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Sample records for gestational trophoblastic tumors

  1. SALL4 expression in gestational trophoblastic tumors: a useful tool to distinguish choriocarcinoma from placental site trophoblastic tumor and epithelioid trophoblastic tumor.

    PubMed

    Stichelbout, Morgane; Devisme, Louise; Franquet-Ansart, Hélène; Massardier, Jérôme; Vinatier, Denis; Renaud, Florence; Kerdraon, Olivier

    2016-08-01

    SALL4 has important functions in embryonic stem cells. The aim of this study was to investigate SALL4 expression in gestational trophoblastic neoplasia. We hypothesized that it could help to distinguish choriocarcinoma, the presumed most primitive form of gestational trophoblastic neoplasia, from placental site trophoblastic tumor and epithelioid trophoblastic tumor, which would be more differentiated variants. This study included 31 gestational trophoblastic neoplasias: 19 choriocarcinomas, 9 placental site trophoblastic tumors, 1 epithelioid trophoblastic tumor, and 2 mixed tumors comprising a placental site trophoblastic tumor and an epithelioid trophoblastic tumor. Unlike usual markers of gestational trophoblastic neoplasia (p63, human chorionic gonadotrophin and human placental lactogen), SALL4 was expressed in 100% of choriocarcinomas and it was not detected in any placental site trophoblastic tumor and epithelioid trophoblastic tumor. However, the proportion of positive cells varied in a wide range, from 10% to 70%, reflecting the fact that SALL4 was specifically present in mononuclear cells consistent with neoplastic cytotrophoblast. So, SALL4 may be helpful in the differential diagnosis of gestational trophoblastic neoplasias. Copyright © 2016 Elsevier Inc. All rights reserved.

  2. Gestational trophoblastic tumor with liver metastasis after misoprostol abortion.

    PubMed

    Mousavi, S A; Behnamfar, F

    2009-04-01

    Early elective medical abortion is performed frequently in different countries of the world. Serious complications like gestational trophoblastic neoplasia (GTN) are uncommon and mostly nonmetastatic. High risk metastatic GTN following medical abortion is a rare event which may occur coincidentally. A 26 year-old-woman, gravida 2 para 1, 6 weeks after misoprostol abortion presented with sever nausea, vomiting, and right upper abdominal pain. Human chorionic gonadotropin (hCG) level was 2,500,000 mIU/ml and metastatic work up revealed multiple liver metastases. She totally received nine cycles of EMA-CO (ethoposide- methotrexate- actinomycin- cyclophosphamide, vincristine) regimen for treatment and consolidation. Six months after treatment she is in complete remission. Follow up of patients after medical abortion by means of single serum hCG measurement is highly recommended for early diagnosis of complications including gestational trophoblastic tumor. EMA-CO regimen seems to be an effective and safe treatment for liver metastatic gestational trophoblastic neoplasia.

  3. Clinicopathologic Analysis of Postchemotherapy Gestational Trophoblastic Neoplasia: An Entity Overlapping With Epithelioid Trophoblastic Tumor.

    PubMed

    Lu, Bingjian; Zhang, Xiaofei; Liang, Yun

    2016-11-01

    Surgery is generally not required for the majority of gestational trophoblastic neoplasias (GTNs) because they are potentially curable by chemotherapy alone. The histologic assessment is rarely available although the identification of a specific subtype of GTN is relevant to clinical intervention and prognostic prediction. In this study, we analyzed the clinicopathologic features of 4 postchemotherapy GTNs. They presented as a persistent uterine (Cases 1, 2, and 3) or pelvic mass (Case 4) with a raised serum β-hCG level after multiple courses of chemotherapy. All patients were alive without evidence of disease at follow-up periods of 58 to 109 mo after surgery and salvage chemotherapy except for Case 4 which had a recurrent pelvic mass. These GTNs had a characteristic histopathologic pattern of extensive necrosis and a rim of scant viable mononucleated tumor cells at the periphery of the lesion. Immunostaining showed that these tumor cells had a lower Ki67 index than choriocarcinoma, and epithelioid trophoblastic cell tumor although they exhibited an epithelioid trophoblastic cell tumor-like immunostaining pattern (CD146, hPL, and p63). A small number of β-hCG-positive multinucleated trophoblastic cells were also present in 3 of the 4 cases. We suggest that these postchemotherapy GTNs may represent a "snap shot" of the hypothetical choriocarcinoma-epithelioid trophoblastic cell tumor transition. Our findings should provide insights into the pathogenesis of GTNs.

  4. [Gestational trophoblastic disease].

    PubMed

    Allias, Fabienne; Bolze, Pierre-Adrien; Gaillot-Durand, Lucie; Devouassoux-Shisheboran, Mojgan

    2014-12-01

    Gestational trophoblastic disease encompresses a group of interrelated diseases, following a pregnancy after a variable period of time. Hydatiform mole corresponds to premalignant disorders composed of villi with excess of paternal genetic material, with a malignant potential more important for complete mole than partial mole. Gestational trophoblastic neoplasia includes invasive mole, choriocarcinoma, placental site trophoblatic tumor and epithelioid trophoblastic tumor. Their histological diagnosis may be problematic on curettage material and needs to be correlated to serum hCG level and radiological findings. The use of chemotherapy has dramatically improved the prognosis of these lesions. All patients with this rare disease need to be registered in the national service for gestational trophoblastic disease (http://www.mole-chorio.com), which coordinates their management at the national level. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  5. Gestational trophoblastic disease

    MedlinePlus

    ... page: //medlineplus.gov/ency/article/007333.htm Gestational trophoblastic disease To use the sharing features on this page, please enable JavaScript. Gestational trophoblastic disease (GTD) is a group of conditions in which ...

  6. Gestational trophoblastic disease.

    PubMed

    Seckl, Michael J; Sebire, Neil J; Berkowitz, Ross S

    2010-08-28

    Gestational trophoblastic disease encompasses a range of pregnancy-related disorders, consisting of the premalignant disorders of complete and partial hydatidiform mole, and the malignant disorders of invasive mole, choriocarcinoma, and the rare placental-site trophoblastic tumour. These malignant forms are termed gestational trophoblastic tumours or neoplasia. Improvements in management and follow-up protocols mean that overall cure rates can exceed 98% with fertility retention, whereas most women would have died from malignant disease 60 years ago. This success can be explained by the development of effective treatments, the use of human chorionic gonadotropin as a biomarker, and centralisation of care. We summarise strategies for management of gestational trophoblastic disease and address some of the controversies and future research directions. Copyright 2010 Elsevier Ltd. All rights reserved.

  7. Color Doppler energy and related quantitative analysis of gestational trophoblastic tumors.

    PubMed

    Xie, H; Hata, K; Lu, M; Kong, Q; Miyazaki, K

    1999-06-01

    To assess the reliability of color Doppler energy (CDE) and a related quantitative analysis for detection and follow-up of uterine involvement in gestational trophoblastic tumor. CDE was performed in 19 patients with trophoblastic tumor, in 25 women in early pregnancy and 25 non-pregnant women. The blood flow area ratio (BFAR) in CDE was used as an index representing uterine involvement. In nine of the 19 patients, BFAR was measured before, during and at termination of chemotherapy. The BFAR (mean +/- S.D.) of uterine profiles in 19 patients (39.9 +/- 1.3%) was significantly higher than that in 25 pregnant women (24.6 +/- 10.1%, P = 0.002) and in 25 non-pregnant women (14.8 +/- 5.7%, P = 0.001). In the follow-up of nine patients, when beta-hCG was less than 3.1 ng/ml during the treatment, the BFAR (38.7 +/- 11.9%) decreased below that (44.2 +/- 14.6%) seen prior to treatment (P = 0.009) and was much lower at termination of treatment (27.5 +/- 12.3%, P = 0.048). These data support the use of CDE and the related quantitative analysis as a new method for detecting and follow-up of uterine involvement in patients with trophoblastic tumors.

  8. Gestational trophoblastic disease.

    PubMed

    Tse, K Y; Ngan, Hextan Y S

    2012-06-01

    Most women with gestational trophoblastic disease are of reproductive age. Because the disease is readily treatable with favourable prognosis, fertility becomes an important issue. Hydatidiform mole is a relatively benign disease, and most women do not require chemotherapy after uterine evacuation. A single uterine evacuation has no significant effect on future fertility, and pregnancy outcomes in subsequent pregnancies are comparable to that of the general population, despite a slight increased risk of developing molar pregnancy again. If women develop persistent trophoblastic disease, single or combined chemotherapy will be needed. Although ovarian dysfunction after chemotherapy is a theoretical risk, a term live birth rate of higher than 70% has been reported without increased risk of fetal abnormalities. Successful pregnancies have also been reported after choriocarcinoma. Only a few case reports have been published on fertility-sparing treatment in placental-site trophoblastic tumour, and the successful rate is about 67%. Women are advised to refrain from pregnancy for at least 6 months after a molar pregnancy, and at least 12 months after a gestational trophoblastic neoplasia. Most of the contraceptive methods do not have an adverse effect on the return of fertility. Finally, at least one-half of these women suffer from some form of psychological or sexual problems. Careful counselling and involvement of a multi-disciplinary team are mandated. Copyright © 2012 Elsevier Ltd. All rights reserved.

  9. Gestational trophoblastic disease I: epidemiology, pathology, clinical presentation and diagnosis of gestational trophoblastic disease, and management of hydatidiform mole.

    PubMed

    Lurain, John R

    2010-12-01

    Gestational trophoblastic disease includes hydatidiform mole (complete and partial) and gestational trophoblastic neoplasia (invasive mole, choriocarcinoma, placental site trophoblastic tumor, and epithelioid trophoblastic tumor). The epidemiology, pathology, clinical presentation, and diagnosis of each of these trophoblastic disease variants are discussed. Particular emphasis is given to management of hydatidiform mole, including evacuation, twin mole/normal fetus pregnancy, prophylactic chemotherapy, and follow-up. Copyright © 2010 Mosby, Inc. All rights reserved.

  10. Gestational trophoblastic disease II: classification and management of gestational trophoblastic neoplasia.

    PubMed

    Lurain, John R

    2011-01-01

    Gestational trophoblastic neoplasia (GTN) includes invasive mole, choriocarcinoma, placental site trophoblastic tumor, and epithelioid trophoblastic tumor. The overall cure rate in treating these tumors is currently >90%. Thorough evaluation and staging allow selection of appropriate therapy that maximizes chances for cure while minimizing toxicity. Nonmetastatic (stage I) and low-risk metastatic (stages II and III, score <7) GTN can be treated with single-agent chemotherapy resulting in a survival rate approaching 100%. High-risk GTN (stages II-IV, score ≥7) requires initial multiagent chemotherapy with or without adjuvant radiation and surgery to achieve a survival rate of 80-90%. Copyright © 2011 Mosby, Inc. All rights reserved.

  11. Gestational Trophoblastic Disease: Clinical and Imaging Features.

    PubMed

    Shaaban, Akram M; Rezvani, Maryam; Haroun, Reham R; Kennedy, Anne M; Elsayes, Khaled M; Olpin, Jeffrey D; Salama, Mohamed E; Foster, Bryan R; Menias, Christine O

    2017-01-01

    Gestational trophoblastic disease (GTD) is a spectrum of both benign and malignant gestational tumors, including hydatidiform mole (complete and partial), invasive mole, choriocarcinoma, placental site trophoblastic tumor, and epithelioid trophoblastic tumor. The latter four entities are referred to as gestational trophoblastic neoplasia (GTN). These conditions are aggressive with a propensity to widely metastasize. GTN can result in significant morbidity and mortality if left untreated. Early diagnosis of GTD is essential for prompt and successful management while preserving fertility. Initial diagnosis of GTD is based on a multifactorial approach consisting of clinical features, serial quantitative human chorionic gonadotropin (β-hCG) titers, and imaging findings. Ultrasonography (US) is the modality of choice for initial diagnosis of complete hydatidiform mole and can provide an invaluable means of local surveillance after treatment. The performance of US in diagnosing all molar pregnancies is surprisingly poor, predominantly due to the difficulty in differentiating partial hydatidiform mole from nonmolar abortion and retained products of conception. While GTN after a molar pregnancy is usually diagnosed with serial β-hCG titers, imaging plays an important role in evaluation of local extent of disease and systemic surveillance. Imaging also plays a crucial role in detection and management of complications, such as uterine and pulmonary arteriovenous fistulas. Familiarity with the pathogenesis, classification, imaging features, and treatment of these tumors can aid in radiologic diagnosis and guide appropriate management. (©)RSNA, 2017.

  12. Gestational trophoblastic disease: an overview.

    PubMed

    Monchek, Ruth; Wiedaseck, Susan

    2012-01-01

    This article reviews the different disease entities that fall under the classification of gestational trophoblastic disease (GTD). The conditions included range from molar pregnancy to the malignant forms of gestational trophoblastic neoplasm (GTN). These disorders all arise from abnormal placental trophoblastic development. The different types of GTD, symptomatology, and diagnostic modalities are examined. The various methods of treatment are reviewed. Although the management of GTD and GTN falls outside the scope of midwifery practice, midwives need to be aware of the incidence, risk factors, and symptoms for specific types of GTD in order to be able to diagnose and refer for treatment in a timely manner. Psychosocial aspects that affect the woman who has not only had a pregnancy loss but also may be faced with a life-threatening illness are examined. The role of the midwife in the management, counseling, and follow-up of GTD and GTN is discussed. © 2012 by the American College of Nurse-Midwives.

  13. Is Doppler ultrasound useful for evaluating gestational trophoblastic disease?

    PubMed

    Lin, Lawrence H; Bernardes, Lisandra S; Hase, Eliane A; Fushida, Koji; Francisco, Rossana P V

    2015-12-01

    Doppler ultrasound is a non-invasive method for evaluating vascularization and is widely used in clinical practice. Gestational trophoblastic neoplasia includes a group of highly vascularized malignancies derived from placental cells. This review summarizes data found in the literature regarding the applications of Doppler ultrasound in managing patients with gestational trophoblastic neoplasia. The PubMed/Medline, Web of Science, Cochrane and LILACS databases were searched for articles published in English until 2014 using the following keywords: "Gestational trophoblastic disease AND Ultrasonography, Doppler." Twenty-eight articles met the inclusion criteria and were separated into the 4 following groups according to the aim of the study. (1) Doppler ultrasound does not seem to be capable of differentiating partial from complete moles, but it might be useful when evaluating pregnancies in which a complete mole coexists with a normal fetus. (2) There is controversy in the role of uterine artery Doppler velocimetry in the prediction of development of gestational trophoblastic neoplasia. (3) Doppler ultrasound is a useful tool in the diagnosis of gestational trophoblastic neoplasia because abnormal myometrial vascularization and lower uterine artery Doppler indices seem to be correlated with invasive disease. (4) Lower uterine artery Doppler indices in the diagnosis of gestational trophoblastic neoplasia are associated with methotrexate resistance and might play a role in prognosis. Several studies support the importance of Doppler ultrasound in the management of patients with gestational trophoblastic neoplasia, particularly the role of Doppler velocimetry in the prediction of trophoblastic neoplasia and the chemoresistance of trophoblastic tumors. Doppler findings should be used as ancillary tools, along with human chorionic gonadotropin assessment, in the diagnosis of gestational trophoblastic neoplasia.

  14. Is Doppler ultrasound useful for evaluating gestational trophoblastic disease?

    PubMed Central

    Lin, Lawrence H; Bernardes, Lisandra S; Hase, Eliane A; Fushida, Koji; Francisco, Rossana P V

    2015-01-01

    Doppler ultrasound is a non-invasive method for evaluating vascularization and is widely used in clinical practice. Gestational trophoblastic neoplasia includes a group of highly vascularized malignancies derived from placental cells. This review summarizes data found in the literature regarding the applications of Doppler ultrasound in managing patients with gestational trophoblastic neoplasia. The PubMed/Medline, Web of Science, Cochrane and LILACS databases were searched for articles published in English until 2014 using the following keywords: “Gestational trophoblastic disease AND Ultrasonography, Doppler.” Twenty-eight articles met the inclusion criteria and were separated into the 4 following groups according to the aim of the study. 1 Doppler ultrasound does not seem to be capable of differentiating partial from complete moles, but it might be useful when evaluating pregnancies in which a complete mole coexists with a normal fetus. 2 There is controversy in the role of uterine artery Doppler velocimetry in the prediction of development of gestational trophoblastic neoplasia. 3 Doppler ultrasound is a useful tool in the diagnosis of gestational trophoblastic neoplasia because abnormal myometrial vascularization and lower uterine artery Doppler indices seem to be correlated with invasive disease. 4 Lower uterine artery Doppler indices in the diagnosis of gestational trophoblastic neoplasia are associated with methotrexate resistance and might play a role in prognosis. CONCLUSION: Several studies support the importance of Doppler ultrasound in the management of patients with gestational trophoblastic neoplasia, particularly the role of Doppler velocimetry in the prediction of trophoblastic neoplasia and the chemoresistance of trophoblastic tumors. Doppler findings should be used as ancillary tools, along with human chorionic gonadotropin assessment, in the diagnosis of gestational trophoblastic neoplasia. PMID:26735221

  15. [Gestational trophoblastic disease--literature review].

    PubMed

    Milenković, Vera; Lazović, Biljana

    2011-01-01

    Gestational trophoblastic disease is characterized by abnormal proliferation of pregnancy-associated trophoblastic tissue with malignant potential. Gestational trophoblastic disease covers a spectrum of conditions including hydatidiform mole, invasive mole, choriocarcinoma and placental site trophoblastic tumour. It is very important to understand the pathophysiology and natural history of the disease in order to achieve faster recognition and effective treatment. The presence and course of the disease can be monitored with quantitative levels of human chorionic gonadotrophin in all cases. Clinical signs and symptoms are usually insufficient to diagnose and predict the extent of disease. Nowadays, gestational trophoblastic diseases are the best treated gynaecological malignancy thanks to modern technology. This review covers various aspects of gestational trophoblastic disease: its development, epidemiology, aetiology and pathogenesis, as well as its classification, clinical manifestations and diagnostic methods.

  16. Effects of single-agent and combination chemotherapy for gestational trophoblastic tumors on risks of second malignancy and early menopause.

    PubMed

    Savage, Philip; Cooke, Rosie; O'Nions, Jenny; Krell, Jon; Kwan, Amy; Camarata, Michelle; Dancy, Gairin; Short, Dee; Seckl, Michael J; Swerdlow, Anthony

    2015-02-10

    To assess the risks of second malignancy and early menopause in a large cohort of patients with gestational trophoblastic tumor who were treated with chemotherapy. A survey of patients treated at Charing Cross Hospital between 1958 and 2000 was performed in 2006 to assemble incidence data for subsequent malignancies and the age at menopause. Treatment records were reviewed for the regimens and durations, and the incidence of subsequent malignancies was compared with that in the national age-matched population. Data were obtained for 1,903 patients, with a mean follow-up of 16.9 years. Eighty-six patients developed a subsequent malignancy compared with an expected number of 79 (standardized incidence ratio [SIR], 1.1; 95% CI, 0.9 to 1.3). The overall risk was low for patients treated with single-agent methotrexate and folinic acid (MTX-FA; SIR, 0.7; 95% CI, 0.5 to 1.1) and also for patients treated with etoposide, methotrexate, and dactinomycin followed by cyclophosphamide and vincristine on alternating weeks (EMA-CO) with an SIR of 0.9 (95% CI, 0.4 to 2.2), but there were significantly increased risks of oral cancer, melanoma, meningioma, and leukemia. The cumulative risk of early menopause was low after MTX-FA but was substantial after EMA-CO, reaching 13% by age 40 years and 36% by age 45 years. Subsequent cancer risks for patients cured of gestational trophoblastic tumors with modern chemotherapy appear similar to those of the normal population with no overall increased risk of malignancy after MTX-FA or EMA-CO. However, there was evidence of an increased risk of leukemia after EMA-CO and some evidence of other site-specific increased risks based on small patient numbers. All major treatments except MTX-FA increased the risk of early menopause. © 2014 by American Society of Clinical Oncology.

  17. Gestational trophoblastic tumours: an update for 2014.

    PubMed

    Froeling, Fieke E M; Seckl, Michael J

    2014-11-01

    Gestational trophoblastic disease describes a variety of pregnancy-related diseases including the premalignant conditions of a partial and complete hydatidiform mole and the malignant disorders of invasive mole, choriocarcinoma and the rare placental-site trophoblastic tumour and epithelioid trophoblastic tumour. The availability of a highly sensitive tumour marker in the form of human chorionic gonadotrophin, the chemosensitive character of the disease with effective treatment strategies and centralization of care of a rare group of diseases has resulted in excellent survival rates, which can exceed 98 %. This review gives a general overview of gestational trophoblastic disease, the most recent insights in aetiology and pathology and a summary of the different management strategies.

  18. Current Chemotherapeutic Management of Patients with Gestational Trophoblastic Neoplasia

    PubMed Central

    May, Taymaa; Goldstein, Donald P.; Berkowitz, Ross S.

    2011-01-01

    Gestational trophoblastic neoplasia (GTN) describes a heterogeneous group of interrelated lesions that arise from abnormal proliferation of placental trophoblasts. GTN lesions are histologically distinct, malignant lesions that include invasive hydatidiform mole, choriocarcinoma, placental site trophoblastic tumor (PSTT) and epithelioid trophoblastic tumor (ETT). GTN tumors are generally highly responsive to chemotherapy. Early stage GTN disease is often cured with single-agent chemotherapy. In contrast, advanced stage disease requires multiagent combination chemotherapeutic regimens to achieve a cure. Various adjuvant surgical procedures can be helpful to treat women with GTN. Patients require careful followup after completing treatment and recurrent disease should be aggressively managed. Women with a history of GTN are at increased risk of subsequent GTN, hence future pregnancies require careful monitoring to ensure normal gestational development. This article will review the workup, management and followup of women with all stages of GTN as well as with recurrent disease. PMID:22312558

  19. [Belgian register and reference centers for gestational trophoblastic diseases].

    PubMed

    Delcominette, S; Timmermans, M; Delbecque, K; Delvenne, P; Marbaix, E; Noel, J C; Moerman, P; Golfier, F; Kridelka, F; Nisolle, M; Vergote, I; Goffin, F

    2015-11-01

    Gestational trophoblastic diseases include placental pathologies comprising fertilization abnormalities (hydatidiform moles) and malignant lesions (choriocarcinoma, placental site trophoblastic tumor and epithelioid trophoblastic tumor). Due to their low incidence and heterogeneity, their diagnosis, management and treatment are not always optimal. Following the example of other European countries, a national registration system with two reference centers has been set up to guide physicians and patients and to propose individualized management. The centers offer their expertise through a systematic centralised pathology review by a panel of experts. HCG values are plotted in regression curves. In case of gestational trophoblastic neoplasia, an imaging work-up is proposed, from which the FIGO score and stage are derived and will guide the choice of treatment. Belgian centers offer a multidisciplinary approach, in partnership with the referent physician. More information for practitioners and patients is available on a web site: www.mole-chorio-bgog.eu, which also harbours a forum of discussion.

  20. Drugs Approved for Gestational Trophoblastic Disease

    Cancer.gov

    This page lists cancer drugs approved by the Food and Drug Administration (FDA) for gestational trophoblastic disease. The list includes generic names and brand names. The drug names link to NCI's Cancer Drug Information summaries.

  1. Two cases of epithelioid trophoblastic tumors in postmenopausal women.

    PubMed

    Rodríguez-Trujillo, Adriano; Martínez-Serrano, María José; Saco, Adela; Torné, Aureli

    2017-06-05

    Epithelioid trophoblastic tumor is a rare gestational trophoblastic neoplasm usually presenting in women of reproductive age, with a history of a prior gestational event. Its presentation in postmenopausal women is extremely rare. Immunohistochemical staining is a helpful aid to distinguish epithelioid trophoblastic tumor from other gestational trophoblastic neoplasms. Correct diagnosis is crucial for clinical management that can vary according to the type of gestational trophoblastic neoplasm. We report the case of a 63-year-old postmenopausal woman 33 years after her last full-term pregnancy and another case of a 57-year-old postmenopausal woman who had had a first-trimester abortion 30 years previously as her last gestational event, both presenting cervical epithelioid trophoblastic tumors. In both cases, immunohistochemistry played an important role in differentiating this entity from other gestational trophoblastic neoplasms. Surgery was the primary treatment in both cases. The first patient remained disease-free and died 5 years later due to a rectal adenocarcinoma, and the second patient remains disease-free at publication. In both cases, the hysterectomy specimen confirmed the presence of two large epithelioid trophoblastic tumors arising in the endocervix and lower uterine segment with no extrauterine disease. Nuclear positivity for p63 allowed differentiation from a placental site trophoblastic tumor. The Ki67 proliferative index was 20% and 35%, respectively. Epithelioid trophoblastic tumors may occur a long time after a prior gestational event and should even be excluded in postmenopausal women with uterine masses. Immunohistochemical staining is helpful to make the differential diagnosis with other gestational trophoblastic neoplasms.

  2. FBI-1 Is Overexpressed in Gestational Trophoblastic Disease and Promotes Tumor Growth and Cell Aggressiveness of Choriocarcinoma via PI3K/Akt Signaling.

    PubMed

    Mak, Victor C Y; Wong, Oscar G W; Siu, Michelle K Y; Wong, Esther S Y; Ng, Wai-Yan; Wong, Richard W C; Chan, Ka-Kui; Ngan, Hextan Y S; Cheung, Annie N Y

    2015-07-01

    Human placental trophoblasts can be considered pseudomalignant, with tightly controlled proliferation, apoptosis, and invasiveness. Gestational trophoblastic disease (GTD) represents a family of heterogeneous trophoblastic lesions with aberrant apoptotic and proliferative activities and dysregulation of cell signaling pathways. We characterize the oncogenic effects of factor that binds to the inducer of short transcripts of HIV-1 [FBI-1, alias POZ and Krüppel erythroid myeloid ontogenic factor (POKEMON)/ZBTB7A] in GTD and its role in promoting cell aggressiveness in vitro and tumor growth in vivo. IHC studies showed increased nuclear expression of FBI-1, including hydatidiform moles, choriocarcinoma (CCA), and placental site trophoblastic tumor, in GTD. In JAR and JEG-3 CCA cells, ectopic FBI-1 expression opposed apoptosis through repression of proapoptotic genes (eg, BAK1, FAS, and CASP8). FBI-1 overexpression also promoted Akt activation, as indicated by Akt-pS473 phosphorylation. FBI-1 overexpression promoted mobility and invasiveness of JEG-3 and JAR, but not in the presence of the phosphoinositide 3-kinase inhibitor LY294002. These findings suggest that FBI-1 could promote cell migration and invasion via phosphoinositide 3-kinase/Akt signaling. In vivo, nude mice injected with CCA cells with stable FBI-1 knockdown demonstrated reduced tumor growth compared with that in control groups. These findings suggest that FBI-1 is clinically associated with the progression of, and may be a therapeutic target in, GTD, owing to its diverse oncogenic effects on dysregulated trophoblasts. Copyright © 2015 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  3. Coexisting epithelioid trophoblastic tumor and placental site trophoblastic tumor of the uterus following a term pregnancy: report of a case and review of literature.

    PubMed

    Zhang, Xiaofei; Zhou, Caiyun; Yu, Minghua; Chen, Xiaoduan

    2015-01-01

    Gestational trophoblastic neoplasms are a group of fetal trophoblastic tumors including choriocarcinomas, epithelioid trophoblastic tumors (ETTs), and placental site trophoblastic tumors (PSTTs). Mixed gestational trophoblastic neoplasms are extremely rare. The existence of mixed gestational trophoblastic neoplasms that were composed of choriocarcinoma and/or PSTT and/or ETT was also reported. Herein, we present a case of uterine mixed gestational trophoblastic neoplasm which is ETT admixed with PSTT, and reviewed 9 cases of mixed gestational trophoblastic neoplasms reported in English literature available. The most common combination was a choriocarcinoma admixed with an ETT and/or PSTT. Mixed gestational trophoblastic neoplasms present in women of reproductive age and rare in postmenopausal, Abnormal vaginal bleeding is the most common presenting symptom, serum β-HCG levels are elevated, mostly below 2500 mIU/ml, the tumor was limited to uterus in 7 cases, the rest of 3 with pulmonary metastases at the time of diagnosis. Mixed gestational trophoblastic neoplasms have more similar clinical features with intermediate trophoblastic tumors (ITTs). Total hysterectomy with lymph node dissection is recommended treatment for mixed gestational trophoblastic neoplasms, and chemotherapy should be used in patients with metastatic disease and with nonmetastatic disease who have adverse prognostic factors.

  4. Coexisting epithelioid trophoblastic tumor and placental site trophoblastic tumor of the uterus following a term pregnancy: report of a case and review of literature

    PubMed Central

    Zhang, Xiaofei; zhou, Caiyun; Yu, Minghua; Chen, Xiaoduan

    2015-01-01

    Gestational trophoblastic neoplasms are a group of fetal trophoblastic tumors including choriocarcinomas, epithelioid trophoblastic tumors (ETTs), and placental site trophoblastic tumors (PSTTs). Mixed gestational trophoblastic neoplasms are extremely rare. The existence of mixed gestational trophoblastic neoplasms that were composed of choriocarcinoma and/or PSTT and/or ETT was also reported. Herein, we present a case of uterine mixed gestational trophoblastic neoplasm which is ETT admixed with PSTT, and reviewed 9 cases of mixed gestational trophoblastic neoplasms reported in English literature available. The most common combination was a choriocarcinoma admixed with an ETT and/or PSTT. Mixed gestational trophoblastic neoplasms present in women of reproductive age and rare in postmenopausal, Abnormal vaginal bleeding is the most common presenting symptom, serum β-HCG levels are elevated, mostly below 2500 mIU/ml, the tumor was limited to uterus in 7 cases, the rest of 3 with pulmonary metastases at the time of diagnosis. Mixed gestational trophoblastic neoplasms have more similar clinical features with intermediate trophoblastic tumors (ITTs). Total hysterectomy with lymph node dissection is recommended treatment for mixed gestational trophoblastic neoplasms, and chemotherapy should be used in patients with metastatic disease and with nonmetastatic disease who have adverse prognostic factors. PMID:26261623

  5. Chemoresistant Gestational Trophoblastic Neoplasia: A Case Report

    PubMed Central

    M, Sahana

    2014-01-01

    Gestational trophoblastic neoplasia (GTN) is a disease of women in reproductive age. It is one of the most chemotherapy responsive and highly curable cancer. It is diagnosed when there is clinical, radiologic, pathologic, and/or hormonal evidence of persistent or relapsed gestational trophoblastic disease. In most instances, it is cured by surgical evacuation of the uterus. If persistent, it is treated with chemotherapy which provides response in >90% of the cases. In the unresponsive persistent cases and if the women has completed her child bearing, hysterectomy is generally recommended. Here, we report a rare case of chemoresistant GTN which was confirmed to be placental-site trophoblastic tumour (PSTT) on biopsy. PMID:25177610

  6. Optimal management of low-risk gestational trophoblastic neoplasia.

    PubMed

    Goldstein, Donald P; Berkowitz, Ross S; Horowitz, Neil S

    2015-01-01

    Low-risk gestational trophoblastic neoplasia is a highly curable form of gestational trophoblastic neoplasia that arises largely from molar pregnancy and, on rare occasions, from other types of gestations. Risk is defined as the risk of developing drug resistance as determined by the WHO Prognostic Scoring System. All patients with non-metastatic disease and patients with risk scores <7 are considered to have low-risk disease. The sequential use of methotrexate and actinomycin D is associated with a complete remission rate of 80%. The most commonly utilized regimen for the treatment of patients resistant to single-agent chemotherapy is a multiagent regimen consisting of etoposide, methotrexate, actinomycin D, vincristine and cyclophosphamide. The measurement of human chorionic gonadotropin provides an accurate and reliable tumor marker for diagnosis, monitoring the effects of chemotherapy and follow-up to determine recurrence. Pregnancy is allowed after 12 months of normal serum tumor marker. Pregnancy outcomes are similar to those of normal population.

  7. Gestational Trophoblastic Disorders: An Update in 2015

    PubMed Central

    Stevens, F. T.; Katzorke, N.; Tempfer, C.; Kreimer, U.; Bizjak, G. I.; Fleisch, M. C.; Fehm, T. N.

    2015-01-01

    Gestational trophoblastic diseases (GTD) are a group of pregnancy-related disorders representing rare human tumours. They encompass premalignant disorders including complete (CHM), partial hydatidiform mole (PHM), exaggerated placental site (EPS), and placental-site nodule (PSN) as well as malignant disorders (also known as “gestational trophoblastic neoplasia [GTN]”) including invasive mole, choriocarcinoma (CC), placenta-site trophoblastic tumour (PSTT), and epitheloid trophoblastic tumours (ETT) (Fig. 1). Originally, GTD develop from abnormal proliferation of trophoblastic tissue and form botryoid arranged vesicles. Premalignant moles are usually treated by suction curettage while persistent and recurrent moles and malignant forms require systemic therapy with methotrexate or combination chemotherapy consisting of etoposide, actimomycin D, methotrexate, vincristine, and cyclophosphamide (EMA-CO). β-human chorion gonadotropin (β-hCG) plays a crucial role in diagnosis and monitoring therapeutic effects. Since the definitive diagnosis cannot be obtained by histology in most cases, persistent or recurrent disease is diagnosed by elevated or persistent serum levels of β-hCG. While curing rates are described to be as high as 98 %, GTD may initially present, recur, or end up as a metastasising systemic disease. This underlines the importance of a regular and consistent follow-up after treatment. PMID:26556906

  8. Gestational Trophoblastic Disorders: An Update in 2015.

    PubMed

    Stevens, F T; Katzorke, N; Tempfer, C; Kreimer, U; Bizjak, G I; Fleisch, M C; Fehm, T N

    2015-10-01

    Gestational trophoblastic diseases (GTD) are a group of pregnancy-related disorders representing rare human tumours. They encompass premalignant disorders including complete (CHM), partial hydatidiform mole (PHM), exaggerated placental site (EPS), and placental-site nodule (PSN) as well as malignant disorders (also known as "gestational trophoblastic neoplasia [GTN]") including invasive mole, choriocarcinoma (CC), placenta-site trophoblastic tumour (PSTT), and epitheloid trophoblastic tumours (ETT) (Fig. 1). Originally, GTD develop from abnormal proliferation of trophoblastic tissue and form botryoid arranged vesicles. Premalignant moles are usually treated by suction curettage while persistent and recurrent moles and malignant forms require systemic therapy with methotrexate or combination chemotherapy consisting of etoposide, actimomycin D, methotrexate, vincristine, and cyclophosphamide (EMA-CO). β-human chorion gonadotropin (β-hCG) plays a crucial role in diagnosis and monitoring therapeutic effects. Since the definitive diagnosis cannot be obtained by histology in most cases, persistent or recurrent disease is diagnosed by elevated or persistent serum levels of β-hCG. While curing rates are described to be as high as 98 %, GTD may initially present, recur, or end up as a metastasising systemic disease. This underlines the importance of a regular and consistent follow-up after treatment.

  9. Extrauterine epithelioid trophoblastic tumor in hysterectomized woman.

    PubMed

    Kim, Ji-Hye; Lee, Sun Kyung; Hwang, Soo Hyun; Kim, Jung-Sun; Yoon, Gun; Lee, Yoo-Young; Kim, Tae-Joong; Choi, Chel Hun; Kim, Byoung-Gie; Bae, Duk-Soo; Lee, Jeong-Won

    2017-01-01

    Epithelioid trophoblastic tumor (ETT) is a very rare variant of gestational trophoblastic disease (GTD) which arises in reproductive age women with prior gestational history. Although abnormal vaginal bleeding is the most common symptom of ETT, there are no reported pathognomonic symptoms of ETT because of its rarity. ETT is similar to placental site trophoblastic tumor in terms of its slow growing characteristic and microscopic findings. Therefore, it could be misdiagnosed as placental site trophoblastic tumor or other types of GTD. Unlike other types of GTD, primary treatment of ETT is surgical resection because of its chemo-resistant nature. Accordingly, immunohistochemical staining is essential for accurate diagnosis and appropriate treatment. Here, we report a case of a 42-year-old hysterectomized woman with pelvic masses who suffered from abdominal pain. Through laparotomy, tumors were resected completely and they were diagnosed as ETT through immunohistochemical stain. This report provides more evidence about its clinical features, diagnosis, and treatment including a brief review of the literature.

  10. Extrauterine epithelioid trophoblastic tumor in hysterectomized woman

    PubMed Central

    Kim, Ji-Hye; Lee, Sun Kyung; Hwang, Soo Hyun; Kim, Jung-Sun; Yoon, Gun; Lee, Yoo-Young; Kim, Tae-Joong; Choi, Chel Hun; Kim, Byoung-Gie; Bae, Duk-Soo

    2017-01-01

    Epithelioid trophoblastic tumor (ETT) is a very rare variant of gestational trophoblastic disease (GTD) which arises in reproductive age women with prior gestational history. Although abnormal vaginal bleeding is the most common symptom of ETT, there are no reported pathognomonic symptoms of ETT because of its rarity. ETT is similar to placental site trophoblastic tumor in terms of its slow growing characteristic and microscopic findings. Therefore, it could be misdiagnosed as placental site trophoblastic tumor or other types of GTD. Unlike other types of GTD, primary treatment of ETT is surgical resection because of its chemo-resistant nature. Accordingly, immunohistochemical staining is essential for accurate diagnosis and appropriate treatment. Here, we report a case of a 42-year-old hysterectomized woman with pelvic masses who suffered from abdominal pain. Through laparotomy, tumors were resected completely and they were diagnosed as ETT through immunohistochemical stain. This report provides more evidence about its clinical features, diagnosis, and treatment including a brief review of the literature. PMID:28217684

  11. Worldwide survey of the results of treating gestational trophoblastic disease.

    PubMed

    Kohorn, Ernest I

    2014-01-01

    To determine factors influencing outcome for patients with gestational trophoblastic disease (GTD) from throughout the world. Physicians known to treat GTD were sent a questionnaire. There were 32 responses from 17 countries, totaling 26,153 patients. Of 14,093 patients with complete mole 20.6% developed trophoblastic neoplasia, and 5.7% died. There were 10,230 patients with partial mole, of whom 6.5% received therapy for neoplasia. There were 548 patients with post-term pregnancy choriocarcinoma, of whom 13.4% died. Of 137 patients with placental site trophoblastic tumor 16.1% died. The remaining 1,165 patients did not fit into a designated diagnostic category. The mortality rate for 2,818 patients with GTD primarily treated at a trophoblast center was 2.1%, as compared with 8% among 1,854 patients referred after failure of primary treatment (p < 0.01). Patients treated by physicians experienced in the management of trophoblastic disease have better results and survival.

  12. Uterine Rupture Due to Invasive Metastatic Gestational Trophoblastic Neoplasm

    PubMed Central

    Bruner, David I.; Pritchard, Amy M.; Clarke, Jonathan

    2013-01-01

    While complete molar pregnancies are rare, they are wrought with a host of potential complications to include invasive gestational trophoblastic neoplasia. Persistent gestational trophoblastic disease following molar pregnancy is a potentially fatal complication that must be recognized early and treated aggressively for both immediate and long-term recovery. We present the case of a 21-year-old woman with abdominal pain and presyncope 1 month after a molar pregnancy with a subsequent uterine rupture due to invasive gestational trophoblastic neoplasm. We will discuss the complications of molar pregnancies including the risks and management of invasive, metastatic gestational trophoblastic neoplasia. PMID:24106538

  13. Uterine rupture due to invasive metastatic gestational trophoblastic neoplasm.

    PubMed

    Bruner, David I; Pritchard, Amy M; Clarke, Jonathan

    2013-09-01

    While complete molar pregnancies are rare, they are wrought with a host of potential complications to include invasive gestational trophoblastic neoplasia. Persistent gestational trophoblastic disease following molar pregnancy is a potentially fatal complication that must be recognized early and treated aggressively for both immediate and long-term recovery. We present the case of a 21-year-old woman with abdominal pain and presyncope 1 month after a molar pregnancy with a subsequent uterine rupture due to invasive gestational trophoblastic neoplasm. We will discuss the complications of molar pregnancies including the risks and management of invasive, metastatic gestational trophoblastic neoplasia.

  14. The effect of distance traveled on disease outcomes in gestational trophoblastic neoplasia.

    PubMed

    Clark, Leslie H; Staley, S Allison; Barber, Emma L; Wysham, Weiya Z; Kim, Kenneth H; Soper, John T

    2016-08-01

    Gestational trophoblastic neoplasia is a rare gynecological malignancy often treated at tertiary referral centers. Patients frequently travel long distances to obtain care for gestational trophoblastic neoplasia, which may affect cancer outcomes in these patients. We examined the association between distance traveled to obtain care and disease burden at time of presentation as well as recurrence. We performed a retrospective cohort analysis of all patients diagnosed with gestational trophoblastic neoplasia from January 1995 to June 2015 at a high-volume tertiary referral center. Patients were included if they met International Federation of Gynecology and Obstetrics 2000 criteria for postmolar gestational trophoblastic neoplasia or had choriocarcinoma, placental-site trophoblastic tumor, or epithelioid trophoblastic tumor. Sixty patients were identified. Disease burden at presentation was examined using both the World Health Organization prognostic score and International Federation of Gynecology and Obstetrics. Patients who traveled more than 50 miles were considered long-distance travelers based on previous literature on the effect of distance traveled on cancer outcomes. Demographic, clinical, and pathological data were obtained by chart review. Bivariable comparisons were performed using the χ(2) test or Fisher exact test for categorical variables. The t test or Wilcoxon rank-sum test was used to compare continuous variables when normally or not normally distributed. Most patients presented at stage I (61%) with low-risk gestational trophoblastic neoplasia (70%). Median distance to care was 40 miles (range, 4-384). Eighteen patients (30%) had no insurance and 42 (70%) had either private or public insurance. Patients traveling more than 50 miles for care were more likely to have high-risk gestational trophoblastic neoplasia (46% vs 19%, P = .03), but there was no difference in recurrence (13% vs 11%, P = .89). Patients with high-risk gestational

  15. PD-L1 Expression in Human Placentas and Gestational Trophoblastic Diseases.

    PubMed

    Veras, Emanuela; Kurman, Robert J; Wang, Tian-Li; Shih, Ie-Ming

    2017-03-01

    One of the major immune checkpoints responsible for immune evasion in cancer cells is the interaction between programmed cell death-1 (PD-1) and its ligand (PD-L1). As human trophoblastic cells display many of the features of malignant cells such as the ability to invade normal tissue including blood vessels and are apparently not eradicated by the host immune system, we undertook the present study to determine whether PD-L1 was upregulated in different types of trophoblastic cells during normal pregnancy and in gestational trophoblastic diseases. Immunohistochemistry using an anti-PD-L1-specific antibody demonstrated that in early and term normal placentas, PD-L1 was highly expressed in syncytiotrophoblast and to a much lower extent in intermediate trophoblastic cells located in the chorion laeve and implantation site. PD-L1 immunoreactivity was undetectable in cytotrophoblastic cells. This staining pattern in normal placenta was recapitulated in various types of gestational trophoblastic disease. PD-L1 was highly expressed by syncytiotrophoblast in complete moles and choriocarcinomas. The intermediate trophoblastic neoplasms, placental site trophoblastic tumors, and epithelioid trophoblastic tumors showed variable PD-L1 immunoreactivity but at a lower intensity than in the neoplastic syncytiotrophoblast in choriocarcinoma. In addition, we observed PD-1-positive lymphocytes located within the implantation site and in trophoblastic tumors. In summary, this study describes a novel mechanism for trophoblastic cells to create a tolerogenic feto-maternal interface by upregulating PD-L1 in syncytiotrophoblast and in intermediate trophoblast. Trophoblastic tumors may also use PD-L1 expression to evade the host immune response thereby promoting their survival.

