pain. CONCLUSIONS: The preponderance of the inflammatory milieu and subsequent hyperinnervation might be involved in the pathophysiology of pain generation in women with endometriosis.

Evaluation of the relation between patient characteristics and the state of chemotherapy-induced nausea and vomiting in patients with gynecologic cancer receiving paclitaxel and carboplatin.

PURPOSE: An antiemetic regimen for patients taking paclitaxel and carboplatin (TC) includes dexamethasone (20 mg) to protect against hypersensitivity. Chemotherapy-induced nausea and vomiting (CINV), however, is difficult to adequately control in patients receiving TC. In the present study, we retrospectively investigated risk factors for CINV in patients receiving TC with this antiemetic regimen based on a questionnaire. METHODS: Eligible patients were diagnosed with gynecologic cancer and receiving paclitaxel (175 mg/m(2)) intravenously for 3 h and carboplatin (area under the curve 5 mg/mL per min) on day 1 every 3 weeks in our institution, and treated with granisetron (3 mg) and dexamethasone (20 mg) for antiemesis. Data of nausea and vomiting assessed by Common Terminology Criteria for Adverse Events version4.0 were collected from the medical records. Patients were asked to complete a questionnaire including items such as age and hyperemesis. Logistic regression analysis was used to evaluate univariate and independent multivariate associations with items on nausea of grade 2 or greater and vomiting of grade 1 or greater. RESULTS: On univariate logistic analysis, no item was significantly associated with nausea of grade 2 or greater. Hypertension and hyperemesis gravidarum and adjuvant chemotherapy were significantly associated with delayed vomiting of grade 1 or greater. Multivariate analysis was performed with delayed vomiting of grade 1 or greater as an endpoint, and the resulting independent items were hypertension and hyperemesis gravidarum. CONCLUSIONS: The present study showed that the risk factor for delayed vomiting of grade 1 or higher was a history of hyperemesis gravidarum in patients receiving conventional TC with dexamethasone (20 mg) and granisetron. Therefore, in patients with this risk factor, criteria of major organizations should be followed first.

Risk factors for wound complications after surgery for gynecologic malignancies.

INTRODUCTION: Factors in wound complications such as surgical duration and suture methods are surgeon-side problems. The purpose of the present study was to retrospectively evaluate the incidence of wound complications in patients who underwent wound closure with stainless steel staples or subcuticular sutures in surgery for gynecologic malignancies and to retrospectively determine the risk factors for wound complications. PATIENTS AND METHODS: From April 2007 through March 2012, a cohort of 317 consecutive patients undergoing surgery for gynecologic malignancies was evaluated in the retrospective study. The skin was closed with stainless steel staples before March 2010 (staples group). From April 2010, the skin was closed by subcuticular suturing (subcuticular group). We compared the incidence of wound complications between 2 groups and evaluated independent multivariate associations with the effect of clinical parameters on occurrence of wound complications. RESULTS: The incidence of wound disruption was 7.3% (23/317): 12.1% (17/140) in the staples group and 3.4% (6/177) in the subcuticular group (P = 0.0029). The incidence of wound infection was 2.5% (8/317): 5.0% (7/140) in the staples group and 0.6% (1/177) in the subcuticular group (P = 0.0124). Multivariate analyses performed with wound disruption as the end point revealed long-term steroid treatment, subcutaneous thickness, and skin staples as independent predictors. Subcutaneous thickness and skin staples were independent factors significantly associated with the possibility of wound infection. CONCLUSION: The findings of the present study indicated that risk factors for wound complications after surgeries for gynecologic malignancies include, as a surgeon-side problem, the use of staples for skin closure, and as a patient-side problem, a subcutaneous thickness of more than 30 mm.

[A case of recurrent endometrial cancer metastasis successfully treated with zoledronic Acid].