  16. Advances in the clinical laboratory detection of gestational trophoblastic disease.

    PubMed

    Seki, Katsuyoshi; Matsui, Hideo; Sekiya, Souei

    2004-11-01

    Gestational trophoblastic disease (GTD) consists of a spectrum of disorders that are characterized by an abnormal proliferation of trophoblastic tissue. Gestational trophoblastic neoplasia (GTN) refers to a subset of GTD with a persistently elevated serum hCG in the absence of a normal pregnancy and with a history of normal or abnormal pregnancy. Although previously a lethal disease, GTN is considered today the most curable gynecologic cancer. However, a delay in the diagnosis may increase the patient's risk of developing malignant GTN, and therefore the prompt identification of GTN is important. hCG test is essential for detection of GTN. It has emerged that there are problems with hCG tests. In addition to regular hCG, at least five major variants of hCG are present in serum samples. False-positive hCG (phantom hCG) can occur in the absence of GTN. Low-level real hCG may occasionally persist in the absence of clinical evidence of pregnancy or GTD. Alternatively, low-level real hCG may be due to pituitary hCG. Other placental hormones, human placental lactogen (hPL), inhibin and activin, and progesterone have also been evaluated as tumor markers for GTD. hCG has high diagnostic sensitivity, approaching 100% sensitivity, for managing the treatment of GTN and for detecting recurrences of disease. It is recommended to use hCG test that recognizes all forms of the hCG molecule. In cases where low-level hCG persists, it must be differentiated whether it is real or false. Real-hCG may be due to quiescent gestational trophoblastic disease or pituitary hCG. It has not yet been established whether measurement of markers other than hCG (hPL, inhibin, activin, and progesterone) is useful in the detection and follow-up of GTD.

  17. Apoptotic index for prediction of postmolar gestational trophoblastic neoplasia.

    PubMed

    Braga, Antonio; Maestá, Izildinha; Rocha Soares, Renan; Elias, Kevin M; Custódio Domingues, Maria Aparecida; Barbisan, Luis Fernando; Berkowitz, Ross S

    2016-09-01

    Although 85% of patients with a complete hydatidiform mole achieve spontaneous remission after a few months, 15% of them will experience gestational trophoblastic neoplasia, which requires chemotherapy. To date, there is no biomarker to predict post-molar gestational trophoblastic neoplasia before the initiation of human chorionic gonadotropin surveillance. The purpose of this study was to assess the relationship between the expression of apoptosis markers in the molar villous trophoblasts and the subsequent development of gestational trophoblastic neoplasia after the evacuation of a complete hydatidiform mole. This was a retrospective cohort study of patients with complete hydatidiform mole who were diagnosed, treated, and followed at the Center of Trophoblastic Diseases (Botucatu/São Paulo State and Rio de Janeiro/Rio de Janeiro State, Brazil) from 1995-2014. Patients were divided temporally into derivation (1995-2004) and validation (2005-2014) cohorts. Immunohistochemistry was used to examine tissue expression of the apoptosis inhibitor survivin or the pro-apoptotic enzyme caspase-3. Survivin stains for cytoplasmic and nuclear expression were evaluated independently. Caspase-3 expression was measured as an apoptotic index of positive staining cells over negative staining cells multiplied by 100. Receiver operating characteristic curves were then constructed, and the area under the curve was calculated to test the performance characteristics of the staining to predict the subsequent development of gestational trophoblastic neoplasia. The final study population comprised 780 patients, with 390 patients in each temporal cohort: 590 patients entered spontaneous remission, and 190 patients experienced post-molar gestational trophoblastic neoplasia. Neither nuclear nor cytoplasmic survivin expression performed well as a predictor of subsequent gestational trophoblastic neoplasia. The caspase-3 apoptotic index was a strong risk factor for subsequent gestational

  18. Fatal Cases of Gestational Trophoblastic Neoplasia in a National Trophoblastic Disease Reference Center in Dakar Senegal.

    PubMed

    Gueye, Mamour; Ndiaye-Gueye, Mame Diarra; Kane Gueye, Serigne Modou; Moreau, Jean Charles

    2016-01-01

    The objectives of this study were to analyze deaths after gestational trophoblastic neoplasia and to determine the factors of treatment failure. This is a retrospective study in Aristide Le Dantec teaching Hospital in Dakar, Senegal, between 1 January 2006 and 31 December 2014. We took into account socio-epidemiological characteristics of patients, initial diagnosis, time between uterine evacuation and admission, time to onset of gestational trophoblastic neoplasia (GTN), treatment received (deadlines, protocols), difficulties experienced in the diagnosis and the initiation of treatment and survival. In total, 1044 patients were admitted during the study period; 164 cases of GTN were diagnosed (15.7%); and 21 deaths occurred leading to a specific lethality of 12.8%. The average age was 30 years. Almost all patients (n = 18; 85.7%) had low income or no income. Eight out of 21 patients (38.1%) were seen in our department after GTN onset. The mean time to onset of GTN of all patients was 22.1 weeks. For 66.6%, histology was not available; the diagnosis of hydatidiform mole was made on the clinical history and sonographic features and GTN on human chorionic gonadotrophin (hCG) evolution and ultrasound findings. None of the patients had regular chemotherapy due to financial reasons. Patients who died within 3 months after diagnosis had metastatic tumors (7 of 21). All these women had resistance to treatment or progressed after three courses of chemotherapy. Ten of the 12 women with high-risk GTN were not treated with multi-agent chemotherapy (EMA-CO) for purely financial reasons. The high incidence and mortality require a profound reorganization of our health system and a high awareness of practitioners to refer to time or to declare all suspected cases of hydatidiform mole or gestational trophoblastic neoplasia.

  19. Do We Know What Causes Gestational Trophoblastic Disease?

    MedlinePlus

    ... Know What Causes Gestational Trophoblastic Disease? Normally, the sperm and egg cells each provide a set of ... hydatidiform (HY-duh-TIH-dih-form) moles , a sperm cell fertilizes an abnormal egg cell that has ...

  20. Color Doppler sonography as an adjunct to repeat uterine evacuation for gestational trophoblastic disease: case report.

    PubMed

    Tsuyoshi, Hideaki; Sugita, Genki; Kurokawa, Tetsuji; Yoshida, Yoshio

    2013-01-01

    Repeat uterine evacuation is a therapeutic option for preserving fertility in patients with gestational trophoblastic neoplasms and chemoresistance, but remains controversial due to the risks of hemorrhage and perforation. A 25-year-old patient with low-risk gestational trophoblastic neoplasm became chemoresistant; however, chemotherapy reduced intrauterine tumor vascularity as observed by color Doppler sonography, suggesting that patients could undergo uterine evacuation without major risk of bleeding. After 18 months, she achieved a normal pregnancy. Serial assessment of tumor vascularity with color Doppler sonography may provide information regarding the appropriate time to perform a repeat uterine evacuation without significant bleeding. Copyright © 2013 Wiley Periodicals, Inc.

  1. Klippel-Trenaunay syndrome and gestational trophoblastic neoplasm.

    PubMed

    Sreenivasan, Priya; Kumar, Sobha; Kumar, K K Santhosh

    2014-09-01

    Klippel-Trenaunay syndrome is a non-heritable venous malformation with bone and soft tissue hypertrophy and cutaneous nevi. Neonate with Klippel Trenaunay syndrome born to a mother with past history of Gestational trophoblastic neoplasm. Antenatally, a fetal vascular malformation was identified ultrasonologically at 29 weeks gestation. Acute myeloid leukemia was diagnosed in mother at 33 weeks gestation. A rare association of Klippel Trenaunay syndrome and gestational trophoblastic neoplasm with the possible role of either hyperglycosylated Human Chorionic Gonadotropin or chemotherapy as a link is highlighted.

  2. Salvage chemotherapy for gestational trophoblastic neoplasia: Utility or futility?

    PubMed

    Essel, Kathleen G; Bruegl, Amanda; Gershenson, David M; Ramondetta, Lois M; Naumann, R Wendel; Brown, Jubilee

    2017-07-01

    To determine the efficacy of chemotherapy after failed initial treatment in patients with high risk gestational trophoblastic neoplasia (GTN). We performed a retrospective IRB-approved chart review of all patients with GTN seen at a single institution from 1985 to 2015, including all patients who failed initial treatment. We summarized clinical characteristics with descriptive statistics and estimated progression-free survival (PFS) and overall survival (OS) with the Kaplan-Meier method. Of 68 identified patients, 38 required >2 chemotherapy regimens. Patients were treated for GTN (n=53), including choriocarcinoma, persistent GTN, and invasive mole; for placental site trophoblastic tumor (PSTT) (n=5); and for intermediate trophoblastic tumor (ITT) (n=10). Patients with GTN had a median of 2 salvage regimens, median PFS of 4.0months, and median OS was not reached at median follow-up of 71.2months. Active regimens included EMACO, MAC, BEP, platinum- and etoposide-based combination therapies, and ICE; 8 of 53 patients died of disease (DOD). Patients with PSTT had a median of 3 salvage regimens, median PFS of 2.8months, and median OS of 38.8months. Active regimens included ICE and EMA-EP; 4 of 5 patients DOD. Patients with ITT had a median of 3 salvage regimens, median PFS of 4.1months, and median OS of 38.2months. Active regimens included liposomal doxorubicin, platinum-containing regimens, EMA-CO, and EMA-EP; 7 of 10 patients DOD. Several salvage chemotherapy regimens demonstrate activity in high risk GTN. Multiple regimens may be required and cure is not universal. Copyright © 2017 Elsevier Inc. All rights reserved.

  3. Mortality rate of gestational trophoblastic neoplasia with a FIGO score of ≥13.

    PubMed

    Bolze, Pierre-Adrien; Riedl, Cécilia; Massardier, Jérôme; Lotz, Jean-Pierre; You, Benoit; Schott, Anne-Marie; Hajri, Touria; Golfier, François

    2016-03-01

    Gestational trophoblastic diseases include premalignant (partial and complete hydatidiform moles) and malignant entities referred to as gestational trophoblastic neoplasia. Use of the International Federation of Gynecology and Obstetrics prognostic score is encouraged in cases of gestational trophoblastic neoplasia to predict the potential for the development of resistance to single-agent chemotherapy. An International Federation of Gynecology and Obstetrics score of ≥7 defines a high-risk patient and requires combination chemotherapy. Appropriate and rapid diagnosis, treatment by specialized centers, and reduction of early deaths at the time of chemotherapy initiation have led to significant improvements in survival for patients with high-risk gestational trophoblastic neoplasia. There is a crucial need for the early identification of high-risk patients with gestational trophoblastic neoplasia who have an increased death risk to organize their treatment in highly specialized centers. The purpose of this study was to describe cases of gestational trophoblastic neoplasia that have resulted in death, particularly in a subgroup with an International Federation of Gynecology and Obstetrics prognostic score of ≥13, for whom low-dose etoposide and cisplatin induction chemotherapy recently was shown to reduce early death rate. We identified 974 patients from the French Center for Trophoblastic Diseases who had a diagnosis of gestational trophoblastic neoplasia from November 1999 to March 2014. Among 140 patients who were at high risk of resistance to single-agent chemotherapy (International Federation of Gynecology and Obstetrics score, ≥7), 29 patients (21%) had a score of ≥13. Mortality rate was estimated with the use of the Kaplan-Meier method. The 5-year overall mortality rate, after the exclusion of placental site trophoblastic tumors and epithelioid trophoblastic tumors, was 2% for patients with gestational trophoblastic neoplasia (95% confidence interval, 1

  4. Placental site trophoblastic tumor and choriocarcinoma: an unusual presentation.

    PubMed

    Gari, Abdulrahim

    2015-11-23

    Mixed trophoblastic tumor composed of choriocarcinoma and placental site trophoblastic tumor was diagnosed on histopathology slides review, is a very rare mixed tumor and cured after adjuvant chemotherapy. Twenty-nine years old, Para 2 female presented with 4 months history of irregular vaginal bleeding after an uncomplicated vaginal delivery. Abdominal examination showed 14 weeks uterus with β-hCG level of 14,889 mIU/ml. Slides review confirmed the diagnosis of placental site trophoblastic tumor (PSTT). Patient underwent total abdominal hysterectomy and resection of anterior vaginal wall mass. Post operative (48 h) β-hCG level was 6016 mIU/ml. Final pathology showed mixed trophoblastic tumor composed of choriocarcinoma (CC) and PSTT. Adjuvant chemotherapy started and continued for three cycles after achieving normal β-hCG. PSTT is a rare disease and potentially curable. Differential diagnosis in women presented with vaginal bleeding and a uterine mass in the post partum period must include gestational trophoblastic disease.

  5. Placental site trophoblastic tumors and epithelioid trophoblastic tumors: Biology, natural history, and treatment modalities.

    PubMed

    Horowitz, Neil S; Goldstein, Donald P; Berkowitz, Ross S

    2017-01-01

    Placental site (PSTT) and epithelioid trophoblastic tumor (ETT) are rare types of gestational trophoblastic neoplasia (GTN) that arise from intermediate trophoblast. Given that this cell of origin is different from other forms of GTN, it is not surprising that the clinical presentation, tumor marker profile, and treatment paradigm for PSTT and ETT are quite different as well. The mainstay for therapy for stage I PSTT and ETT is hysterectomy with adjuvant chemotherapy reserved for those presenting greater than four years from the antecedent pregnancy. Surgery is also important for metastatic disease. There is no standardized chemotherapy regimen for advanced stage disease but often consists of a platinum-containing combination therapy, usually EMA-EP or TE/TP. Despite its rarity, PSTT and ETT account for a disproportionate percentage of mortality from GTN likely resulting from their relative chemotherapy resistance. Novel therapeutic modalities therefore are needed to improve the outcomes of women with advanced stage or resistant PSTT and ETT. Copyright © 2016 Elsevier Inc. All rights reserved.

  6. [Potential role of the angiogenic factor "EG-VEGF" in gestational trophoblastic diseases].

    PubMed

    Boufettal, H; Feige, J-J; Benharouga, M; Aboussaouira, T; Nadifi, S; Mahdaoui, S; Samouh, N; Alfaidy, N

    2013-10-01

    Gestational trophoblastic disease (MGT) includes a wide spectrum of pathologies of the placenta, ranging from benign precancerous lesions, with gestational trophoblastic tumors. Metastases are the leading causes of death as a result of this tumor. They represent a major problem for obstetrics and for the public health system. To date, there is no predictor of the progression of molar pregnancies to gestational trophoblastic tumor (GTT). Only an unfavorable plasma hCG monitoring after evacuation of hydatidiform mole is used to diagnose a TTG. The causes of the development of this cancer are still poorly understood. Increasing data in the literature suggests a close association between the development of this tumor and poor placental vascularization during the first trimester of pregnancy. The development of the human placenta depends on a coordination between the trophoblast and endothelial cells. A disruption in the expression of angiogenic factors could contribute to uterine or extra-uterine tissue invasion by extravillous trophoblast, contributing to the development of TTG. This review sheds lights on the phenomenon of angiogenesis during normal and abnormal placentation, especially during the MGT and reports preliminary finding concerning, the variability of expression of "Endocrine Gland-Derived Vascular Endothelial Growth Factor" (EG-VEGF), a specific placental angiogenic factor, in normal and molar placentas, and the potential role of differentiated expressions of the main placental angiogenic factors in the scalability of hydatidiform moles towards a recovery or towards the development of gestational trophoblastic tumor. Deciphering the mechanisms by which the angiogenic factor influences these processes will help understand the pathophysiology of MGT and to create opportunities for early diagnosis and treatment of the latter. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

  7. Expression pattern of the adhesion molecule CEACAM1 (C-CAM, CD66a, BGP) in gestational trophoblastic lesions.

    PubMed

    Bamberger, A M; Sudahl, S; Wagener, C; Löning, T

    2001-04-01

    CEACAM1 (CD66a, BGP, C-CAM) is an adhesion molecule of the carcinoembryonic antigen (CEA) family which has been shown to be normally expressed at the apical pole of epithelial cells and to show a dysregulated expression pattern in tumors derived from the latter. The purpose of the present study was to investigate the expression pattern of CEACAM1 in gestational trophoblastic lesions and to compare this expression with the one observed in the normal trophoblast. For this purpose, we performed immunohistochemistry using the 4D1/C2 monoclonal antibody which specifically recognizes CEACAM1 and does not interact with other members of the CEA family. Immunohistochemistry was performed on a total of 20 cases of gestational trophoblastic lesions including complete hydatidiform moles, one placental site trophoblastic nodule (PSN), one placental site trophoblastic tumor (PSTT), and three choriocarcinomas. Immunostaining for cytokeratin, hPL, hCG, and Ki-67 was also performed. Normal placental samples served as a control. CEACAM1 was absent from villous cyto- and syncytiotrophoblast in both normal placenta and hydatidiform molar samples. It was present in the benign extravillous trophoblast, with stronger expression in the proximal extravillous trophoblast of anchoring villi, but was also observed in interstitial and endovascular intermediate trophoblast and chorionic intermediate-like trophoblast. Partial expression was observed in the trophoblast proliferating from the surface of molar villi. In choriocarcinomas, areas of weak expression could be observed along with large areas without CEACAM1 expression. In the PSN and especially in the PSTT, CEACAM1 expression was stronger and more diffuse. The specific localization to extravillous trophoblast and its expression pattern in gestational trophoblastic lesions indicate that CEACAM1 can potentially be a helpful additional diagnostic marker in the differential diagnosis of such lesions.

  8. Circulating Cell Free DNA in the Diagnosis of Trophoblastic Tumors

    PubMed Central

    Openshaw, Mark R.; Harvey, Richard A.; Sebire, Neil J.; Kaur, Baljeet; Sarwar, Naveed; Seckl, Michael J.; Fisher, Rosemary A.

    2015-01-01

    Gestational trophoblastic neoplasia (GTN) represents a group of diseases characterized by production of human chorionic gonadotropin (hCG). Since non-gestational tumors may occasionally secrete hCG, histopathological diagnosis is important for appropriate clinical management. However, a histopathological diagnosis is not always available. We therefore investigated the feasibility of extracting cell free DNA (cfDNA) from the plasma of women with GTN for use as a “liquid biopsy” in patients without histopathological diagnosis. cfDNA was prepared from the plasma of 20 women with a diagnosis of GTN and five with hCG-secreting tumors of unknown origin. Genotyping of cfDNA from the patient, genomic DNA from her and her partner and DNA from the tumor tissue identified circulating tumor DNA (ctDNA) (from 9% to 53% of total cfDNA) in 12 of 20 patients with GTN. In one case without a tissue diagnosis, ctDNA enabled a diagnosis of GTN originating in a non-molar conception and in another a diagnosis of non-gestational tumor, based on the high degree of allelic instability and loss of heterozygosity in the ctDNA. In summary ctDNA can be detected in the plasma of women with GTN and can facilitate the diagnosis of both gestational and non-gestational trophoblastic tumors in cases without histopathological diagnosis. PMID:26981554

  9. Circulating Cell Free DNA in the Diagnosis of Trophoblastic Tumors.

    PubMed

    Openshaw, Mark R; Harvey, Richard A; Sebire, Neil J; Kaur, Baljeet; Sarwar, Naveed; Seckl, Michael J; Fisher, Rosemary A

    2016-02-01

    Gestational trophoblastic neoplasia (GTN) represents a group of diseases characterized by production of human chorionic gonadotropin (hCG). Since non-gestational tumors may occasionally secrete hCG, histopathological diagnosis is important for appropriate clinical management. However, a histopathological diagnosis is not always available. We therefore investigated the feasibility of extracting cell free DNA (cfDNA) from the plasma of women with GTN for use as a "liquid biopsy" in patients without histopathological diagnosis. cfDNA was prepared from the plasma of 20 women with a diagnosis of GTN and five with hCG-secreting tumors of unknown origin. Genotyping of cfDNA from the patient, genomic DNA from her and her partner and DNA from the tumor tissue identified circulating tumor DNA (ctDNA) (from 9% to 53% of total cfDNA) in 12 of 20 patients with GTN. In one case without a tissue diagnosis, ctDNA enabled a diagnosis of GTN originating in a non-molar conception and in another a diagnosis of non-gestational tumor, based on the high degree of allelic instability and loss of heterozygosity in the ctDNA. In summary ctDNA can be detected in the plasma of women with GTN and can facilitate the diagnosis of both gestational and non-gestational trophoblastic tumors in cases without histopathological diagnosis.

  10. Gestational trophoblastic disease: a multimodality imaging approach with impact on diagnosis and management.

    PubMed

    Dhanda, Sunita; Ramani, Subhash; Thakur, Meenkashi

    2014-01-01

    Gestational trophoblastic disease is a condition of uncertain etiology, comprised of hydatiform mole (complete and partial), invasive mole, choriocarcinoma, and placental site trophoblastic tumor. It arises from abnormal proliferation of trophoblastic tissue. Early diagnosis of gestational trophoblastic disease and its potential complications is important for timely and successful management of the condition with preservation of fertility. Initial diagnosis is based on a multimodality approach: encompassing clinical features, serial quantitative β-hCG titers, and pelvic ultrasonography. Pelvic magnetic resonance imaging (MRI) is sometimes used as a problem-solving tool to assess the depth of myometrial invasion and extrauterine disease spread in equivocal and complicated cases. Chest radiography, body computed tomography (CT), and brain MRI have been recommended as investigative tools for overall disease staging. Angiography has a role in management of disease complications and metastases. Efficacy of PET (positron emission tomography) and PET/CT in the evaluation of recurrent or metastatic disease has not been adequately investigated yet. This paper discusses the imaging features of gestational trophoblastic disease on various imaging modalities and the role of different imaging techniques in the diagnosis and management of this entity.

  11. Gestational Trophoblastic Disease: A Multimodality Imaging Approach with Impact on Diagnosis and Management

    PubMed Central

    Ramani, Subhash; Thakur, Meenkashi

    2014-01-01

    Gestational trophoblastic disease is a condition of uncertain etiology, comprised of hydatiform mole (complete and partial), invasive mole, choriocarcinoma, and placental site trophoblastic tumor. It arises from abnormal proliferation of trophoblastic tissue. Early diagnosis of gestational trophoblastic disease and its potential complications is important for timely and successful management of the condition with preservation of fertility. Initial diagnosis is based on a multimodality approach: encompassing clinical features, serial quantitative β-hCG titers, and pelvic ultrasonography. Pelvic magnetic resonance imaging (MRI) is sometimes used as a problem-solving tool to assess the depth of myometrial invasion and extrauterine disease spread in equivocal and complicated cases. Chest radiography, body computed tomography (CT), and brain MRI have been recommended as investigative tools for overall disease staging. Angiography has a role in management of disease complications and metastases. Efficacy of PET (positron emission tomography) and PET/CT in the evaluation of recurrent or metastatic disease has not been adequately investigated yet. This paper discusses the imaging features of gestational trophoblastic disease on various imaging modalities and the role of different imaging techniques in the diagnosis and management of this entity. PMID:25126425

  12. Second Curettage for Low-Risk Nonmetastatic Gestational Trophoblastic Neoplasia.

    PubMed

    Osborne, Raymond J; Filiaci, Virginia L; Schink, Julian C; Mannel, Robert S; Behbakht, Kian; Hoffman, James S; Spirtos, Nick M; Chan, John K; Tidy, John A; Miller, David S

    2016-09-01

    To evaluate the efficacy and safety of second uterine curettage in lieu of chemotherapy for patients with low-risk, nonmetastatic gestational trophoblastic neoplasia (GTN) and to evaluate whether response to second curettage is independent of patient age, World Health Organization (WHO) risk score, registration human chorionic gonadotropin (hCG) level, lesion size, and depth of myometrial invasion measured on ultrasound examination. This was a cooperative group multicenter prospective phase II study. Prestudy testing included quantitative hCG level, pelvic ultrasonography, and chest radiography. Patients were categorized according to WHO risk scoring criteria (low risk with a score of 0-6). Sixty-four women with newly diagnosed low-risk, nonmetastatic GTN were enrolled. Four patients were excluded. Twenty-four patients (40%) (lower 95% confidence limit 27.6%) were cured after second curettage. An additional two patients (3%) achieved a complete response but did not complete follow-up. Overall, 26 of 60 patients were able to avoid chemotherapy. Surgical failure was observed in 34 women (59%) and was more common in women 19 years old or younger or 40 years old or older. One case of grade 1 uterine perforation was successfully managed by observation. Four grade 1 and one grade 3 uterine hemorrhages were reported. New metastatic disease (lung) was identified in one of these women after second curettage. In three patients (surgical failures), the second curettage pathology was placental site trophoblastic tumor, and it was placental nodule in one additional patient. Second uterine curettage as initial treatment for low-risk, nonmetastatic GTN cures 40% of patients without significant morbidity. ClinicalTrials.gov, https://clinicaltrials.gov/, NCT00521118.

  13. Gestational and Non-gestational Trophoblastic Disease. Guideline of the DGGG, OEGGG and SGGG (S2k Level, AWMF Registry No. 032/049, December 2015).

    PubMed

    Tempfer, C; Horn, L-C; Ackermann, S; Beckmann, M W; Dittrich, R; Einenkel, J; Günthert, A; Haase, H; Kratzsch, J; Kreissl, M C; Polterauer, S; Ebert, A D; Schneider, K T M; Strauss, H G; Thiel, F

    2016-02-01

    Purpose: The aim was to establish an official interdisciplinary guideline, published and coordinated by the German Society of Gynecology and Obstetrics (DGGG). The guideline was developed for use in German-speaking countries. In addition to the Germany Society of Gynecology and Obstetrics, the guideline has also been approved by the Swiss Society of Gynecology and Obstetrics (SGGG) and the Austrian Society of Gynecology and Obstetrics (OEGGG). The aim was to standardize diagnostic procedures and the management of gestational and non-gestational trophoblastic disease in accordance with the principles of evidence-based medicine, drawing on the current literature and the experience of the colleagues involved in compiling the guideline. Methods: This s2k guideline represents the consensus of a representative panel of experts with a range of different professional backgrounds commissioned by the DGGG. Following a review of the international literature and international guidelines on trophoblastic tumors, a structural consensus was achieved in a formalized, multi-step procedure. This was done using uniform definitions, objective assessments, and standardized management protocols. Recommendations: The recommendations of the guideline cover the epidemiology, classification and staging of trophoblastic tumors; the measurement of human chorionic gonadotropin (hCG) levels in serum, and the diagnosis, management, and follow-up of villous trophoblastic tumors (e.g., partial mole, hydatidiform mole, invasive mole) and non-villous trophoblastic tumors (placental site nodule, exaggerated placental site, placental site tumor, epitheloid trophoblastic tumor, and choriocarcinoma).

  14. Gestational and Non-gestational Trophoblastic Disease. Guideline of the DGGG, OEGGG and SGGG (S2k Level, AWMF Registry No. 032/049, December 2015)

    PubMed Central

    Tempfer, C.; Horn, L.-C.; Ackermann, S.; Beckmann, M. W.; Dittrich, R.; Einenkel, J.; Günthert, A.; Haase, H.; Kratzsch, J.; Kreissl, M. C.; Polterauer, S.; Ebert, A. D.; Schneider, K. T. M.; Strauss, H. G.; Thiel, F.

    2016-01-01

    Purpose: The aim was to establish an official interdisciplinary guideline, published and coordinated by the German Society of Gynecology and Obstetrics (DGGG). The guideline was developed for use in German-speaking countries. In addition to the Germany Society of Gynecology and Obstetrics, the guideline has also been approved by the Swiss Society of Gynecology and Obstetrics (SGGG) and the Austrian Society of Gynecology and Obstetrics (OEGGG). The aim was to standardize diagnostic procedures and the management of gestational and non-gestational trophoblastic disease in accordance with the principles of evidence-based medicine, drawing on the current literature and the experience of the colleagues involved in compiling the guideline. Methods: This s2k guideline represents the consensus of a representative panel of experts with a range of different professional backgrounds commissioned by the DGGG. Following a review of the international literature and international guidelines on trophoblastic tumors, a structural consensus was achieved in a formalized, multi-step procedure. This was done using uniform definitions, objective assessments, and standardized management protocols. Recommendations: The recommendations of the guideline cover the epidemiology, classification and staging of trophoblastic tumors; the measurement of human chorionic gonadotropin (hCG) levels in serum, and the diagnosis, management, and follow-up of villous trophoblastic tumors (e.g., partial mole, hydatidiform mole, invasive mole) and non-villous trophoblastic tumors (placental site nodule, exaggerated placental site, placental site tumor, epitheloid trophoblastic tumor, and choriocarcinoma). PMID:26941444

  15. Overexpression of the Parkinson disease protein DJ-1 and its regulator PTEN in gestational trophoblastic disease.

    PubMed

    Zhang, Hui-Juan; Siu, Michelle Kwan-Yee; Jiang, Li-Li; Mak, Victor Chun-Yin; Ngan, Hextan Yuen-Sheung; Cheung, Annie Nga-Yin

    2010-09-01

    DJ-1 is found to be important in human neurodegenerative diseases and cancers by regulating oxidative damage and apoptosis. DJ-1 is also a regulator of PTEN, a frequently mutated tumor suppressor gene in cancers. In this study, we investigated the expression of DJ-1 and PTEN in normal placentas and gestational trophoblastic disease in relation to apoptotic indices and p53 status. A total of 95 trophoblastic samples were retrieved for immunohistochemical study whereas 79 trophoblastic samples, 3 normal trophoblastic and 2 choriocarcinoma cell lines were collected for quantitative real time reverse transcription polymerase chain reaction detection. There was a significant correlation between DJ-1 and PTEN immunostaining indices in the trophoblastic samples (P=0.013). Significantly higher DJ-1 and PTEN immunoreactivity indices were found in the complete mole (P<0.01) and choricarcinoma (P<0.01) compared with the first trimester placenta. Quantitative real time reverse transcription polymerase chain reaction also detected significantly higher messenger ribonucleic acid expressions of DJ-1 and PTEN in hydatidiform moles (P<0.05) and choriocarcinomas (P<0.05) compared with the first trimester placentas. A significant negative correlation was found between DJ-1 and the apoptosis resistant gene Bcl-2 (P=0.031), whereas a positive correlation was shown between PTEN and wild-type p53 (P=0.019). Significant correlations between PTEN and embryonic stem cell transcription factors, Stat3 and Nanog, were also displayed (P=0.001, 0.015). Our findings showed, for the first time, overexpression of DJ-1 at both transcriptional and protein levels in gestational trophoblastic disease. Overexpressed DJ-1 may play a role in regulating apoptotic activities of trophoblasts in relation to PTEN and p53.

  16. Management of Chemoresistant and Quiescent Gestational Trophoblastic Disease.

    PubMed

    Ngu, Siew-Fei; Chan, Karen K L

    2014-01-01

    Gestational trophoblastic neoplasia (GTN) is highly chemosensitive and has a high cure rate. Since the introduction of chemotherapy, reliable measurement of human chorionic gonadotropin (hCG) levels, and individualised risk-based therapy into the management of GTN, almost all low-risk and more than 80 % of high-risk GTN cases are curable. However, approximately 25 % of high-risk GTN developed resistance to chemotherapy or relapsed after completion of initial therapy, which often necessitate salvage combination chemotherapy. On the other end of the spectrum, a proportion of patients with gestational trophoblastic disease (GTD) have persistently low levels of hCG, without clinical or radiological evidence of disease, a condition called quiescent GTD. Recently, measurement of hyperglycosylated hCG has been proposed for the management of patients with quiescent GTD. Although representing a small proportion of GTD cases, the management of patients with chemoresistant and quiescent GTD often poses challenges to medical practitioners.

  17. Gestational Trophoblastic Disease Diagnosis Delayed by the Hook Effect.

    PubMed

    Cormano, Julia; Mackay, Gillian; Holschneider, Christine

    2015-10-01

    A "hook effect" resulting from saturation of antibodies used in pregnancy tests can occur at human chorionic gonadotropin (hCG) levels above 500,000 milliinternational units/mL, resulting in falsely negative values. A 34-year-old woman, gravida 5 para 3, presented to the emergency department after heavy bleeding. Ultrasonogram revealed a uterine mass, urine pregnancy test result was negative, and endometrial biopsy inconclusive. The patient was discharged and presented 10 days later with recurrent bleeding. Urine pregnancy test result was again negative, but serum hCG was 581 milliinternational units/mL. Serial dilution revealed an actual hCG higher than 5 million milliinternational units/mL. She was diagnosed with gestational trophoblastic disease. Awareness of the risk of a false-negative pregnancy test result when hCG levels are extremely high may prevent delayed diagnosis of gestational trophoblastic disease.

  18. The trophoblastic Tower of Babel: classification systems for metastatic gestational trophoblastic neoplasia.

    PubMed

    Kohorn, E I

    1995-02-01

    There are presently three classifications of metastatic gestational trophoblastic tumors (MGTM). The first is that of low-risk and high-risk neoplasia devised by Hammond, now designated the National Cancer Institute classification. The second is that of FIGO that attempts to conform to the staging of other gynecologic malignancies by that organization. The third is a scoring system adopted by World Health Organization (WHO) from the original devised by Bagshawe. This scoring system is finding the widest acceptance and is increasingly being used for treatment planning. However, different investigators not only define risk groups differently from the WHO recommendation, but also modify the WHO scoring system in novel, individualistic ways that changes the total score and outcome assessment. This results in patients with the same risk factors being placed in different WHO risk groups. Comparison of therapy between center is then invalidated. Furthermore, it would appear preferable that the WHO scoring system is restricted to metastatic neoplasia. To achieve a uniform scoring system for MGTN there needs to be consensus (i) whether lung metastases should be detected by chest X ray or CAT scan; (ii) whether the size of metastases should be measured clinically or radiologically (including ultrasound, CAT scan, and MRI); (iii) are multiple lung or brain metastases counted by CAT scan or MRI; (iv) are ABO blood groups to be included so that the number of points is uniform for different centers; and (v) that idiosyncratic and individual categories are not added or omitted from the score.

  19. Atypical epithelioid trophoblastic lesion with cyst and fistula formation after a cesarean section: a rare form of gestational trophoblastic disease.

    PubMed

    Liang, Yun; Zhou, Feng; Chen, Xiaoduan; Zhang, Xiaofei; Lü, Bingjian

    2012-09-01

    We report 2 unusual cases of gestational trophoblastic disease from chorionic-type intermediate trophoblastic cells after a Cesarean section. A 32-year-old woman presented with a 2-year history of vaginal bleeding, while a 41-year-old woman presented with a pelvic mass. Both patients had cystic lesions with a fistula formation beneath their Cesarean scars in the anterior uterine isthmus. Microscopically, both lesions were lined with multiple layers of intermediate trophoblastic cells without penetration into the surrounding myometrium, endometrium, or blood vessels. The trophoblastic cells were generally bland. However, a subset of trophoblastic cells showed large, hyperchromatic nuclei in some areas. The trophoblastic cells were p63 positive and human placental lactogen negative. The Ki67 indexes were 12.7% and 8.6%, respectively. We propose their description as atypical epithelioid trophoblastic lesions with cyst and fistula formation after a Cesarean section.

  20. Clinical and radiological correlations in patients with gestational trophoblastic disease*

    PubMed Central

    Lima, Lana de Lourdes Aguiar; Parente, Raphael Câmara Medeiros; Maestá, Izildinha; Amim Junior, Joffre; de Rezende Filho, Jorge Fonte; Montenegro, Carlos Antonio Barbosa; Braga, Antônio

    2016-01-01

    Gestational trophoblastic disease is an abnormality of pregnancy that encompasses a group of diseases that differ from each other in their propensity for regression, invasion, metastasis, and recurrence. In the past, it was common for patients with molar pregnancy to present with marked symptoms: copious bleeding; theca lutein cysts; uterus larger than appropriate for gestational age; early preeclampsia; hyperemesis gravidarum; and hyperthyroidism. Currently, with early diagnosis made by ultrasound, most patients are diagnosed while the disease is still in the asymptomatic phase. In cases of progression to trophoblastic neoplasia, staging-typically with Doppler flow studies of the pelvis and chest X-ray, although occasionally with computed tomography or magnetic resonance imaging-is critical to the choice of an appropriate antineoplastic therapy regimen. Because it is an unusual and serious disease that affects women of reproductive age, as well as because its appropriate treatment results in high cure rates, it is crucial that radiologists be familiar with gestational trophoblastic disease, in order to facilitate its early diagnosis and to ensure appropriate follow-up imaging. PMID:27777478

  1. Clinical and radiological correlations in patients with gestational trophoblastic disease.

    PubMed

    Lima, Lana de Lourdes Aguiar; Parente, Raphael Câmara Medeiros; Maestá, Izildinha; Amim Junior, Joffre; de Rezende Filho, Jorge Fonte; Montenegro, Carlos Antonio Barbosa; Braga, Antônio

    2016-01-01

    Gestational trophoblastic disease is an abnormality of pregnancy that encompasses a group of diseases that differ from each other in their propensity for regression, invasion, metastasis, and recurrence. In the past, it was common for patients with molar pregnancy to present with marked symptoms: copious bleeding; theca lutein cysts; uterus larger than appropriate for gestational age; early preeclampsia; hyperemesis gravidarum; and hyperthyroidism. Currently, with early diagnosis made by ultrasound, most patients are diagnosed while the disease is still in the asymptomatic phase. In cases of progression to trophoblastic neoplasia, staging-typically with Doppler flow studies of the pelvis and chest X-ray, although occasionally with computed tomography or magnetic resonance imaging-is critical to the choice of an appropriate antineoplastic therapy regimen. Because it is an unusual and serious disease that affects women of reproductive age, as well as because its appropriate treatment results in high cure rates, it is crucial that radiologists be familiar with gestational trophoblastic disease, in order to facilitate its early diagnosis and to ensure appropriate follow-up imaging.

  2. Presentation of Placental Site Trophoblastic Tumor with Amenorrhea

    PubMed Central

    Behnamfar, Fariba; Rouholamin, Safoura; Esteki, Mahboubeh

    2017-01-01

    Placental site throphoblastic tumor (PSTT) is a rare manifestation of gestational trophoblastic neoplasia that may complicate any type of pregnancy. The disease is unique from other type, and is defined by slow growth, low human chorionic gonadotropin (hCG) serum levels, the late-onset metastatic potential, and most significantly, insensitivity to chemotherapy. We describe a case of a 31-year-old woman with prolonged amenorrhea and slightly elevated serum beta hCG (βhCG) level, referred for termination of abnormal pregnancy. During curettage, necrotic tissue was removed and severs vaginal bleeding was controlled with medical therapy. Histology examination showed neoplastic intermediate trophoblastic cells with invasion to the vessel wall compatible with PSTT. After that, hysterectomy was down and serum βhCG declined to undetectable level 2 weeks after surgery and was followed for 2 years without complication. PMID:28401076

  3. Epithelioid trophoblastic tumor: A single institution case series at the New England Trophoblastic Disease Center.

    PubMed

    Davis, M R; Howitt, B E; Quade, B J; Crum, C P; Horowitz, N S; Goldstein, D P; Berkowitz, R S

    2015-06-01

    Epithelioid trophoblastic tumor (ETT) is a rare form of gestational trophoblastic neoplasm which is distinct based on its development from intermediate trophoblast cells and nodular growth pattern. The aim of this study is to describe a case series from a single institution with a review of the literature to better understand the clinical characteristics and outcomes for patients with ETT. A retrospective review was performed using the IRB approved New England Trophoblastic Disease Center (NETDC) database from 1998 to 2014. Eight patients were identified of which seven had complete records. Follow-up data was obtained from the longitudinal medical records. Four (57.1%) patients presented with vaginal bleeding and two (28.6%) patients were asymptomatic at presentation. Three (42.9%) patients had extrauterine disease. All three patients with extrauterine disease who received chemotherapy had stable or progressive disease at follow-up. Only two (29%) patients who presented with non-metastatic disease and underwent hysterectomy were alive with no evidence of disease. The mean interval following antecedent pregnancy was 104months. All patients with an interval >4years demonstrated stable or progressive disease despite intensive chemotherapy. Two patients with non-metastatic disease who declined hysterectomy developed stable or progressive disease despite chemotherapy. This series highlights several features of ETT including the potential for asymptomatic presentation of extrauterine disease. The series also demonstrates chemoresistance, even with multi-agent therapy and a poor prognosis with extrauterine disease and an interval greater than 4years following the antecedent pregnancy suggesting that surgery remains critical in disease control. Copyright © 2015 Elsevier Inc. All rights reserved.

  4. Use of short tandem repeat analysis in unusual presentations of trophoblastic tumors and their mimics.

    PubMed

    Aranake-Chrisinger, John; Huettner, Phyllis C; Hagemann, Andrea R; Pfeifer, John D

    2016-06-01

    Gestational trophoblastic tumors can be difficult to distinguish from nongestational neoplasms. Somatic and germ cell tumors can mimic gestational choriocarcinoma, and epithelioid trophoblastic tumor (ETT) is known for its histologic, and sometimes clinical, resemblance to squamous cell carcinoma. Short tandem repeat (STR) analysis can separate gestational from nongestational neoplasms and can provide useful information about the type of causative conceptus. We present a series of cases which demonstrate the utility of STR analysis in the evaluation of gestational choriocarcinoma, epithelioid trophoblastic tumor, and their mimics. Samples from normal tissue and tumor were microdissected. DNA was extracted, and STR analysis was performed. Five cases were identified in which there was clinical and/or histologic concern for a gestational trophoblastic neoplasm. Case 1 is a choriocarcinoma presenting concurrently with a 16-week gestation. STR testing on the tumor, mother, and fetus showed that the tumor arose from a previous occult complete hydatidiform mole. Case 2 is an ETT presenting as multiple masses in bilateral kidneys, initially diagnosed as urothelial carcinoma. However, because of an elevated human chorionic gonadotropin, additional workup was performed which showed that the tumor was most likely an ETT. STR analysis showed that the tumor arose from a nonmolar pregnancy. Cases 3-5 illustrate somatic carcinomas mimicking gestational neoplasia. In those cases, STR confirmed a somatic origin. STR can be useful in distinguishing gestational from nongestational neoplasms, particularly in unusual settings. Also, STR analysis can add clinically useful information that is not available from clinical or histologic evaluation. Copyright © 2016 Elsevier Inc. All rights reserved.

  5. Atypical placental site nodule (APSN) and association with malignant gestational trophoblastic disease; a clinicopathologic study of 21 cases.

    PubMed

    Kaur, Baljeet; Short, Dee; Fisher, Rosemary A; Savage, Philip M; Seckl, Michael J; Sebire, Neil J

    2015-03-01

    The WHO Classification of Gestational Trophoblastic Tumors classifies placental site nodule (PSN) as a benign tumor-like trophoblastic neoplasm. Cases of PSN with atypical features were described [atypical placental site nodule (APSN)] and we started registering APSN in our unit in 2005. The aim of this study is to present our initial experience with these lesions. The Trophoblastic Disease Unit database was searched to identify all patients who were either referred with, or on review were diagnosed with, APSN from September 2005 to May 2013. Case notes and the pathology findings for these patients were retrieved and reviewed. A total of 21 cases of APSN were included, 3 of which were associated with gestational trophoblastic neoplasm on follow-up or review. Malignant gestational trophoblastic disease was associated with 3/21 (14%) cases of APSN, either concurrently or developing/manifesting within 16 mo of APSN diagnosis. None of these patients had raised serum hCG levels either at presentation or follow-up. Presence of APSN should indicate a thorough clinical and radiologic investigation and follow-up if diagnosed on curettage specimens. With increased recognition of this entity and corresponding larger series with longer follow-up, more accurate patient counseling will be possible.

  6. Gestational trophoblastic disease: a 21-year review of the clinical experience at an Argentinean public hospital.

    PubMed

    Bianconi, Maria Inés; Otero, Silvina; Moscheni, Oriana; Alvarez, Lucia; Storino, Claudio; Jankilevich, Gustavo

    2012-01-01

    To analyze the clinical trends of gestational trophoblastic disease (GTD) in a public hospital of Buenos Aires, Argentina. A review of the clinical records of 358 patients with a diagnosis of GTD admitted to Durand Trophoblastic Disease Center between 1990 and February 2011 was performed. Features of diagnosis, treatment and follow-up were analyzed. A total of 358 cases of GTD were reviewed. Hydatidiform mole was diagnosed in 340 patients; of those 223 (66%) experienced spontaneous remission after evacuation. Of the 135 patients with persistent gestational trophoblastic neoplasia (GTN), 99 (73%) had low-risk GTN, 32 (26%) had high-risk GTN and 4 had either placental site trophoblastic disease or epithelioid trophoblastic tumor. In the low-risk group the first-line treatment was methotrexate and the second-line treatment was actinomycin D, etoposide, cytoxan, and oncovin (EMA/CO), with a complete response rate of 100%. High-risk patients whose WHO prognostic scores were 7-13 were treated initially with EMA/CO. Patients whose scores were >13 were treated with EMA/PE, where platinum and etoposide replaced oncovin and cytoxan. Salvage therapy in patients with relapse or resistant disease were treated with a wide variety of chemotherapy regimens. The complete response rate was 98.2%. Compliance was 100%. Three patients died. In all cases the outcome was related with inadequate initial treatment. This protocol is in agreement with international consensus. It was useful, safe and feasible in our population. The compliance with international guidelines allows reach a successful treatment and follow-up in one Latin-American population.

  7. Mental Representations of Illness in Patients with Gestational Trophoblastic Disease: How Do Patients Perceive Their Condition?

    PubMed

    Di Mattei, Valentina E; Carnelli, Letizia; Mazzetti, Martina; Bernardi, Martina; Di Pierro, Rossella; Bergamini, Alice; Mangili, Giorgia; Candiani, Massimo; Sarno, Lucio

    2016-01-01

    Gestational Trophoblastic Disease comprises a group of benign and malignant disorders that derive from the placenta. Using Leventhal's Common-Sense Model as a theoretical framework, this paper examines illness perception in women who have been diagnosed with this disease. Thirty-one women diagnosed with Gestational Trophoblastic Disease in a hospital in Italy were asked to complete the Illness Perception Questionnaire-Revised to measure the following: illness Identity, illness opinions and causes of Gestational Trophoblastic Disease. High mean scores were observed in the Emotional representations and Treatment control subscales. A significant difference emerged between hydatidiform mole patients and those with gestational trophoblastic neoplasia on the Identity subscale. A significant correlation emerged between "time since diagnosis" and the Treatment control subscale. This study is the first to investigate illness perception in Gestational Trophoblastic Disease. From a clinical perspective the results highlight the need for multidisciplinary support programs to promote a more realistic illness perception.

  8. Gestational trophoblastic disease: psychological aspects and fertility issues.

    PubMed

    Di Mattei, Valentina E; Carnelli, Letizia; Ambrosi, Alessandro; Mangili, Giorgia; Candiani, Massimo; Sarno, Lucio

    2014-01-01

    To evaluate the impact of a forced delay in childbearing during thefollow-up period on the perceived fertility of patients with gestational trophoblastic disease (GTD), and to investigate how women react to the monitoring period, with particular attention to fertility concerns, personal perceptions of the impact of GTD on reproductive outcomes, and psychological symptoms of depression and anxiety. Twenty women treated for GTD at San Raffaele Hospital, Milan, took part in the study. Depression, anxiety, and infertility-related stress were assessed using the Beck Depression Inventory-Short Form, the State-Trait Anxiety Inventory, and the Fertility Problem Inventory, respectively. A significant difference in depression levels was found between women with hydatiform mole and women with gestational trophoblastic neoplasia (p = 0.02). On the contrary, anxiety and depression levels did not vary on the basis of time elapsed since diagnosis, presence of children, and age (< 35 years). A significant correlation was also found between anxiety (state and trait) and depression (rho(s) = 0.62, p = 0.002 and rho(s) = 0.59, p = 0.005. respectively). There was no association between infertility-related stress and anxiety or depression or time elapsed since diagnosis. Additionally, such stress did not change between women with or without children. Women with GTD diagnosis should be followed by a multidisciplinary team so as to be supported in the disease's psychological aspects, too.

  9. Placental site trophoblastic tumor, report of a case with unusual presentation.

    PubMed

    Behnamfar, F; Mousavi, A; Rezapourian, P; Zamani, A

    2013-05-01

    Placental site trophoblastic tumor (PSTT) is the rarest type of gestational trophoblastic tumors. Common presentation is irregular vaginal bleeding. A 26-year-old G1P1 woman presented with 15 month amenorrhea, a large uterine mass and plateau low level of serum human chorionic gonadotropin (hCG) which raised the possibility of PSTT. Since whole myometrium had been substituted with the large tumoral mass, hysterectomy was considered despite the young age of the patient. The patient has been in remission 36 months postoperatively without receiving any adjuvant treatment. It seems that plateau low levels of hCG in the presence of amenorrhea should prompt the possibility of PSTT.

  10. Characterization of antigenic components from circulating immune complexes in patients with gestational trophoblastic neoplasia.

    PubMed

    Lahey, S J; Steele, G; Rodrick, M L; Berkowitz, R; Goldstein, D P; Ross, D S; Ravikumar, T S; Wilson, R E; Byrn, R; Thomas, P

    1984-03-15

    The authors have studied serial circulating immune complex (CIC) levels in 15 patients with gestational trophoblastic neoplasia (GTN) for several reasons. Gestational trophoblastic neoplasia can easily be followed from presentation to remission, and CIC changes can be compared with changes in human chorionic gonadotropin (HCG) which is a specific and quantitative marker of trophoblastic tumor load. Twelve patients with hydatidiform molar pregnancy presented with normal CIC levels (255 delta OD450 +/- 97, mean SE [standard error]) as measured by our antigen nonspecific polyethylene glycol (PEG) turbidity assay. Only after reduction in tumor load as monitored by a fall in HCG did CIC rise. In contrast, three patients with choriocarcinoma presented with significantly elevated CIC levels (513 delta OD450 +/- 147, P less than 0.05 compared to normals) which slowly declined in parallel with HCG levels following evacuation and chemotherapy. Sera at peak PEG-CIC from three patients with molar pregnancy or choriocarcinoma were precipitated with 3.75% polyethylene glycol to concentrate circulating immune complexes. Circulating immune complex levels were fractionated on Sephadex G-200 in an acid buffer (pH = 2.8). An identifiable antigenic component of the CIC in both diseases was found to be paternal HLA antigen. This was demonstrated by the ability of the latest eluting CIC fraction to inhibit paternal lymphocyte lysis using anti-HLA antisera against the husband's HLA tissue type. In each case, this fraction contained no immunoglobulin or beta-2 microglobulin and was antigenically crossreactive with only one of the husband's HLA haplotypes. The authors believe the PEG-CIC assay has allowed them to define the kinetics of host humoral response in GTN, and has provided a method for recovering immunogenic tumor-associated antigens from these complexes which may apply to other solid tumors.

  11. Incidence of gestational trophoblastic disease in Tokat province, Turkey

    PubMed Central

    Çakmak, Bülent; Toprak, Muhammet; Nacar, Mehmet Can; Köseoğlu, Reşid Doğan; Güneri, Nihan

    2014-01-01

    Objective This study investigated the incidence of gestational trophoblastic disease (GTD) in Tokat province, Turkey. Material and Methods The medical records of patients who had been diagnosed and treated at one university hospital, six government hospitals, and one specialist hospital in Tokat province between January 2005 and December 2012 were evaluated retrospectively. Results During the study period, there were 59,754 births and GTD was diagnosed in 73 cases. The calculated GTD incidence was 1.22/1000. The mean age of the patients diagnosed with GTD was 28.6±7.3 (range 17–51) years. In GTD, complete moles occurred in 26%, partial moles in 74%, and no invasive moles, choriocarcinomas, or placental site trophoblastic tumours were found. Only two patients received chemotherapy (methotrexate). There was no mortality associated with the disease during follow-up. Conclusion The incidence of GTD in Tokat province was 1.2 per 1000 births. Early diagnosis, treatment, and follow-up play a critical role in preventing the morbidity and mortality associated with disease. The incidence of GTD, which has a high recovery rate with adequate treatment and follow-up, can be determined from regional and community-based research. PMID:24790512

  12. Reduced systemic toxicity from superselective chemoembolization compared with systemic chemotherapy in patients with high-risk metastatic gestational trophoblastic disease

    SciTech Connect

    Lang, Erich K.

    1997-07-15

    Purpose. The efficacy of chemoembolization of primary and metastatic gestational trophoblastic neoplasms was studied. Methods. Six female patients, 19-33 years old, with high-risk trophoblastic disease were subjected to one to five chemoembolizations in 3-week intervals. Three of the patients had metastases to the liver, 2 had local tumor extension to the pelvic wall, and all 5 had failed initial systemic chemotherapy. The sixth patient was treated for a trophoblastic remnant following surgical expression of a tubal pregnancy. For follow-up, beta hCG levels in urine and serum and dynamic or angiocomputed tomograms were obtained in biweekly to 6-month intervals. Results. Two of 3 patients with liver metastases are alive and free of disease 6 and 7 years after initial chemoembolization. The third is alive at 3 years but with evidence of recurrent disease. Two patients treated for locally invasive trophoblastic disease died 3 months and 4 years, respectively, after initial chemoembolization. One had a 21/2-year remission. The patient treated for a trophoblastic remnant in the tube is alive and free of disease at 6-year follow-up. Hematologic toxicity occurred in only one. Conclusion. Selective chemoembolization in our small series of patients with high-risk trophoblastic disease was equally effective as results reported for multi-drug systemic chemotherapy but had markedly lower renal, liver, and hematologic toxicity.

  13. Extrauterine epithelioid trophoblastic tumor arising in the ovary with multiple metastases: a case report.

    PubMed

    Arafah, Maria A; Tulbah, Asma M; Al-Husaini, Hamed; Al-Sabban, Mohannad; Al-Shankiti, Hanan; Al-Badawi, Ismail A

    2015-06-01

    Epithelioid trophoblastic tumor is a neoplasm of the chorionic-type intermediate trophoblasts. It is considered a rare gestational trophoblastic disease and is frequently misdiagnosed as carcinoma. Extrauterine epithelioid trophoblastic tumor has been reported in multiple anatomical sites. We report a case of a 50-year-old woman who presented with abdominal pain and distension. Her initial β-human chorionic gonatotropin level was 806.7 IU/L. Imaging showed a large complex ovarian mass with peritoneal and subcapsular hepatic deposits as well as pulmonary nodules. Morphological features of the tumor and its immunohistochemical reactivity to CK8/18, CK7, p63, and CD10 were consistent with the diagnosis of an extrauterine epithelioid trophoblastic tumor arising from the ovary. The differential diagnoses, including other ovarian tumors, were ruled out on the basis of morphology and negative immunostaining to a relatively extended panel of antibodies. A prolonged follow up of these cases and the recognition of such rare tumors in unusual sites are crucial to the diagnosing pathologist and treating physician. © The Author(s) 2015.

  14. Characterization of apoptosis and autophagy through Bcl-2 and Beclin-1 immunoexpression in gestational trophoblastic disease.

    PubMed

    Wargasetia, Teresa Liliana; Shahib, Nurhalim; Martaadisoebrata, Djamhoer; Dhianawaty, Diah; Hernowo, Bethy

    2015-07-01

    The pathogenesis of Gestational Trophoblastic Disease (GTD) is not clearly known. In this study, immunoexpression of proteins Bcl-2 and Beclin-1 in trophoblastic lesions and normal trophoblastic tissue was conducted to study the mechanism of apoptotic and autophagic cell death that is expected to complete the study of GTD pathogenesis. Bcl-2 and Beclin-1 immunoexpression were studied on complete hydatidiform mole, partial hydatidiform mole, invasive mole, choriocarcinoma and normal placenta slides. The average total scores of Bcl-2 immunoexpression had a decreasing value, starting from partial hydatidiform mole (3.09), complete hydatidiform mole (2.36), invasive mole (1.18) to choriocarcinoma (0) when compared to normal placenta (6). The results showed no significant difference in Beclin-1 immunoexpression total score between complete hydatidiform mole, partial hydatidiform mole and invasive mole, namely that the value of the average total score of Beclin-1 was low (2.27, 2.45 and 2.36), but on the contrary choriocarcinoma showed an increasing strong Beclin-1 expression with the average total score of 4.57. Bcl-2 expression decreases in line with the excessive proliferation of trophoblast cells in hydatidiform mole and leads to malignancy in invasive mole and choriocarcinoma. The decreased expression of Beclin-1 that leads to autophagy defects in complete hydatidiform mole, partial hydatidiform mole and invasive mole shows the role of autophagy as tumor suppressor, whereas strong Beclin-1 expression shows the survival role of autophagy in choriocarcinoma. The change of Bcl-2 activity as antiapoptosis and Beclin-1 as proautophagy plays a role in pathogenesis of GTD.

  15. Characterization of apoptosis and autophagy through Bcl-2 and Beclin-1 immunoexpression in gestational trophoblastic disease

    PubMed Central

    Wargasetia, Teresa Liliana; Shahib, Nurhalim; Martaadisoebrata, Djamhoer; Dhianawaty, Diah; Hernowo, Bethy

    2015-01-01

    Background: The pathogenesis of Gestational Trophoblastic Disease (GTD) is not clearly known. Objective: In this study, immunoexpression of proteins Bcl-2 and Beclin-1 in trophoblastic lesions and normal trophoblastic tissue was conducted to study the mechanism of apoptotic and autophagic cell death that is expected to complete the study of GTD pathogenesis. Materials and Methods: Bcl-2 and Beclin-1 immunoexpression were studied on complete hydatidiform mole, partial hydatidiform mole, invasive mole, choriocarcinoma and normal placenta slides. Results: The average total scores of Bcl-2 immunoexpression had a decreasing value, starting from partial hydatidiform mole (3.09), complete hydatidiform mole (2.36), invasive mole (1.18) to choriocarcinoma (0) when compared to normal placenta (6). The results showed no significant difference in Beclin-1 immunoexpression total score between complete hydatidiform mole, partial hydatidiform mole and invasive mole, namely that the value of the average total score of Beclin-1 was low (2.27, 2.45 and 2.36), but on the contrary choriocarcinoma showed an increasing strong Beclin-1 expression with the average total score of 4.57. Conclusion: Bcl-2 expression decreases in line with the excessive proliferation of trophoblast cells in hydatidiform mole and leads to malignancy in invasive mole and choriocarcinoma. The decreased expression of Beclin-1 that leads to autophagy defects in complete hydatidiform mole, partial hydatidiform mole and invasive mole shows the role of autophagy as tumor suppressor, whereas strong Beclin-1 expression shows the survival role of autophagy in choriocarcinoma. The change of Bcl-2 activity as antiapoptosis and Beclin-1 as proautophagy plays a role in pathogenesis of GTD. PMID:26494988

  16. [Persistent trophoblastic tumor. Report of 15 cases at the National Institute of Perinatal Medicine].

    PubMed

    Lira Plascencia, J; Tenorio González, F; Novoa Vargas, A; Gómezpedroso Rea, J; Aranda Flores, C; Ibargüengoitia Ochoa, F

    1995-10-01

    Fifteen (18%) out of 83 patients with gestational trophoblastic disease, developed persistent trophoblastic tumor, from January, 1988 to March, 1994. Average age of patient was 25.5. There was antecedent of molar pregnancy in two cases. Beta fraction of chorionic gonadotrophin hormone at the time of diagnosis was 152,200 m UI/ml, average. During control it was in 80% of anovulatory oral cases. The treatment was based on metotrexate, and folinic acid; there was 100% remission. There was a total of 46.6% of pregnancies, after treatment; and 40% of them were normal.

  17. Subsequent pregnancy outcomes after complete and partial molar pregnancy, recurrent molar pregnancy, and gestational trophoblastic neoplasia: an update from the New England Trophoblastic Disease Center.

    PubMed

    Vargas, Roberto; Barroilhet, Lisa M; Esselen, Katharine; Diver, Elisabeth; Bernstein, Marilyn; Goldstein, Donald P; Berkowitz, Ross S

    2014-01-01

    To review and update the subsequent reproductive outcomes in patients with complete, partial, and recurrent hydatidiform moles, as well as gestational trophoblastic neoplasia (GTN) at the New England Trophoblastic Disease Center. Patients with complete and partial hydatidiform mole, recurrent hydatidiform mole, and GTN were identified from the Donald P. Goldstein, M.D., Trophoblastic Tumor Registry. Questionnaires regarding subsequent pregnancies were mailed to patients with current mailing addresses available. Additional patient data was obtained from electronic medical records. A total of 2,432 subsequent pregnancies have been reported since 1965. Of those, 1,388 pregnancies were after complete mole, 357 after partial mole, and 667 after GTN. The subsequent reproductive outcomes in patients with complete and partial molar pregnancies and persistent GTN remain similar to those in the general population. However, approximately 1.7% of patients with a prior molar pregnancy had a molar pregnancy in a later gestation. Furthermore, after successful chemotherapy for GTN the incidence of stillbirth was slightly increased to 1.3% in later pregnancies. Patients with molar pregnancies and GTN should expect similar reproductive outcomes as compared to the general population. However, patients receiving chemotherapy for GTN have a slightly increased risk stillbirth in subsequent pregnancies.

  18. Classification systems in Gestational trophoblastic neoplasia - Sentiment or evidenced based?

    PubMed

    Parker, V L; Pacey, A A; Palmer, J E; Tidy, J A; Winter, M C; Hancock, B W

    2017-05-01

    The classification system for Gestational trophoblastic neoplasia (GTN) has proved a controversial topic for over 100years. Numerous systems simultaneously existed in different countries, with three main rival classifications gaining popularity, namely histological, anatomical and clinical prognostic systems. Until 2000, prior to the combination of the FIGO and WHO classifications, there was no worldwide consensus on the optimal classification system, largely due to a lack of high quality data proving the merit of one system over another. Remarkably, a validated, prospectively tested classification system is yet to be conducted. Over time, increasing criticisms have emerged regarding the currently adopted combined FIGO/WHO classification system, and its ability to identify patients most likely to develop primary chemotherapy resistance or disease relapse. This is particularly pertinent for patients with low-risk disease, whereby one in three patients are resistant to first line therapy, rising to four out of five women who score 5 or 6. This review aims to examine the historical basis of the GTN classification systems and critically appraise the evidence on which they were based. This culminates in a critique of the current FIGO/WHO prognostic system and discussion surrounding clinical preference versus evidence based practice. Copyright © 2017 Elsevier Ltd. All rights reserved.

  19. Postmolar gestational trophoblastic neoplasia: beyond the traditional risk factors.

    PubMed

    Bakhtiyari, Mahmood; Mirzamoradi, Masoumeh; Kimyaiee, Parichehr; Aghaie, Abbas; Mansournia, Mohammd Ali; Ashrafi-Vand, Sepideh; Sarfjoo, Fatemeh Sadat

    2015-09-01

    To investigate the slope of linear regression of postevacuation serum hCG as an independent risk factor for postmolar gestational trophoblastic neoplasia (GTN). Multicenter retrospective cohort study. Academic referral health care centers. All subjects with confirmed hydatidiform mole and at least four measurements of β-hCG titer. None. Type and magnitude of the relationship between the slope of linear regression of β-hCG as a new risk factor and GTN using Bayesian logistic regression with penalized log-likelihood estimation. Among the high-risk and low-risk molar pregnancy cases, 11 (18.6%) and 19 cases (13.3%) had GTN, respectively. No significant relationship was found between the components of a high-risk pregnancy and GTN. The β-hCG return slope was higher in the spontaneous cure group. However, the initial level of this hormone in the first measurement was higher in the GTN group compared with in the spontaneous recovery group. The average time for diagnosing GTN in the high-risk molar pregnancy group was 2 weeks less than that of the low-risk molar pregnancy group. In addition to slope of linear regression of β-hCG (odds ratio [OR], 12.74, confidence interval [CI], 5.42-29.2), abortion history (OR, 2.53; 95% CI, 1.27-5.04) and large uterine height for gestational age (OR, 1.26; CI, 1.04-1.54) had the maximum effects on GTN outcome, respectively. The slope of linear regression of β-hCG was introduced as an independent risk factor, which could be used for clinical decision making based on records of β-hCG titer and subsequent prevention program. Copyright © 2015 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

  20. The evolving role of hysterectomy in gestational trophoblastic neoplasia at the New England Trophoblastic Disease Center.

    PubMed

    Clark, Rachel M; Nevadunsky, Nicole S; Ghosh, Sue; Goldstein, Donald P; Berkowitz, Ross S

    2010-01-01

    To identify indications for hysterectomy in patients with gestational trophoblastic neoplasia (GTN) and to evaluate outcomes of hysterectomy in those patients. Patients who underwent hysterectomy were identified utilizing hospital medical records and the New England Trophoblastic Disease Center (NETDC) database from January 1, 1959-January 1, 2009. Demographic data as well as indication for hysterectomy, stage, World Health Organization score, chemotherapeutic regimens and outcomes were recorded. We further stratified our population into patients with hysterectomies before and after 1980 to assess how indications for and outcomes after hysterectomy may have changed at our institution over time. A total of 98 patients were identified to have undergone hysterectomy for GTN. In the entire cohort 85% (n = 83) achieved remission and 48% (n = 47) required chemotherapy after hysterectomy. Among the patients in the early cohort (n = 49), indications for hysterectomy included 15 (31%) for primary definitive management, 14 (29%) for chemotherapy resistant disease, 14 (29%) for bleeding and 6 (11%) for other reasons. Of the patients with hysterectomy for chemotherapy resistance, 9 (64%) achieved remission. In the more recent cohort (n = 49) indications for hysterectomy included 24 (49%) for primary definitive management, 19 (39%) for drug-resistant disease, 4 (8%) for bleeding and 2 (4%) for other reasons. Of the patients with hysterectomy for chemotherapy resistance, 16 (84%) achieved remission. There was a statistically significant decline in the number of hysterectomies performed for bleeding. Hysterectomy was performed for bleeding in the early cohort (1959-1980) in 14 (29%) of 49 patients but in only 4 (8%) of 49 patients in the later cohort (1981-2009) (p = 0.02). During the years 1959-2009 the number of hysterectomies performed for GTN at the NETDC has remained stable. However, at our center there has been a decline in the incidence of hysterectomy for life

  1. Mental Representations of Illness in Patients with Gestational Trophoblastic Disease: How Do Patients Perceive Their Condition?

    PubMed Central

    Di Mattei, Valentina E.; Carnelli, Letizia; Mazzetti, Martina; Bernardi, Martina; Di Pierro, Rossella; Bergamini, Alice; Mangili, Giorgia; Candiani, Massimo; Sarno, Lucio

    2016-01-01

    Background Gestational Trophoblastic Disease comprises a group of benign and malignant disorders that derive from the placenta. Using Leventhal’s Common-Sense Model as a theoretical framework, this paper examines illness perception in women who have been diagnosed with this disease. Methods Thirty-one women diagnosed with Gestational Trophoblastic Disease in a hospital in Italy were asked to complete the Illness Perception Questionnaire-Revised to measure the following: illness Identity, illness opinions and causes of Gestational Trophoblastic Disease. Results High mean scores were observed in the Emotional representations and Treatment control subscales. A significant difference emerged between hydatidiform mole patients and those with gestational trophoblastic neoplasia on the Identity subscale. A significant correlation emerged between “time since diagnosis” and the Treatment control subscale. Discussion This study is the first to investigate illness perception in Gestational Trophoblastic Disease. From a clinical perspective the results highlight the need for multidisciplinary support programs to promote a more realistic illness perception. PMID:27101144

  2. Imaging and Clinical Data of Placental Site Trophoblastic Tumor: A Case Report

    PubMed Central

    Niknejadi, Maryam; Ahmadi, Firoozeh; Akhbari, Farnaz

    2016-01-01

    Placental site trophoblastic tumor (PSTT) is a very rare variant of gestational trophoblastic tumor. It can occur after normal termination of pregnancy or spontaneous abortion and ectopic or molar pregnancy. There is a wide range of clinical manifestations from a benign condition to an aggressive disease with fatal outcome. One of the most important characteristics of PSTT, unlike other forms of gestational trophoblastic diseases (GTD) is the presence of low beta-subunit of human chorionic gonadotropin (β-hCG) levels because it is a neoplastic proliferation of intermediate trophoblastic cells. However, human placental lactogen (hPL) is increased on histologic section and in the serum of patients too. We present a case of PSTT and discuss the differential diagnosis in order to further familiarize physicians with the diagnosis and treatment of this disease. It has a varied clinical spectrum and usually presents with irregular vaginal bleeding or amenorrhea. Diagnosis is confirmed by dilatation and curettage (D and C) and hysterectomy. Because chemotherapy is not effective, surgery is the cornerstone of treatment. This case is presented because it is a rare neoplasm with different treatments and it should be differentiated from molar pregnancy. PMID:27679689

  3. Abnormal expression of plasminogen activator inhibitors in patients with gestational trophoblastic disease.

    PubMed Central

    Estellés, A.; Grancha, S.; Gilabert, J.; Thinnes, T.; Chirivella, M.; España, F.; Aznar, J.; Loskutoff, D. J.

    1996-01-01

    We previously reported significantly elevated levels of plasminogen activator inhibitor type 1 (PAI-1) in plasma and placenta from pregnant women with severe pre-eclampsia, and pre-eclampsia is a frequent problem in molar pregnancies. As increases in PAI-1 may contribute to the placental alterations that occur in pre-eclampsia, we have begun to investigate changes in PAI-1 as well as PAI-2 and several other components of the fibrinolytic system in patients with trophoblastic disease. Significant increases in plasma PAI-1 and decreases in plasma PAI-2 levels were observed in molar pregnancies when compared with the levels in normal pregnant women of similar gestational age. PAI-1 antigen levels also were increased, and PAI-2 levels were decreased in placenta from women with molar pregnancies compared with placenta obtained by spontaneous abortion. Immunohistochemical analysis revealed strong positive and specific staining of PAI-1 in trophoblastic epithelium in molar pregnancies and relatively weak staining of PAI-2. No association between the distribution of PAI-1 and vitronectin was found, and no specific signal for tissue type PA, urokinase type PA, tumor necrosis factor-alpha, or interleukin-1 was detected. In situ hybridization revealed an increase in PAI-1 but not PAI-2 mRNAs in placenta from molar pregnancies in comparison with placenta from abortions. These results demonstrate increased PAI-1 protein and mRNA in trophoblastic disease and suggest that localized elevated levels of PAI-1 may contribute to the hemostatic problems associated with this disorder. Images Figure 1 Figure 2 Figure 3 PMID:8863672

  4. Prognosis of Patients with Gestational Trophoblastic Neoplasia and Obstetric Outcomes of Those Conceiving After Chemotherapy.

    PubMed

    Gadducci, Angiolo; Cosio, Stefania; Fanucchi, Antonio; Tana, Roberta; Manacorda, Simona; Pistolesi, Sabina; Strigini, Francesca Letizia

    2016-07-01

    To assess prognosis of gestational trophoblastic neoplasia (GTN) and obstetric outcome after chemotherapy. Sixty-six patients had diagnosis of hydatiform mole on curettage and 18 developed GTN. Two patients were referred with pathological diagnosis of GTN. Chemotherapy was tailored according to International Federation of Gynecology and Obstetrics risk scoring system. All patients with GTN but one, were recovered by chemotherapy and had no evidence of disease after a median follow-up of 80 months. Only the patient with epithelioid trophoblastic tumor died of disease. Seven out of the eight women who tried to conceive after chemotherapy became pregnant. Ten conceptions occurred, resulting in no molar pregnancy, three miscarriages and seven term-live healthy births (70.0%). All seven babies showed normal development and growth after a median follow-up of 38 months. The prognosis of women with GTN is very good, and obstetric outcomes of those who conceive after chemotherapy are similar to those of the general population. Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  5. The Role of Surgery in the Management of Gestational Trophoblastic Neoplasia The Hungarian Experience.

    PubMed

    Fülöp, Vilmos; Szigetvári, Iván; Szepesi, János; Végh, György; Zsirai, László; Berkowitz, Ross S

    2016-01-01

    To review the role of surgery in the management of gestational trophoblastic neoplasia (GTN) over the past 38 years in our national trophoblastic disease center. Between January 1, 1977, and December 31, 2014, 371 patients with low-risk GTN and 190 patients with high-risk GTN were treated with chemotherapy, surgical interventions, or both. The indications for hysterectomy included excision of large uterine tumor masses, uterine hemorrhage or sepsis, or a drug-resistant uterine focus. Metastases were excised due to the presence of drug-resistant foci or complications of disease such as hemorrhage. Over the period of 1977-2014 74 hysterectomies, 15 resections of vaginal metastases, 3 omentectomies, 13 adnexectomies, 9 lung resections, I nephrectomy, 1 lung resection and nephrectomy, and 2 craniotomies were performed among our patients. While hysterectomy was performed in 51 (26.8%) of 190 high-risk patients, hysterectomy was performed in only 23 (6.2%) of 371 low-risk patients (p < 0.01). From 1977-2006 metastases were resected in 18.3% (26/142) and from 2007-2014 in 16.7% (8/48) of high-risk patients. In our center surgery, particularly in the form of hysterectomy, still plays a valuable role in the management of both low- and high-risk GTN.

  6. Epithelioid trophoblastic tumor after induced abortion with previous broad choriocarcinoma: a case report and review of literature

    PubMed Central

    Zhang, Xiaofei; Shi, Haiyan; Chen, Xiaoduan

    2014-01-01

    Epithelioid trophoblastic tumor (ETT) is a rare trophoblastic tumor originating from chorionic-type intermediate trophoblasts (ITs). It is usually associated with a prior gestational event. We present a 44-year-old woman who had unusual pregnancy related history. The patient received her second spontaneous abortion at the age of 25 years and had suffered from choriocarcinoma in left board ligament at the age of 29 years. She admitted no more treatment after 3 courses of multiagent chemotherapy when serum β-hCG returned to normal. Then she had Full-term delivery, induced abortion at the ages of 32, 33 years. The patient had high serum levels of beta-human chorionic gonadotropin (6587 IU/L). Microscopically, the tumor was composed of mainly mononuclear tumor cells, grew in cords, nests, and sheets within which were aggregates of hyaline material. Most were with distinct cell borders, eosinophilic cytoplasm. Immunohistochemical staining revealed strong diffuse reactivity for cytokeratins (AE1/AE3, CK18), P63, focal reactivity for beta-human chorionic gonadotropin, human placental lactogen, and inhibin-alpha. The Ki-67 index was 77%. The histological and immunohistochemical features were characteristic of epithelioid trophoblastic tumor. This is the first reported case of these two gestational trophoblastic tumor happened on one person with the intervening normal pregnancy. PMID:25550880

  7. Placental site trophoblastic tumor: a case report and review of the literature

    PubMed Central

    Lucas, Rita; Cunha, Teresa Margarida; Santos, Filipa Batista

    2015-01-01

    We present a case of a gravida 1 para 1 woman, who presented with an 11-month history of amenorrhea after cesarean delivery. The patient was taking birth control pills at the time of presentation. She was observed with a slight elevation of serum β-hCG level, an enlarged heterogeneous uterus and hematometra. A biopsy was performed, and the patient was diagnosed with placental site trophoblastic tumor; the patient then underwent surgery. Placental site trophoblastic tumor is the rarest form of gestational trophoblastic disease, derived from intermediate trophoblast cells. It does not have a pathognomonic appearance; therefore, correlation with medical history, as well as results of laboratory tests and pathological analysis is mandatory. It is a relatively chemoresistant tumor, posing considerable therapeutic challenges; patients with localized disease are managed with surgery and those with metastatic disease require additional chemotherapy. Herein, we review the main features of this entity and top differential diagnosis, as the rarity of this tumor is associated with imaging and pathological pitfalls, reinforcing the need for further experience in this field. PMID:26622924

  8. Placental site trophoblastic tumor: a case report and review of the literature.

    PubMed

    Lucas, Rita; Cunha, Teresa Margarida; Santos, Filipa Batista

    2015-04-01

    We present a case of a gravida 1 para 1 woman, who presented with an 11-month history of amenorrhea after cesarean delivery. The patient was taking birth control pills at the time of presentation. She was observed with a slight elevation of serum β-hCG level, an enlarged heterogeneous uterus and hematometra. A biopsy was performed, and the patient was diagnosed with placental site trophoblastic tumor; the patient then underwent surgery. Placental site trophoblastic tumor is the rarest form of gestational trophoblastic disease, derived from intermediate trophoblast cells. It does not have a pathognomonic appearance; therefore, correlation with medical history, as well as results of laboratory tests and pathological analysis is mandatory. It is a relatively chemoresistant tumor, posing considerable therapeutic challenges; patients with localized disease are managed with surgery and those with metastatic disease require additional chemotherapy. Herein, we review the main features of this entity and top differential diagnosis, as the rarity of this tumor is associated with imaging and pathological pitfalls, reinforcing the need for further experience in this field.

  9. Gestational trophoblastic disease: does central nervous system chemoprophylaxis have a role?

    PubMed Central

    Gillespie, A M; Siddiqui, N; Coleman, R E; Hancock, B W

    1999-01-01

    In the UK there are standardized surveillance procedures for gestational trophoblastic disease. However, there are differences in practice between the two treatment centres in terms of definition of persistent gestational trophoblastic disease, prognostic risk assessment and chemotherapeutic regimens. The role of prophylactic chemotherapy for cerebral micrometastatic disease in persistent gestational trophoblastic disease is unclear. We have analysed the outcome of 69 patients with lung metastases who elsewhere might have received prophylactic intrathecal chemotherapy. Of the 69 patients, 67 received intravenous chemotherapy only. The other two patients had cerebral metastases at presentation. One patient who received only intravenous chemotherapy subsequently developed a cerebral metastasis, but this patient's initial treatment was compromised by non-compliance. This experience supports our current policy of not treating patients with pulmonary metastases, without clinical evidence of central nervous system (CNS) involvement, with prophylactic intrathecal therapy. © 1999 Cancer Research Campaign PMID:10098770

  10. Gestational trophoblastic neoplasia, an ancient disease: new light and potential therapeutic targets.

    PubMed

    Alazzam, Mo'iad; Tidy, John; Hancock, Barry W; Powers, Hilary

    2010-02-01

    Gestational trophoblastic neoplasia is a rare malignancy, which can occur after any type of pregnancy. The incidence varies according to the geographical location and ethnic origin. Although most patients with gestational trophoblastic neoplasia are cured by conventional chemotherapy and surgery, some suffer resistant disease and may die. New therapeutic agents are needed to reduce the toxicity associated with conventional chemotherapy and treat those with resistant or refractory disease. Molecular targeted treatment provides an exciting avenue, however, the biology of gestational trophoblastic neoplasia is not well understood. This review briefly summarises the recent advances in understanding the pathogenesis and molecular biology of this group of diseases and sheds light on molecules that could provide potential therapeutic targets.

  11. Diagnosis, Treatment and Outcome of Gestational Trophoblastic Neoplasia in a Low Resource Income Country.

    PubMed

    Gueye, Mamour; Ndiaye-Gueye, Mame D; Kane-Gueye, Serigne M; Gassama, Omar; Diallo, Moussa; Moreau, Jean C

    2016-01-01

    Gestational trophoblastic disease (GTD) is a disease of the proliferative trophoblastic allograft. Diagnosis and treatment of GTN in low resource-income countries is challenging due to numerous factors. The objective of this study was to review outcomes of gestational trophoblastic neoplasia in women of low socioeconomic status with limited resources and social support. This study was performed at Gynecologic and Obstetric Clinic of Dakar Teaching Hospital, the reference Centre of Gestational trophoblastic diseases in Senegal from 2006 to 2015. Out of 1088 patients followed for gestational trophoblastic disease during the study period, 108 patients were diagnosed and treated for GTN: 88 low-risk and 20 high-risk. Low-risk patients received an average of 6.9 cycles of initial single-agent chemotherapy. Twelve patients had persistent disease and were switched to a second line multi-agent chemotherapy. Finally 94.3% of low-risk patients achieved remission. All high-risk patients were initially treated with multi-agent chemotherapy, averaging 7 cycles. Five of the eighty-eight low-risk patients and twelve of the 20 high-risk patients died of disease. Early adequate treatment ensures an excellent prognosis for patients with GTN. In low-income countries, difficulties encountered in diagnosis and treatments worsen the prognosis of GTN patients. Clinical trials are needed to find out affordable schedules or drugs for a better treatment.

  12. Stages of Gestational Trophoblastic Tumors and Neoplasia

    MedlinePlus

    ... uterus to scrape out abnormal tissue (last panel). Hysterectomy : Surgery to remove the uterus, and sometimes the ... the vagina , the operation is called a vaginal hysterectomy. If the uterus and cervix are taken out ...

  13. Microvesicles of women with gestational hypertension and preeclampsia affect human trophoblast fate and endothelial function.

    PubMed

    Shomer, Einat; Katzenell, Sarah; Zipori, Yaniv; Sammour, Rami N; Isermann, Berend; Brenner, Benjamin; Aharon, Anat

    2013-11-01

    Microvesicles shedding from cell membrane affect inflammation, apoptosis, and angiogenesis. We hypothesize that microvesicles of women with gestational vascular complications reflect pathophysiological state of the patients and affect their endothelial and trophoblast cell function. Microvesicles of healthy pregnant women, women with gestational hypertension, mild, or severe preeclampsia/toxemia, were characterized, and their effects on early-stage or term trophoblasts and endothelial cells were evaluated using apoptosis, migration, and tube formation assays. Patient subgroups differed significantly only in proteinuria levels, therefore their microvesicles were assessed as 1 group, demonstrating higher levels of inflammatory and angiogenic proteins compared with those of healthy pregnant women. In endothelial cells, microvesicles of healthy pregnant women reduced caspase 3/7 activity, increased migration, and induced tube formation. These processes were suppressed by microvesicles of women with gestational vascular complications. In early-stage trophoblasts, microvesicles of healthy pregnant women decreased apoptosis compared with untreated cells (6±5% versus 13.8±5.8%; P<0.001) and caspase 3/7 activity and induced higher migration (39.7±10.1 versus 20.3±8.3 mm2; P<0.001). This effect was mediated through extracellular signal-regulated kinase pathway. Conversely, microvesicles of women with gestational vascular complications increased term trophoblast apoptosis compared with cells exposed to microvesicles of healthy pregnant women (15.1±3.3% versus 6.5±2.1%; P<0.001) and inhibited early-stage trophoblasts migration (21.4±18.5 versus 39.7±10.1 mm2; P<0.001). In conclusion, microvesicle content and effects on endothelial and trophoblast cells vary according to the physiological/pathological state of a pregnant woman. Microvesicles seem to play a pivotal role in the course of pregnancy, which could potentially result in gestational vascular complications.

  14. Uterine artery Doppler flow velocimetry parameters for predicting gestational trophoblastic neoplasia after complete hydatidiform mole, a prospective cohort study

    PubMed Central

    Asmar, Flavia Tarabini Castellani; Braga-Neto, Antonio Rodrigues; de Rezende-Filho, Jorge; Villas-Boas, Juliana Marques Simões; Charry, Rafael Cortés; Maesta, Izildinha

    2017-01-01

    OBJECTIVES: Doppler ultrasonography can be used to assess neoangiogenesis, a characteristic feature of postmolar gestational trophoblastic neoplasia. However, there is limited information on whether uterine artery Doppler flow velocimetry parameters can predict gestational trophoblastic neoplasia following a complete hydatidiform mole. The purpose of this study was as follows: 1) to compare uterine blood flow before and after complete mole evacuation between women who developed postmolar gestational trophoblastic neoplasia and those who achieved spontaneous remission, 2) to assess the usefulness of uterine Doppler parameters as predictors of postmolar gestational trophoblastic neoplasia and to determine the best parameters and cutoff values for predicting postmolar gestational trophoblastic neoplasia. METHODS: This prospective cohort study included 246 patients with a complete mole who were treated at three different trophoblastic diseases centers between 2013 and 2014. The pulsatility index, resistivity index, and systolic/diastolic ratio were measured by Doppler flow velocimetry before and 4-6 weeks after molar evacuation. Statistical analysis was performed using Wilcoxon’s test, logistic regression, and ROC analysis. RESULTS: No differences in pre- and post-evacuation Doppler measurements were observed in patients who developed postmolar gestational trophoblastic neoplasia. In those with spontaneous remission, the pulsatility index and systolic/diastolic ratio were increased after evacuation. The pre- and post-evacuation pulsatility indices were significantly lower in patients with gestational trophoblastic neoplasia (odds ratio of 13.9-30.5). A pre-evacuation pulsatility index ≤1.38 (77% sensitivity and 82% specificity) and post-evacuation pulsatility index ≤1.77 (79% sensitivity and 86% specificity) were significantly predictive of gestational trophoblastic neoplasia. CONCLUSIONS: Uterine Doppler flow velocimetry measurements, particularly pre- and post

  15. Downregulation of ASPP1 in gestational trophoblastic disease: correlation with hypermethylation, apoptotic activity and clinical outcome.