Although metastasis to the bone is common in solid tumors, it seldom occurs in endometrial cancer. A rare case of endometrial carcinoma that presented wth symptoms of bone metastasis in the right ischium and treated successfully by zoledronic acid is described. A 57-year-old woman presented with pain of the right ischium. Computed tomography and magnetic resonance imaging revealed bone metastasis and enlargement of the uterus. Endometrial biopsy confirmed endometrial adenocarcinoma. The patient underwent total abdominal hysterectomy, bilateral salpingo-oophorectomy and biopsy of the ischium. Postoperatively, the patient received six courses of chemotherapy using paclitaxel and carboplatin. However, pain of the right-ischium reappeared 9 months after surgery. The patient was treated with 4 mg of zoledronic acid every 4 weeks. After 4 cycles of treatment, the visual analogue scale regressed from 70 to 10. Zoledronic acid can palliate bone pain caused by a variety of endometrial cancers.

Role of Oxidative Stress in Epigenetic Modification in Endometriosis.

Aberrant DNA methylation and histone modification are associated with an increased risk of reproductive disorders such as endometriosis. However, a cause-effect relationship between epigenetic mechanisms and endometriosis development has not been fully determined. This review provides current information based on oxidative stress in epigenetic modification in endometriosis. This article reviews the English-language literature on epigenetics, DNA methylation, histone modification, and oxidative stress associated with endometriosis in an effort to identify epigenetic modification that causes a predisposition to endometriosis. Oxidative stress, secondary to the influx of hemoglobin, heme, and iron during retrograde menstruation, is involved in the expression of CpG demethylases, ten-eleven translocation, and jumonji (JMJ). Ten-eleven translocation and JMJ recognize a wide range of endogenous DNA methyltransferases (DNMTs). The increased expression levels of DNMTs may be involved in the subsequent downregulation of the decidualization-related genes. This review supports the hypothesis that there are at least 2 distinct phases of epigenetic modification in endometriosis: the initial wave of iron-induced oxidative stress would be followed by the second big wave of epigenetic modulation of endometriosis susceptibility genes. We summarize the recent advances in our understanding of the underlying epigenetic mechanisms focusing on oxidative stress in endometriosis.

Pathogenesis and malignant transformation of adenomyosis (review).

The aim of our review was to identify the current information with regard to the pathogenesis and malignant transformation of adenomyosis. The current literature was reviewed by searching MEDLINE/PubMed, using the following keywords: adenomyosis, myometrium, stromal cells, malignant transformation, pathogenesis, etiology, genome-wide and microarray. Early signs of the development of adenomyosis are considered to be the penetration of stromal cells into the inner layer of the myometrium. Adenomyosis smooth muscle cells are developed, possibly, through a remodeling pathway via reactivation of coelomic epithelial cells as a result of estrogen-induced epithelial mesenchymal transition. Smooth muscle cell hyperplasia and hypertrophy are a reflection of a reaction of the surrounding tissue. The development of adenocarcinoma arising from adenomyosis is a relatively rare occurrence. In our literature review, to date, 44 cases of malignant tumors arising from adenomyosis have been documented. Studies reporting results of genetic abnormalities, epigenetic changes, monoclonal expansion, mutational analysis and the inactivation of specific tumor suppressor genes are very few in this field. In conclusion, adenomyosis can be a precursor of some carcinomas. The exact molecular mechanisms that lead to the malignant transformation are poorly understood.

The biology of uterine sarcomas: A review and update.

Uterine sarcoma is a rare neoplasm, accounting for only 5% of uterine malignancies. The pathogenesis of uterine sarcoma remains largely unknown, although recent basic science and pre-clinical animal models have provided a better understanding of tumor biology. The aim of this study was to review the clinical features, imaging characteristics, genetic aberrations and therapeutic approaches in uterine sarcoma. This study reviewed the English-language literature on clinical and basic studies on uterine sarcoma. The common variants of uterine sarcoma are carcinosarcoma, leiomyosarcoma and endometrial stromal sarcoma (ESS). Genetic profiling efforts have identified amplification, overexpression and mutation, while the molecular mechanisms of tumorigenesis driven by these genomic and genetic aberrations have yet to be fully elucidated yet. Recent genome-wide studies have also identified complex chromosomal rearrangements as oncogenic mechanisms. The cell cycle regulators, p16 and p53, are frequently over-expressed and appear to be involved in key modifications of sarcomagenesis. Molecular-targeted therapy has now been evaluated in clinical trials for certain subtypes. In conclusion, aberrations of cell cycle control would be a critical step in the development of uterine sarcoma. This review has provided new areas of study targeting molecular and genetic pathways.