    PubMed

    Mak, Victor C Y; Lee, Lee; Siu, Michelle K Y; Wong, Oscar G W; Lu, Xin; Ngan, Hextan Y S; Wong, Esther S Y; Cheung, Annie N Y

    2011-04-01

    Gestational trophoblastic disease encompasses a spectrum of trophoblastic lesions including true neoplasms such as choriocarcinomas and the potentially malignant hydatidiform moles, which may develop persistent disease requiring chemotherapy. ASPP1, a member of apoptosis-stimulating proteins of p53 (ASPPs), is a proapoptotic protein that can stimulate apoptosis through its interaction with p53. We evaluated the promoter methylation and expression profiles of ASPP1 in different trophoblastic tissues and its in vitro functional effect on two choriocarcinoma cell lines, namely JEG-3 and JAR. Significant downregulation of ASPP1 mRNA and protein levels was demonstrated in hydatidiform moles and choriocarcinomas, when compared with normal placentas by quantitative-PCR and immunohistochemistry. The ASPP1 mRNA level was significantly correlated with its hypermethylation status, evaluated with methylation-specific PCR, in placenta and gestational trophoblastic disease samples (P=0.024). Moreover, lower ASPP1 immunoreactivity was shown in hydatidiform moles that progressed to persistent gestational trophoblastic neoplasms than in those that regressed (P=0.045). A significant correlation was also found between expression of ASPP1 and proliferative indices (assessed by Ki67 and MCM7), apoptotic activity (M30 CytoDeath antibody), p53 and caspase-8 immunoreactivities. An in vitro study showed that ectopic expression of ASPP1 could trigger apoptosis through intrinsic and extrinsic pathways as indicated by an increase in cleaved caspase-9 and Fas ligand protein expression. The latter suggests a hitherto unreported novel link between ASPP1 and the extrinsic pathway of apoptosis. Our findings suggest that downregulation of ASPP1 by hypermethylation may be involved in the pathogenesis and progress of gestational trophoblastic disease, probably through its effect on apoptosis.

  16. The Role of Surgery and Radiation Therapy in the Management of Gestational Trophoblastic Disease

    PubMed Central

    Hanna, Rabbie K.

    2010-01-01

    The primary management of hydatidiform moles remains surgical evacuation followed by human chorionic gonadotropin level monitoring. Although suction dilatation and evacuation is the most frequent technique for molar evacuation, hysterectomy is a viable option in older patients who do not wish to preserve fertility. Despite advances in chemotherapy regimens for treating malignant gestational trophoblastic neoplasia, hysterectomy and other extirpative procedures continue to play a role in the management of patients with both low-risk and high-risk gestational trophoblastic neoplasia. Primary hysterectomy can reduce the amount of chemotherapy required to treat low-risk disease, whereas surgical resections, including hysterectomy, pulmonary resections, and other extirpative procedures, can be invaluable for treating highly selected patients with persistent, drug-resistant disease. Radiation therapy is also often incorporated into the multimodality therapy of patients with high-risk metastatic disease. This review discusses the indications for and the role of surgical interventions during the management of women with hydatidiform moles and malignant gestational trophoblastic neoplasia and reviews the use of radiation therapy in the treatment of women with malignant gestational trophoblastic neoplasia. PMID:20495216

  17. Clinical Analysis and Management of Gestational Trophoblastic Diseases: A 90 Cases Study

    PubMed Central

    Riadh, Ben Temime; Abdellatif, Chechia; Wissal, Hannachi; Leila, Attia; Taher, Makhlouf; Abdelhamid, Koubaa

    2009-01-01

    Objective: The aim of the study was to identify the incidence, diagnosis, therapeutic and histological particularities of molar pregnancies and to evaluate our management of gestational trophoblastic tumors (GTT) according to the recommendations of FIGO. Methods: This was a retrospective study of 90 patients who were diagnosed with molar pregnancy from January 1991 to December 2007. After remission, post molar pregnancy surveillance was continued for one year. Patients whose condition required chemotherapy for GTT were attributed a FIGO/WHO score. Results: Molar pregnancy occurred in 90 women. The frequency of molar pregnancy was 1 per 1124 pregnancies. The mean age was 32.21 years. Molar pregnancies were more frequent in pauciparous patients (52.24%). At diagnosis, the median gestational age was 13 weeks. The main presenting symptom was metrorrhagia (90%). Treatment consisted in uterine evacuation by suction curettage. Histological findings were complete mole in 66.66% of the cases and partial mole in 33.33% of the cases. 81 patients (90%) achieved remission without chemotherapy and 9 patients (10%) had FIGO stage I GTT. They achieved remission with a monochemotherapy. Conclusion: The practice of ultrasonography in the first trimester of pregnancy allows an early diagnosis of molar pregnancy and an adequate treatment and follow-up. PMID:23675154

  18. [Results of gestational trophoblastic neoplasia treatment in the Slovak Republic in the years from 1993 to 2012].

    PubMed

    Korbeľ, M; Šufliarsky, J; Danihel, Ľ; Vojtaššák, J; Nižňanská, Z

    2016-01-01

    Analysis and epidemiology of gestational trophoblastic neoplasia treatment in the Slovak Republic in the years 1993-2012. Retrospective epidemiological national study. Centre for gestational trophoblastic disease Ministry of Health the Slovak Republic, Bratislava. Retrospective analysis results of gestational trophoblastic neoplasia treatment according to prognostic scoring and staging system FIGO/WHO in Centre for gestational trophoblastic disease Ministry of Health the Slovak Republic Bratislava in the years 1993-2012. The treatment of gestational trophoblastic neoplasia (GTN) in the Czech and Slovak Republics started in 1955 and lasted till 1993. After the split of the former Czechoslovakia the Centre for gestational trophoblastic disease was created in Slovakia. 75 patients were treated in this Centre in the years 1993-2012. According to prognostic scoring and staging system FIGO/WHO 56 (75%) patients had low-risk gestational trophoblastic neoplasia and 19 (25%) of patients had high-risk gestational trophoblastic neoplasia. There were 41 patients (55%), 2 (3%), 24 (32%) and 8 (11%) in stage I., II., III. and IV. respectively. Total curability rate was 94.7% and mortality rate was 5.3%. Curability rate 100% was achieved in stage I & II and all placental site trophoblastic tumours (PSTT), 98.3% in stage III and 50% stage IV. In the years 1993-2012 the incidence of choriocarcinoma was one in 76 273 pregnancies and one in 53 203 deliveries. The incidence of other gestational trophoblastic neoplasia in the same years was for PSTT one in 533 753 pregnancies and one in 372 422 deliveries, invasive mole one in 145 611 pregnancies and one in 101 569 deliveries, and persistent GTN one in 40 043 pregnancies and one in 27 932 deliveries. 225-241 patients were treated in the same period of time in the Czech Republic with curability rate 98.2-98. 3%. Early detection and treatment in the centre for trophoblastic disease are crucial points in the manage-ment of gestational

  19. Selective uterine artery embolization: a new therapeutic approach in a patient with low-risk gestational trophoblastic disease.

    PubMed

    Carlini, Laura; Villa, Antonella; Busci, Luisa; Trezzi, Gaetano; Agazzi, Roberto; Frigerio, Luigi

    2006-07-01

    We report a case of persistent gestational trophoblastic disease (GTD) in which a selective uterine artery embolization instead of invasive surgery achieved both the control of pelvic hemorrhage and of disease.

  20. Prophylactic chemotherapy for hydatidiform mole to prevent gestational trophoblastic neoplasia.

    PubMed

    Wang, Qiuyi; Fu, Jing; Hu, Lina; Fang, Fang; Xie, Lingxia; Chen, Hengxi; He, Fan; Wu, Taixiang; Lawrie, Theresa A

    2017-09-11

    This is an update of the original Cochrane Review published in Cochrane Library, Issue 10, 2012.Hydatidiform mole (HM), also called a molar pregnancy, is characterised by an overgrowth of foetal chorionic tissue within the uterus. HMs may be partial (PM) or complete (CM) depending on their gross appearance, histopathology and karyotype. PMs usually have a triploid karyotype, derived from maternal and paternal origins, whereas CMs are diploid and have paternal origins only. Most women with HM can be cured by evacuation of retained products of conception (ERPC) and their fertility preserved. However, in some women the growth persists and develops into gestational trophoblastic neoplasia (GTN), a malignant form of the disease that requires treatment with chemotherapy. CMs have a higher rate of malignant transformation than PMs. It may be possible to reduce the risk of GTN in women with HM by administering prophylactic chemotherapy (P-Chem). However, P-Chem given before or after evacuation of HM to prevent malignant sequelae remains controversial, as the risks and benefits of this practice are unclear. To evaluate the effectiveness and safety of P-Chem to prevent GTN in women with a molar pregnancy. To investigate whether any subgroup of women with HM may benefit more from P-Chem than others. For the original review we performed electronic searches in the Cochrane Gynaecological Cancer Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL, Issue 2, 2012), MEDLINE (1946 to February week 4, 2012) and Embase (1980 to 2012, week 9). We developed the search strategy using free text and MeSH. For this update we searched the Cochrane Central Register of Controlled Trials (CENTRAL, Issue 5, 2017), MEDLINE (February 2012 to June week 1, 2017) and Embase (February 2012 to 2017, week 23). We also handsearched reference lists of relevant literature to identify additional studies and searched trial registries. We included randomised controlled trials

  1. Formalised consensus of the European Organisation for Treatment of Trophoblastic Diseases on management of gestational trophoblastic diseases.

    PubMed

    Bolze, Pierre-Adrien; Attia, Jocelyne; Massardier, Jérôme; Seckl, Michael J; Massuger, Leon; van Trommel, Nienke; Niemann, Isa; Hajri, Touria; Schott, Anne-Marie; Golfier, François

    2015-09-01

    Gestational trophoblastic disease (GTD) is a spectrum of cellular proliferations arising from trophoblast. Their invasive and metastatic potential sometimes requires chemotherapy and/or surgery. Current management is generally associated with favourable prognosis. Therefore, treatments must be chosen according to the desire for further childbearing of each patient. The European Organisation for Treatment of Trophoblastic Diseases (EOTTD) is dedicated to optimise diagnosis, treatment, follow-up and research in GTD by bringing together knowledge of clinicians and researchers from 29 countries working in the field of GTD in Europe. This study assessed the level of agreement among an expert panel of the EOTTD in order to rationalise the management of patients in Europe. The RAND/UCLA Appropriateness Method was used to combine the best available scientific evidence with the collective judgment of experts to yield a statement regarding the appropriateness of performing a procedure at the level of patient-specific symptoms, medical history and test results. There was an agreement for 54 statements while the experts showed a disagreement for two statements. As there is little evidence from randomised trials on which to base recommendations about management of GTD, many of these recommendations are based on expert opinion derived from changes in management fact that have improved outcomes from nearly 100% fatality to nearly 100% cure rates. However, a large agreement among experts is invaluable to the individual clinician who is struggling to decide whether a fertility-sparing treatment of hydatidiform mole or a low-risk GTN can be chosen and how it must be conducted. Copyright © 2015 Elsevier Ltd. All rights reserved.

  2. The role of surgery in the management of women with gestational trophoblastic disease.

    PubMed

    Lima, Lana DE Lourdes Aguiar; Padron, Lílian; Câmara, Raphael; Sun, Sue Yazaki; Rezende, Jorge; Braga, Antônio

    2017-01-01

    The Gestational Trophoblastic Disease includes an interrelated group of diseases originating from placental tissue, with distinct behaviors concerning local invasion and metastasis. The high sensitivity of the serial dosages of human chorionic gonadotrophin, combined with advances in chemotherapy treatment, have made gestational trophoblastic neoplasia curable, most often through chemotherapy. However, surgery remains of major importance in the management of patients with gestational trophoblastic disease, improving their prognosis. Surgery is necessary in the control of the disease's complications, such as hemorrhage, and in cases of resistant/relapsed neoplasia. This review discusses the indications and the role of surgical interventions in the management of women with molar pregnancy and gestational trophoblastic neoplasia. RESUMO Doença trofoblástica gestacional inclui um grupo interrelacionado de doenças originadas do tecido placentário, com tendências distintas de invasão local e metástase. A alta sensibilidade das dosagens seriadas de gonadotrofina coriônica humana aliada aos avanços do tratamento quimioterápico tornou a neoplasia trofoblástica gestacional, curável, na maioria das vezes, através da quimioterapia. No entanto, a cirurgia permanece ainda, da maior importância na condução de pacientes com doença trofoblástica gestacional, melhorando seu prognóstico. A cirurgia é necessária no controle de complicações da doença, tais como hemorragia, e em casos de neoplasia resistente/recidivada. Esta revisão discute as indicações e o papel das intervenções cirúrgicas durante o manejo de mulheres com gravidez molar e neoplasia trofoblástica gestacional.

  3. 15years of progress in gestational trophoblastic disease: Scoring, standardization, and salvage.

    PubMed

    Brown, Jubilee; Naumann, R Wendel; Seckl, Michael J; Schink, Julian

    2017-01-01

    Significant improvements in treatment and the understanding of gestational trophoblastic neoplasia have occurred in the last 15years. These diseases are almost always curable, and refractory patients have more options for salvage therapy. Recent improvements in the understanding of epidemiology, diagnosis, and cell biology have resulted in changes in staging, advances in treatment options, and opportunities for fertility preservation. Copyright © 2016. Published by Elsevier Inc.

  4. Proportion hyperglycosylated hCG: a new test for discriminating gestational trophoblastic diseases.

    PubMed

    Cole, Laurence A

    2014-11-01

    Hyperglycosylated human chorionic gonadotropin (hCG) is a variant of hCG with large oligosaccharide side chains. Although hCG is produced by syncytiotrophoblast cells, hyperglycosylated hCG marks cytotrophoblast cell. Hyperglycosylated hCG signals placental implantation. Total hCG in serum and urine is measured by the Siemens Immulite hCG pregnancy test; the result is in milli-international unit per milliliter. Hyperglycosylated hCG is determined by the B152 microtiter plate assay; the result is in nanogram per milliliter. Hyperglycosylated hCG results can be converted to milli-international unit per milliliter equivalents by multiplying by 11. The test measures proportion hyperglycosylated hCG, hyperglycosylated hCG / total hCG. Proportion hyperglycosylated hCG marks cases intent on developing persistent hydatidiform mole (68% detection at 17% false detection). Proportion hyperglycosylated hCG also marks persistent hydatidiform mole (100% detection at 5.1% false detection). Proportion hyperglycosylated hCG distinguishes choriocarcinoma and gestational trophoblastic neoplasm cases, absolutely discriminating aggressive cases and minimally aggressive cases. Proportion hyperglycosylated hCG identifies quiescent gestational trophoblastic disease cases. It recognizes quiescent cases that become persistent disease (100% detection at 0% false positive). Proportion hyperglycosylated hCG is an invaluable test for discriminating gestational trophoblastic diseases.

  5. A profile of cases of gestational trophoblastic neoplasia at a large tertiary centre in dubai.

    PubMed

    Rangwala, Tasneem H; Badawi, Faiza

    2011-01-01

    Objectives. To study (1) the prevalence of different types of gestational trophoblastic neoplasia (GTN) in the local and nonlocal population of women at Al Wasl Hospital, a tertiary level referral centre for northern Emirates, (2) the safety of cervical preparation before uterine evacuation, (3) the role of repeat uterine evacuation in curing these cases, and (4) the percentage of cases ultimately requiring chemotherapy. Material and Methods. Retrospective analysis of case records of 35 women with diagnosis of gestational trophoblastic neoplasia were managed in the Department of Obstetrics and Gynecology at Al Wasl Hospital, over a 2-year period between January 2007 to December 2008. Results. 35 cases of gestational trophoblastic neoplasia were seen in a 2-year period (January 2007 to December 2008) at Al Wasl Hospital, with 7000 deliveries per year, prevalence being 1 in 400 live births. 60% cases were local Arabs. Histopathology revealed complete mole in 13 cases, partial mole in 17 cases, hydropic degeneration of villi in 4 cases, and no identifiable tissue in 1 case. No cases of choriocarcinoma or placental site trophoblastic tumour were seen during the study period. 34% cases received cervical preparation with prostaglandins prior to surgical curettage. Complications were minor. 62% were cured by primary suction curettage, 12% after second (repeat) uterine evacuation, and 25% needed single drug chemotherapy. 8% cases defaulted after primary evacuation and were lost to followup. Conclusions. Prevalence of GTN in the local Arab population is similar to other Asian populations. The majority of cases are cured by simple suction uterine curettage. Cervical preparation with prostaglandins should be done in selected cases to avoid perforation during evacuation. Second (repeat) uterine evacuation can be curative in some cases with strict selection criteria and avoid the need for chemotherapy. Regional registry of cases is needed to estimate the true incidence of this

  6. The added value of hysterectomy in the management of gestational trophoblastic neoplasia.

    PubMed

    Eysbouts, Y K; Massuger, L F A G; IntHout, J; Lok, C A R; Sweep, F C G J; Ottevanger, P B

    2017-06-01

    Despite the undoubted effectiveness of chemotherapeutic treatment in gestational trophoblastic neoplasia (GTN), problems related to toxicity of chemotherapy and chemo-resistant disease have led to reconsideration of the use of hysterectomy. Aim of the present study was to evaluate indications for and outcome of hysterectomy in patients with GTN in a nation-wide cohort. Between 1977 and 2012, we identified all patients diagnosed with GTN and treated with hysterectomy from the Dutch national databases. Demographics, clinical characteristics and follow-up were recorded retrospectively. One hundred and nine patients (16.5% of all registered patients with GTN) underwent hysterectomy as part of their management for GTN. The majority of patients was classified as low-risk disease (74.3%), post-molar GTN (73.5%) and disease confined to the uterus (65.1%). After hysterectomy, complete remission was achieved in 66.2% of patients with localized disease and in 15.8% of patients with metastatic disease. For patients with localized disease, treated with primary hysterectomy, treatment duration was significantly shorter (mean 3.2weeks and 8.0weeks respectively, p=0.01) with lower number of administered chemotherapy cycles (mean 1.5 and 5.8 respectively, p<0.01) than patients in a matched control group. In selected cases, a hysterectomy may be an effective means to either reduce or eliminate tumor bulk. Primary hysterectomy should mainly be considered in older patients with localized disease and no desire to preserve fertility, whereas patients with chemotherapy-resistant disease may benefit from additional hysterectomy, especially when disease is localized. For patients with widespread metastatic disease, the benefit of hysterectomy lies in the removal of chemotherapy-resistant tumor bulk with subsequent effect on survival. Copyright © 2017 Elsevier Inc. All rights reserved.

  7. Historical, morphological and clinical overview of placental site trophoblastic tumors: from bench to bedside.

    PubMed

    Santoro, Giuseppe; Laganà, Antonio Simone; Micali, Antonio; Barresi, Valeria; Giacobbe, Valentina; Palmara, Vittorio

    2017-01-01

    Placental site trophoblastic tumor (PSTT) is a form of gestational trophoblastic disease that originates from the implantation of an intermediate trophoblast. It was described for the first time by Von F. Marchand in 1895 as belonging to chorioepithelioma sui generis, a pathological condition with many variations and a progressive degree of malignancy. We have conducted a literature review in MEDLINE about epidemiology, etiopathogenesis and clinical features of PSTT. Moreover, a case that occurred in our institution was reported. Our research has highlighted that existing published data about PSTT are not uniform. The number of cases described in the literature has updated and the clinical features of selected "case series" of patients diagnosed with PSTT were showed. The etiopathogenesis was discussed. It was noted that current prognostic factors still allow important information regarding PSTT to be obtained, albeit fragmentary. The lack of uniformity in data collection seen so far has limited full knowledge of PSTT. For this reason, we suggest a model (PSTT model) that collects and unifies PSTT evidence as this would be useful to identify worldwide precise prognostic factors, which are still lacking. When PSTT is diagnosed, the proper procedure seems to be total hysterectomy, with sampling of pelvic lymph nodes and ovarian conservation. For advanced-stage diseases, (stage III and IV) a combination of surgery and polychemotherapy is suggested.

  8. Persistent gestational trophoblastic disease after an androgenetic/biparental fetal chimera: a case report and review.

    PubMed

    Surti, Urvashi; Hoffner, Lori; Kolthoff, Marta; Dunn, Jeanette; Hunt, Jennifer; Sniezek, Lynn; Macpherson, Trevor

    2006-10-01

    We present a case of a dichorionic/diamniotic twin pregnancy in which one twin presented with ultrasound findings suggestive of molar changes in the placenta. The placenta of twin A seemed to be grossly enlarged and cystic, and twin A was small for gestation. After an inevitable abortion, a detailed histological and genetic evaluation was performed on the fetus and placenta from twin A, including traditional cytogenetic techniques, microsatellite marker analysis, fluorescent in situ hybridization, and p57 immunostaining. It was determined that twin A was a chimera with a biparental XX cell line and an androgenetic XY cell line. The 2 cell lines were present in both the placenta and the fetus. The patient later developed and was treated for persistent gestational trophoblastic disease, which has been shown to have an increased risk after an androgenetic conception. Cases of mosaicism or chimerism involving an androgenetic cell line may be difficult to diagnose histologically but are critical to identify because of the increased risk for persistent gestational trophoblastic disease. Therefore, we emphasize the importance of using multiple molecular, cytogenetic, and immunohistochemical techniques when diagnosing cases involving such unusual placental abnormalities. To our knowledge, this is the first reported case of persistent gestational disease after a fetal chimera.

  9. A 10-Year Clinical Experience of Gestational Trophoblastic Disease at Rajavithi Hospital, 2001-2010.

    PubMed

    Yanaranop, Marut; Potikul, Chalermrat; Tuipae, Suphet

    2016-02-01

    Gestational trophoblastic disease (GTD) develops from abnormal cellular proliferation of trophoblasts following fertilization and is categorized as either an hydatidiform mole (HM) or a gestational trophoblastic neoplasia (GTN). To analyze the clinical characteristics, incidence and treatment outcomes of GTD at Rajavithi Hospital. Medical records of women diagnosed with GTD at Rajavithi Hospital from January 1, 2001 to December 31, 2010 were retrospectively reviewed. Disease diagnosis, treatment and follow-up data were analyzed. A total of 329 cases of GTD were reviewed. HM was diagnosed in 167 patients (incidence 2.32 per 1,000 deliveries); 26 patients were lost to follow-up; and 49 of the remaining 141 patients (34.8%) developed post-molar GTN. In multivariable analysis, uterus >16 week size and pre-treatment human chorionic gonadotropin (hCG) level >250,000 mIU/mL were the significant risk factors for developing post-molar GTN. Of 162 patients with GTN (incidence 2.25 per 1,000 deliveries), 15 patients were lost to follow-up, and 116 patients, 29 patients and 2 patients were classified as having low-risk GTN, high-risk GTN and placental site trophoblastic disease respectively. The overall survival rate in the low-risk group was 100% whereas in the high-risk group it was 86.2%. A modified WHO prognostic score of more than five was the significant risk factor for developing resistant GTN. GTD treatment at Rajavithi Hospital showed excellent clinical outcomes. Uterus >16 weeks size and pre- treatment hCG > 250,000 mIU/mL were the significant risk factors for developing post-molar GTN in HM patients. Classifying GTN patients into low- and high-risk groups was useful in planning treatment and counseling.

  10. Gestational trophoblastic neoplasia after achieving a nondetectable serum human chorionic gonadotrophin level.

    PubMed

    Gueye, M; Kane-Gueye, S M; Ndiaye-Gueye, M D; Mbaye, M; Diouf, A A; Niang, M M; Diallo, M; Moreau, J C

    2014-10-01

    To determine the risk of recurrent trophoblastic disease after normalisation of human chorionic gonadotrophin (hCG) levels in women with hydatidiform mole. A retrospective review of data from a national gestational trophoblastic disease centre. The Trophoblastic Disease Unit, Dakar, Senegal. Women with pregnancies affected by hydatidiform mole registered between 2006 and 2012. The women were followed up in accordance with the hospital protocol 'Score de Dakar'. For women who progressed to gestational trophoblastic neoplasia (GTN) the time to onset of GTN, treatment and evolution were evaluated. The rate of evolution to GTN after normalisation of hCG was determined. Rate of occurrence of GTN after chemotherapy for hydatidiform mole. Five hundred and thirty-one women were diagnosed to have molar pregnancies. According to the hospital's protocol, 107 (20.2%) of these had chemotherapy and 224 (42.2%) had prophylactic chemotherapy. Five hundred and thirteen women (96.4%; 95% confidence interval [95% CI] 95.05-98.14%) achieved remission. Eighteen women (3.4%; 95% CI 1.86-4.94%) developed GTN (11 before remission and seven after remission). Seven women out of the 18 developed GTN after hCG normalisation (1.3%). Five of these seven were diagnosed beyond the recommended period of follow up. The mean interval to diagnosis of GTN was 18.7 months. These seven women underwent combination chemotherapy: five achieved complete remission whereas two died from GTN. Cytotoxic therapy for hydatidiform mole does not prevent GTN, it delays its diagnosis and promotes GTN after normalisation of hCG. © 2014 Royal College of Obstetricians and Gynaecologists.

  11. LINE-1 Methylation Patterns as a Predictor of Postmolar Gestational Trophoblastic Neoplasia

    PubMed Central

    Lertkhachonsuk, Ruangsak; Paiwattananupant, Krissada; Tantbirojn, Patou; Rattanatanyong, Prakasit; Mutirangura, Apiwat

    2015-01-01

    Objective. To study the potential of long interspersed element-1 (LINE-1) methylation change in the prediction of postmolar gestational trophoblastic neoplasia (GTN). Methods. The LINE-1 methylation pattern from first trimester placenta, hydatidiform mole, and malignant trophoblast specimens were compared. Then, hydatidiform mole patients from 11999 to 2010 were classified into the following 2 groups: a remission group and a group that developed postmolar GTN. Specimens were prepared for a methylation study. The methylation levels and percentages of LINE-1 loci were evaluated for their sensitivity, specificity, and accuracy for the prediction of postmolar GTN. Results. First, 12 placentas, 38 moles, and 19 malignant trophoblast specimens were compared. The hydatidiform mole group had the highest LINE-1 methylation level (p = 0.003) and the uCuC of LINE-1 increased in the malignant trophoblast group (p ≤ 0.001). One hundred forty-five hydatidiform mole patients were classified as 103 remission and 42 postmolar GTN patients. The %mCuC and %uCmC of LINE-1 showed the lowest p value for distinguishing between the two groups (p < 0.001). The combination of the pretreatment β-hCG level (≥100,000 mIU/mL) with the %mCuC and %uCmC, sensitivity, specificity, PPV, NPV, and accuracy modified the levels to 60.0%, 92.2%, 77.4%, 83.8%, and 82.3%, respectively. Conclusions. A reduction in the partial methylation of LINE-1 occurs early before the clinical appearance of malignant transformation. The %mCuC and %uCmC of LINE-1s may be promising markers for monitoring hydatidiform moles before progression to GTN. PMID:26448937

  12. Changes in the management of high-risk gestational trophoblastic neoplasia in the National Trophoblastic Disease Center of Hungary.

    PubMed

    Fülöp, Vilmos; Szigetvári, Iván; Szepesi, János; Végh, György; Berkowitz, Ross S

    2014-01-01

    To compare the clinical management of patients with high-risk gestational trophoblastic neoplasia (GTN) among the periods of 1977-1990, 1991-2000, and 2001-2012 at the National Trophoblastic Disease Center of Hungary and to assess the efficacy of the FIGO 2000 staging and risk factor scoring system in comparison to the original WHO prognostic scoring system (1983). We reviewed the medical records of 185 patients with high-risk GTN. From 1977-2000, patients were classified according to the original WHO prognostic scoring system (1983). From 2001-2012, high-risk patients were categorized by the FIGO 2000 system. We assessed the efficacy of MAC and EMA-CO primary combination chemotherapies. For 1977-2006 and 2007-2012 we assessed the efficacy of MAC and EMA-CO primary combination chemotherapies. From 1977-1990, 63 high-risk patients (average, 4-5 patients/year), from 1991-2000, 50 high-risk patients (average, 5 patients/year), and from 2001-2012, 72 high-risk patients (average, 6 patients/year) were treated primarily with combination chemotherapy (MAC and/or EMA-CO and/or CEB). From 1977-2006, 100 high-risk patients received MAC primary combination chemotherapy and 17 cases received EMA-CO. The ratio of primary MAC primarily with and EMA-CO therapy among our high-risk patients was 5.9 (100/17) over the referred period. From 2007-2012, 21 high-risk patients were treated with primary MAC chemotherapy and 16 patients received EMA-CO. The MAC/EMA-CO ratio over this time interval was 1.3 (21/16). We attained complete remission in 95.7% of the high-risk patients. During the last 6 years the use of EMA-CO primary combination chemotherapy increased among our high-risk patients, which has resulted in increased efficacy and fewer side effects.

  13. Early Onset of Metastatic Gestational Trophoblastic Disease after Full-Term Pregnancy

    PubMed Central

    Ghaemmaghami, Fatemeh; Zarchi, Mojgan Karimi

    2008-01-01

    Choriocarcinoma is a curable malignancy that occurred approximately 50% after term pregnancies, and prognosis in this form of gestational trophoblastic Disease (GTD) is Poor. The earliest onset choriocarcinoma after term pregnancy in one study was reported 3 weeks after delivery, but in current study, choriocarcinoma was diagnosed 2 weeks after delivery. 28 years-old women gravidity 2, parity 2 delivered a healthy infant at term. Frequent episodes of vaginal bleeding occurred after 10 days of delivery. On admission to hospital, she had lesions in the lungs. The pretreatment human chorionic gonadotropin (HCG) level was 84,000 mIU/ml and her FIGO risk factor score was 8 (high risk group). The EMA/CO regimen was administered as first line chemotherapy and the patient achieved complete remission after 7 courses. Although early onset postpartum hemorrhage is due to complication of delivery, but gestational trophoblastic disease (GTD) may be occurred and assessment of human chorionic gonadotropin could be help to early diagnose of GTD. PMID:23675070

  14. Leukemia Inhibitory Factor (LIF) Inhibition during Mid-Gestation Impairs Trophoblast Invasion and Spiral Artery Remodelling during Pregnancy in Mice

    PubMed Central

    Winship, Amy; Correia, Jeanne; Zhang, Jian-Guo; Nicola, Nicos A.; Dimitriadis, Evdokia

    2015-01-01

    The placenta forms the interface between the maternal and fetal circulation and is critical for the establishment of a healthy pregnancy. Trophoblast cell proliferation, migration and invasion into the endometrium are fundamental events in the initiation of placentation. Leukemia inhibitory factor (LIF) has been shown to promote trophoblast invasion in vitro, however its precise role in trophoblast invasion in vivo is unknown. We hypothesized that LIF would be required for normal trophoblast invasion and spiral artery remodeling in mice. Both LIF and its receptor (LIFRα) co-localized with cytokeratin-positive invasive endovascular extravillous trophoblasts (EVT) in mouse implantation sites during mid-gestation. Temporally blocking LIF action during specific periods of placental development via administration of our unique LIFRα antagonist, PEGLA, resulted in abnormal trophoblast invasion and impaired spiral artery remodeling compared to PEG control. PEGLA-treated mouse decidual vessels were characterized by retention of α-smooth muscle actin (αSMA)-positive vascular smooth muscle cells (VSMCs), while PEG control decidual vessels were remodelled by cytokeratin-positive trophoblasts. LIF blockade did not alter F4/80-positive decidual macrophage numbers between treatment groups, but resulted in down-regulation of decidual transcript levels of monocyte chemoattractant protein-1 (MCP-1) and interleukin-10 (IL-10), which are important immune cell activation factors that promote spiral artery remodeling during pregnancy. Our data suggest that LIF plays an important role in trophoblast invasion in vivo and may facilitate trophoblast-decidual-immune cell cross talk to enable adequate spiral artery remodeling. PMID:26479247

  15. Human placental growth hormone: a potential new biomarker in gestational trophoblastic disease.

    PubMed

    Hübener, Christoph; Bidlingmaier, Martin; Wu, Zida; Diebold, Joachim; Delius, Maria; Friese, Klaus; Strasburger, Christian J; Hasbargen, Uwe

    2015-02-01

    Gestational trophoblastic disease (GTD) involves a spectrum of abnormal proliferations arising from the placental villous trophoblast. Although the incidence is low, a biomarker with short serum half-life would be a major clinical advance to monitor surgical and medical treatment reducing the socioeconomic burden of multiple control visits as well as patient's anxiety. Placental growth hormone (hGH-V) plays an important role in the regulation of normal placental growth and has shown angiogenic effects. We aimed to determine by immunohistochemistry (IHC) whether hGH-V is expressed in GTD and whether it can be detected in the patient's blood for potential monitoring of surgical or medical treatment procedures. Tissue and sera were collected from women undergoing treatment for GTD in a tertiary care university hospital. We evaluated partial and complete hydatidiform moles, invasive moles and choriocarcinoma, n=16. Trophoblast specimens were examined by a newly developed IHC set-up for hGH-V in addition to gross morphologic and histopathological examination. Serum samples were analyzed by a highly sensitive hGH-V specific immunoassay. hGH-V was localized in all entities of GTD to the syncytiotrophoblast by immunohistochemistry. Serum hGH-V was detected for the first time in GTD and was present in a high percentage of all analyzed entities. hGH-V can be detected in all entities of GTD by IHC as well as by serum analysis and may therefore serve as a novel biomarker for the disease. Its clinical utility in diagnosis of GTD and monitoring surgical or medical treatment needs to be determined in further studies. Copyright © 2014 Elsevier Inc. All rights reserved.

  16. Predictive factors of relapse in low-risk gestational trophoblastic neoplasia patients successfully treated with methotrexate alone.

    PubMed

    Couder, Florence; Massardier, Jérôme; You, Benoît; Abbas, Fatima; Hajri, Touria; Lotz, Jean-Pierre; Schott, Anne-Marie; Golfier, François

    2016-07-01

    Patients with 2000 FIGO low-risk gestational trophoblastic neoplasia are commonly treated with single-agent chemotherapy. Methotrexate is widely used in this indication in Europe. Analysis of relapse after treatment and identification of factors associated with relapse would help understand their potential impacts on 2000 FIGO score evolution and chemotherapy management of gestational trophoblastic neoplasia patients. This retrospective study analyzes the predictive factors of relapse in low-risk gestational trophoblastic neoplasia patients whose hormone chorionic gonadotropin (hCG) normalized with methotrexate alone. Between 1999 and 2014, 993 patients with gestational trophoblastic neoplasia were identified in the French Trophoblastic Disease Reference Center database, of which 465 were low-risk patients whose hCG normalized with methotrexate alone. Using univariate and multivariate analysis we identified significant predictive factors for relapse after methotrexate. The Kaplan-Meier method was used to plot the outcome of patients. The 5-year recurrence rate of low-risk gestational trophoblastic neoplasia patients whose hCG normalized with methotrexate alone was 5.7% (confidence interval [IC], 3.86-8.46). Univariate analysis identified an antecedent pregnancy resulting in a delivery (HR = 5.96; 95% CI, 1.40-25.4, P = .016), a number of methotrexate courses superior to 5 courses (5-8 courses vs 1-4: HR = 6.19; 95% CI, 1.43-26.8, P = .015; 9 courses and more vs 1-4: HR = 6.80; 95% CI, 1.32-35.1, P = .022), and hCG normalization delay centered to the mean as predictive factors of recurrence (HR = 1.27; 95% CI, 1.09-1.49, P = .003). Multivariate analysis confirmed the type of antecedent pregnancy and the number of methotrexate courses as independent predictive factors of recurrence. A low-risk gestational trophoblastic neoplasia arising after a normal delivery had an 8.66 times higher relapse risk than that of a postmole gestational trophoblastic neoplasia

  17. Intracytoplasmic sperm injection combined with preimplantation genetic diagnosis for the prevention of recurrent gestational trophoblastic disease.

    PubMed

    Reubinoff, B E; Lewin, A; Verner, M; Safran, A; Schenker, J G; Abeliovich, D

    1997-04-01

    A strategy for the prevention of repeated molar pregnancies by using intracytoplasmic sperm injection (ICSI) coupled with preimplantation genetic diagnosis (PGD) with fluorescence in-situ hybridization (FISH) was developed. In this approach, complete moles which arise from dispermic fertilization are avoided by the use of ICSI. ICSI is followed by preimplantation selection against the transfer of 46,XX embryos, thus preventing complete moles resulting from a fertilization of an inactive oocyte, by a haploid X-bearing spermatozoon which subsequently duplicates. Triploid partial moles which arise mainly from dispermic fertilization may also be prevented by ICSI. The preimplantation confirmation of diploidy by FISH guards against triploid partial moles which may result from mechanisms other than dispermic fertilization. The employment of this strategy in an attempt to prevent a repeated event of molar pregnancy in a patient with a history of two previous episodes of gestational trophoblastic disease is reported.

  18. Unusual Presentation of Hypothyroidism in a Pregnant Woman, Mimicking Gestational Trophoblastic Neoplasm

    PubMed Central

    Aminimoghaddam, Soheila; Mazloomi, Maryam; Rahimi, Maryam

    2016-01-01

    Hypothyroidism is a common health issue worldwide with varying clinical manifestations. We report a woman who experienced an incomplete abortion and undiagnosed hypothyroidism who was referred to the oncologist with the suspicion of metastatic gestational trophoblastic neoplasm (GTN). A 29-year-old woman with incomplete abortion was referred to an oncologist for possible GTN due to persistent active vaginal bleeding, an elevated beta human chorionic gonadotropin (hCG), abnormal cervical inspection exam, abnormal liver function tests, ovarian enlargement, ascites, and a pleural effusion. She was found to have hypothyroidism in further work-up. She was managed with thyroid hormone replacement therapy and her condition improved after 6 weeks. Complete resolution of the ovarian mass and pericardial and pleural effusion was achieved. This case describes an important experience; hypothyroidism should be considered in the differential diagnosis of any woman with an incomplete abortion presenting with an ovarian mass. Evaluation and correct diagnosis are important to prevent mismanagement. PMID:27034864

  19. Methotrexate on a 21-day cycle for low-risk gestational trophoblastic neoplasia.

    PubMed

    Diaz, Juan; Thomas, M Bijoy; Paz-Pabon, Charlotte; Hernandez, Enrique

    2012-01-01

    To perform an outcome analysis of patients with low-risk gestational trophoblastic neoplasia (GTN) treated with a 5-day intramuscular methotrexate (MTX) regimen on a 21-day cycle. A retrospective review of 31 patients with low-risk GTN treated with a 5-day MTX regimen. A total of 31 patients with low-risk GTN (WHO score < 7) received single-agent MTX at a dose of 0.4 mg/kg daily for 5 days every 21 days (mean number of cycles, 3; 83% remission). The only significant toxicity encountered was grade 2 stomatitis in 8 (26%) patients. A 5-day MTX regimen given every 21 days is convenient, well-tolerated and effective for patients with low-risk GTN.

  20. Gestatational trophoblastic disease: multimodality imaging assessment with special emphasis on spectrum of abnormalities and value of imaging in staging and management of disease.

    PubMed

    Kani, Kimia Khalatbari; Lee, Jean H; Dighe, Manjiri; Moshiri, Mariam; Kolokythas, Orpheus; Dubinsky, Theodore

    2012-01-01

    Gestational trophoblastic disease is a spectrum of disorders of varying malignant potential arising from trophoblastic cells and encompassing hydatidiform moles and persistent trophoblastic neoplasia. Ultrasound is the initial imaging investigation of choice when gestational trophoblastic disease is suspected. Complete hydatiform mole, the most common form of molar pregnancy, usually has a characteristic "cluster of grapes" appearance, especially on second-trimester ultrasounds. Persistent trophobastic neoplasia usually appears as a focal, hypervascular myometrial mass on pelvic ultrasound. Pelvic magnetic resonance imaging is often used as a problem-solving tool in equivocal or complicated cases of gestational trophoblastic disease to assess the degree of invasion into the myometrium and surrounding tissues. Chest x-ray, brain magnetic resonance imaging, and body computed tomography scans are primarily used for the evaluation of metastatic disease, which usually occurs in the context of choriocarcinomas. Choriocarcinoma metastases are usually hypervascular and have a tendency to bleed, features that are reflected in their imaging appearance. Published by Mosby, Inc.

  1. Comparison of 2 Human Chorionic Gonadotropin Immunoassays Commercially Available for Monitoring Patients With Gestational Trophoblastic Disease.

    PubMed

    de Souza, Juliana Maria Quinalha; Braga, Antonio; Sanches Dos Santos, Rafael; Ramos, Marcos Montanha; Cortés-Charry, Rafael; Maestá, Izildinha

    2017-09-01

    The aim of this study was to compare serum human chorionic gonadotropin (hCG) levels in patients with gestational trophoblastic disease (GTD) using 2 commercially available hCG immunoassays. Serum samples were obtained from patients with GTD attending the Botucatu Medical School Trophoblastic Diseases Center of São Paulo State University (UNESP), from November 2014 to October 2015. Serum hCG levels were measured with both Architect i2000SR and Immulite 2000 XPi chemiluminescence assays. Serum hCG levels were compared against the null hypothesis. Agreement in clinical management decisions based on the hCG results was determined by comparing baseline hCG measurements and the hCG curves obtained with both assays. Seventy-three patients with GTD were included in the analysis. Of these, 45 had hydatidiform mole and spontaneous remission, whereas 28 had gestational trophoblastic neoplasia (GTN). There was a perfect (zero difference) agreement in mean hCG levels between Immulite 2000 XPi and Architect i2000 when hCG is less than 100 mIU/mL. For hCG values greater than 100 mIU/mL, there was a significant difference between assays (P < 0.05), with levels measured via Architect i2000SR being higher than those measured by Immulite 2000 XPi in patients with hydatidiform mole/spontaneous remission (R = 90%, P < 0.01) and GTN (R = 98%, P < 0.01). Baseline clinical management decisions showed agreement in 100% (73/37) of cases (κ = 1.0, P < 0.001), whereas decisions based on hCG curve agreed in 98% (71/72) of cases (κ = 0.93, P < 0.001). Immulite 2000 XPi is the most frequently recommended assay for diagnosing and monitoring patients with GTD. However, our results suggest that because Immulite 2000 XPi and Architect i2000 show very similar performance in measuring hCG levels and in determining clinical management, Architect may be used as an alternative.

  2. Epidemiological report on the treatment of patients with gestational trophoblastic disease in 10 Brazilian referral centers: results after 12 years since International FIGO 2000 Consensus.

    PubMed

    Braga, Antonio; Uberti, Elza Maria Hartmann; Fajardo, Maria do Carmo; Viggiano, Maurício; Sun, Sue Yazaki; Grillo, Bruno Maurizio; Padilha, Sérgio Lunardon; de Andrade, Jurandyr Moreira; de Souza, Christiani Bisinoto; Madi, José Mauro; Maestá, Izildinha; Silveira, Eduardo

    2014-01-01

    To evaluate treatment of Brazilian patients with gestational trophoblastic disease (GTD). A retrospective cohort study with analysis of medical reports performed in 10 Brazilian referral centers from January 2000 to December 2011. Of 5,250 patients 3 died (0.06%) at the time of uterine evacuation. Spontaneous remission of GTD (group G1) was observed in 4,103 cases, and 1,144 (21.8%) progressed to gestational trophoblastic neoplasia (GTN) (G2). In G1 2,716 (66.2%) had complete hydatidiform mole (HM) and 1,210, partial HM (29.5%); 3,772 patients (92.7%) recovered as noted in December 2012. In G2, of 1,118 patients treated, initial histopathological results of previous gestation were complete HM (77.5% [n = 886]), partial HM (8.8% [n = 100]), and choriocarcinoma (8.0% [n = 92]); 930 (81.3%) were low-risk, 200 (17.5%) were high-risk GTN, and 14 had placental site trophoblastic tumor (PSTT) (1.2%); cure was achieved in 1,078 cases (96.4%), but 26 patients (2.3%) died (4 low-risk [0.4%], 19 high-risk [9.5%], and 3 PSTT [21.4%]). The highest death rates were due to high-risk GTN and PSTT. Patients with molar pregnancy should be referred to a referral center for an early diagnosis and prompt treatment of GTN in order to reduce the morbidity and mortality found in advanced stages.

  3. Malignant placental site trophoblastic tumor: a cytogenetic study using comparative genomic hybridization and chromosome in situ hybridization.

    PubMed

    Xue, Wei-Cheng; Guan, Xin-Yuan; Ngan, Hextan Y S; Shen, Dan-Hua; Khoo, Ui-Soon; Cheung, Annie N Y

    2002-04-15

    Placental site trophoblastic tumor (PSTT) is a rare form of gestational trophoblastic neoplasm composed predominantly of intermediate trophoblast. Most showed benign behavior whereas 10-15% of PSTTs were clinically malignant with later recurrence and metastasis. Currently, there are no reliable means to predict clinical outcome, and cytogenetic information is scanty. The clinicopathologic features of two cases of malignant PSTT were analyzed. Cytogenetic analysis was performed by comparative genomic hybridization (CGH) and chromosome in situ hybridization (CISH) using frozen tissue and paraffin embedded sections, respectively. Both patients were 32 years old at time of diagnosis. One patient with PSTT presented with menorrhagia, and the other presented with symptoms of missed abortion. Elevated serum human chorionic gonadotropin (HCG) was detected in both patients. Histologic examination showed the typical features of PSTT with high mitotic count (> 5/10 high-power fields). Ovarian and lung metastasis occurred in both patients. Immunohistochemical staining revealed an equal distribution of HCG and human placental lactogen. Cytogenetic studies by CISH showed that karyotypes of these two malignant PSTTs were diploid. Analysis of the tumor tissue by CGH did not show any changes in DNA copy numbers. The authors' study indicated that the two metastasizing PSTTs had balanced diploid karyotype. The malignant behavior of PSTTs may be not related to the DNA copy number changes. Such cytogenetic study may be useful in distinguishing metastatic PSTT from choriocarcinoma. Copyright 2002 American Cancer Society.

  4. Timing of Referral to the New England Trophoblastic Disease Center: Does Referral with Molar Pregnancy Versus Postmolar Gestational Trophoblastic Neoplasia Affect Outcomes?

    PubMed

    Diver, Elisabeth J; Horowitz, Neil S; Goldstein, Donald P; Bernstein, Marilyn; Berkowitz, Ross S; Growdon, Whitfield B

    2016-01-01

    To assess if referral of patients with molar pregnancy who then developed postmolar gestational trophoblastic neoplasia (PMGTN) is associated with different outcomes when compared to referral of patients already with a diagnosis of PMGTN. The records of the New England Trophoblastic Disease Center (NETDC) were queried for all patients with molar pregnancy or PMGTN from 1993-2013. Retrospective chart review was performed to extract relevant clinical and demographic data. Parametric and nonparametric tests were utilized to compare variables. From 1993-2013, 429 women with molar disease were evaluated at the NETDC. Of those, 68% were referred with molar pregnancy and 32% were referred with PMGTN. Comparing women with PMGTN who were referred with a molar pregnancy versus referred with PMGTN, the women were of equivalent stage and World Health Organization (WHO) score. Additionally, referral with molar pregnancy or PMGTN did not associate with time to persistence, time to remission, or number of lines of chemotherapy administered. In this trophoblastic disease specialty center in the United States, referral at the time of PMGTN as opposed to at diagnosis of molar pregnancy did not appear to affect the stage or WHO score at diagnosis, the need for multiple chemotherapy lines, or time to remission.

  5. Changing presentation of complete hydatidiform mole at the New England Trophoblastic Disease Center over the past three decades: does early diagnosis alter risk for gestational trophoblastic neoplasia?

    PubMed

    Sun, Sue Yazaki; Melamed, Alexander; Goldstein, Donald P; Bernstein, Marilyn R; Horowitz, Neil S; Moron, Antonio Fernandes; Maestá, Izildinha; Braga, Antonio; Berkowitz, Ross S

    2015-07-01

    To compare the clinical presentation and incidence of postmolar gestational trophoblastic neoplasia (GTN) among recent (1994-2013) and historical (1988-1993) cases of complete hydatidiform mole (CHM). This study included two non-concurrent cohorts (1988-1993 versus 1994-2013) of patients from the New England Trophoblastic Disease Center (NETDC). Clinical and pathologic reports of patients diagnosed with CHM between 1994 and 2013 were reviewed. Gestational age at evacuation, features of clinical presentation, human chorionic gonadotropin (hCG) levels, and the rate of progression to GTN were compared. In the current cohort (1994 to 2013) the median gestational age at diagnosis continued to decline compared to our prior cohort (1988-1993) (9weeks versus 12weeks). Patients from the current cohort were significantly more likely to be diagnosed prior to the 11th week of gestation (56 versus 41%, p=0.04). Patients in the current cohort were also significantly less likely to present with vaginal bleeding (46 versus 84%, p<0.001). Earlier diagnosis of complete mole did not result in a decrease in the rate of postmolar GTN. The frequencies of postmolar GTN in the current (1994-2013) and prior (1988-1993) cohorts were 19 and 23%, respectively. In the current cohort, even diagnosis prior to ten weeks gestation did not decrease the risk of developing GTN. This study indicates that complete mole continues to be diagnosed progressively earlier resulting in a further decrease in some classical presenting symptoms. However, despite earlier detection, the risk of development of postmolar GTN has not been affected. Copyright © 2015 Elsevier Inc. All rights reserved.

  6. Investigation of Risk Factors, Stage and Outcome in Patients with Gestational Trophoblastic Disease since 2001 to 2011 in Iran-Yazd.

    PubMed

    Karimi-Zarchi, Mojgan; Mortazavizadeh, Mohammad Reza; Soltani-Gerdefaramrzi, Malihe; Rouhi, Mitra; Yazdian-Anari, Pouria; Ahmadiyeh, Mohammad Hosain

    2015-12-01

    Gestational trophoblastic disease (GTN) is one of the high-risk forms of pregnancy that requires a lot of attention in terms of research studies, considering its incidence and the importance of the disease in advanced form. The aim of this study was to investigate the risk factors and clinical procedure of patients with gestational trophoblastic disease from 2001 to 2002. This is a retrospective descriptive study, which was carried out on 150 patients with trophoblastic disease. These patients' files were obtained from Shohadaye Kargar and Shahid Sadoughi hospitals and women's oncology offices of Yazd city. The patients were contacted one by one and their disease situation was determined. The data obtained were recorded in a questionnaire and analyzed by SPSS software. The results indicated that the average age of the patients was 27.65 ± 8.22 with variations in age ranging from 15 to 35 year. In addition, majorities were in the age group of 20 to 40 years. 43.2 percent of the women were affected during their first gestation. 4% had molar gestation record, and 9.4% had positive family record. Mean time of survival was 93.38 ± 0.62 months (MIN ± SE), and only one died owing to chemotherapy complication. Vaginal bleeding (90%) was the most common symptom. 54.6 percent of the disease had complete mole, 30% had incomplete mole, 8.6% had invasive mole, 4.6% had choriocarcinoma and 2% had placenta site trophoblastic tumor (PSTT). Among the patients studied, 28.7% were benign in GTN group while 71.3 % were malignant in the GTN group. The malignant patients were divided into three groups per risk, and 41.2% were in the high-risk group. There was theca-lutein cyst in 54% of the patients, which had a significant relationship with the disease risk of persistent GTN. Choriocarcinoma and invasive mole is the most malignant pathology. There was significant relationship between disease interval and the beginning of chemotherapy, and theca lutein cyst and persistent GTN.

  7. The tumor suppressor gastrokine-1 is expressed in placenta and contributes to the regulation of trophoblast migration.

    PubMed

    Fahlbusch, F B; Ruebner, M; Huebner, H; Volkert, G; Zuern, C; Thiel, F; Koch, M; Menendez-Castro, C; Wachter, D L; Hartner, A; Rascher, W

    2013-11-01

    Gastrokine-1 (GKN1) is a secreted auto-/paracrine protein, described to be expressed in the gastric mucosa. In gastric cancers GKN1 expression is commonly down-regulated. While current research focusses on the exploration of tumor-suppressive properties of GKN1 with regard to its potential clinical use in the treatment of gastroenterologic tumor disease, nothing is known about GKN1 expression and function in other organ systems. We investigated GKN1 expression in placental tissue and cells. GKN1 was localized using immunohistochemistry in first and third trimester placental tissue, hydatidiform moles and various gestational trophoblastic neoplasias. We determined the expression of GKN1 in immunomagnetic bead-separated term placental cells and in choriocarcinoma cell lines. The role of GKN1 for JEG-3 migration was studied using live cell imaging. E-cadherin, MMP-2 and -9, TIMP-1 and -2, as well as urokinase (uPA) expression levels were determined. GKN1 is expressed in healthy third trimester placentas. Its expression is specifically limited to the extravillous trophoblast (EVT). GKN1 expression is significantly reduced in choriocarcinoma cell lines and gestational trophoblastic neoplasias. GKN1 attenuates the migration of JEG-3 choriocarcinoma cells in vitro, possibly via AKT-mediated induction of E-cadherin. GKN1 treatment reduced MMP-9 expression in JEG-3. Besides its role in gastric physiology our results clearly indicate regulatory functions of GKN1 in the EVT at the feto-maternal interface during pregnancy. Based on our findings in the JEG-3 choriocarcinoma cell line, an auto-/paracrine role of GKN1 for EVT motility and villous anchorage at the basal plate is conceivable. Thus, the tumor suppressor GKN1 is expressed in placental EVT and might contribute to the regulation of EVT migration/invasion. Copyright © 2013 Elsevier Ltd. All rights reserved.

  8. Fatal gestational trophoblastic neoplasia: An analysis of treatment failures at the Brewer Trophoblastic Disease Center from 1979-2012 compared to 1962-1978.

    PubMed

    Neubauer, Nikki L; Strohl, Anna E; Schink, Julian C; Lurain, John R

    2015-08-01

    To determine clinical factors that contributed to death from gestational trophoblastic neoplasia (GTN) at the Brewer Trophoblastic Disease Center from 1979-2012 compared to 1962-1978. Nineteen women who died of GTN from 1979-2012 were retrospectively identified and compared to 45 women previously reported on who died of GTN from 1962-1978. Clinical factors analyzed included demographics, pretreatment human chorionic gonadotropin (hCG) level, duration of disease, antecedent pregnancy, number and sites of metastases, FIGO stage and score, treatment, and cause of death. Death from GTN occurred in 19 (4%) of 483 patients treated from 1979-2012 compared to 45 (11%) of 396 patients treated from 1962-1978 (P<0.001). Pretreatment hCG level >100,000 mIU/mL, time from pregnancy event to treatment >4 months, nonmolar antecedent pregnancy and use of surgery to control metastatic disease were similar between the two treatment eras. Patients in the recent series were more likely to have presented with FIGO IV disease or brain metastasis, been initially treated with multiagent chemotherapy, and received treatment before referral to our center compared to the earlier series. The most common causes of death from 1979-2012 and 1962-1978 were hemorrhage from one or more metastatic sites (11% vs. 42%), respiratory failure (37% vs. 31%), and multiorgan failure due to widespread chemoresistant disease (42% vs. 8%), respectively. Our overall survival rate in patients with gestational trophoblastic neoplasia improved from 89% in 1962-1978 to 96% in 1979-2012. More patients treated between 1979-2012 died from widespread chemoresistant disease rather than hemorrhagic complications. Copyright © 2015 Elsevier Inc. All rights reserved.

  9. Gestational trophoblastic diseases - clinical guidelines for diagnosis, treatment, follow-up, and counselling.

    PubMed

    Niemann, Isa; Vejerslev, Lars O; Frøding, Ligita; Blaakær, Jan; Maroun, Lisa Leth; Hansen, Estrid Stæhr; Grove, Anni; Lund, Helle; Havsteen, Hanne; Sunde, Lone

    2015-11-01

    Hydatidiform mole is treated with surgical uterine evacuation with suction and blunt curettage (D). Medical uterine evacuation should not be used (C). On clinical suspicion of hydatidiform mole, one representative sample of the evacuated tissue is fixed for histopathologic investigation and one is forwarded unfixed for genetic analysis (D). Serum hCG is measured on suspicion of hydatidiform mole. At the time of the uterine evacuation, the initial hCG is measured (A). After a hydatidiform mole that is both triploid and partial, serum hCG is measured weekly until there are two consecutive undetectable values (< 1 or < 2), after which the patient can be discharged from follow-up (C). After a diploid hydatidiform mole, a complete mole, or a hydatidiform mole without valid ploidy determination, serum hCG is measured weekly until the value is undetectable (< 1 or < 2). If serum hCG is undetectable within 56 days after evacuation, the patient can be discharged from follow-up after an additional four monthly measurements. If serum hCG is first normalised after 56 days, the patient is follow-up with monthly serum hCG measurement for six months. Safe contraception should be used during the follow-up period (A). If hCG stagnates (less than 10% fall over three measurements), increases, or if hCG can be demonstrated for longer than 6 months, the patient by definition has persistent trophoblastic disease (PTD). A chest X-ray should be taken and a gynaecologic ultrasound scanning performed. The patient is referred to oncologic treatment (A). Uterine re-evacuation as a treatment for PTD can, in general, not be recommended because the rate of remission is low, and there is the risk of perforation of the uterus (C). In all following pregnancies, the woman is offered an early ultrasound scan, e.g. in gestational week eight (D). Eight weeks after termination of all future pregnancies, serum hCG is measured (D). In PTD and invasive hydatidiform mole, the primary treatment is MTX

  10. Interleukin-12 in Treating Patients With Hematologic Cancers or Solid Tumors

    ClinicalTrials.gov

    2014-09-09

    Breast Cancer; Chronic Myeloproliferative Disorders; Gestational Trophoblastic Tumor; Kidney Cancer; Leukemia; Lymphoma; Multiple Myeloma and Plasma Cell Neoplasm; Myelodysplastic Syndromes; Neuroblastoma; Ovarian Cancer; Testicular Germ Cell Tumor

  11. Residual lung lesions after completion of chemotherapy for gestational trophoblastic neoplasia: should we operate?

    PubMed Central

    Powles, T; Savage, P; Short, D; Young, A; Pappin, C; Seckl, M J

    2006-01-01

    The significance of residual lung metastasis from malignant gestational trophoblastic neoplasm (GTN) after the completion of chemotherapy is unknown. We currently do not advocate resection of these masses. Here, we investigate the outcome of these patients. Patients with residual lung abnormalities after the completion of treatment for GTN were compared to those who had a complete radiological resolution of the disease. None of the residual masses post-treatment were surgically removed. In all, 76 patients were identified. Overall 53 (70%) patients had no radiological abnormality on CXR or CT after completion of treatment. Eight (11%) patients had residual disease on CXR alone 15 patients had residual disease on CT (19%). During follow-up, two patients (2.6%) relapsed. One of these had had a complete radiological response post-treatment whereas the other had residual disease on CT. Patients with residual lung lesions after completing treatment for GTN do not appear to have an increased chance of relapse compared to those with no residual abnormality. We continue to recommend that these patients do not require pulmonary surgery for these lesions. PMID:16404359

  12. A comparison of patients with relapsed and chemo-refractory gestational trophoblastic neoplasia

    PubMed Central

    Powles, T; Savage, P M; Stebbing, J; Short, D; Young, A; Bower, M; Pappin, C; Schmid, P; Seckl, M J

    2007-01-01

    The majority of women requiring chemotherapy for gestational trophoblastic disease (GTN) are cured with their initial chemotherapy treatment. However, a small percentage either become refractory to treatment, or relapse after the completion of treatment. This study investigates the characteristics and outcome of these patients. Patients were identified from the Charing Cross Hospital GTD database. The outcome of these patients with relapsed disease was compared to those with refractory disease. Between 1980 and 2004, 1708 patients were treated with chemotherapy for GTN. Sixty (3.5%) patents relapsed following completion of initial therapy. The overall 5-year survival for patients with relapsed GTN was 93% (95% CI 86–100%). The overall survival for patients with low-risk and high-risk disease at presentation, who subsequently relapsed was 100% (n=35), and 84% (n=25) (95% CI: 66–96%: P<0.05), respectively. Eleven patients were identified who failed to enter remission and had refractory disease. These patients had a worse outcome compared to patients with relapsed disease (5-year survival 43% (95% CI:12–73% P<0.01)). The outcome of patients with relapsed GTN is good. However, patients with primary chemo-refractory disease do poorly and novel therapies are required for this group of patients. PMID:17299394

  13. Uterine artery pulsatility index: a predictor of methotrexate resistance in gestational trophoblastic neoplasia

    PubMed Central

    Agarwal, R; Harding, V; Short, D; Fisher, R A; Sebire, N J; Harvey, R; Patel, D; Savage, P M; Lim, A K P; Seckl, M J

    2012-01-01

    Background: Neo-angiogenesis is a hallmark of cancer. The aim of this study was to test the hypothesis, in a prospective patient cohort, that in low-risk gestational trophoblastic neoplasia (LR-GTN) the uterine artery pulsatility index (UAPI), a measure of tumour vascularity, can predict resistance to methotrexate chemotherapy (MTX-R). Methods: 286 LR-GTN patients (Charing Cross Hospital (CXH) score 0–8, or FIGO score 0–6) were treated with methotrexate between January 2008 and June 2011 at CXH. During staging investigations, patients underwent a Doppler ultrasound to assess the UAPI. Results: 239 patients were assessable for both UAPI and MTX-R. The median UAPI was lower (higher vascularity) in MTX-R compared with MTX-sensitive patients (0.8 vs 1.4, P<0.0001). In multivariate logistic regression, UAPI⩽1 predicted MTX-R, independent of both CXH and FIGO scores. The risk of MTX-R in patients with a FIGO score of 6 and UAPI⩽1 was 100% vs 20% in patients with UAPI>1 (χ2 P<0.0001). Conclusion: UAPI represents an independently validated clinically useful predictor of MTX-R in LR-GTN. Further, consideration of whether to incorporate UAPI into the FIGO scoring system is now warranted so that patients with a score of 6 and a UAPI ⩽1 might be upstaged and offered combination chemotherapy rather than MTX. PMID:22374461

  14. 20-year experience of managing profuse bleeding in gestational trophoblastic disease.

    PubMed

    Tse, Ka Yu; Chan, Karen K L; Tam, Kar Fai; Ngan, Hextan Yuen Sheung

    2007-05-01

    To review the outcomes of different methods in the treatment of severe bleeding or acute abdomen in gestational trophoblastic disease (GTD). In a tertiary referral center, the records of patients diagnosed with GTD and presenting with heavy vaginal bleeding or acute abdomen between January 1986 and December 2005 were retrieved. Seventeen patients presenting with heavy bleeding or acute abdomen and requiring emergency management were identified. Ten patients had heavy vaginal bleeding, and 7 had shock or signs of hemoperitoneum. Eleven patients had total abdominal hysterectomy with or without bilateral salpingo-oophorectomy (TAH +/- BSO), 2 had arterial ligation, 3 had embolization, and 1 had suturing of a vaginal defect due to a metastatic nodule. The median ages of the patients having TAH +/- BSO and other conservative treatments were 37 (21-52) and 32.5 (26-48), respectively. Fifteen patients received chemotherapy after surgical treatment. All patients survived except 1, who died of concurrent disease. Profuse bleeding in GTD is rare. Hysterectomy, arterial ligation and angiographic embolization can effectively treat this condition. With more experience, angiographic embolization should be the treatment of choice, especially for those who are hemodynamically stable and wish to retain their fertility potential.

  15. Gestational trophoblastic disease in the western region of Saudi Arabia (single-institute experience).

    PubMed

    Anfinan, Nisrin; Sait, Khalid; Sait, Hesham

    2014-09-01

    To estimate the prevalence of gestational trophoblastic disease (GTD) in the western region of Saudi Arabia, and to evaluate the success of treatment and the effect of age and risk group on survival. Between January 2001 and December 2010, all patients treated for GTD were identified from the King Abdulaziz University Hospital database. Patients with persistent disease were evaluated according to their clinical treatment outcomes. In total, 122 cases of GTD were identified in the database. Of these, 77 (63%) cases were diagnosed and received initial treatment at the study centre, resulting in an incidence of 1.26 cases per 1000 deliveries. The mean (±standard deviation) age of the study participants was 31.52 ± 10.8 years, mean gestational age at diagnosis was 12.42 ± 3.2 weeks, and mean follow-up for each patient was 24 months. There were 20 cases (26%) of persistent GTD after treatment. The majority of patients with low-risk disease were treated with single-agent methotrexate, with an overall success rate of 83%. The overall 5-year survival rate for all patients was 98%. Using the Wilcoxon (Gehan) test, risk group and age (cut-off 40 years) were not found to be significantly associated with survival (p=0.69). This single-institute study reports the first survival data for GTD for Saudi Arabia. However, the overall incidence of GTD in Saudi Arabia will be defined by establishment of a GTD registry. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  16. Dysregulated activation of c-Src in gestational trophoblastic disease contributes to its aggressive progression.

    PubMed

    Wu, W; Wang, Y; Xu, Y; Liu, Y; Wang, Y; Zhang, H

    2014-10-01

    Gestational trophoblastic disease (GTD) is a heterogeneous group of pregnancy-related disorders. Hydatidiform mole (HM) is the most common type of GTD, whereas gestational choriocarcinoma is the most aggressive. Non-receptor tyrosine kinase c-Src contributes to the transformation to a malignant phenotype in various cancers. However, the role of c-Src in the pathogenesis of GTD remains largely unknown. The expression level of phosphorylated c-Src was determined by immunohistochemistry and Western blotting assay. JAR and JEG-3 cells were treated with hCG, specific c-Src inhibitor saracatinib and PP2, and PKA specific inhibitor, PKI. Cell growth rate and cell migration/invasion ability was determined by cell proliferation and transwell assays respectively. c-Src was highly activated in HM tissues and choriocarcinoma cells (JAR and JEG-3). c-Src was activated by hCG in a time and concentration-dependent manner, which was abrogated by specific c-Src and PKA inhibitors. Inhibition of c-Src activity in JAR and JEG-3 cells by saracatinib leaded to a decrease in the rate of cell growth and cell migration/invasion ability. Furthermore, inhibition of c-Src phosphorylation induced cell cycle arrest and reduced expressions of cyclin A2, cyclin B1, cyclin E1, FOXD3 and NANOG. Moreover, inhibition of c-Src activity resulted in decreased p-FAK(Tyr397) phosphorylation. Our findings indicate an important role of c-Src in the pathogenesis of GTD, and we propose that c-Src inhibitors are potential adjuvant chemotherapeutic drugs for the treatment of GTD. Copyright © 2014 Elsevier Ltd. All rights reserved.

  17. Change in human chorionic gonadotropin in gestational trophoblastic disease observed during the course of chemotherapy.

    PubMed

    Huang, S C; Hsieh, C Y; Ouyang, P C

    1991-01-01

    This study investigates the physicochemical characteristics of human chorionic gonadotropin (hCG) in gestational trophoblastic disease (GTD), with special reference to the clinical course of chemotherapy and prognosis. In gel high performance liquid chromatography (HPLC), the hCG molecules from normal pregnancy and from the hydatidiform mole had the same molecular form as standard purified hCG, whereas hCG from choriocarcinoma was inconsistent in molecular form, containing molecules which are smaller, the same or larger than those of standard purified hCG. In two fatal choriocarcinoma patients, large hCG and large hCG alpha were found in the urine samples collected within one month prior to death. In a chromatofocusing study, the chromatofocusing pattern of hCG from GTD was acidic and similar to that of early pregnancy. The chromatofocusing patterns did not alter or were altered only slightly during the course of chemotherapy. In a Concanavalin A-Sepharose (Con A) chromatography study, the Con A binding shifted from low to high binding in patients with GTD who were responsive to chemotherapy. In summary, the molecular form, electric charge and Con A binding of hydatidiform mole hCG are similar to those of early pregnancy hCG and standard purified hCG, whereas the molecular form and Con A binding of choriocarcinoma are different from those of early pregnancy hCG and standard purified hCG. The presence of smaller or larger molecular forms of hCG may be an ominous sign, whereas the presence of high Con A binding may be a favorable sign. The chromatofocusing pattern seems to be unrelated to the clinical course of chemotherapy.

  18. Management of gestational trophoblastic disease: a survey of New Zealand O&G practice.

    PubMed

    Kladnitski, Maria; Kenwright, Diane

    2016-03-11

    The aim of the study was to obtain information on pathways for diagnosis and management of molar pregnancy/gestational trophoblastic disease (GTD) across New Zealand, the protocols used, and, in addition, to consider the view of O&G Specialists on a national GTD reference centre. An electronic survey approved by the RANZCOG Continues Professional Development Committee was distributed amongst registered O&G Specialists currently working in New Zealand. Data were analysed using Microsoft Excel 2011. Frequency distributions were used to determine the percentage of participants responding to the listed alternatives for each question. There were 234 potential responders, but only 68 complete questionnaires were received and available for analysis. The diagnosis of GTD requires histopathological analysis of pregnancy tissue, however only 79.7% of participants request this test routinely. Sixty-five percent of Fellows thought that a number of molar pregnancies can be missed with increasing proportion of medically-managed miscarriages, reliance on ultrasound and appearance of the tissue being contributing factors. Sixty-six percent of specialists were directly involved in the management of patients with GTD to various degrees. Follow-up responsibilities were divided between designated O&G specialists (52.3%), specialised gynaecology clinics (29.2%), acute assessment units (13.8%), nurse specialists (12%), O&G registrars (10.8%), GPs (6.2%), and others (6.2%). NZGCG guidelines were used by the majority of responders (54.8%), followed by local (29%) and RCOG (27.4%) guidelines. Seventy-two percent of specialists felt that some form of centralisation in the management of GTD is needed. In spite of the low response rate, our research demonstrates existing practice heterogeneity at every level of care. It also confirms that there is a desire for some form of centralisation in diagnosis and management of GTD, and a definite need for data collection in the form of a national

  19. Gestational Trophoblastic Neoplasia Treatment at the Butaro Cancer Center of Excellence in Rwanda

    PubMed Central

    Nzayisenga, Ignace; Segal, Roanne; Pritchett, Natalie; Xu, Mary J.; Park, Paul H.; Mpanumusingo, Edgie V.; Umuhizi, Denis G.; Goldstein, Donald P.; Berkowitz, Ross S.; Hategekimana, Vedaste; Muhayimana, Clemence; Rubagumya, Fidel; Fadelu, Temidayo; Tapela, Neo; Mpunga, Tharcisse

    2016-01-01

    Purpose Gestational trophoblastic neoplasia (GTN) is a highly treatable disease, most often affecting young women of childbearing age. This study reviewed patients managed for GTN at the Butaro Cancer Center of Excellence (BCCOE) in Rwanda to determine initial program outcomes. Patients and Methods A retrospective medical record review was performed for 35 patients with GTN assessed or treated between May 1, 2012, and November 30, 2014. Stage, risk score, and low or high GTN risk category were based on International Federation of Gynecology and Obstetrics staging and the WHO scoring system and determined by beta human chorionic gonadotropin level, chest x-ray, and ultrasound per protocol guidelines for resource-limited settings. Pathology reports and computed tomography scans were assessed when possible. Treatment was based on a predetermined protocol stratified by risk status. Results Of the 35 patients (mean age, 32 years), 26 (74%) had high-risk and nine (26%) had low-risk disease. Nineteen patients (54%) had undergone dilation and curettage and 11 (31%) had undergone hysterectomy before evaluation at BCCOE. Pathology reports were available in 48% of the molar pregnancy surgical cases. Systemic chemotherapy was initiated in 30 of the initial 35 patients: 13 (43%) received single-agent oral methotrexate, 15 (50%) received EMACO (etoposide, methotrexate, dactinomycin, cyclophosphamide, and vincristine), and two (7%) received alternate regimens. Of the 13 patients initiating methotrexate, three had their treatment intensified to EMACO. Four patients experienced treatment delays because of medication stockouts. At a median follow-up of 7.8 months, the survival probability for low-risk patients was 1.00; for high-risk patients, it was 0.63. Conclusion This experience demonstrates the feasibility of GTN treatment in rural, resource-limited settings. GTN is a curable disease and can be treated following the BCCOE model of cancer care. PMID:28717722

  20. Thyroid storm-induced multi-organ failure in the setting of gestational trophoblastic disease.

    PubMed

    Kofinas, Jason D; Kruczek, Alexis; Sample, Jason; Eglinton, Gary S

    2015-01-01

    Thyroid storm is a potentially life-threatening complication of gestational trophoblastic disease (GTD), with varying clinical severity. It should be considered in patients with GTD, abnormal vital signs, and clinical signs of hyperthyroidism. A 45-year-old non-English-speaking patient presented to a New York City hospital in November 2011 with an aborting molar pregnancy and severe hemorrhage. Initial presentation was concerning for GTD. Laboratory values were obtained that confirmed the diagnosis of GTD, which was also by thyroid storm and congestive heart failure. This was evidenced by laboratory values of free thyroxine of 4.9 and beta human chorionic gonadotropin of 1,488,021 IU/mL. Dilation and curettage with 16-mm suction catheter was performed until all products of conception were removed and bleeding was controlled. The patient was admitted to the surgical intensive care unit and proceeded to have multi-organ failure, and remained intubated and unresponsive to verbal/visual and tactile stimuli. On postoperative day 13 the patient suddenly became alert and self-extubated, began to communicate verbally, and resolution of her multi-organ failure became evident. The patient was discharged with Gynecologic Oncology follow-up. Why should an emergency care physician be aware of this? This case represents the dangers associated with poor prenatal care and late diagnosis of molar pregnancy. It also represents the need for immediate recognition of the condition and initiation of appropriate medical care. Although this patient's clinical outcome was good, the event could have been prevented had she received reliable medical care. Copyright © 2015 Elsevier Inc. All rights reserved.

  1. Quantitative urine hCG and urine pregnancy test in gestational trophoblastic disease patients with low hCG titer.

    PubMed

    Lertkhachonsuk, Ruangsak

    2015-01-01

    To study the correlation between serum and urine hCG levels in gestational trophoblastic disease (GTD) patients with low hCG level. The correlation between serum hCG and results from urine pregnancy tests are evaluated along with quantitative measurement. In this prospective study, 86 cases of gestational trophoblastic disease patients with positive and low level of serum hCG (< 100 mIU/ml) were recruited. Quantitative serum hCG urine hCG and urine pregnancy test were performed. The correlation coefficients between serum and urine hCG were then analyzed by SPSS 16.0. Furthermore, the levels of serum hCG were compared to the results of the urine pregnancy test. From February 2006 to June 2008, 86 cases were recruited for this study. The correlation coefficient between serum and urine hCG levels in all cases was 0.44 (using Pearson correlation), p = 0.01. In subgroup analysis, the correlation coefficient between serum and urine hCG levels in chemosensitive gestational trophoblastic neoplasia (GTN) patients (n = 27) was 0.73, p ≤ 0.01. The correlation coefficient in chemoresistant GTN patients (n = 38) was 0.29, p = 0.07; and the correlation coefficient in hydatidiform mole patients (n = 21) was 0.47, p = 0.03. A urine pregnancy test was positive only in 10 of 86 specimens. The correlation coefficient between serum and urine hCG in GTD patients with low hCG level showed significant correlation. However, patients with chemoresistance had less correlation than those with chemosensitivity and hydatidiform mole. Urine pregnancy test had low correlation with urine hCG and was not useful in this group of patients.

  2. [Analysis of the treatment and prognosis for gestational trophoblastic neoplasia patients with urinary system and adrenal glands metastasis].

    PubMed

    Yang, Junjun; Ren, Tong; Wang, Dan; Feng, Fengzhi; Wan, Xirun; Xiang, Yang

    2014-10-01

    To analyze the treatment and prognosis of patients with gestational trophoblastic neoplasia with urinary system and adrenal glands metastasis. The treatment and prognoses of 32 patients with gestational trophoblastic neoplasia with urinary system and adrenal glands metastasis from Dec. 1990 to Dec. 2010 at Peking Union Medical College Hospital, Chinese Academy of Medical Sciences were respectively reviewed. Treatment methods: all 32 patients received 9 courses(in average) of a multi- drug chemotherapy in our hospital (range 1-24 coures). Among them, 3 patients with bladder metastasis received intravesical chemotherapy of fluorouracil. 9 patients received surgical treatments in other hospital and 15 patients received surgical treatments while undergoing chemotherapy in our hospital. Treatment results: after the treatments, of the 32 patients, 21 (66%) patients achieved complete remission, 3(9%) exhibited partial remission and 8 (25%) progressed. Seven patients with renal metastasis achieved complete remission. Two patients with adrenal glands metastasis achieved complete remission. Nine patients with urinary bladder metastasis achieved complete remission. Seven patients with ureters metastasis achieved complete remission. Two (10% ) of 21 patients with complete remission relapsed. Multidrug and multiroute chemotherapy is the main strategy for patients with gestational trophoblastic neoplasia with urinary system and adrenal glands metastasis. The prognoses of patients with renal or adrenal glands metastasis are much worse than those in patients with bladder and ureters metastasis because of concomitant multiogran metastasis. Adequate attention should be given to patients with renal or adrenal glands metastasis. Individual treatment, assisted by surgery when necessary, may be carried out for these patients to achieve a better outcome.

  3. GATA-3 EXPRESSION IN TROPHOBLASTIC TISSUES: An Immunohistochemical Study of 445 Cases, Including Diagnostic Utility

    PubMed Central

    Banet, Natalie; Gown, Allen M.; Shih, Ie-Ming; Li, Qing Kay; Roden, Richard B.S.; Nucci, Marisa R.; Cheng, Liang; Przybycin, Christopher G.; Nasseri-Nik, Niloofar; Wu, Lee-Shu-Fune; Netto, George J.; Ronnett, Brigitte M.; Vang, Russell

    2014-01-01

    Immunohistochemical expression of GATA-3 is seen predominantly in non-neoplastic bladder and breast epithelium and their respective carcinomas; however, data on expression in normal and lesional trophoblastic tissues are limited. Immunohistochemical staining for GATA-3 was assessed in a range of normal/lesional trophoblastic tissues and tumors in the differential diagnosis (n=445), including non-molar products of conceptions/2nd and 3rd trimester placentas/ ectopic pregnancies, hydatidiform moles, placental site nodules, normal/exaggerated implantation sites, choriocarcinomas, epithelioid trophoblastic tumors, placental site trophoblastic tumors, atypical smooth muscle tumors (including leiomyosarcoma), and cervical and pulmonary squamous cell carcinomas. The extent of expression (0 to 4+) and intensity (weak to strong) were recorded. All cases with developing trophoblast/non-neoplastic trophoblastic proliferations and 81% of trophoblastic neoplasms were positive. Of all non-neoplastic trophoblast cell types, expression was observed in cytotrophoblast in 89% of cases, syncytiotrophoblast in 50%, intermediate trophoblast in 100%, and villous trophoblastic columns in 100%. Increasing gestational age was associated with a decrease in extent/intensity of expression in non-neoplastic cytotrophoblast and syncytiotrophoblast while intermediate trophoblast maintained diffuse and strong expression from early to late gestation (p<0.0001). Eighty-nine percent of normal/exaggerated implantation sites showed 3+ or 4+ expression while staining in 55% of placental site nodules was 1+ or 2+. Staining for GATA-3 was present in 78% of choriocarcinomas, 95% of epithelioid trophoblastic tumors, and 71% of placental site trophoblastic tumors. While the number of choriocarcinomas and placental site trophoblastic tumors that showed a spectrum of expression ranging from negative to diffuse was relatively evenly distributed, 81% of epithelioid trophoblastic tumors had 3+ or 4+ staining

  4. What do women with gestational trophoblastic disease understand about the condition?

    PubMed

    Stafford, Lesley; Judd, Fiona

    2011-01-01

    Little is known about patients' understanding of the causes, treatments, and implications of gestational trophoblastic disease (GTD). Clinical observation suggests that such health literacy is limited. We report on the perceptions of causes and treatment of GTD and its impact on fertility and reproductive outcomes. Cross-sectional analysis of 176 Australian women previously diagnosed with GTD (no longer receiving follow-up/treatment) recruited from a state-wide registry. Participants comprised 149 (85%) women with GTD who did not require chemotherapy and 27 (15%) women who required chemotherapy for malignancy or persistent molar disease. Data were collected from medical records and via self-report questionnaire. Participants were 94 women (53%) with partial mole, 75 (43%) with complete mole, 4 (2%) with choriocarcinoma, and 3 (2%) with hydatidiform mole not otherwise specified. Mean (SD) age at diagnosis and time since diagnosis were 32.1 (6.3) and 4.7 (3.3) years, respectively. Chance/bad luck was the most endorsed cause (n = 146, 83%); 23 (13%) thought GTD was hereditary and 10 (6%) identified a chromosomal etiology. Between 24% and 32% were unsure of the role of alcohol/drugs, venereal diseases, smoking, pollution, contraceptives, and lowered immunity. Surgical/medical procedure (n = 127, 72%) and healthy diet (n = 53, 30%) were the most endorsed treatments. Between 18% and 23% were unsure of the treatment effectiveness of diet, vitamins, exercise, complementary therapy, and contraception. All women treated with chemotherapy understood the rationale thereof; 23 (85%) perceived chemotherapy to be successful, and 19 (70%) could name the agent. Few women perceived a negative impact on their fertility (n = 28, 16%); 52 (30%) were reluctant to conceive again and 100 (57%) questioned their ability to have healthy children. After diagnosis, 111 (63%) had at least 1 live birth. Notwithstanding limitations, this study is the largest of its type to date. These descriptive

  5. Implementation and Monitoring of a Gestational Trophoblastic Disease Management Program in a Tertiary Hospital in Morocco: Opportunities and Challenges

    PubMed Central

    Alami, Mohamed Hassan; Bezad, Rachid

    2017-01-01

    Objective. Gestational Trophoblastic Disease (GTD) management requires clear guidelines for diagnosis, treatment, and follow-up. Unequal management skills among practitioners, inadequate treatment, irregular surveillance, and drop-out are common in resource-limited settings and can lead to life-threatening complications and morbidities. To address these challenges, we implemented a GTD Management Program at the National Center for Reproductive Health in Rabat, Morocco. Methods and Program Description. In-depth review of management protocols was carried out, and concise guidelines were developed, with targeted training for physicians. A physical space and a weekly fixed GTD consultation were set, and personalized follow-up was established for each patient. An electronic database documenting patients' surveillance was created, allowing immediate outreach in case of irregularities. Results. During the period from October 2013 to June 2016, 50 patients were included in this program. Patients' mean age was 33 years; 92% were illiterate and 82% had a low socioeconomic status. 68% had a positive evolution, while 32% developed gestational trophoblastic neoplasia, requiring 2 to 6 chemotherapy sessions. An average of 2.8 outreach reminders were necessary for each patient. 94% fully adhered to the program of care and completed properly their follow-up. Conclusion. Implementation and thorough monitoring of this program helped optimize patients' care, avoiding drop-outs and delays in diagnosing and treating complications. PMID:28567058

  6. Placental site trophoblastic tumor presenting as an intramural mass with negative markers: an opportunity for novel diagnosis and treatment with robotic hysterectomy.

    PubMed

    Namaky, Devin; Basil, Jack; Pavelka, James

    2010-05-01

    A patient presented with persistent levels of quantitative human chorionic gonadotropin despite therapy with methotrexate. A dilation and curettage procedure did not provide a pathologic diagnosis. Gestational trophoblastic disease was suspected, but serum biomarkers were unable to provide a pre-operative diagnosis. A mass was found in the uterus by ultrasound and subsequent computed tomography scans. There was no evidence of extrauterine disease, but the uterine mass was continuous with the endometrial cavity, evoking the suspicion of an invasive endometrial mass. The patient underwent robotic hysterectomy for both therapy and diagnosis of suspected gestational trophoblastic disease (GTD). The final pathologic diagnosis was placental site trophoblastic tumor. The robotic approach allows for a minimally invasive surgical procedure with thorough examination of the pelvic cavity and adnexae and does not require a uterine manipulator which may be contra-indicated in the setting of uterine GTD. For patients with suspected persistent uterine GTD who are otherwise candidates for minimally invasive surgery, a robotic procedure offers advantages when compared to traditional laparoscopy or vaginal hysterectomy.

  7. Transcriptional expression of genes involved in cell invasion and migration by normal and tumoral trophoblast cells.

    PubMed

    Janneau, Jean-Louis; Maldonado-Estrada, Juan; Tachdjian, Gérard; Miran, Isabelle; Motté, Nelly; Saulnier, Patrick; Sabourin, Jean-Christophe; Coté, Jean-François; Simon, Bénédicte; Frydman, René; Chaouat, Gérard; Bellet, Dominique

    2002-11-01

    Once initiated, invasion of trophoblast cells must be tightly regulated, particularly in early pregnancy. The mechanisms necessary for the invasion and migration of trophoblast cells are thought to be related to those involved in the invasive and metastatic properties of cancer cells. Quantitative PCR was used to measure, in trophoblast cells, the transcriptional expression profiles of four genes, INSL4, BRMS1, KiSS-1 and KiSS-1R, reported to be implicated in tumor invasion and metastasis. Laser capture microdissection and purification of trophoblast cells demonstrate that, as already known for INSL4, BRMS1, KiSS-1 and KiSS-1R are expressed by the trophoblast subset of placental tissues. Expression profiles of these genes studied in early placentas (7-9 weeks, n=55) and term placentas (n=11) showed that expression levels of BRMS1 are higher in term than in early placentas, while expression levels of KiSS-1R are higher in early than in term placentas. Low levels of expression of BRMS1 were observed in normal pregnancies, in molar pregnancies and in choriocarcinoma cell lines BeWo, JAR and JEG3 while, in striking contrast, the expression levels of INSL4, KiSS-1 and Kiss-1R were increased in both early placentas and molar pregnancies and were reduced in choriocarcinoma cells. These transcriptional expression profiles are in favor of a predominant role of INSL4, KiSS-1 and KiSS-1R in the control of the invasive and migratory properties of trophoblast cells.

  8. Characterization of androgenetic/biparental mosaic/chimeric conceptions, including those with a molar component: morphology, p57 immnohistochemistry, molecular genotyping, and risk of persistent gestational trophoblastic disease.

    PubMed

    Lewis, Gloria H; DeScipio, Cheryl; Murphy, Kathleen M; Haley, Lisa; Beierl, Katie; Mosier, Stacy; Tandy, Sharon; Cohen, Debra S; Lytwyn, Alice; Elit, Laurie; Vang, Russell; Ronnett, Brigitte M

    2013-03-01

    trophoblastic hyperplasia. Two cases without trophoblastic hyperplasia had uniformly diploid villous stromal cells but 1 had triploid and 1 had tetraploid cytotrophoblast; 1 case with trophoblastic hyperplasia had uniformly diploid villous stromal cells but a mixture of diploid, triploid, and tetraploid cytotrophoblast. In 3 cases with a CHM component, persistent gestational trophoblastic disease developed. These results indicate that androgenetic/biparental mosaic/chimeric conceptions are most often an admixture of androgenetic diploid (p57-negative) and biparental diploid (p57-positive) cell lines but some have localized hyperdiploid components. Recognition of their distinctive p57 expression patterns and genotyping results can prevent misclassification as typical CHMs, PHMs, or nonmolar specimens. The presence of androgenetic cell lines, particularly in those with a purely androgenetic CHM component, warrants follow-up because of some risk of persistent gestational trophoblastic disease.