CA-125 cut-off value as a predictor for complete interval debulking surgery after neoadjuvant chemotherapy in patients with advanced ovarian cancer.

OBJECTIVE: In the present study, we evaluated changes in CA-125 cut-off values predictive of complete interval debulking surgery (IDS) after neoadjuvant chemotherapy (NAC) using receiver operating characteristic (ROC) analysis. METHODS: This retrospective single-institution study included patients with International Federation of Gynecology and Obstetrics (FIGO) stage III epithelial ovarian cancer and a pre-NAC serum CA-125 level of greater than 40 U/mL who were treated with neoadjuvant platinum-based chemotherapy followed by IDS between 1994 and 2009. Logistic regression analysis was used to evaluate univariate and independent multivariate associations with the effect of clinical, pathological, and CA-125 parameters on complete IDS, and ROC analysis was used to determine potential cut-off values of CA-125 for prediction of the possibility of complete IDS. RESULTS: Seventy-five patients were identified. Complete IDS was achieved in 46 (61.3%) patients and non-complete IDS was observed 29 (38.7%). Median pre-NAC CA-125 level was 639 U/mL (range, 57 to 6,539 U/mL) in the complete IDS group and 1,427 U/mL (range, 45 to 10,989 U/mL) in the non-complete IDS group. Median pre-IDS CA-125 level was 15 U/mL (range, 2 to 60 U/mL) in the complete IDS group and 53 U/mL (range, 5 to 980 U/mL) in the non-complete IDS group (p<0.001). Multivariate analyses performed with complete IDS as the endpoint revealed only pre-IDS CA-125 as an independent predictor. The odds ratio of non-complete IDS was 10.861 when the pre-IDS CA-125 level was greater than 20 U/mL. CONCLUSION: The present data suggest that in the setting of IDS after platinum-based NAC for advanced ovarian cancer, a pre-IDS CA-125 level less than 20 U/mL is an independent predictor of complete IDS.

Endometrial cancer diagnosed by the presence of bone metastasis and treated with zoledronic Acid: a case report and review of the literature.

Bone metastasis from endometrial cancer is rare. We report a case of endometrial cancer which was diagnosed by the presence of bone metastasis and treated with zoledronic acid. A 57-year-old woman complaining of progressive right hip pain consulted an orthopedist. She had no gynecologic complaints. X-rays revealed an osteolytic lesion of the right ischium. Bone scintigraphy was subsequently carried out and showed isotope accumulation in the right ischium. Computed tomography revealed an enlarged uterus; the patient consequently consulted a gynecologist. Histological sections of an endometrial biopsy showed endometrioid adenocarcinoma. Hysterectomy and bilateral salpingo-oophorectomy, as well as bone biopsy of the right ischium, were therefore carried out. A moderately differentiated endometrioid adenocarcinoma was expressed in the corpus. Histopathological examination of the bone biopsy also revealed adenocarcinoma. The final diagnosis was stage IVB endometrial cancer with bone and lung metastasis. Good pain relief was achieved due to chemotherapy. However, 2 months after completion of the chemotherapy, the patient was administered zoledronic acid because her hip pain had gradually increased. Following zoledronic acid administration, the hip pain reduced. Radiotherapy was then given for the right ischial metastasis after the ninth course of zoledronic acid therapy because the metastasis site had increased and the possibility of a pathological fracture had risen. However, the patient died 21 months after the initial treatment because of disease progression.