  9. Relapse rates after two versus three consolidation courses of methotrexate in the treatment of low-risk gestational trophoblastic neoplasia.

    PubMed

    Lybol, C; Sweep, F C G J; Harvey, R; Mitchell, H; Short, D; Thomas, C M G; Ottevanger, P B; Savage, P M; Massuger, L F A G; Seckl, M J

    2012-06-01

    Methotrexate (MTX) alternating with folinic acid is a commonly used treatment regimen for low-risk gestational trophoblastic neoplasia (GTN). In The Netherlands, two courses of MTX are administered after normalization of serum human chorionic gonadotrophin (hCG) levels (consolidation courses), whereas in the United Kingdom, three consolidation courses are given. In a retrospective setting we compared relapse rates of women completing MTX therapy for low-risk GTN in The Netherlands and the UK. From 1980 to 2008, 351 patients were collected from the Dutch Central Registry for Hydatidiform Moles and records from the Dutch Working Party on Trophoblastic Disease. From the Charing Cross Hospital Trophoblast Disease Centre (London), 600 low-risk GTN patients were identified from 1992 to 2008. In 4.0% of patients relapse occurred after MTX treatment with three consolidation courses, whereas 8.3% of patients relapsed after MTX treatment with two consolidation courses (p=0.006). Although patients from The Netherlands had a higher level of hCG (p<0.001) and more patients had metastases before the start of treatment (p=0.012), the number of courses of MTX to achieve a normal hCG did not differ significantly between patients from The Netherlands and the UK (p=0.375). Relapse rates were higher in patients treated with two consolidation courses of MTX. Although other factors might have influenced the observed difference in relapse rates, three courses of consolidation chemotherapy may be preferable to two in the treatment of low-risk GTN in order to decrease the risk of disease relapse. A prospective randomized study would be required to confirm these findings. Copyright © 2012 Elsevier Inc. All rights reserved.

  10. Complete molar pregnancy in adolescents from North and South America: Clinical presentation and risk of gestational trophoblastic neoplasia.

    PubMed

    Soares, Renan Rocha; Maestá, Izildinha; Colón, José; Braga, Antonio; Salazar, Aleydah; Charry, Rafael Cortés; Sun, Sue Yazaki; Goldstein, Donald P; Berkowitz, Ross S

    2016-09-01

    To compare complete hydatidiform mole (CHM) clinical presentation and risk factors associated with GTN development between North American and South American adolescents. This non-concurrent cohort study was undertaken including adolescents with CHM referred to centers in North America (New England Trophoblastic Disease Center, Harvard University, USA), and South America (Botucatu Trophoblastic Disease Center-São Paulo State University, Brazil; Trophoblastic Unit of Central University of Venezuela and Maternidad Concepcion Palacios of Caracas, Venezuela) between 1990 and 2012. Data were obtained from medical records and pathology reports. Study participants were allocated into 2 groups: North America (NA) and South America (SA). In NA and SA, 13.1% and 30.9% of patients with hydatidiform mole were adolescents, respectively. Of these, 77.6% in NA and 86.1% in SA had pathologic diagnosis of CHM (p=0.121). Vaginal bleeding (SA=69% vs NA=51%; p=0.020), anemia (SA=48% vs NA=18%; p<0.001), and elevated serum hCG (SA=232,860mIU/mL vs NA=136,412mIU/mL; p=0.039) were more frequent in SA than in NA. Median gestational age at diagnosis (SA=12weeks, NA=11weeks; p=0.030) differed whereas GTN development rate (SA=20%, NA=27%; p=0.282) showed no significant difference between groups. Compared to NA, medical complications and clinical factors associated with post-molar GTN were more frequent among SA adolescents. Medical complications and clinical factors associated with GTN development were more frequent in SA than in NA adolescents with CHM, suggesting that, in South America, awareness about the importance of diagnosing molar pregnancy early and considering CHM in the differential diagnosis in adolescents suspected to be pregnant should be raised. Copyright © 2016 Elsevier Inc. All rights reserved.

  11. Role of 18F-FDG PET in the management of gestational trophoblastic neoplasia.

    PubMed

    Mapelli, P; Mangili, G; Picchio, M; Gentile, C; Rabaiotti, E; Giorgione, V; Spinapolice, E G; Gianolli, L; Messa, C; Candiani, M

    2013-04-01

    Gestational trophoblastic neoplasia (GTN) is a rare and aggressive tumour that is usually sensitive to chemotherapy. The usefulness of conventional imaging modalities in evaluating treatment response is limited, mainly due to the difficulty in differentiating between residual tumour tissue and necrosis. The aim of the present study was to evaluate the role of FDG PET or PET/CT in primary staging and in monitoring treatment efficacy. The effect of FDG PET and combined PET/CT on the management of patients with GTN was also evaluated comparing the differences between standard treatments based on conventional imaging and alternative treatments based on PET. This retrospective study included 41 patients with GTN referred to San Raffaele Hospital between 2002 and 2010. All patients were studied by either PET or PET/CT in addition to conventional imaging. Of the 41 patients, 38 were evaluated for primary staging of GTN and 3 patients for chemotherapy resistance after first-line chemotherapy performed in other Institutions. To validate the PET data, PET and PET/CT findings were compared with those from conventional imaging, including transvaginal ultrasonography (TV-US) in those with uterine disease, CT and chest plain radiography in those with lung disease and whole-body CT in those with systemic metastases. Conventional imaging was considered positive for the presence of uterine disease and/or metastases when abnormal findings relating to GTN were reported. PET and PET/CT were considered concordant with conventional imaging when metabolic active disease was detected at the sites corresponding to the pathological findings on conventional imaging. In addition, in 12 of the 41 patients showing extrauterine disease, FDG PET/CT was repeated to monitor treatment efficacy, in 8 after normalization of beta human chorionic gonadotropin (βHCG) and in 4 with βHCG resistance. In some patients, PET or PET/CT findings led to an alternative nonconventional treatment, and this was

  12. First-line chemotherapy in low-risk gestational trophoblastic neoplasia

    PubMed Central

    Alazzam, Mo’iad; Tidy, John; Hancock, Barry W; Osborne, Raymond; Lawrie, Theresa A

    2014-01-01

    Background This is an update of a Cochrane review that was first published in Issue 1, 2009. Gestational trophoblastic neoplasia (GTN) is a rare but curable disease arising in the fetal chorion during pregnancy. Most women with low-risk GTN will be cured by evacuation of the uterus with or without single-agent chemotherapy. However, chemotherapy regimens vary between treatment centres worldwide and the comparable benefits and risks of these different regimens are unclear. Objectives To determine the efficacy and safety of first-line chemotherapy in the treatment of low-risk GTN. Search methods In September 2008, we electronically searched the Cochrane Gynaecological Cancer Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL Issue 3, 2008), MEDLINE and EMBASE. In addition, we searched online trial registers, conference proceedings and reference lists of identified studies. We re-ran these searches in February 2012 for this updated review. Selection criteria For the original review, we included randomised controlled trials (RCTs), quasi-RCTs and non-RCTs that compared first-line chemotherapy for the treatment of low-risk GTN. For this updated version of the review, we included only RCTs. Data collection and analysis Two review authors independently assessed studies for inclusion and extracted data to a pre-designed data extraction form. Meta-analysis was performed by pooling the risk ratio (RR) of individual trials. Main results We included five moderate to high quality RCTs (517 women) in the updated review. These studies all compared methotrexate with dactinomycin. Three studies compared weekly intramuscular (IM) methotrexate with bi-weekly pulsed intravenous (IV) dactinomycin (393 women), one study compared five-day IM methotrexate with bi-weekly pulsed IV dactinomycin (75 women) and one study compared eight-day IM methotrexate-folinic acid (MTX-FA) with five-day IV dactinomycin (49 women). Overall, dactinomycin was associated

  13. The significance of the time interval between antecedent pregnancy and diagnosis of high-risk gestational trophoblastic tumours

    PubMed Central

    Powles, T; Young, A; Sammit, A; Stebbing, J; Short, D; Bower, M; Savage, P M; Seckl, M J; Schmid, P

    2006-01-01

    It is thought that the time interval between the antecedent pregnancy and diagnosis of gestational trophoblastic tumours (GTTs) may influence the outcome of these patients. In this study, we investigate the significance of this time interval. Multivariate analysis was used to investigate if the time interval was of prognostic significance from our cohort of 241 high-risk patients with GTT. Subsequent cutpoint analysis was used to determine an optimal cutpoint for the interval covariate. The outcome of these patients was plotted according to the Kaplan–Meier method. The time interval was of prognostic significance on multivariate analysis. A period of greater than 2.8 years after pregnancy was found to be of most significance. The 5-year overall survival was 62.0% (95% CI: 47–76%) for greater than 2.8 years vs 94% (95% CI: 91–97%) for less than 2.8 years (P<0.001). Multivariate analysis showed the presence of liver metastasis and the number of metastasis was also of prognostic importance. The interval between antecedent pregnancy and diagnosis in high-risk GTT is of prognostic significance. This gives some insight into the pathogenesis of the disease. PMID:17031399

  14. Centralized Coordination of Decentralized Assistance for Patients with Gestational Trophoblastic Disease in Brazil: A Viable Strategy for Developing Countries.

    PubMed

    Braga, Antonio; Burlá, Marcelo; Freitas, Fernanda; Uberti, Elza; Viggiano, Mauricio; Sun, Sue Yazaki; Maestá, Izildinha; Elias, Kevin M; Berkowitz, Ross S

    2016-01-01

    To report on the Brazilian Association of Gestational Trophoblastic Disease's (GTD) formation of a network of regional care at specialized centers for women with GTD. We developed a questionnaire composed of 15 questions, which was sent by email to the 38 Brazilian GTD Reference Center (BGTDRC) Directors who are members of the Brazilian Association of GTD, in order to characterize the professionals involved in the care of patients with GTD and the type of assistance provided. The Directors of the BGTDRCs are usually specialists in Gynecology and Obstetrics (97%), with a median experience of a decade in treating women with GTD. The BGTDRCs are linked to university hospitals in 75% of centers and provide completely free medical care in 87%. However, 52% of centers do not perform chemotherapy in their reference center, and patients are referred elsewhere for chemotherapy. Despite some difficulties, the rate of patients lost to follow-up before human chorionic gonadotropin remission is 9%, and the GTD mortality rate is 0.9%. Due to large regional disparities, the BGTDRCs are not uniformly organized. However, under the coordination of the Brazilian Association of GTD there is now strong communication and collaboration among reference centers, which has significantly advanced both patient care and research into the management of these diseases.

  15. The roles of surgery and EMA/CO chemotherapy regimen in primary refractory and non-refractory gestational trophoblastic neoplasia.

    PubMed

    Aydiner, Adnan; Keskin, Serkan; Berkman, Sinan; Bengisu, Ergin; Ilhan, Huseyin Ridvan; Tas, Faruk; Topuz, Erkan

    2012-06-01

    To determine the characteristics and outcome of patients with refractory gestational trophoblastic neoplasia (GTN) after primary chemotherapy (CTx). The outcome of low- and high-risk patients with refractory GTN (n = 14, 37%) was compared to those with non-refractory GTN (n = 24, 63%). Methotrexate treatment was used for patients with low-risk disease and EMA/CO for patients with high-risk disease. Median follow-up time was 53 months (range 1-173 months). All non-refractory patients and 11 refractory patients (79%) survived (p = 0.015). Factors related to resistance to primary CTx was age (p = 0.012), duration between causal pregnancy and initial treatment (p = 0.003), surgery (p = 0.014), hCG level before CTx (p = 0.09) and half-life of hCG (p = 0.061). Six out of 10 low-risk refractory patients treated with EMA/CO regimen in the second-line setting had been followed by no evidence of disease. Nine of 38 (24%) patients underwent surgery (TAH ± BSO) for GTN. All of the patients treated with surgery were in the non-refractory group, but none of refractory patients underwent surgery (p = 0.014). Surgery and EMA/CO regimen are one of the main factors that play a role in the management of refractory low-risk GTN.

  16. Serial color Doppler flow of uterine vasculature combined with serum beta-hCG measurements for improved monitoring of patients with gestational trophoblastic disease. A preliminary report.

    PubMed

    Maymon, R; Schneider, D; Shulman, A; Bukowsky, I; Weinraub, Z

    1996-01-01

    Weekly serum beta-hCG measurements and transvaginal ultrasound scans coupled with color Doppler flow were performed on 8 patients with hydatidiform mole. Two patients later developed persistent trophoblastic disease, necessitating chemotherapy. The correlation coefficients between Doppler flow indices, systolic-diastolic (S/D) ratio and pulsatility index (PI) with log beta-hCG were -0.96 and -0.97, respectively. The weekly S/D and PI indices were plotted on an individual curve. Only the 2 patients who developed persistent gestational trophoblastic disease had PI index levels of < or = 1.5 as early as 2 weeks after molar evacuation. At that stage their serum beta-hCG levels were not different from some of the other patients. In this preliminary report, the regression of the disease could be reliably assessed by observing the changes in low resistance flow which paralleled the gradual decrements in serial beta-hCG levels. Thus, the contribution of this noninvasive imaging technique encourages the authors to further investigate Doppler flow monitoring among a larger sample of patients suffering from various gestational trophoblastic diseases.

  17. Placental-site trophoblastic tumor with PET scan-detected surgically treated lung metastasis.

    PubMed

    Nieves, Lucybeth; Hoffman, James; Allen, Gretchen; Currie, John; Sorosky, Joel I

    2008-06-01

    Metastatic placental-site trophoblastic tumor (PSTT) continues to be a diagnostic and management dilemma due to its relative resistance to chemotherapy and the difficulties in diagnosing such a rare tumor. We describe a 35-year-old woman with PSTT presenting with irregular bleeding and a mass in the lung. Dilation and curettage provided the diagnosis of PSTT by frozen section of the specimen. Subsequently, a total abdominal hysterectomy was performed and the patient received three cycles of EMA-CO (etoposide, methotrexate, actinomycin D, cyclophosphamide, and vincristine) Positron emission tomography (PET) scan confirmed a persistent lung nodule that was treated with wedge resection. She is currently in clinical remission. Surgery may have a role in salvaging a patient with persistent PET-positive disease after chemotherapy.

  18. Effect of race/ethnicity on clinical presentation and risk of gestational trophoblastic neoplasia in patients with complete and partial molar pregnancy at a tertiary care referral center.

    PubMed

    Gockley, Allison A; Joseph, Naima T; Melamed, Alexander; Sun, Sue Yazaki; Goodwin, Benjamin; Bernstein, Marilyn; Goldstein, Donald P; Berkowitz, Ross S; Horowitz, Neil S

    2016-09-01

    The reported incidence of molar pregnancy varies widely among different geographic locations. This variation has been attributed, at least in part, to racial/ethnic differences. While the incidence of molar pregnancies is decreasing, certain ethnic groups such as Hispanics, Asians, and American Indians continue to have an increased risk of developing gestational trophoblastic disease across the globe. We sought to describe the potential effect of ethnicity/race on the presentation and clinical course of complete mole and partial mole. All patients followed up for complete mole and partial mole at a single institution referral center from 1994 through 2013 were identified. Variables including age, race, gravidity, parity, gestational age, presenting signs/symptoms, serum human chorionic gonadotropin values, and development of gestational trophoblastic neoplasia were extracted from medical records and patient surveys. Patients with complete mole and partial mole were categorized into race/ethnicity groups defined as white, black, Asian, or Hispanic. Due to low numbers of non-white patients with partial mole in each non-white category, patients with partial mole were grouped as white or non-white. Continuous variables were compared using the Kruskal-Wallis test and binary variables were compared using the Fisher exact test. A total of 167 complete mole patients with known race/ethnicity status were included (57.48% white, 14.97% Asian, 14.37% black, 13.17% Hispanic). Hispanics presented at younger age (median 24.5 years) compared to whites (median 32.0 years, P = .04) and Asians (median 31.0 years, P = .03). Blacks had higher gravidity than whites (P < .001) and Hispanics (P = .05). There was no significant difference in presenting symptoms, gestational age at diagnosis, and preevacuation serum human chorionic gonadotropin level by race/ethnicity. Hispanics were significantly less likely than whites to develop gestational trophoblastic neoplasia (absolute risk

  19. Comparing and evaluating the efficacy of methotrexate and actinomycin D as first-line single chemotherapy agents in low risk gestational trophoblastic disease.

    PubMed

    Lee, Young Jae; Park, Jeong Yeol; Kim, Dae Yeon; Suh, Dae Shik; Kim, Jong Hyeok; Kim, Yong Man; Kim, Young Tak; Nam, Joo Hyun

    2017-03-01

    The aim of this study was to compare responses to single-agent chemotherapies and evaluate the predictive factors of resistance in low risk (LR) gestational trophoblastic disease (GTD). The chemotherapy agents included methotrexate (MTX) and actinomycin D (ACT-D). We conducted a retrospective study of 126 patients with GTD who were treated between 2000 and 2013. A total of 71 patients with LR GTD were treated with MTX (8-day regimen or weekly regimen, n=53) or ACT-D (bi-weekly pulsed regimen or 5-day regimen, n=18). The successful treatment group and the failed treatment group were compared and analyzed to identify prognostic factors. The complete response rates were 83.3% for ACT-D and 62.2% for MTX, with no statistically significant difference. There was no severe adverse effect reported for either group. Longer interval durations from the index pregnancy (>2 months, p=0.040) and larger tumor size (>3 cm, p=0.020) were more common in non-responders than in responders; these results were statistically significant. Based on our results, ACT-D may be a better option than MTX as a first-line single chemotherapy agent for LR GTD. The bi-weekly pulsed ACT-D regimen had minimal, or at least the same, toxicities compared with MTX. However, due to the lack of strong supporting evidence, it cannot be conclusively stated that this is the best single agent for first-line chemotherapy in LR GTD patients. Further larger controlled trials will be necessary to establish the best guidelines for GTD treatment.

  20. Comparing and evaluating the efficacy of methotrexate and actinomycin D as first-line single chemotherapy agents in low risk gestational trophoblastic disease

    PubMed Central

    Kim, Dae-Yeon; Suh, Dae-Shik; Kim, Jong-Hyeok; Kim, Young-Tak

    2017-01-01

    Objective The aim of this study was to compare responses to single-agent chemotherapies and evaluate the predictive factors of resistance in low risk (LR) gestational trophoblastic disease (GTD). The chemotherapy agents included methotrexate (MTX) and actinomycin D (ACT-D). Methods We conducted a retrospective study of 126 patients with GTD who were treated between 2000 and 2013. A total of 71 patients with LR GTD were treated with MTX (8-day regimen or weekly regimen, n=53) or ACT-D (bi-weekly pulsed regimen or 5-day regimen, n=18). The successful treatment group and the failed treatment group were compared and analyzed to identify prognostic factors. Results The complete response rates were 83.3% for ACT-D and 62.2% for MTX, with no statistically significant difference. There was no severe adverse effect reported for either group. Longer interval durations from the index pregnancy (>2 months, p=0.040) and larger tumor size (>3 cm, p=0.020) were more common in non-responders than in responders; these results were statistically significant. Conclusion Based on our results, ACT-D may be a better option than MTX as a first-line single chemotherapy agent for LR GTD. The bi-weekly pulsed ACT-D regimen had minimal, or at least the same, toxicities compared with MTX. However, due to the lack of strong supporting evidence, it cannot be conclusively stated that this is the best single agent for first-line chemotherapy in LR GTD patients. Further larger controlled trials will be necessary to establish the best guidelines for GTD treatment. PMID:27819410

  1. Trends in incidence for gestational trophoblastic disease over the last 20 years in a population-based study.

    PubMed

    Eysbouts, Y K; Bulten, J; Ottevanger, P B; Thomas, C M G; Ten Kate-Booij, M J; van Herwaarden, A E; Siebers, A G; Sweep, F C G J; Massuger, L F A G

    2016-01-01

    Gestational trophoblastic disease (GTD) represents a heterogeneous group of disorders. Wide variations in incidence rates are reported worldwide, probably explained by a lack of centralized databases and heterogeneity in case definition. The aim of the present study was to determine the trends in incidence of GTD in the last 20 years with the use of population-based data. Data on patients with pathologically confirmed diagnosis of GTD between 1994 and 2013 were obtained from PALGA, a nationwide archive containing all pathology reports in the Netherlands. In the 20-year period 6343 cases were registered with GTD, representing an overall incidence rate of 1.67 per 1000 deliveries per year. An initial rise in incidence rate was seen over the first 10 years (0.075 per year, 95% CI 0.040-0.109), followed by a stabilization from 2004 to 2013 (increase per year 0.011, 95% CI -0.017-0.040). Although partial hydatidiform mole (HM) was more common in earlier years, complete and partial HM reached comparable incidence rates of 0.68 and 0.64 per 1000 deliveries respectively from 2009 onwards. In the last decade, unspecified HM diagnosis declined significantly from 0.14 per 1000 deliveries in 2003 to 0.03 per 1000 deliveries (per year -0.011, CI -0.016-0.06), suggesting improved diagnostic analyses. After an initial rise in GTD incidence in the Netherlands rates remained steady from 2004 onwards. As pathological confirmation is currently the norm and advanced pathological techniques are now widely available, true steady incidence rates may have been reached. Copyright © 2015 Elsevier Inc. All rights reserved.

  2. EMA-CO chemotherapy for high-risk gestational trophoblastic neoplasia: a clinical analysis of 54 patients.

    PubMed

    Lu, W-G; Ye, F; Shen, Y-M; Fu, Y-F; Chen, H-Z; Wan, X-Y; Xie, X

    2008-01-01

    This study was designed to analyze the outcomes of chemotherapy for high-risk gestational trophoblastic neoplasia (GTN) with EMA-CO regimen as primary and secondary protocol in China. Fifty-four patients with high-risk GTN received 292 EMA/CO treatment cycles between 1996 and 2005. Forty-five patients were primarily treated with EMA-CO, and nine were secondarily treated after failure to other combination chemotherapy. Adjuvant surgery and radiotherapy were used in the selected patients. Response, survival and related risk factors, as well as chemotherapy complications, were retrospectively analyzed. Thirty-five of forty-five patients (77.8%) receiving EMA-CO as first-line treatment achieved complete remission, and 77.8% (7/9) as secondary treatment. The overall survival rate was 87.0% in all high-risk GTN patients, with 93.3% (42/45) as primary therapy and 55.6% (5/9) as secondary therapy. The survival rates were significantly different between two groups (chi(2)= 6.434, P =0.011). Univariate analysis showed that the metastatic site and the number of metastatic organs were significant risk factors, but binomial distribution logistic regression analysis revealed that only the number of metastatic organs was an independent risk factor for the survival rate. No life-threatening toxicity and secondary malignancy were found. EMA-EP regimen was used for ten patients who were resistant to EMA-CO and three who relapsed after EMA-CO. Of those, 11 patients (84.6%) achieved complete remission. We conclude that EMA-CO regimen is an effective and safe primary therapy for high-risk GTN, but not an appropriate second-line protocol. The number of metastatic organs is an independent prognostic factor for the patient with high-risk GTN. EMA-EP regimen is a highly effective salvage therapy for those failing to EMA-CO.

  3. Clinical characteristics and prognosis of ultra high-risk gestational trophoblastic neoplasia patients: A retrospective cohort study.

    PubMed

    Kong, Yujia; Yang, Junjun; Jiang, Fang; Zhao, Jun; Ren, Tong; Li, Jie; Wang, Xiaoyu; Feng, Fengzhi; Wan, Xirun; Xiang, Yang

    2017-07-01

    The gestational trophoblastic neoplasia (GTN) patients with the International Federation of Gynecology and Obstetrics (FIGO) score≥12 are defined as ultra high-risk GTN. This study aims to investigate the clinical characteristics, the treatment efficiency, and the prognosis of ultra high-risk GTN patients. Between January 2002 and December 2015, medical record data of 143 GTN patients with FIGO score≥12 at Peking Union Medical College Hospital (PUMCH) were reviewed. Ratios were compared using chi-square test, and prognostic risk factors were analyzed by univariate analysis and multivariate analysis. Among the 143 ultra high-risk GTN patients, 94 (65.7%) patients had achieved complete remission and 15.9% (15/94) patients relapsed after complete remission. The 5-year overall survival (OS) rate of the entire cohort approached 67.9%. The results of the multivariate analysis revealed that non-molar antecedent pregnancy [Relative risk (RR) 4.689, 95% CI 1.448-15.189, P=0.010], brain metastases (RR 2.280, 95% CI 1.248-4.163, P=0.007), previous failed multiagent chemotherapy (RR 5.345, 95% CI 2.222-12.857, P=0.000) and surgery (RR 0.336, 95% CI 0.177-0.641, P=0.001) all had influence on the prognosis of ultra high-risk GTN patients. GTN patients with FIGO score≥12 have a poor prognosis. More emphasis should be placed on non-molar antecedent pregnancy, brain metastases, and previous multiagent chemotherapy failure. Moreover, salvage surgery may improve the prognosis. Floxuridine-based multiagent chemotherapy is effective with manageable toxicity for ultra high-risk GTN patients. Copyright © 2017. Published by Elsevier Inc.

  4. Primary Cystic Trophoblastic Tumor of the Testis: A Study of 14 Cases.

    PubMed

    Gondim, Dibson D; Ulbright, Thomas M; Cheng, Liang; Idrees, Muhammad T

    2017-06-01

    Cystic trophoblastic tumor (CTT) has been described in postchemotherapy retroperitoneal lymph node dissections of patients with testicular germ cell tumors. Prognostically, this lesion is similar to teratoma and no further treatment is required after surgery in the absence of other components. CTT has not, however, been reported in the testis. We identified 14 CTTs in the treated (4) and untreated (9; no information for 1 patient) testes of patients 15 to 43 years old (median, 25) with mixed germ cell tumors. The CTT was a minor component (<1% to 10%) and associated with teratoma (14), embryonal carcinoma (7), yolk sac tumor (7), seminoma (1), and choriocarcinoma (1). At follow-up, CTT and teratoma were also found in 2 subsequent resections (spermatic cord and pelvis mass) in 2 patients. The CTTs were not grossly distinct but on microscopic examination were cystic to partly solid, with cysts often containing fibrinoid material and lined by mononucleated squamoid cells with eosinophilic to pale, frequently vacuolated cytoplasm and having pleomorphic nuclei with dense, often smudged chromatin. Mitotic activity was inconspicuous. Immunostains for hCG (6/6), inhibin (6/6), and p63 (2/6) were focally positive. The pathogenesis of CTT is not completely understood. As untreated patients without choriocarcinoma may have CTT in the testis, it is suggested that testicular CTT represents a form of regressed choriocarcinoma or a late morphologic phase in the transformation of choriocarcinoma to teratoma.

  5. Obstetric ultrasound aids prompt referral of gestational trophoblastic disease in marginalized populations on the Thailand-Myanmar border.

    PubMed

    McGregor, Kathryn; Myat Min, Aung; Karunkonkowit, Noaeni; Keereechareon, Suporn; Tyrosvoutis, Mary Ellen; Tun, Nay Win; Rijken, Marcus J; Hoogenboom, Gabie; Boel, Machteld; Chotivanich, Kesinee; Nosten, François; McGready, Rose

    2017-01-01

    The use of obstetric ultrasound in the diagnosis of gestational trophoblastic disease (GTD) in high-income settings is well established, leading to prompt management and high survival rates. Evidence from low-income settings suggests ultrasound is essential in identifying complicated pregnancies, but with limited studies reviewing specific conditions including GTD. The aim of this study is to review the role of ultrasound in diagnosis and management of GTD in a marginalized population on the Thailand-Myanmar border. Antenatal ultrasound became available in this rural setting in 2001 and care for women with GTD has been provided by Thailand public hospitals for 20 years. Retrospective record review. The incidence of GTD was 103 of 57,004 pregnancies in Karen and Burmese women on the Thailand-Myanmar border from 1993-2013. This equates to a rate of 1.8 (95% CI 1.5-2.2) per 1000 or 1 in 553 pregnancies. Of the 102 women with known outcomes, one (1.0%) died of haemorrhage at home. The median number of days between first antenatal clinic attendance and referral to hospital was reduced from 20 (IQR 5-35; range 1-155) to 2 (IQR 2-6; range 1-179) days (p = 0.002) after the introduction of ultrasound. The proportion of severe outcomes (death and total abdominal hysterectomy) was 25% (3/12) before ultrasound compared to 8.9% (8/90) with ultrasound (p = 0.119). A recurrence rate of 2.5% (2/80) was observed in the assessable population. The presence of malaria parasites in maternal blood was not associated with GTD. The rate of GTD in pregnancy in this population is comparable to rates previously reported within South-East Asia. Referral time for uterine evacuation was significantly shorter for those women who had an ultrasound. Ultrasound is an effective method to improve diagnosis of GTD in low-income settings and an effort to increase availability in marginalized populations is required.

  6. Gestational Trophoblastic Disease Treatment

    MedlinePlus

    ... uterus to scrape out abnormal tissue (last panel). Hysterectomy : Surgery to remove the uterus, and sometimes the ... the vagina , the operation is called a vaginal hysterectomy. If the uterus and cervix are taken out ...

  7. An investigative study into psychological and fertility sequelae of gestational trophoblastic disease: the impact on patients' perceived fertility, anxiety and depression.

    PubMed

    Di Mattei, Valentina E; Carnelli, Letizia; Bernardi, Martina; Pagani Bagliacca, Elena; Zucchi, Paola; Lavezzari, Luca; Giorgione, Veronica; Ambrosi, Alessandro; Mangili, Giorgia; Candiani, Massimo; Sarno, Lucio

    2015-01-01

    Gestational Trophoblastic Disease (GTD) comprises a group of disorders that derive from the placenta. Even if full recovery is generally expected, women diagnosed with GTD have to confront: the loss of a pregnancy, a potentially life-threatening diagnosis and delays in future pregnancies. The aim of the study is to evaluate the psychological impact of GTD, focusing on perceived fertility, depression and anxiety. 37 patients treated for GTD at San Raffaele Hospital, Milan, took part in the study. The STAI-Y (State-Trait Anxiety Inventory), the BDI-SF (Beck Depression Scale-Short Form) and the FPI (Fertility Problem Inventory) were used. Patients were grouped on the basis of presence of children (with or without), age (< or ≥35) and type of diagnosis (Hydatidiform Mole, HM, or Gestational Trophoblastic Neoplasia, GTN). Differences in the values between variables were assessed by a t-type test statistic. Three-way ANOVAs were also carried out considering the same block factors. The study highlights that women suffering from GTN had higher depression scores compared to women suffering from HM. A significant correlation was found between anxiety (state and trait) and depression. Younger women presented higher Global Stress scores on the FPI, especially tied to Need for Parenthood and Relationship Concern subscales. Need for Parenthood mean scores significantly varied between women with and without children too. We can conclude that fertility perception seems to be negatively affected by GTD diagnosis, particularly in younger women and in those without children. Patients should be followed by a multidisciplinary team so as to be supported in the disease's psychological aspects too.

  8. An Investigative Study into Psychological and Fertility Sequelae of Gestational Trophoblastic Disease: The Impact on Patients’ Perceived Fertility, Anxiety and Depression

    PubMed Central

    Di Mattei, Valentina E.; Carnelli, Letizia; Bernardi, Martina; Pagani Bagliacca, Elena; Zucchi, Paola; Lavezzari, Luca; Giorgione, Veronica; Ambrosi, Alessandro; Mangili, Giorgia; Candiani, Massimo; Sarno, Lucio

    2015-01-01

    Objectives Gestational Trophoblastic Disease (GTD) comprises a group of disorders that derive from the placenta. Even if full recovery is generally expected, women diagnosed with GTD have to confront: the loss of a pregnancy, a potentially life-threatening diagnosis and delays in future pregnancies. The aim of the study is to evaluate the psychological impact of GTD, focusing on perceived fertility, depression and anxiety. Methods 37 patients treated for GTD at San Raffaele Hospital, Milan, took part in the study. The STAI-Y (State-Trait Anxiety Inventory), the BDI-SF (Beck Depression Scale-Short Form) and the FPI (Fertility Problem Inventory) were used. Patients were grouped on the basis of presence of children (with or without), age (< or ≥35) and type of diagnosis (Hydatidiform Mole, HM, or Gestational Trophoblastic Neoplasia, GTN). Differences in the values between variables were assessed by a t-type test statistic. Three-way ANOVAs were also carried out considering the same block factors. Results The study highlights that women suffering from GTN had higher depression scores compared to women suffering from HM. A significant correlation was found between anxiety (state and trait) and depression. Younger women presented higher Global Stress scores on the FPI, especially tied to Need for Parenthood and Relationship Concern subscales. Need for Parenthood mean scores significantly varied between women with and without children too. Conclusions We can conclude that fertility perception seems to be negatively affected by GTD diagnosis, particularly in younger women and in those without children. Patients should be followed by a multidisciplinary team so as to be supported in the disease’s psychological aspects too. PMID:26030770

  9. Presence of the methylenetetrahydrofolate reductase gene polymorphism MTHFR C677T in molar tissue but not maternal blood predicts failure of methotrexate treatment for low-risk gestational trophoblastic neoplasia.

    PubMed

    Qu, Jia; Usui, Hirokazu; Kaku, Hiroshi; Shozu, Makio

    2017-01-05

    Gestational trophoblastic neoplasia (GTN) is a rare tumor, and its genomic constitution is different from the maternal genome because of its gestational origin. Methotrexate (MTX) is a standard chemotherapeutic agent for low-risk GTN. An association between polymorphisms of the methylenetetrahydrofolate reductase (MTHFR) gene and MTX treatment outcome has been reported in various diseases. Thus, we examined the association between clinical outcome and MTHFR polymorphisms in both tumor and blood DNA of low-risk GTN patients. MTHFR C677T (rs1801133) and A1298C (rs1801131) were genotyped using high-resolution melting assays in 62 Japanese low-risk GTN patients and in 52 antecedent molar tissues. We compared the genotypes of MTHFR polymorphisms with the clinical outcome of 5-day MTX treatment. Twenty-five patients entered remission and 37 patients developed drug resistance or adverse effects that necessitated a drug change. The MTHFR 677T allele in molar tissue was significantly related to the need for drug change (P=0.006; odds ratio [OR], 3.13; 95% confidence interval [CI], 1.31-7.49), in contrast to MTHFR 1298C (P=0.18; OR, 0.63; 95% CI, 0.32-1.25). The MTHFR 677T and 1298C alleles obtained from patients' blood DNA were not related to MTX treatment outcome (P=0.49; OR 1.31; 95% CI, 0.61-2.91 and P=0.10; OR 0.52; 95% CI, 0.22-1.15, respectively). These data demonstrate for the first time that the genotype of MTHFR 677TT in molar tissue is associated with ineffective MTX treatment in Japanese low-risk GTN patients. Copyright © 2016 Elsevier B.V. All rights reserved.

  10. GDM alters paracrine regulation of feto-placental angiogenesis via the trophoblast.

    PubMed

    Loegl, Jelena; Nussbaumer, Erika; Cvitic, Silvija; Huppertz, Berthold; Desoye, Gernot; Hiden, Ursula

    2017-04-01

    Feto-placental angiogenesis and vascular development are tightly regulated by pro- and anti-angiogenic factors. Villous trophoblast may be a major source of these factors. It forms the classical placental barrier between mother and fetus, and is thus exposed to maternal influences as well. Metabolic and hormonal derangements in gestational diabetes mellitus (GDM) affect feto-placental angiogenesis and vascular growth. Here we hypothesized that GDM alters the trophoblast secretome, which will modulate the paracrine regulation of feto-placental angiogenesis. Primary term trophoblasts were isolated from normal (n=6) and GDM (n=6) pregnancies. Trophoblast conditioned medium (CM) was used to investigate paracrine effects of normal and GDM-exposed trophoblasts on feto-placental endothelial cells (fpECs; n=7), using functional assays for 2D network formation, wound healing, chemotaxis, and proliferation. Gene expression of 23 pro- and anti-angiogenic factors was analyzed. Four trophoblast-derived paracrine regulators of angiogenesis were specifically measured in CM. CM from GDM trophoblasts increased 2D network formation of fpEC by 2.4-fold (P<0.001), whereas wound healing was attenuated by 1.8-fold (P=0.02) and chemo-attraction to the CM was reduced by 33±9% (P=0.02). The effect of CM on proliferation was unchanged between normal and GDM trophoblasts. Expression analysis of pro- and anti-angiogenic molecules in normal and GDM trophoblasts revealed significant differences in ANGPT2, HGF, KISS1 and PLGF expression. Analysis of secreted proteins demonstrated reduced pigment epithelium derived factor and tumor necrosis factor-α secretion by GDM trophoblasts. GDM alters the balance of trophoblast derived, angiogenesis modulating paracrine factors. This may contribute to GDM-associated changes in placental angiogenesis and vascular structure.

  11. Relationship between race and clinical characteristics, extent of disease, and response to chemotherapy in patients with low-risk gestational trophoblastic neoplasia.

    PubMed

    Maestá, Izildinha; Berkowitz, Ross S; Goldstein, Donald P; Bernstein, Marilyn R; Ramírez, Luz Angela C; Horowitz, Neil S

    2015-07-01

    To evaluate the potential effects of race on clinical characteristics, extent of disease, and response to chemotherapy in women with postmolar low-risk gestational trophoblastic neoplasia (GTN). This non-concurrent cohort study was undertaken including patients with FIGO-defined postmolar low-risk GTN treated with comparable doses and schedules of chemotherapy at the New England Trophoblastic Disease Center (NETDC) between 1973 and 2012. Racial groups investigated included whites, African American and Asians. Information on patient characteristics and response to chemotherapy (need for second line chemotherapy, reason for changing to an alternative chemotherapy, number of cycles/regimens, need for combination chemotherapy, and time to hCG remission) was obtained. Of 316 women, 274 (86.7%) were white, 19 (6%) African American, and 23 (7.3%) Asian. African Americans were significantly younger than white and Asian women (p=0.008). Disease presentation, and extent of disease, including antecedent molar histology, median time to persistence, median hCG level at persistence, rate of D&C at persistence, presence of metastatic disease, and FIGO stage and risk score were similar among races. Need for second line chemotherapy (p=0.023), and median number of regimens (p=0.035) were greater in Asian women than in other races. Low-risk GTN was more aggressive in Asian women, who were significantly more likely to need second line chemotherapy and a higher number of chemotherapy regimens to achieve complete remission than women of African American and Asian descent. Further studies involving racial differences related to clinical, biological and environmental characteristics are needed. Copyright © 2015. Published by Elsevier Inc.

  12. Human Chorionic Gonadotropin (hCG) Regression Curve for Predicting Response to EMA/CO (Etoposide, Methotrexate, Actinomycin D, Cyclophosphamide and Vincristine) Regimen in Gestational Trophoblastic Neoplasia.

    PubMed

    Rattanaburi, Athithan; Boonyapipat, Sathana; Supasinth, Yuthasak

    2015-01-01

    An hCG regression curve has been used to predict the natural history and response to chemotherapy in gestational trophoblastic disease. We constructed hCG regression curves in high-risk gestational trophoblastic neoplasia (GTN) treated with EMA/CO and identified an optimal hCG level to detect EMA/CO resistance in GTN. Eighty-one women with GTN treated with EMA/CO were classified as primary high-risk GTN (n=65) and single agent-resistance GTN (n=16). The hCG levels prior to each course of chemotherapy were plotted in the 10th, 50th, and 90th percentiles to construct the hCG regression curves. Diagnostic performance was evaluated for an optimal cut-off value. The median hCG levels were 264,482 mIU/mL mIU/mL and 495.5 mIU/mL mIU/mL for primary high-risk GTN and single agent-resistance GTN, respectively. The 50th percentile of the hCG level in primary high-risk GTN and single agent-resistance turned to normal before the 4th and the 2nd course of chemotherapy, respectively. The 90th percentile of the hCG level in primary high-risk GTN and single agent-resistance turned to normal before the 9th and the 2nd course of chemotherapy, respectively. The hCG level of ≥118.6 mIU/mL mIU/mL at the 5thcourse of EMA/CO predicted the EMA/CO resistance in primary high-risk GTN patients with a sensitivity of 85.7% and a specificity of 100%. EMA/CO resistance in primary high-risk GTN can be predicted by using an hCG regression curve in combination with the cut-off value of 118.6 mIU/mL at the 5thcourse of chemotherapy.

  13. Treatment outcomes for 618 women with gestational trophoblastic tumours following a molar pregnancy at the Charing Cross Hospital, 2000–2009

    PubMed Central

    Sita-Lumsden, A; Short, D; Lindsay, I; Sebire, N J; Adjogatse, D; Seckl, M J; Savage, P M

    2012-01-01

    Background: Post-molar pregnancy gestational trophoblastic tumours (GTT) have been curable with chemotherapy treatment for over 50 years. Because of the rarity of the diagnosis, detailed structured information on prognosis, treatment escalations and outcome is limited. Methods: We have reviewed the demographics, prognostic variables, treatment course and clinical outcomes for the post-mole GTT patients treated at Charing Cross Hospital between 2000 and 2009. Results: Of the 618 women studied, 547 had a diagnosis of complete mole, 13 complete mole with a twin conception and 58 partial moles. At the commencement of treatment, 94% of patients were in the FIGO low-risk group (score 0–6). For patients treated with single-agent methotrexate, the primary cure rate ranged from 75% for a FIGO score of 0–1 through to 31% for those with a FIGO score of 6. Conclusion: In the setting of a formal follow-up programme, the expected cure rate for GTT after a molar pregnancy should be 100%. Prompt treatment and diagnosis should limit the exposure of most patients to combination chemotherapy. Because of the post-treatment relapse rate of 3% post-chemotherapy, hCG monitoring should be performed routinely. PMID:23059744

  14. SAPKgamma/JNK1 and SAPKalpha/JNK2 mRNA transcripts are expressed in early gestation human placenta and mouse eggs, preimplantation embryos, and trophoblast stem cells.

    PubMed

    Zhong, Wenjing; Sun, Tong; Wang, Q Tian; Wang, Yingchun; Xie, Yufen; Johnson, Anthony; Leach, Richard; Puscheck, Elizabeth E; Rappolee, Daniel A

    2004-10-01

    To test early-gestation human placenta, a human trophoblast cell line, mouse eggs, preimplantation embryos, and a mouse trophoblast cell line for the expression of mRNA transcripts for stress-activated protein kinase/c-Jun N-terminal kinase (SAPKgamma/JNK1, SAPKalpha/JNK2, and SAPKbeta/JNK3). Whole RNA was isolated from the tissue sources listed above and control tissues, and reverse transcription-polymerase chain reaction (RT-PCR) was performed to assay for the qualitative and semiquantitative presence of SAPKgamma/JNK1, SAPKalpha/JNK2, and SAPKbeta/JNK3. None. None. None. The presence and magnitude of amplimer amounts in gels or gene hybridization on Affymetrix cDNA arrays of RT-PCR products of reactions for SAPKgamma/JNK1, SAPKalpha/JNK2, and SAPKbeta/JNK3. SAPKgamma/JNK1 and SAPKalpha/JNK2 mRNA transcripts are present in early-gestation human placenta, a human trophoblast cell line, mouse eggs, preimplantation embryos, and a mouse trophoblast cell line at levels similar to positive control levels. SAPKalpha/JNK2 is expressed at the highest level of the three transcripts in the family. SAPKbeta/JNK3 is present at levels that are 1/100-1/1,000 those of the positive control and in some cases at the apparent level of the negative control (previously measured by the less-sensitive Northern blot analysis). Analysis with an Affymetrix cDNA array suggested that SAPKalpha/JNK2 and 38 kDa mitogen-activated protein kinase had the highest mRNA expression measured for each of three family members. Mitotic placental trophoblast cell lines and primary conceptus/embryo samples containing early placental trophoblasts express SAPKalpha/JNK2 at higher levels than SAPKgamma/JNK1, but not (only low background levels of) SAPKbeta/JNK3 mRNA transcripts. This suggests that SAPKgamma/JNK1 and SAPKalpha/JNK2 may be important mediators of stress-induced responses in early implanting conceptuses that could mediate embryo loss.

  15. Comparison of MACT and 5Fu+ACT-D chemotherapy regimens in the treatment of low-risk gestational trophoblastic neoplasia.

    PubMed

    Wang, Yu; Miao, Jin-Wei; Wang, Tong; Wang, Yan; Wu, Yu-Mei; Kong, Wei-Min; Su, Li; Duan, Wei

    2016-04-01

    The study aimed to compare the efficacy of methotrexate (MTX) cervical injections + actinomycin-D (ACT-D)(MACT) and 5-fluorouracil (5-Fu) + actinomycin-D (5-Fu plus ACT-D) chemotherapy regimens for low-risk gestational trophoblastic neoplasia (LR-GTN). Clinical data from 66 LR-GTN patients, admitted to the Beijing Obstetrics and Gynecology Hospital from January 2010 to April 2012, were analysed retrospectively. In total, 32 patients were treated with a MACT therapeutic regimen and the remaining 34 with a 5Fu + ACT-D therapeutic regimen. Complete remission rates (CR), duration of treatment, hospital stay and toxicity effects were compared. There was no statistical difference in CR for the MACT (90.63%) or the 5-Fu plus ACT-D (100%) therapeutic regimens (p = 0.0676) or in the duration of treatment [MACT (3.50) or 5-Fu plus ACT-D (3.71; p = 0.2021)]. Moreover, the hospital stay in the 5-Fu plus ACT-D group (32.88 days) was significantly longer than for the MACT group (22.09 days; p < 0.001). Furthermore, the degree of myelosuppression, nausea and vomiting, diarrhoea, stomatitis and alopecia was more severe in the 5Fu + ACT-D group (p < 0.01). However, there was no statistical difference in the severity of liver function damage between the two groups. A shorter hospital stay, lower hospitalization cost and slightly more toxic effects were observed in LR-GTN patients treated with the MACT therapeutic regimen. We suggest that the MACT regimen should be used as first-line chemotherapy for LR-GTN.

  16. Early prediction of treatment resistance in low-risk gestational trophoblastic neoplasia using population kinetic modelling of hCG measurements

    PubMed Central

    You, B; Harvey, R; Henin, E; Mitchell, H; Golfier, F; Savage, P M; Tod, M; Wilbaux, M; Freyer, G; Seckl, M J

    2013-01-01

    Background: In low-risk gestational trophoblastic neoplasia (GTN) patients, a predictive marker for early identification of methotrexate (MTX) resistance would be useful. We previously demonstrated that kinetic modelling of human chorionic gonadotrophin (hCG) measurements could provide such a marker. Here we validate this approach in a large independent patient cohort. Methods: Serum hCG measurements of 800 low-risk GTN patients treated with MTX were analysed. The cohort was divided into Model and Test data sets. hCG kinetics were described from initial treatment day to day 50 using: ‘(hCG(time))=hCG0*exp(–k*time)+hCGres', where hCGres is the modelled residual production, hCG0 is the baseline hCG level, and k is the rate constant. HCGres-predictive value was investigated against previously reported predictors of MTX resistance. Results: Declining hCG measurements were well fitted by the model. The best discriminator of MTX resistance in the Model data set was hCGres, categorised by an optimal cut-off value of >20.44 IU l−1: receiver-operating characteristic (ROC) area under the curve (AUC)=0.87; Se=0.91; Sp=0.83. The predictive value of hCGres was reproducible using the Test data set: ROC AUC=0.87; Se=0.88; Sp=0.86. Multivariate analyses revealed hCGres as a better predictor of MTX resistance (HR=1.01, P<0.0001) and MTX failure-free survival (HR=13.25, P<0.0001) than other reported predictive factors. Conclusion: hCGres, a modelled kinetic parameter calculated after fully dosed three MTX cycles, has a reproducible value for identifying patients with MTX resistance. PMID:23591194

  17. Qualitative and quantitative analysis of diffusion-weighted imaging of gestational trophoblastic disease: Can it predict progression of molar pregnancy to persistent form of disease?

    PubMed

    Sefidbakht, Sepideh; Hosseini, Fatemeh; Bijan, Bijan; Hamedi, Bahareh; Azizi, Tayyebeh

    2017-03-01

    To describe the diffusion-weighted imaging (DWI) appearance of gestational trophoblastic disease (GTD) and to determine its apparent diffusion coefficient (ADC) values. To evaluate the feasibility of DWI to predict progression of hydatidiform mole (HM) to persistent disease. During a period of 6 months, women with preliminary diagnosis of GTD, based on ultrasound and ßhCG levels, underwent 1.5T MRI (T2 high-resolution and DWI; b values 50, 400, 800; sagittal and perpendicular to the endometrium; and T1, T2 Turbo Spin Echo [TSE] axial images). Patients were followed for 6-12 months to monitor progression to persistent form of the disease. ADC values and image characteristics were compared between HM and persistent neoplasia and between GTD and non-molar pregnancy using Mann-Whitney U and Fisher's exact tests, respectively. Among the 23 studied patients, 19 (83%) were classified as molar and 4 (17%) as non-molar, based on pathology reports. After 6-12 months of follow-up, 5 (26%) cases progressed to persistent disease and 14 (74%) cases were benign HM. There was no significant difference between ADC values for HM (1.93±0.33×10(-3)mm(2)/s) and persistent neoplasia (2.03±0.28×10(-3)mm(2)/s) (P=0.69). The ADC of non-molar pregnancies was (0.96±0.46×10(-3)mm(2)/s), which was significantly different from GTD (1.96 ±0.32×10(-3)mm(2)/s) (P=0.001). Heterogeneous snowstorm appearance, focal intratumoral hemorrhage, myometrial contraction, and prominent myometrial vascularity were more common in GTD compared to non-molar pregnancy (P<0.05). Heterogeneous snowstorm appearance, focal intratumoral hemorrhage, myometrial contraction, and prominent myometrial vascularity are among the imaging characteristics of GTD. We cannot use ADC values to predict progression to persistent disease. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

  18. Follow-up of gestational trophoblastic disease/neoplasia via quantification of circulating nucleic acids of placental origin using C19MC microRNAs, hypermethylated RASSF1A, and SRY sequences.

    PubMed

    Hromadnikova, Ilona; Kotlabova, Katerina; Krofta, Ladislav; Hron, Filip

    2017-04-01

    The aim of the study was to evaluate the effectiveness of placental-specific markers, extracellular fetal DNA (sex-determining region Y and hypermethylated RASSF1A sequences) and circulating C19MC microRNAs (miR-516-5p, miR-517-5p, miR-518b, miR-520a-5p, miR-520h, miR-525, and miR-526a) for the diagnosis and consecutive follow-up of gestational trophoblastic disease/neoplasia. Increased levels of extracellular fetal DNA and C19MC microRNAs were detected in patients with active disease when compared with the period when the patients reached remission of the disease. The positive correlation between plasma levels of hypermethylated RASSF1A sequence, C19MC microRNAs, and human chorionic gonadotropin serum levels was found. MiR-520a-5p had the best performance to detect patients with active disease (a positive predictive value of 100% at a null false positive ratio (FPR)). MiR-516-5p and miR-525 were able to diagnose 100% of women with active disease at the FPR 3.9%/7.7%. The overall predictive capacity of single miR-526a (81.8% at null FPR), miR-517-5p (90.9% at 15.4% FPR), miR-518b (100% at 38.5% FPR), and miR-520h (90.9% at 26.9% FPR) biomarkers to detect active disease cases was slightly lower. Transient increase in C19MC microRNA plasma levels after the first cycle of chemotherapy indicated the decay of placental trophoblast residual tissue. The increased levels of extracellular fetal DNA and placental-specific C19MC microRNAs are associated with gestational trophoblastic disease/neoplasia. Screening of extracellular placental-specific biomarkers may represent an additional option to identify a significant proportion of women with active disease and to monitor the therapy response. Non-invasive follow-up of the decomposing residual tissue in the form of extracellular nucleic acids of placental origin packed into apoptotic bodies derived from placental trophoblasts is available.

  19. Control of human trophoblast function

    PubMed Central

    Lunghi, Laura; Ferretti, Maria E; Medici, Silvia; Biondi, Carla; Vesce, Fortunato

    2007-01-01

    The trophoblast, i.e. the peripheral part of the human conceptus, exerts a crucial role in implantation and placentation. Both processes properly occur as a consequence of an intimate dialogue between fetal and maternal tissues, fulfilled by membrane ligands and receptors, as well as by hormone and local factor release. During blastocyst implantation, generation of distinct trophoblast cell types begins, namely the villous and the extravillous trophoblast, the former of which is devoted to fetal-maternal exchanges and the latter binds the placental body to the uterine wall. Physiological placentation is characterized by the invasion of the uterine spiral arteries by extravillous trophoblast cells arising from anchoring villi. Due to this invasion, the arterial structure is replaced by amorphous fibrinoid material and endovascular trophoblastic cells. This transformation establishes a low-resistance, high-capacity perfusion system from the radial arteries to the intervillous space, in which the villous tree is embedded. The physiology of pregnancy depends upon the orderly progress of structural and functional changes of villous and extravillous trophoblast, whereas a derangement of such processes can lead to different types of complications of varying degrees of gravity, including possible pregnancy loss and maternal life-threatening diseases. In this review we describe the mechanisms which regulate trophoblast differentiation, proliferation, migration and invasiveness, and the alterations in these mechanisms which lead to pathological conditions. Furthermore, based on the growing evidence that proper inflammatory changes and oxidative balance are needed for successful gestation, we explain the mechanisms by which agents able to influence such processes may be useful in the prevention and treatment of pregnancy disorders. PMID:17288592

  20. Differential expression of the metastasis suppressor KAI1 in decidual cells and trophoblast giant cells at the feto-maternal interface

    PubMed Central

    Koo, Tae Bon; Han, Min-Su; Tadashi, Yamashita; Seong, Won Joon; Choi, Je-Yong

    2013-01-01

    Invasion of trophoblasts into maternal uterine tissue is essential for establishing mature feto-maternal circulation. The trophoblast invasion associated with placentation is similar to tumor invasion. In this study, we investigated the role of KAI1, an anti-metastasis factor, at the maternal-fetal interface during placentation. Mouse embryos were obtained from gestational days 5.5 (E5.5) to E13.5. Immunohistochemical analysis revealed that KAI1 was expressed on decidual cells around the track made when a fertilized ovum invaded the endometrium, at days E5.5 and E7.5, and on trophoblast giant cells, along the central maternal artery of the placenta at E9.5. KAI1 in trophoblast giant cells was increased at E11.5, and then decreased at E13.5. Furthermore, KAI1 was upregulated during the forskolinmediated trophoblastic differentiation of BeWo cells. Collectively, these results indicate that KAI1 is differentially expressed in decidual cells and trophoblasts at the maternal-fetal interface, suggesting that KAI1 prevents trophoblast invasion during placentation. [BMB Reports 2013; 46(10): 507-512] PMID:24148772

  1. Persistent gestational trophoblastic disease: results of MEA (methotrexate, etoposide and dactinomycin) as first-line chemotherapy in high risk disease and EA (etoposide and dactinomycin) as second-line therapy for low risk disease

    PubMed Central

    Dobson, L S; Lorigan, P C; Coleman, R E; Hancock, B W

    2000-01-01

    Persistent gestational trophoblastic disease is potentially fatal, but the majority of patients are cured with chemotherapy. Any developments in treatment are therefore being directed towards maintaining efficacy and reducing toxicity. We evaluated efficacy and toxicity of methotrexate, etoposide and dactinomycin (MEA) as first-line therapy for high risk disease and etoposide and dactinomycin (EA) as second-line therapy for methotrexate-refractory low risk disease in a retrospective analysis of 73 patients (38 MEA, 35 EA) treated since 1986 at a supra-regional centre. The median follow-up period was 5.5 years and the median number of cycles received was 7. The overall complete response rate was 85% (97% for EA, 75% for MEA). Of eight patients who failed to respond, four have since died and four were cured with platinum-based chemotherapy. Alopecia was universal. Grade II or worse nausea, emesis, or stomatitis was observed in 29%, 30% and 37% respectively. Fifty-one per cent experienced grade II/III anaemia, 8% grade II or higher thrombocytopenia and 64% grade III or IV neutropenia; in six cases this was complicated by sepsis. Fifty-four per cent of patients went on to have a normal pregnancy. No patient has developed a second malignancy. In conclusion, the MEA and EA chemotherapy regimens for persistent trophoblastic disease are very well tolerated, do not appear to affect future fertility and are associated with excellent, sustained complete response rates. © 2000 Cancer Research Campaign PMID:10789722

  2. Definitive class I human leukocyte antigen expression in gestational placentation: HLA-F, HLA-E, HLA-C, and HLA-G in extravillous trophoblast invasion on placentation, pregnancy, and parturition.

    PubMed

    Hackmon, Rinat; Pinnaduwage, Lakmini; Zhang, Jianhong; Lye, Stephen J; Geraghty, Daniel E; Dunk, Caroline E

    2017-06-01

    The extravillous trophoblasts (EVT) express HLA-C and HLA-G, but HLA-E and HLA-F are the subject of conflicting reports. In this study, we define the HLA expression profile during active EVT placental implantation, pregnancy development, and parturition. Immunohistochemistry, q-PCR, and Western blot were used to investigate HLA-C, HLA-E, and HLA-F placental expression across gestation from the early first trimester, late first trimester, second trimester (n=10 in each), preterm gestation (n=6) to elective term cesarean section and term vaginal deliveries (n=12, 38-41 weeks). EVT explants and Swan71 cells were used to assess HLA-C and HLA-F during active EVT migration. HLA-G, HLA-C, and HLA-F were expressed by 1st-trimester EVT and became intracellular and weaker as gestation progressed. HLA-E was only expressed in 1st-trimester placenta. HLA-F and HLA-C mRNA and protein expression levels showed a significant increase in the fetal villous mesenchyme across gestation. HLA-C levels increased with labor. We detected a 100-kDa HLA-F band in early pregnancy suggesting dimer formation on the EVT surface. These results were confirmed in EVT outgrowths and Swan71 trophoblast which showed that HLA-F and HLA-G are increased on the cell surface of migrating EVT, while HLA-C was internalized. Expression of HLA-F and HLA-G on the cell surface of actively migrating EVT supports their specific role in early EVT invasion and interactions with uterine natural killer cells. HLA-C's limited expression to the proliferative EVT suggests a protective role in the earliest events of implantation but not in active EVT invasion. We also show for the first time that HLA-C may be involved in parturition. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  3. Genome-wide analysis of DNA methylation changes induced by gestational arsenic exposure in liver tumors.

    PubMed

    Suzuki, Takehiro; Yamashita, Satoshi; Ushijima, Toshikazu; Takumi, Shota; Sano, Tomoharu; Michikawa, Takehiro; Nohara, Keiko

    2013-12-01

    Inorganic arsenic is known to be a human carcinogen. Previous studies have reported that DNA methylation changes are involved in arsenic-induced carcinogenesis, therefore, DNA methylation changes that are specific to arsenic-induced tumors would be useful to distinguish tumors induced by arsenic from tumors caused by other factors and to dissect arsenic carcinogenesis. Previous studies have shown that gestational arsenic exposure of C3H mice, which tend to spontaneously develop liver tumors, increases the incidence of tumors in male offspring. In this study we used the same experimental protocol as in those previous studies and searched for DNA regions where methylation status was specifically altered in the liver tumors of arsenic-exposed offspring by using methylated DNA immunoprecipitation-CpG island microarrays. The methylation levels of the DNA regions selected were measured by quantitative methylation-specific PCR and bisulfite sequencing. The results of this study clarified a number of regions where DNA methylation status was altered in the liver tumors in the C3H mice compared to normal liver tissues. Among such regions, we showed that a gene body region of the oncogene Fosb underwent alteration in DNA methylation by gestational arsenic exposure. We also showed that Fosb expression significantly increased corresponding to the DNA methylation level of the gene body in the arsenic-exposed group. These findings suggest that the DNA methylation status can be used to identify tumors increased by gestational arsenic exposure. © 2013 Japanese Cancer Association.

  4. Gestational choriocarcinoma.

    PubMed

    Baergen, R N

    1997-11-01

    The malignant transformation of trophoblast is interesting to contemplate, as trophoblast normally behaves in a manner that is interpreted as indicative of malignancy. First of all, trophoblasts show "controlled invasion" at the placental site as part of the normal process of implantation. Secondly, it is estimated that 100,000 syncytiotrophoblastic cells are deported to the maternal circulation daily and these are commonly identified in the pulmonary circulation of pregnant women (38). These trophoblastic cells do not ordinarily produce disease and presumably are rejected by the mother, unlike true metastases. When trophoblastic malignancy does develop, however, the trophoblast continues to invade and grow without limit, eventually metastasizing and ultimately leading to death. Choriocarcinoma is, therefore, unique in that it represents a malignant transformation of a tissue that inherently has "invasive" and "metastatic" properties. It is also the only tumor which contains DNA foreign to the host, as it is derived from a conception which contains paternal genetic material. Thus, choriocarcinoma is a complex neoplasm, and to study it, one must study and understand graft rejection, immunologic mechanisms and a multitude of genetic concepts in addition to the mechanisms of invasion and metastasis.

  5. Intrauterine trophoblast migration: A comparative view of humans and rodents

    PubMed Central

    Silva, Juneo F.; Serakides, Rogéria

    2016-01-01

    ABSTRACT Trophoblast migration and invasion through the decidua and maternal uterine spiral arteries are crucial events in placentation. During this process, invasive trophoblast replace vascular endothelial cells as the uterine arteries are remodeled to form more permissive vessels that facilitate adequate blood flow to the growing fetus. Placentation failures resulting from either extensive or shallow trophoblastic invasion can cause pregnancy complications such as preeclampsia, intrauterine growth restriction, placenta creta, gestational trophoblastic disease and even maternal or fetal death. Consequently, the use of experimental animal models such as rats and mice has led to great progress in recent years with regards to the identification of mechanisms and factors that control trophoblast migration kinetics. This review aims to perform a comparative analysis of placentation and the mechanisms and factors that coordinate intrauterine trophoblast migration in humans, rats and mice under physiological and pathological conditions. PMID:26743330

  6. Intrauterine trophoblast migration: A comparative view of humans and rodents.

    PubMed

    Silva, Juneo F; Serakides, Rogéria

    2016-03-03

    Trophoblast migration and invasion through the decidua and maternal uterine spiral arteries are crucial events in placentation. During this process, invasive trophoblast replace vascular endothelial cells as the uterine arteries are remodeled to form more permissive vessels that facilitate adequate blood flow to the growing fetus. Placentation failures resulting from either extensive or shallow trophoblastic invasion can cause pregnancy complications such as preeclampsia, intrauterine growth restriction, placenta creta, gestational trophoblastic disease and even maternal or fetal death. Consequently, the use of experimental animal models such as rats and mice has led to great progress in recent years with regards to the identification of mechanisms and factors that control trophoblast migration kinetics. This review aims to perform a comparative analysis of placentation and the mechanisms and factors that coordinate intrauterine trophoblast migration in humans, rats and mice under physiological and pathological conditions.

  7. Expression of CD82 in Human Trophoblast and Its Role in Trophoblast Invasion

    PubMed Central

    Zhang, Qian; Tan, Dongmei; Luo, Wenping; Lu, Junjie; Tan, Yi

    2012-01-01

    Background Well-controlled trophoblast invasion at maternal-fetal interface is a critical event for the normal development of placenta. CD82 is a member of transmembrane 4 superfamily, which showed important role in inhibiting tumor cell invasion and migration. We surmised that CD82 are participates in trophoblast differentiation during placenta development. Methodology/Principal Findings CD82 was found to be strongly expressed in human first trimester placental villous and extravillous trophoblast cells as well as in trophoblast cell lines. To investigate whether CD82 plays a role in trophoblast invasion and migration, we further utilized human villous explants culture model on matrigel and invasion/migration assay of trophoblast cell line HTR8/SVneo. CD82 siRNA significantly promoted outgrowth of villous explants in vitro (P<0.01), as well as invasion and migration of HTR8/SVneo cells (P<0.05), whereas the trophoblast proliferation was not affected. The enhanced effect of CD82 siRNA on invasion and migration of trophoblast cells was found associated with increased gelatinolytic activities of matrix metalloproteinase MMP9 while over-expression of CD82 markedly decreased trphoblast cell invasion and migration as well as MMP9 activities. Conclusions/Significance These findings suggest that CD82 is an important negative regulator at maternal-fetal interface during early pregnancy, inhibiting human trophoblast invasion and migration. PMID:22679510

  8. Maternal thyroid dysfunction affects placental profile of inflammatory mediators and the intrauterine trophoblast migration kinetics.

    PubMed

    Silva, Juneo Freitas; Ocarino, Natália Melo; Serakides, Rogéria

    2014-06-01

    The objective of the present study was to evaluate the gene and immunohistochemical expression of inflammatory mediators involved in the immune activity and the intrauterine trophoblast migration of the placentas in hypothyroid and L-thyroxine (L-T4)-treated rats. A total of 144 adult female rats were divided equally into hypothyroid, l-T4-treated, and euthyroid (control) groups. Hypothyroidism was induced by daily administration of propylthiouracil. Rats were killed at 0, 10, 14, 15, 16, 17, 18, and 19 days of gestation. We evaluated the depth of interstitial and endovascular intrauterine trophoblast invasion and the immunohistochemical expression of interferon γ (INFy), migration inhibitory factor (MIF), and inducible nitric oxide synthase (NOS2 (iNOS)). The gene expression of Toll-like receptor 2 (Tlr2) and Tlr4, Infy, Mif, tumor necrosis factor (Tnf (Tnfα)), Il10, Nos2, matrix metalloproteinase 2 (Mmp2) and Mmp9, and placental leptin was also measured in placental disks by real-time RT-PCR. The data were analyzed using an Student-Newman-Keuls (SNK) test. Hypothyroidism reduced the endovascular and interstitial trophoblast migration, and the expression of TLR4, INFy, MIF, interleukin 10 (IL10), NOS2, MMP2 and MMP9, and placental leptin, while increased the expression of TLR2 (P<0.05). T4-treated rats not only increased the expression of IL10 and NOS2 but also reduced the expression of TNF and MIF at 10 days of gestation (P<0.05). However, at 19 days of gestation, expression of INFy and MIF was increased in T4-treated group (P<0.05). Excess of T4 also increased the gene expression of Mmp2 at 10 days of gestation (P<0.05), but reduced the endovascular trophoblast migration at 18 days of gestation (P<0.05). Hypothyroidism and excess of T4 differentially affect the immune profile and the intrauterine trophoblast migration of the placenta, and these effects are dependent on the gestational period.

  9. Myeloid-derived suppressor cells are implicated in regulating permissiveness for tumor metastasis during mouse gestation

    PubMed Central

    Mauti, Laetitia A.; Le Bitoux, Marie-Aude; Baumer, Karine; Stehle, Jean-Christophe; Golshayan, Dela; Provero, Paolo; Stamenkovic, Ivan

    2011-01-01

    Metastasis depends on the ability of tumor cells to establish a relationship with the newly seeded tissue that is conducive to their survival and proliferation. However, the factors that render tissues permissive for metastatic tumor growth have yet to be fully elucidated. Breast tumors arising during pregnancy display early metastatic proclivity, raising the possibility that pregnancy may constitute a physiological condition of permissiveness for tumor dissemination. Here we have shown that during murine gestation, metastasis is enhanced regardless of tumor type, and that decreased NK cell activity is responsible for the observed increase in experimental metastasis. Gene expression changes in pregnant mouse lung and liver were shown to be similar to those detected in premetastatic sites and indicative of myeloid cell infiltration. Indeed, myeloid-derived suppressor cells (MDSCs) accumulated in pregnant mice and exerted an inhibitory effect on NK cell activity, providing a candidate mechanism for the enhanced metastatic tumor growth observed in gestant mice. Although the functions of MDSCs are not yet understood in the context of pregnancy, our observations suggest that they may represent a shared mechanism of immune suppression occurring during gestation and tumor growth. PMID:21646719

  10. Trophoblast Glycoprotein (TPGB/5T4) in Human Placenta: Expression, Regulation, and Presence in Extracellular Microvesicles and Exosomes.

    PubMed

    Alam, S M K; Jasti, S; Kshirsagar, S K; Tannetta, D S; Dragovic, R A; Redman, C W; Sargent, I L; Hodes, H C; Nauser, T L; Fortes, T; Filler, A M; Behan, K; Martin, D R; Fields, T A; Petroff, B K; Petroff, M G

    2017-01-01

    Many parallels exist between growth and development of the placenta and that of cancer. One parallel is shared expression of antigens that may have functional importance and may be recognized by the immune system. Here, we characterize expression and regulation of one such antigen, Trophoblast glycoprotein (TPGB; also called 5T4), in the placenta across gestation, in placentas of preeclamptic (PE) pregnancies, and in purified microvesicles and exosomes. Trophoblast glycoprotein expression was analyzed by real-time reverse transcription-polymerase chain reaction (RT-PCR), Western blot, and immunohistochemistry. Regulation of 5T4 in cytotrophoblast cells was examined under either differentiating conditions of epidermal growth factor or under varying oxygen conditions. Microvesicles and exosomes were purified from supernatant of cultured and perfused placentas. Trophoblast glycoprotein expression was prominent at the microvillus surface of syncytiotrophoblast and on the extravillous trophoblast cells, with minimal expression in undifferentiated cytotrophoblasts and normal tissues. Trophoblast glycoprotein expression was elevated in malignant tumors. In cytotrophoblasts, 5T4 was induced by in vitro differentiation, and its messenger RNA (mRNA) was increased under conditions of low oxygen. PE placentas expressed higher 5T4 mRNA than matched control placentas. Trophoblast glycoprotein was prominent within shed placental microvesicles and exosomes. Given the potential functional and known immunological importance of 5T4 in cancer, these studies reveal a class of proteins that may influence placental development and/or sensitize the maternal immune system. In extravillous trophoblasts, 5T4 may function in epithelial-to-mesenchymal transition during placentation. The role of syncytiotrophoblast 5T4 is unknown, but its abundance in shed syncytial vesicles may signify route of sensitization of the maternal immune system.

  11. Intratubular trophoblasts in the contralateral testis caused elevation of serum human chorionic gonadotropin following complete remission of stage II testicular tumor: a case report.

    PubMed

    Nitta, Satoshi; Kawai, Koji; Onozawa, Mizuki; Ando, Satoshi; Miyazaki, Jun; Nagata, Chigusa; Noguchi, Masayuki; Yamasaki, Kazumitsu; Uchida, Katsunori; Iwamoto, Teruaki; Nishiyama, Hiroyuki

    2013-01-01

    We report the case of a 22-year-old male who had a history of metastatic right testicular tumor successfully treated with chemotherapy and surgery. Twenty-one months after the initial treatment, the serum human chorionic gonadotropin started to increase gradually, but whole body imaging including the left testis revealed no abnormal finding except testicular microlithiasis. A biopsy of the left testis revealed intratubular germ cell neoplasia, unclassified type. After the human chorionic gonadotropin level reached 6.6 mIU/ml, he underwent left high orchiectomy. Histology demonstrated a small malignant germ cell tumor as well as intratubular germ cell neoplasia, unclassified type, both of which were negative for human chorionic gonadotropin staining. Besides these lesions, there were tiny foci of human chorionic gonadotropin-immunoreactive intratubular trophoblasts. Serum human chorionic gonadotropin normalized immediately after the orchiectomy, and he had no sign of recurrence at 6 months. The present case will provide new insight into the diagnosis of testicular tumor recurrence with isolated elevation of a serum tumor marker.

  12. Trophoblast Deportation to the Lungs of Cotton Rats (Sigmodon hispidus)

    PubMed Central

    Perle, Krista M D La; Green, M Gia; Niewiesk, Stefan

    2014-01-01

    Cotton rats (Sigmodon hispidus) have been used to study a variety of infectious agents, particularly human respiratory viral pathogens. During the course of comprehensive pathologic evaluations of aging breeders from our breeding colony, 6 of 22 (27%) female cotton rats had histologic evidence, limited to the lungs, of embolized cells that were confirmed to be trophoblastic in origin by HSD3B1 immunoreactivity. When pulmonary trophoblast emboli were numerous, they usually were associated with additional histologic findings in the lungs, including pulmonary edema and hemorrhage, endothelial hypertrophy, fibrinoid vascular necrosis, and abundant alveolar macrophages containing fresh fibrin and hemolyzing erythrocytes. Of the 6 cotton rats with pulmonary trophoblast emboli, 5 (83%) were at 8 to 18 d of the 27-d gestation period, with the greatest number of emboli per lung present between days 10 through 14. The remaining cotton rat had a focal pulmonary trophoblast embolus and was not pregnant but had delivered a litter 3 mo previously. Three other cotton rats in either the early or late stages of gestation showed no histologic evidence of pulmonary trophoblast deportation. This report is the first to document pulmonary trophoblast emboli in cotton rats. This finding suggests that cotton rats may be an alternative animal model for the study of normal and aberrant trophoblast deportation in routine pregnancies and gestational pathologic conditions in women. PMID:25527025

  13. Pregnancy outcomes after chemotherapy for trophoblastic neoplasia.

    PubMed

    Garcia, Mila Trementosa; Lin, Lawrence Hsu; Fushida, Koji; Francisco, Rossana Pulcineli Vieira; Zugaib, Marcelo

    2016-12-01

    The successful development of chemotherapy enabled a fertilitysparing treatment for patients with trophoblastic neoplasia. After disease remission, the outcome of a subsequent pregnancy becomes a great concern for these women. To analyze existing studies in the literature that describe the reproductive outcomes of patients with trophoblastic neoplasia treated with chemotherapy. Systematic review was performed searching for articles on Medline/ Pubmed, Lilacs and Cochrane Library databases, using the terms "gestational trophoblastic disease" and "pregnancy outcome". A total of 18 articles were included. No evidence of decreased fertility after chemotherapy for trophoblastic neoplasia was observed. The abortion rates in patients who conceived within 6 months after chemotherapy was higher compared to those who waited longer. Some studies showed increased rates of stillbirth and repeat hydatidiform moles. Only one work showed increased congenital abnormalities. The pregnancies conceived after chemotherapy for trophoblastic neoplasia should be followed with clinical surveillance due to higher rates of some pregnancy complications. However, studies in the literature provide reassuring data about reproductive outcomes of these patients.

  14. Immunohistochemistry Study of P53 and C-erbB-2 Expression in Trophoblastic Tissue and Their Predictive Values in Diagnosing Malignant Progression of Simple Molar Pregnancy

    PubMed Central

    Hasanzadeh, Malihe; Sharifi, Norrie; Farazestanian, Marjaneh; Nazemian, Seyed Saman; Madani Sani, Faezeh

    2016-01-01

    Background Finding a tumor marker to predict the aggressive behavior of molar pregnancy in early stages has yet been a topic for studies. Objectives In this survey we planned to study patients with molar pregnancy to 1) assess the p53 and c-erbB-2 expression in trophoblastic tissue, 2) to study the relationship between their expression intensity and progression of a molar pregnancy to gestational trophoblastic neoplasia, and 3) to determine a cut off value for the amount of p53 and c-erbB-2 expression which might correlate with aggressive behavior of molar pregnancy. Patients and Methods In a prospective cross sectional study by using a high accuracy technique EnVision Tm system for immunohistochemistry staining of molar pregnancy samples, we evaluated p53 and c-erbB-2 expression in cytotrophoblast and syncytiotrophoblast and the correlation of their expression with progression of molar pregnancy to gestational trophoblastic neoplasia (GTN). Normal prostatic tissue and Breast cancer tissue were used as positive controls. Results We studied 28 patients with simple molar pregnancy (SMP) and 30 with GTN. Cytotrophobalst had significantly higher expression of p53 and c-erbB-2 and syncytiotrophoblast had greater expression of p53 in GTN group as compared to SMP group. The cut off values for percentage of p53 positive immunostained cytotrophoblast and syncytiotrophoblast were 5.5% and 2.5%. In c-erbB-2 positive membranous stained cytotrophoblast the cut off was 12.5%. Conclusions Our data suggests that over expression of p53 and c-erbB-2 is associated with malignant progression of molar pregnancy. We encountered that high expression of p53 and c-erbB-2 in trophoblastic cells could predict gestational trophoblastic neoplasia during the early stages. PMID:27703642

  15. Trophoblast biology: Forum introduction

    PubMed Central

    Spencer, Thomas E; Bazer, Fuller W

    2004-01-01

    In mammals, a carefully orchestrated dialogue between the mother and conceptus (embryo/fetus and associate extraembryonic membranes) is initiated during the peri-implantation period of pregnancy as the trophoblast develops, functions to signal pregnancy recognition, and initiates implantation. The purpose of this Forum is to highlight comparative aspects of trophoblast morphogenesis and function in mammals.

  16. [Quiscent trophoblastic disease].

    PubMed

    Hron, F; Hejda, V; Feyereisl, J; Safár, P; Sochová, H

    2011-12-01

    Case report. Center for trophoblastic disease in Czech Republic, Institute for care of mother and child, 3rd Faculty of Medicine of Charles University Prague. The autors present a case of quiscent trophoblastic disease diagnosed at 27 years old primipara, secundigravida after previous molar pregnancy. The patient had low levels of serum hCG present for more than 18 months after the termination of pregnancy. After this period there was a malignant transformation associated with rapid elevation of hCG levels with need for chemotherapy which was succesfully completed. Quiscent (dormant, noninvasive) trophoblastic disease is a recently described unit defined by low levels of hCG present in patients serum and urine samples without any evidence of trophoblastic tumour or other source of hCG production. Quiscent trophoblastic disease is associated with high risk of malignant transformation.

  17. The management and outcome of women with post-hydatidiform mole ‘low-risk' gestational trophoblastic neoplasia, but hCG levels in excess of 100 000 IU l−1

    PubMed Central

    McGrath, S; Short, D; Harvey, R; Schmid, P; Savage, P M; Seckl, M J

    2010-01-01

    Background: Gestational trophoblastic neoplasia (GTN) after a hydatidiform mole is either treated with single- or multi-agent chemotherapy determined by a multifactorial scoring system. Women with human chorionic gonadotrophin (hCG) levels >100 000 IU l−1 can remain within the low-risk/single-agent category and usually choose one drug therapy. Here we compare the success and duration of single- vs multi-agent chemotherapy in this patient group. Methods: Between 1980 and 2008, 65 women had a pre-treatment hCG >100 000 IU l−1 and were low risk. The initial hCG level, treatment regimens, changes and duration and overall survival were recorded. Results: Of 37 patients starting low-risk/single-agent treatment, 11 (29.7%) were treated successfully, whereas 26 (70.3%) required additional multi-agent chemotherapy to achieve complete remission (CR). Combination chemotherapy was initially commenced in 28 women, and 2 (7%) required additional drugs for CR. The overall duration of therapy for those commencing and completing single- or multi-agent chemotherapy was 130 and 123 days (P=0.78), respectively. The median-treatment duration for patients commencing single-agent but changing to multi-agent chemotherapy was 13 days more than those receiving high-risk treatment alone (136 vs 123 days; P=0.07). All 3 patients with an initial hCG >400 000 IU l−1 and treated with single-agent therapy developed drug resistance. Overall survival for all patients was 100%. Conclusion: Low-risk post-molar GTN patients with a pre-treatment hCG >100 000 and <400 000 IU l−1 can be offered low-risk single-agent therapy, as this will cure 30%, is relatively non-toxic and only prolongs treatment by 2 weeks if a change to combination agents is required. Patients whose hCG is >400 000 IU l−1 should receive multi-agent chemotherapy from the outset. PMID:20160727

  18. Gastric Cancer Presenting as a Krukenberg Tumor at 22 Weeks' Gestation

    PubMed Central

    Gupta, Ashutosh; Attar, Bashar M; Demetria, Melchor

    2014-01-01

    Gastric cancer is rare during pregnancy, and often advanced upon presentation. A Krukenberg tumor presents a diagnostic and therapeutic challenge in the pregnant patient. We present a case of a 38-year-old woman at 22 weeks' gestation who presented with worsening epigastric pain, and was found to have a left pelvic mass on ultrasound, which was confirmed by magnetic resonance imaging. She went into active labor and delivered a viable infant via vaginal delivery. An exploratory laparotomy revealed a large mass originating from her left ovary and diffuse thickening of the lesser curvature of the stomach. Frozen section investigation revealed the presence of signet cell adenocarcinoma. Subsequent upper endoscopy showed linitis plastica, while biopsy confirmed the presence of adenocarcinoma. In conclusion, the occurrence of gastric cancer in pregnancy is rare despite extremely common symptoms. The management poses a challenge because of the need for early treatment, and the continuation of the pregnancy. PMID:25580361

  19. Spontaneous triplet, tubal ectopic gestation.

    PubMed Central

    Nwanodi, Oroma; Berry, Robert

    2006-01-01

    Only six cases of spontaneous, unilateral, triplet ectopic gestations have previously been reported. We now present a seventh case. The patient's prior obstetrical history was significant for a term stillbirth and a term cesarean section for breech. Quantitative betahCG was normal for gestational age; however, the increased trophoblastic mass of an inappropriately implanted multiple gestation may produce sufficient betahCG to mimic an intrauterine singleton gestation. Resolution was achieved via salpingostomy. This case is significant for being spontaneously conceived and not the result of assisted reproductive technologies. Furthermore, this case supports an association between prior cesarean section and ectopic gestation. Images Figure 1 PMID:16775922

  20. General Information about Gestational Trophoblastic Disease

    MedlinePlus

    ... uterus to scrape out abnormal tissue (last panel). Hysterectomy : Surgery to remove the uterus, and sometimes the ... the vagina , the operation is called a vaginal hysterectomy. If the uterus and cervix are taken out ...

  1. How Is Gestational Trophoblastic Disease Diagnosed?

    MedlinePlus

    ... provides helpful information about your whole body. Some machines are able to perform both a PET and CT scan at the same time (PET/CT scan). This allows the radiologist to compare areas of higher radioactivity on the PET with the appearance of that area on the CT. Other ... Information, ...

  2. [¹⁸F]fluorodeoxyglucose positron emission tomography/computed tomography and trophoblastic disease: the gynecologist perspective.

    PubMed

    Mangili, Giorgia; Bergamini, Alice; Giorgione, Veronica; Picchio, Maria; Petrone, Micaela; Mapelli, Paola; Rabaiotti, Emanuela; Incerti, Elena; Candiani, Massimo

    2016-06-01

    Gestational trophoblastic disease (GTD) is a group of different pregnancy-related diseases that includes hydatidiform mole (HM), invasive mole, gestational choriocarcinoma (CC), placental site trophoblastic tumor (PSTT) and epithelioid trophoblastic tumor (ETT). The potential role of 18F-2-fluoro-2-deoxy-D-glucose ([18F]FDG) positron emission tomography (PET) in diagnostic setting and follow up phase of GTD is still largely debated. The aim of this review is to examine the role of [18F]FDG PET/computed tomography (CT) in diagnosis, treatment and follow up of different disease subtypes. A systematic computerized search of the literature, from 1996 until December 2015 was performed in PubMed and MEDLINE to identify relevant papers to be included for this purpose. All pertinent articles and their reference lists were systematically reviewed in order to identify other studies for potential inclusion. Regarding HM a potential prognostic relevance of maximum standardized uptake value (SUV max) of molar tissue within the uterus before evacuation has been suggested. Considering CC staging, most [18F]FDG PET evaluations confirmed the results of conventional imaging. However [18F]FDG PET played a key role in discriminating ambiguous lesions on routine imaging work-up. [18F]FDG PET was particularly useful in evaluating disease recurrence and chemo-resistance, thanks to the possibility of an early identification of the active tumor site. Since the main treatment of PSTT is surgery, the contribution of [18F]FDG PET in differential diagnosis and in providing a more precise mapping of resectable metastasis or the complete response to treatment is advisable. Since the role of [18F]FDG PET and PET/CT in diagnostic setting and follow up of GTN is still controversial, further studies are required to clarify this issue.

  3. Trophoblastic disease review for diagnosis and management: a joint report from the International Society for the Study of Trophoblastic Disease, European Organisation for the Treatment of Trophoblastic Disease, and the Gynecologic Cancer InterGroup.

    PubMed

    Mangili, Giorgia; Lorusso, Domenica; Brown, Jubilee; Pfisterer, Jacobus; Massuger, Leon; Vaughan, Michelle; Ngan, Hextan Y S; Golfier, Francois; Sekharan, Paradan K; Charry, Rafael Cortés; Poveda, Andres; Kim, Jae-Weon; Xiang, Yang; Berkowtiz, Ross; Seckl, Michael J

    2014-11-01

    The objective of this study was to provide a consensus review on gestational trophoblastic disease diagnosis and management from the combined International Society for the Study of Trophoblastic Disease, European Organisation for the Treatment of Trophoblastic Disease, and the Gynecologic Cancer InterGroup. A joint committee representing various groups reviewed the literature obtained from PubMed searches. Guidelines were constructed on the basis of literature review. After initial diagnosis in local centers, centralization of pathology review and ongoing care is recommended to achieve the best outcomes.

  4. The proprotein convertase furin is required for trophoblast syncytialization

    PubMed Central

    Zhou, Z; Zhang, Q; Lu, X; Wang, R; Wang, H; Wang, Y-L; Zhu, C; Lin, H-Y; Wang, H

    2013-01-01

    The multinucleated syncytial trophoblast, which forms the outermost layer of the placenta and serves multiple functions, is differentiated from and maintained by cytotrophoblast cell fusion. Deficiencies in syncytial trophoblast differentiation or maintenance likely contribute to intrauterine growth restriction and pre-eclampsia, two common gestational diseases. The cellular and molecular mechanisms governing trophoblast syncytialization are poorly understood. We report here that the proprotein convertase furin is highly expressed in syncytial trophoblast in the first trimester human placentas, and expression of furin in the syncytiotrophoblast is significantly lower in the placentas from pre-eclamptic patients as compared with their gestational age-matched control placentas. Using multiple experimental models including induced fusion of choriocarcinoma BeWo cells and spontaneous fusion of primary cultured cytotrophoblast cells or placental explants, we demonstrate that cytotrophoblast cell fusion and syncytialization are accompanied by furin expression. Furin-specific siRNAs or inhibitors inhibit cell fusion in BeWo cells, as well as trophoblast syncytialization in human placental explants. Furthermore, type 1 IGF receptor (IGF1R) is indicated in this study as a substrate of furin, and processing of IGF1R by furin is an essential mechanism for syncytialization. Finally, using lentivirus-mediated RNAi targeting to mouse trophectoderm, we demonstrate that furin function is required for the development of syncytiotrophoblast structure in the labyrinth layer, as well as for normal embryonic development. PMID:23598405

  5. Persistent trophoblastic tissue following salpingostomy for unruptured ectopic pregnancy

    SciTech Connect

    Rivlin, M.E.; Meeks, G.R.; Cowan, B.D.; Bates, G.W.

    1985-02-01

    Radioimmunoassay of beta-hCG was used to diagnose an ectopic pregnancy in a 30 year old patient and the site of pregnancy was determined by ultrasonography. A salpingostomy was performed; the ectopic pregnancy and the residual trophoblastic tissue were removed. Six weeks later a right salpingectomy was performed to remove persistent trophoblastic tissue. Histologic examination of the surgical specimen demonstrated viable chorionic villi. Serial measurements of beta-hCG are recommended following conservative surgery for ectopic gestation to assure the patient and the surgeon that the tube contains no residual products of conception.

  6. Placentation in the degu (Octodon degus): analogies with extrasubplacental trophoblast and human extravillous trophoblast.

    PubMed

    Bosco, Cleofina; Buffet, Chosica; Bello, M Angélica; Rodrigo, Ramón; Gutierrez, Michelle; García, Gernika

    2007-04-01

    This study examined the placentation in the degu, the origin of the extrasubplacental trophoblast (EST) (extravillous trophoblast in human), and the activity of Na+/K+ ATPase in the placental barrier during different gestational ages, as part of a wider effort to understand the reproductive biology of this species. Fifteen degus at the first stage of gestation, midgestation and at term of pregnancy were studied. At day 27 of gestation, the subplacenta is formed under the wall of the central excavation. Simultaneously, the outermost trophoblast of the ectoplacental cone differentiated into secondary trophoblast giant cells that lie on the outside of the placenta, forming an interface with the maternal cells in the decidua. These giant cells immunostained positive for cytokeratin (CK) and placental lactogen (hPL) until term. During this period, the EST merged from the subplacenta to the decidua and immunostained negative for CK, but at term, immunostained for CK and hPL in the maternal vessels. The vascular mesenchyme of the central excavation invaded the chorioallantoic placenta during this period, forming two fetal lobules of labyrinthine-fine syncytium, the zone of the placental barrier. The activity of Na+/K+ ATPase in the placental barrier was constant during the gestational period. The residual syncytium at the periphery of the placental disc and between the lobules was not invaded by fetal mesenchyme and formed the marginal and interlobular labyrinthine syncytium that immunostained first for CK, and later for hPL, as in the labyrinthine fine syncytium. The presence of intracytoplasmic electron-dense material in the interlobular labyrinthine syncytium suggested a secretory process in these cells that are bathed in maternal blood. Placentas obtained from vaginal births presented a large, single lobe, absence of the subplacenta, and a reduced interlobular labyrinthine syncytium. At day 27, the inverted visceral yolk sac is observed and its columnar epithelium

  7. Identification of human trophoblast membrane antigens in maternal blood during pregnancy.

    PubMed Central

    O'Sullivan, M J; McIntyre, J A; Prior, M; Warriner, G; Faulk, W P

    1982-01-01

    The development of an immunoradiometric assay for the detection of human trophoblast-specific membrane antigens is described. The test revealed for the first time circulating trophoblast-specific cell membrane antigens in the peripheral blood of pregnant women, but none in non-pregnant female or male controls. Comparison of the circulating levels of these trophoblast-specific proteins between normal and pre-eclamptic blood samples showed no significant differences, thus casting doubt on the role of differential trophoblast antigen deportation in the etiology of toxaemic pregnancy. Matched retroplacental cord blood from several normal and pre-eclamptic pregnancies were examined and found either negative or near the lower sensitivity limit of the assay, suggesting that deportation of trophoblast membrane antigens during gestation is limited to the maternal aspect of the placenta. PMID:6177463

  8. Notch1 controls development of the extravillous trophoblast lineage in the human placenta

    PubMed Central

    Haider, Sandra; Meinhardt, Gudrun; Saleh, Leila; Fiala, Christian; Pollheimer, Jürgen; Knöfler, Martin

    2016-01-01

    Development of the human placenta and its different epithelial trophoblasts is crucial for a successful pregnancy. Besides fusing into a multinuclear syncytium, the exchange surface between mother and fetus, progenitors develop into extravillous trophoblasts invading the maternal uterus and its spiral arteries. Migration into these vessels promotes remodelling and, as a consequence, adaption of blood flow to the fetal–placental unit. Defects in remodelling and trophoblast differentiation are associated with severe gestational diseases, such as preeclampsia. However, mechanisms controlling human trophoblast development are largely unknown. Herein, we show that Notch1 is one such critical regulator, programming primary trophoblasts into progenitors of the invasive differentiation pathway. At the 12th wk of gestation, Notch1 is exclusively detected in precursors of the extravillous trophoblast lineage, forming cell columns anchored to the uterine stroma. At the 6th wk, Notch1 is additionally expressed in clusters of villous trophoblasts underlying the syncytium, suggesting that the receptor initiates the invasive differentiation program in distal regions of the developing placental epithelium. Manipulation of Notch1 in primary trophoblast models demonstrated that the receptor promotes proliferation and survival of extravillous trophoblast progenitors. Notch1 intracellular domain induced genes associated with stemness of cell columns, myc and VE-cadherin, in Notch1− fusogenic precursors, and bound to the myc promoter and enhancer region at RBPJκ cognate sequences. In contrast, Notch1 repressed syncytialization and expression of TEAD4 and p63, two regulators controlling self-renewal of villous cytotrophoblasts. Our results revealed Notch1 as a key factor promoting development of progenitors of the extravillous trophoblast lineage in the human placenta. PMID:27849611

  9. Effect of shear stress on migration and integrin expression in macaque trophoblast cells.

    PubMed

    Soghomonians, Arlen; Barakat, Abdul I; Thirkill, Twanda L; Blankenship, Thomas N; Douglas, Gordon C

    2002-05-08

    During fetal development, trophoblast cells enter endometrial capillaries, migrate within the uterine vasculature, and eventually reside within spiral arteries of the uterus. This invasive activity is accompanied by upregulation of trophoblast beta1 integrin expression. Fluid mechanical shear stress regulates migration and expression of adhesion molecules in vascular endothelial cells, but nothing is known about the effects of shear stress on trophoblast cells. We tested the hypothesis that shear stress regulates the motility and beta1 integrin expression of trophoblast cells. Early gestation macaque trophoblast cells were cultured in 1 x 1-mm square cross-section capillary tubes within which the flow field was determined using three-dimensional computational fluid dynamic simulations. Trophoblast cells in the capillary tubes were exposed to a steady shear stress of 7.5, 15, or 30 dyn/cm2 for up to 24 h. In the absence of flow, trophoblast cells were highly dynamic with constant nondirectional positional shifts but with no net cell migration. Exposure of the cells to shear stress within 24-72 h of cell plating significantly increased the level of this activity and led to net cell migration in the direction of flow. Shear stress also increased the expression and altered the topography of beta1 integrin. These results suggest that shear stress regulates trophoblast motility and beta1 integrin expression in vitro.

  10. Invasion and replication of Brucella abortus in three different trophoblastic cell lines.

    PubMed

    Samartino, L E; Traux, R E; Enright, F M

    1994-06-01

    This study was performed to compare the replication of the pathogenic strain Brucella abortus 2308 in three trophoblastic cell lines derived bovine placentas at different gestational stages. The trophoblastic cell lines were obtained from a 13-15 day embryo, from 5-month placentomal tissue and from an 8-month extra-placentomal portion of the placenta. The infection rate was similar in all cell lines at 4 h. Colony-forming Units were counted at 4, 8, 12, 24 and 30 h post-inoculation. At 12, 16, 24 and 30 h B. abortus rapidly replicated within the 5-month and 8-month trophoblastic cell lines, but grew slowly within trophoblastic cells derived from embryonic tissue. Electron microscopic studies consistently showed clusters of B. abortus in trophoblastic cells derived from 5- and 8-month placentas, while few cells of the embryonic line were infected and these contained only 1-2 bacteria per cell. It was concluded that B. abortus can infect trophoblastic cells throughout the gestational period but bacterial multiplication does not occur in these cells before middle or late gestation.

  11. Successful laparoscopic bipolar coagulation of a large arteriovenous malformation due to invasive trophoblastic disease: a case report.

    PubMed

    Corusic, Ante; Barisic, Dubravko; Lovric, Helena; Despot, Albert; Planinic, Pavao

    2009-01-01

    We report the case of an acquired large arteriovenous malformation due to invasive gestational trophoblastic tumor that was treated successfully with laparoscopic surgery. After 4 cycles of methotrexate chemotherapy, a vascular tangle (volume, 28 cm(3)) was noted that emerged from the right uterine horn, invading the broad ligament adjacent to the uterine artery. Doppler ultrasonography along with magnetic resonance arteriography confirmed the diagnosis. The location, size and relation of this arteriovenous malformation to the uterine vasculature demanded urgent intervention. Laparoscopy was performed, and bipolar coagulation of the ovarian and uterine artery feeding branches was achieved after surgical resection of the tumor. The defect in the uterine wall with an intact uterine cavity was reconstructed using sutures. There were no intraoperative or postoperative complications. The patient underwent chemotherapy, and at 2-month follow-up was cured and has since had regular menstrual cycles.

  12. Differential Effects of Sodium Butyrate and Lithium Chloride on Rhesus Monkey Trophoblast Differentiation

    PubMed Central

    Kumar, Priyadarsini; Thirkill, Twanda L.; Ji, Jennifer; Monte, Louise H.; Douglas, Gordon C.

    2015-01-01

    Trophoblast differentiation during early placental development is critical for successful pregnancy and aberrant differentiation causes preeclampsia and early pregnancy loss. During the first trimester, cytotrophoblasts are exposed to low oxygen tension (equivalent to~2%-3% O2) and differentiation proceeds along an extravillous pathway (giving rise to invasive extravillous cytotrophoblasts) and a villous pathway (giving rise to multinucleated syncytiotrophoblast). Interstitial extravillous cytotrophoblasts invade the decidua, while endovascular extravillous cytotrophoblasts are involved in re-modelling uterine spiral arteries. We tested the idea that sodium butyrate (an epigenetic modulator) induces trophoblast differentiation in early gestation rhesus monkey trophoblasts through activation of the Wnt/β-catenin pathway. The results show that syncytiotrophoblast formation was increased by butyrate, accompanied by nuclear accumulation of β-catenin, and increased expression of EnvV2 and galectin-1 (two factors thought to be involved in trophoblast fusion). Surprisingly, the expression of GCM1 and syncytin-2 was not affected by sodium butyrate. When trophoblasts were incubated with lithium chloride, a GSK3 inhibitor that mimics Wnt activation, nuclear accumulation of β-catenin also occurred but differentiation into syncytiotrophoblast was not observed. Instead the cells differentiated to mononucleated spindle-shaped cells and showed molecular and behavioral characteristics of endovascular trophoblasts. Another highly specific inhibitor of GSK3, CHIR99021, failed to induce endovascular trophoblast characteristics. These observations suggest that activation of the Wnt/β-catenin pathway correlates with both trophoblast differentiation pathways, but that additional factors determine specific cell fate decisions. Other experiments suggested that the differential effects of sodium butyrate and lithium chloride might be explained by their effects on TNFα production. The

  13. Endothelin-1 down-regulates matrix metalloproteinase 14 and 15 expression in human first trimester trophoblasts via endothelin receptor type B

    PubMed Central

    Majali-Martinez, Alejandro; Velicky, Philipp; Pollheimer, Jürgen; Knöfler, Martin; Yung, Hong wa; Burton, Graham J.; Tabrizi-Wizsy, Nassim Ghaffari; Lang, Uwe; Hiden, Ursula; Desoye, Gernot; Dieber-Rotheneder, Martina

    2017-01-01

    STUDY QUESTION Does endothelin-1 (ET-1) regulate matrix metalloproteinase (MMP) 14 and 15 production and invasion of human first trimester trophoblasts? SUMMARY ANSWER ET-1 in pathophysiological concentrations down-regulates MMP14 and MMP15 expression via endothelin receptor (ETR) type B and decreases trophoblast migration and invasion. WHAT IS KNOWN ALREADY MMP14 and MMP15 are involved in trophoblast invasion. Impairment of invasion has been linked to pregnancy complications such as pre-eclampsia (PE). ET-1 is up-regulated in PE. STUDY DESIGN, SIZE, DURATION In vitro study using primary human trophoblasts from 50 first trimester placentas (gestational week 7–12). PARTICIPANTS/MATERIALS, SETTING, METHODS Trophoblasts were cultured in the absence or presence of 10–100 nM ET-1. MMP14 and MMP15 mRNA and protein were quantified by RT-qPCR and Western blotting, respectively. Selective antagonists for ETRA (BQ-123) or ETRB (BQ-788) were used to identify ETR subtypes involved. Functional ET-1 effects were tested in first trimester chorionic villous explants and transwell invasion assays. The roles of tumor necrosis factor (TNF)-α (25 ng/ml) and oxygen (1%) in ET-1 regulation of MMP14 and 15 expression were assessed by Western blotting. MAIN RESULTS AND THE ROLE OF CHANCE ET-1 down-regulated MMP14 and MMP15 mRNA (−21% and −26%, respectively, P < 0.05) and protein levels (–18% and –22%, respectively, P < 0.05). This effect was mediated via ETRB. ET-1 decreased trophoblast outgrowth in placental explants (−24%, P < 0.05) and trophoblast invasion (−26%, P ≤ 0.01). TNF-α enhanced ET-1 mediated MMP15 down-regulation (by 10%, P < 0.05), whereas hypoxia abolished the effect of ET-1 on both MMPs. LARGE SCALE DATA N/A. LIMITATIONS, REASONS FOR CAUTION Only primary trophoblasts were used in this study. Since trophoblast yield from first trimester placental material is limited, further aspects of MMP14 and 15 regulation could not be characterized. Other anti

  14. Choline inadequacy impairs trophoblast function and vascularization in cultured human placental trophoblasts.

    PubMed

    Jiang, Xinyin; Jones, Sara; Andrew, Benjamin Y; Ganti, Anita; Malysheva, Olga V; Giallourou, Natasa; Brannon, Patsy M; Roberson, Mark S; Caudill, Marie A

    2014-08-01

    Maternal choline intake during gestation may influence placental function and fetal health outcomes. Specifically, we previously showed that supplemental choline reduced placental and maternal circulating concentrations of the anti-angiogenic factor, fms-like tyrosine kinase-1 (sFLT1), in pregnant women as well as sFLT1 production in cultured human trophoblasts. The current study aimed to quantify the effect of choline on a wider array of biomarkers related to trophoblast function and to elucidate possible mechanisms. Immortalized HTR-8/SVneo trophoblasts were cultured in different choline concentrations (8, 13, and 28 µM [control]) for 96-h and markers of angiogenesis, inflammation, apoptosis, and blood vessel formation were examined. Choline insufficiency altered the angiogenic profile, impaired in vitro angiogenesis, increased inflammation, induced apoptosis, increased oxidative stress, and yielded greater levels of protein kinase C (PKC) isoforms δ and ϵ possibly through increases in the PKC activators 1-stearoyl-2-arachidonoyl-sn-glycerol and 1-stearoyl-2-docosahexaenoyl-sn-glycerol. Notably, the addition of a PKC inhibitor normalized angiogenesis and apoptosis, and partially rescued the aberrant gene expression profile. Together these results suggest that choline inadequacy may contribute to placental dysfunction and the development of disorders related to placental insufficiency by activating PKC.

  15. The trophoblast model of cancer.

    PubMed

    Ross, Colin A

    2015-01-01

    John Beard, the British embryologist and histologist, first proposed his trophoblast model of cancer in 1902. The model has subsequently been expanded by Kelley, and in current times, Gonzalez and Isaacs. The trophoblast model of cancer can be stated as a specified, scientifically testable model, including its core predictions that 1) adult stem cells are ectopic trophoblasts that have migrated to other tissues early in embryogenesis; 2) pancreatic enzymes are the key signal that converts the trophoblast into the stable placenta; 3) cancer arises from trophoblasts that have escaped regulatory control; and 4) pancreatic enzymes can be used to treat cancer. The author reviewed the literature on the trophoblast model of cancer and the use of pancreatic enzymes for the treatment of cancer and organized its key tenets into a set of specified scientific hypotheses. The trophoblast model of cancer can be stated as a set of 11 core predictions and 3 adjunctive or nonessential components. The trophoblast model of cancer is a detailed, testable model that should be investigated within an overlapping set of fields including oncology, histology, physiology, molecular biology, and embryology.

  16. Gestational age

    MedlinePlus

    Fetal age - gestational age; Gestation; Neonatal gestational age; Newborn gestational age ... Gestational age can be determined before or after birth. Before birth, your health care provider will use ultrasound to ...

  17. Effects of Phytoestrogen Extracts Isolated from Elder Flower on Hormone Production and Receptor Expression of Trophoblast Tumor Cells JEG-3 and BeWo, as well as MCF7 Breast Cancer Cells

    PubMed Central

    Schröder, Lennard; Richter, Dagmar Ulrike; Piechulla, Birgit; Chrobak, Mareike; Kuhn, Christina; Schulze, Sandra; Abarzua, Sybille; Jeschke, Udo; Weissenbacher, Tobias

    2016-01-01

    Herein we investigated the effect of elderflower extracts (EFE) and of enterolactone/enterodiol on hormone production and proliferation of trophoblast tumor cell lines JEG-3 and BeWo, as well as MCF7 breast cancer cells. The EFE was analyzed by mass spectrometry. Cells were incubated with various concentrations of EFE. Untreated cells served as controls. Supernatants were tested for estradiol production with an ELISA method. Furthermore, the effect of the EFE on ERα/ERβ/PR expression was assessed by immunocytochemistry. EFE contains a substantial amount of lignans. Estradiol production was inhibited in all cells in a concentration-dependent manner. EFE upregulated ERα in JEG-3 cell lines. In MCF7 cells, a significant ERα downregulation and PR upregulation were observed. The control substances enterolactone and enterodiol in contrast inhibited the expression of both ER and of PR in MCF7 cells. In addition, the production of estradiol was upregulated in BeWo and MCF7 cells in a concentration dependent manner. The downregulating effect of EFE on ERα expression and the upregulation of the PR expression in MFC-7 cells are promising results. Therefore, additional unknown substances might be responsible for ERα downregulation and PR upregulation. These findings suggest potential use of EFE in breast cancer prevention and/or treatment and warrant further investigation. PMID:27740591

  18. Increased placental trophoblast inclusions in placenta accreta.

    PubMed

    Adler, E; Madankumar, R; Rosner, M; Reznik, S E

    2014-12-01

    Trophoblast inclusions (TIs) are often found in placentas of genetically abnormal gestations. Although best documented in placentas from molar pregnancies and chromosomal aneuploidy, TIs are also associated with more subtle genetic abnormalities, and possibly autism. Less than 3% of non-aneuploid, non-accreta placentas have TIs. We hypothesize that placental genetics may play a role in the development of placenta accreta and aim to study TIs as a potential surrogate indicator of abnormal placental genetics. Forty cases of placenta accreta in the third trimester were identified in a search of the medical records at one institution. Forty two third trimester control placentas were identified by a review of consecutively received single gestation placentas with no known genetic abnormalities and no diagnosis of placenta accreta. Forty percent of cases with placenta accreta demonstrated TIs compared to 2.4% of controls. More invasive placenta accretas (increta and percreta) were more likely to demonstrate TIs than accreta (47% versus 20%). Prior cesarean delivery was more likely in accreta patients than controls (67% versus 9.5%). Placenta accreta is thought to be the result of damage to the endometrium predisposing to abnormal decidualization and invasive trophoblast growth into the myometrium. However, the etiology of accreta is incompletely understood with accreta frequently occurring in women without predisposing factors and failing to occur in predisposed patients. This study has shown that TIs are present at increased rates in cases of PA. Further studies are needed to discern what underlying pathogenic mechanisms are in common between abnormal placentation and the formation of TIs. Published by Elsevier Ltd.

  19. L-methionine placental uptake: characterization and modulation in gestational diabetes mellitus.

    PubMed

    Araújo, João R; Correia-Branco, Ana; Ramalho, Carla; Gonçalves, Pedro; Pinho, Maria J; Keating, Elisa; Martel, Fátima

    2013-12-01

    Our aim was to investigate the influence of gestational diabetes mellitus (GDM) and GDM-associated conditions upon the placental uptake of (14)C-l-methionine ((14)C-l-Met). The (14)C-l-Met uptake by human trophoblasts (TBs) obtained from normal pregnancies (normal trophoblast [NTB] cells) is mainly system l-type amino acid transporter 1 (LAT1 [L])-mediated, although a small contribution of system y(+)LAT2 is also present. Comparison of (14)C-l-Met uptake by NTB and by human TBs obtained from GDM pregnancies (diabetic trophoblast [DTB] cells) reveals similar kinetics, but a contribution of systems A, LAT2, and b(0+) and a greater contribution of system y(+)LAT1 appears to exist in DTB cells. Short-term exposure to insulin and long-term exposure to high glucose, tumor necrosis factor-α, and leptin decrease (14)C-l-Met uptake in a human TB (Bewo) cell line. The effect of leptin was dependent upon phosphoinositide 3-kinase, extracellular-signal-regulated kinase 1/2 (ERK/MEK 1/2), and p38 mitogen-activated protein kinase. In conclusion, GDM does not quantitatively alter (14)C-l-Met placental uptake, although it changes the nature of transporters involved in that process.

  20. Discovery of a Cell: Reflections on the Checkered History of Intermediate Trophoblast and Update on its Nature and Pathologic Manifestations

    PubMed Central

    Kurman, Robert J.; Shih, Ie-Ming

    2015-01-01

    Summary In 1976, a series of 12 cases describing a lesion that had previously not been well characterized was reported as “trophoblastic pseudotumor of the uterus.” Up until that time rare reports of the lesion had classified it most often as an unusual type of sarcoma associated with pregnancy. All patients in that series were alive and well except for one who died from complications of a uterine perforation occurring at the time of a diagnostic curettage. Thus, it appeared to be a benign neoplasm but subsequently it was found that some exhibited malignant behavior and the tumor was renamed “placental site trophoblastic tumor.” A variety of observations pointed to an origin in a distinctive cell of the placental site, designated “intermediate trophoblast,” which physiologically is seen in the normal implantation site. Subsequently, another subset of intermediate trophoblast cells originating from the chorion laeve have been shown to give rise to the placental site nodule/plaque, a well-circumscribed and usually microscopic incidental finding as well as the epithelioid trophoblastic tumor, its putative malignant counterpart. The initial description of “trophoblastic pseudotumor” opened a new area of research which brought to bear immunohistochemical and molecular genetic analyses that eventually has led to new insights in the diverse morphologic changes occurring in early placentation and also led to the development of a new classification of trophoblastic tumors and tumor-like lesions. PMID:24901393

  1. DNA methyltransferases and TETs in the regulation of differentiation and invasiveness of extra-villous trophoblasts

    PubMed Central

    Logan, Philip C.; Mitchell, Murray D.; Lobie, Peter E.

    2013-01-01

    Specialized cell types of trophoblast cells form the placenta in which each cell type has particular properties of proliferation and invasion. The placenta sustains the growth of the fetus throughout pregnancy and any aberrant trophoblast differentiation or invasion potentially affects the future health of the child and adult. Recently, the field of epigenetics has been applied to understand differentiation of trophoblast lineages and embryonic stem cells (ESC), from fertilization of the oocyte onward. Each trophoblast cell-type has a distinctive epigenetic profile and we will concentrate on the epigenetic mechanism of DNA methyltransferases and TETs that regulate DNA methylation. Environmental factors affecting the mother potentially regulate the DNA methyltransferases in trophoblasts, and so do steroid hormones, cell cycle regulators, such as p53, and cytokines, especially interlukin-1β. There are interesting questions of why trophoblast genomes are globally hypomethylated yet specific genes can be suppressed by hypermethylation (in general, tumor suppressor genes, such as E-cadherin) and how invasive cell-types are liable to have condensed chromatin, as in metastatic cancer cells. Future work will attempt to understand the interactive nature of all epigenetic mechanisms together and their effect on the complex biological system of trophoblast differentiation and invasion in normal as well as pathological conditions. PMID:24363660

  2. [Mechanism of insulin-like growth factor-I affecting adhesion of trophoblast cells in vitro].

    PubMed

    Liu, Jie; Zhang, Han-wang; Wei, Yu-lan; Li, Yu-feng

    2005-06-01

    To investigate the mechanism of insulin-like growth factor-I (IGF-I) affecting adhesion of trophoblast cells in vitro. Trophoblast cells were obtained from early gestation at artificial abortion to set up the in vitro trophoblast cell adhesion model. The trophoblast cells were incubated with or without 10 nmol/L IGF-I and were divided into three groups (10 nmol/L IGF-I, 10 nmol/L IGF-I + alpha v beta3Ab, and control). The amount of adhered cells was assessed by examining absorbency using enzyme-linked immunoassay. Morphological changes were studied using scanning electron microscopy. The expression of phosphorylated focal adhesion kinase was determined by immunocytochemistry. After serum-starved trophoblast cells were incubated only with IGF-I, the mean absorbency was 0.491 +/- 0.049, obviously higher than control 0.198 +/- 0.022 and the difference was dramatic (P < 0.01). When cells were pre-treated with antibody against alpha v beta3 integrin and then incubated with IGF-I, the mean absorbency was only 0.184 +/- 0.031, distinctly lower than that incubated with IGF-I, and the difference was significant (P < 0.01), however, compared with control, there was no significant difference (P > 0.05). Scanning electron microscopy highlighted a dramatic increase in lamellipodial formation and extension in the IGF-I treated cells compared with control. Immunocytochemistry staining showed phosphorylated focal adhesion kinase was expressed in the trophoblast cells treated with IGF-I. 10 nmol/L IGF-I can significantly stimulate trophoblast cells adhesion to fibronectin, but antibody against alpha v beta3 integrin obviously blocks its adhesion. IGF-I can stimulate lamellipodial formation and extension at the adhesion sites, and promote adhesion of trophoblast cells to fibronectin by activating phosphorylated focal adhesion kinase.

  3. Tumor necrosis factor stimulates matrix metalloproteinase 9 secretion from cultured human chorionic trophoblast cells through TNF receptor 1 signaling to IKBKB-NFKB and MAPK1/3 pathway.

    PubMed

    Li, Wei; Li, Han; Bocking, Alan D; Challis, John R G

    2010-09-01

    The identification of proinflammatory signal transduction pathways may suggest new therapeutic targets. In this study, we examine which signaling pathways are involved in tumor necrosis factor (TNF)-induced matrix metalloproteinase 9 (MMP9) secretion in human chorionic trophoblast (CT) cells. Purified CT cells were cultured in the presence of antibodies or chemical inhibitors that specifically block/inhibit distinct TNF receptors and kinase pathways. TNF-induced proMMP9 production, as measured by zymography, was significantly blocked/inhibited by TNF receptor 1 (TNFRSF1A) antibody, NFKB activation inhibitor (NFKBAI), and MAPK1/3 (ERK) inhibitor (U0126) (P < 0.01), but not by TNF receptor 2 (TNFRSF1B) antibody, MAPK14 (p38 MAPK) inhibitor (SB203580), and MAPK8/9/10 (JNK) inhibitor (SP600125). By Western blot analysis, we found that TNF rapidly and significantly increased phosphorylation of IKBKB, MAPK1/3, and MAPK8/9/10 and that the phosphorylation of these kinases by TNF was reduced significantly by TNFRSF1A neutralizing antibody, but not by TNFRSF1B neutralizing antibody. Moreover, we found that TNF increased TNF receptor-associated factor (TRAF) 1 and decreased TRAF2 protein expression through TNFRSF1A, but not TNFRSF1B. The CT cells that had increased TRAF1 and decreased TRAF2 after an initial TNF treatment demonstrated a dramatic deficiency in phosphorylation of the above protein kinases following a secondary TNF treatment. Localization of RELA subunit by immunocytochemistry was shifted to the nuclei after TNF treatment compared to cytosol in untreated controls. We also found cross-talk between the phosphoinositide 3-kinase pathway and ERK pathway. In summary, we have demonstrated that TNF stimulates proMMP9 production in CT cells through TNFRSF1A-TRAFs-IKBKB-NFKB and ERK signaling pathways, but not through TNFRSF1B and JNK/p38-AP-1 pathways.

  4. PLAC1 expression increases during trophoblast differentiation: evidence for regulatory interactions with the fibroblast growth factor-7 (FGF-7) axis.

    PubMed

    Massabbal, Eltayab; Parveen, Shanaz; Weisoly, D L; Nelson, D Michael; Smith, S D; Fant, Michael

    2005-07-01

    PLAC1 is a recently described, trophoblast-specific gene that localizes to a region of the X-chromosome important in placental development. Immunohistochemical analysis demonstrated that PLAC1 polypeptide localizes to the differentiated syncytiotrophoblast throughout gestation (8-41 weeks) as well as a small population of villous cytotrophoblasts. Consistent with these observations, quantitative RT-PCR demonstrated that PLAC1 mRNA increases more than 300-fold during cytotrophoblast differentiation in culture to form syncytiotrophoblasts. Agents known to be relevant to trophoblast differentiation were then tested for the ability to influence PLAC1 expression. Fibroblast growth factor-7 (FGF-7), also known as keratinocyte growth factor (KGF), stimulated PLAC1 mRNA expression approximately two-fold in the BeWo(b30) trophoblast cell line. FGF-7 stimulation was significantly inhibited by PD-98059 and wortmannin suggesting mediation via MAP kinase and PI-3 kinase-dependent signaling pathways. Interestingly, epidermal growth factor (EGF) treatment of trophoblasts had no effect on PLAC1 expression alone, but potentiated the effect of FGF-7, suggesting the presence of a regulatory interaction of the two growth factors. FGF-7 and its receptor, FGFR-2b, exhibited spatial overlap with PLAC1 suggesting these regulatory interactions are physiologically relevant during gestation. These data demonstrate PLAC1 expression is upregulated during trophoblast differentiation, localizing primarily to the differentiated syncytiotrophoblast. Furthermore PLAC1 expression is specifically regulated by peptide growth factors relevant to trophoblast differentiation. Copyright 2005 Wiley-Liss, Inc

  5. Atypical postcesarean epithelioid trophoblastic lesion with cyst formation: a case report and literature review.

    PubMed

    Zhou, Feng; Lin, Kaiqing; Shi, Haiyan; Qin, Jiale; Lu, Bingjian; Huang, Lili

    2015-07-01

    We report an extremely rare case of atypical postcesarean epithelioid trophoblastic lesion with cyst formation. A 41-year-old Chinese woman presented with lower abdominal pain and menstrual disorder. Her serum human chorionic gonadotropin (hCG) was low (0.373 IU/L), and her urine hCG was negative. Ultrasound images showed a 3.7×2.8×2.5 cm(3) mass on the surface of the lower uterine segment, and a laparoscopy indicated a cystic mass in the serosal surface of the lower uterine segment. Histology indicated a cystic lesion consisting of epithelioid trophoblastic cells with an intermediate pattern between a classical placental site nodule and an epithelioid trophoblastic tumor; thus, the term atypical postcesarean epithelioid trophoblastic lesion with cyst formation was appropriate. As in atypical placental site nodule, serum hCG monitoring after treatment is necessary. Copyright © 2015. Published by Elsevier Inc.

  6. The impact of ionizing radiation on placental trophoblasts

    PubMed Central

    Kanter, D.J.; O'Brien, M.B.; Shi, X.-H.; Chu, T.; Mishima, T.; Beriwal, S.; Epperly, M.W.; Wipf, P.; Greenberger, J.S.; Sadovsky, Y.

    2014-01-01

    Introduction Exposure to low-dose radiation is widespread and attributable to natural sources. However, occupational, medical, accidental, and terrorist-related exposures remain a significant threat. Information on radiation injury to the feto-placental unit is scant and largely observational. We hypothesized that radiation causes trophoblast injury, and alters the expression of injury-related transcripts in vitro or in vivo, thus affecting fetal growth. Methods Primary human trophoblasts (PHTs), BeWo or NCCIT cells were irradiated in vitro, and cell number and viability were determined. Pregnant C57Bl/6HNsd mice were externally irradiated on E13.5, and placentas examined on E17.5. RNA expression was analyzed using microarrays and RT-qPCR. The experiments were repeated in the presence of the gramicidin S (GS)-derived nitroxide JP4-039, used to mitigate radiation-induced cell injury. Results We found that survival of in vitro–irradiated PHT cell was better than that of irradiated BeWo trophoblast cell line or the radiosensitive NCCIT mixed germ cell tumor line. Radiation altered the expression of several trophoblast genes, with a most dramatic effect on CDKN1A (p21, CIP1). Mice exposed to radiation at E13.5 exhibited a 25% reduction in mean weight by E17.5, and a 9% reduction in placental weight, which was associated with relatively small changes in placental gene expression. JP4-039 had a minimal effect on feto-placental growth or on gene expression in irradiated PHT cells or mouse placenta. Discussion and conclusion While radiation affects placental trophoblasts, the established placenta is fairly resistant to radiation, and changes in this tissue may not fully account for fetal growth restriction induced by ionizing radiation. PMID:24418702

  7. CD74-downregulation of placental macrophage-trophoblastic interactions in preeclampsia

    PubMed Central

    Przybyl, Lukasz; Haase, Nadine; Golic, Michaela; Rugor, Julianna; Solano, Maria Emilia; Arck, Petra Clara; Gauster, Martin; Huppertz, Berthold; Emontzpohl, Christoph; Stoppe, Christian; Bernhagen, Jürgen; Leng, Lin; Bucala, Richard; Schulz, Herbert; Heuser, Arnd; Weedon-Fekjær, M. Susanne; Johnsen, Guro M.; Peetz, Dirk; Luft, Friedrich C; Staff, Anne Cathrine; Müller, Dominik N; Dechend, Ralf; Herse, Florian

    2017-01-01

    RATIONALE We hypothesized that Cluster of differentiation 74 (CD74) downregulation of placental macrophages, leading to altered macrophage-trophoblast interaction, is involved in preeclampsia. OBJECTIVE Preeclamptic pregnancies feature hypertension, proteinuria and placental anomalies. Feto-placental macrophages regulate villous trophoblast differentiation during placental development. Disturbance of this well-balanced regulation can lead to pathological pregnancies. METHODS AND RESULTS We performed whole genome expression analysis of placental tissue. CD74 was one of the most downregulated genes in placentas from preeclamptic women. By RT-PCR, we confirmed this finding in early onset (<34 gestational week, n=26) and late onset (≥34 gestational week, n=24) samples from preeclamptic women, compared to healthy pregnant controls (n=28). CD74 protein levels were analyzed by Western blot and flow cytometry. We identified placental macrophages to express CD74 by immunofluorescence, flow cytometry and RT-PCR. CD74-positive macrophages were significantly reduced in preeclamptic placentas compared to controls. CD74-silenced macrophages showed that the adhesion molecules ALCAM, ICAM4, and Syndecan-2, as well as macrophage adhesion to trophoblasts were diminished. Naïve and activated macrophages lacking CD74 showed a shift towards a pro-inflammatory signature with an increased secretion of TNFα, CCL5, and MCP-1, when co-cultured with trophoblasts compared to control macrophages. Trophoblasts stimulated by these factors express more CYP2J2, sFlt1, TNFα and IL-8. CD74-knockout mice showed disturbed placental morphology, reduced junctional zone, smaller placentas and impaired spiral artery remodeling with fetal growth restriction. CONCLUSIONS CD74 downregulation in placental macrophages is present in preeclampsia. CD74 downregulation leads to altered macrophage activation towards a pro-inflammatory signature and a disturbed crosstalk with trophoblasts. PMID:27199465

  8. Microvesicles of pregnant women receiving low molecular weight heparin improve trophoblast function.

    PubMed

    Shomer, Einat; Katzenell, Sarah; Zipori, Yaniv; Rebibo-Sabbah, Annie; Brenner, Benjamin; Aharon, Anat

    2016-01-01

    Microvesicles including exosomes and microparticles, participate in the placental-maternal crosstalk in normal pregnancies and gestational vascular complications (GVC). Low molecular weight heparin (LMWH) is known to reduce the risk of placenta-mediated pregnancy complications. This study was aimed to characterize microvesicles of pregnant women receiving LMWH and explore microvesicle involvement in trophoblast and endothelial cell function. Microvesicles were isolated from blood samples obtained from non-pregnant women, healthy pregnant women (HP) and pregnant woman treated with LMWH. Microvesicle protein contents were assessed by protein array and ELISA. Microvesicle effects on early stage trophoblasts, term trophoblasts and endothelial cell migration, angiogenesis and apoptosis were evaluated. Microvesicles derived from the group treated with LMWH contained higher levels of several proangiogenic proteins compared to those of HP women. Exposure of endothelial cells to circulating microvesicles derived from HP and LMWH treated groups induced significantly higher cell migration and branch tube formation compared to untreated cells. The effect of microvesicles from HP- and LMWH groups on early-stage trophoblast migration was similar. Microvesicles derived from these two study groups significantly decreased early-stage trophoblast apoptosis, while microvesicles derived from the HP-group (but not from the LMWH-group) significantly increased the term trophoblast apoptosis (TUNEL assay) compared to untreated cells. Therapy with LMWH affects patients' microvesicle content, leading to normalization of invasion, angiogenesis activity and survival of endothelial and trophoblast cells in vitro. The effects of LMWH on microvesicles may point to an additional mechanism of heparin action in high-risk pregnancy. Copyright © 2015 Elsevier Ltd. All rights reserved.

  9. NADPH-diaphorase activity and nitric oxide synthase isoforms in the trophoblast of Calomys callosus

    PubMed Central

    MORAES, NECI; ZAGO, DOUGLAS; GAGIOTI, SONIA; HOSHIDA, MARA SANDRA; BEVILACQUA, ESTELA

    2001-01-01

    The pattern of expression of a variety of placental nitric oxide synthase isoforms has contributed to elucidating the regulatory mechanisms of nitric oxide (NO) synthesis during gestation. The maintenance of vascular tone, attenuation of vasoconstriction, prevention of platelet and leukocyte adhesion to the trophoblast surface, and possible participation in uterine blood flow seem to be the main functions of NO generated at the fetal-maternal interface in humans and mice. Extending this knowledge to other rodent species commonly used as laboratory animals, in this study we focus on NADPH-diaphorase activity and the distribution of nitric oxide synthase isoforms (NOS) in the trophoblast cells of Calomys callosus during different phases of pregnancy. NADPH-diaphorase activity was evaluated cytochemically and the presence of NOS isoforms detected by immunohistochemistry. These techniques were performed on pre- and postimplantation embryos in situ and in vitro, as well as in placentae on d 14 and 18 of pregnancy. Neither NADPH-diaphorase activity nor inducible or endothelial NOS isoforms were found in pre-implanting embryos except after culturing for at least 48 h, when some of the embryonic cells were positive for the diaphorase reaction. On d 6·5 of pregnancy, trophoblast cells showed intense diaphorase activity both in situ and under in vitro conditions. A positive reaction was also found in the different placental trophoblast cells on d 14 and 18 of pregnancy. The inducible NOS (iNOS) isoform, but not the endothelial isoform, was immunodetected in trophoblast cells from the placenta and from postimplantation embryos in situ and under in vitro conditions. These results strongly suggest the production of NO by the iNOS isoform in the trophoblast of Calomys callosus after embryo implantation. The data also emphasise a possible role for the trophoblast in producing and releasing cytotoxic molecules at the fetal-maternal interface. PMID:11327206

  10. Review: Human trophoblast fusion and differentiation: lessons from trisomy 21 placenta.

    PubMed

    Pidoux, G; Gerbaud, P; Cocquebert, M; Segond, N; Badet, J; Fournier, T; Guibourdenche, J; Evain-Brion, D

    2012-02-01

    The syncytiotrophoblast layer plays a major role throughout pregnancy, since it is the site of numerous placental functions, including ion and nutrient exchange and the synthesis of steroid and peptide hormones required for fetal growth and development. Inadequate formation and regeneration of this tissue contributes to several pathologies of pregnancy such as intrauterine growth restriction and preeclampsia, which may lead to iatrogenic preterm delivery in order to prevent fetal death and maternal complications. Syncytiotrophoblast formation can be reproduced in vitro using different models. For the last ten years we have routinely purified villous cytotrophoblastic cells (CT) from normal first, second and third trimester placentas and from gestational age-matched Trisomy 21 placentas. We cultured villous CT on plastic dishes to follow the molecular and biochemical aspects of their morphological and functional differentiation. Taking advantage of this unique collection of samples, we here discuss the concept that trophoblast fusion and functional differentiation may be two differentially regulated processes, which are linked but quite distinct. We highlight the major role of mesenchymal-trophoblast cross talk in regulating trophoblast cell fusion. We suggest that the oxidative status of the trophoblast may regulate glycosylation of proteins, including hCG, and thereby modulate major trophoblast cell functions. Copyright © 2012 Elsevier Ltd. All rights reserved.

  11. A fibroid or cancer? A rare case of mixed choriocarcinoma and epithelioid trophoblastic tumour.

    PubMed

    Luk, Wan Yu; Friedlander, Michael

    2013-01-01

    Background. Gestational trophoblastic disease (GTD) is a rare complication of pregnancy which is characterised by abnormal growth of the trophoblasts at the placental site. It is categorised into benign and malignant forms, which include hydatidiform moles (HMs) and gestational trophoblastic neoplasia (GTN), respectively. A mixed choriocarcinoma (CC) and epithelioid trophoblastic tumour (ETT) is an extremely rare subgroup of GTN, which is a highly curable but aggressive form of malignancy. Case. We report a case of mixed CC and ETT in a 41-year-old patient who presented with a 2-year history of menorrhagia and fibroid uterus in the absence of previous history of molar pregnancy. She had a 12-year interval between the antecedent pregnancy and presentation. She was treated with intensive regimen of adjuvant chemotherapy, etoposide, methotrexate, and actinomycin-D with etoposide and cisplatin (EMA-EP). She has remained disease free for more than 5 years. Conclusion. This case highlights the importance of considering GTN as one of the differential diagnoses value of β -HCG in patients presented with menorrhagia and growing fibroids.

  12. Differential gene expression in endometrium, endometrial lymphocytes, and trophoblasts during successful and abortive embryo implantation.

    PubMed

    Tayade, Chandrakant; Black, Gordon P; Fang, Yuan; Croy, B Anne

    2006-01-01

    Prenatal mortality reaching 30% occurs during the first weeks of gestation in commercial swine. Mechanisms for this are unknown although poor uterine blood supply has been postulated. In other species, vascular endothelial growth factor, hypoxia-inducible factor 1-alpha, and IFN-gamma regulate gestational endometrial angiogenesis. Vascular endothelial growth factor and hypoxia-inducible factor 1-alpha are also important for placental angiogenesis while trophoblastic expression of Fas ligand is thought to protect conceptuses against immune-mediated pregnancy loss. In this study, we document dynamic, peri-implantation differences in transcription of genes for angiogenesis, cytokine production, and apoptosis regulation in the endometrium, and laser capture microdissected endometrial lymphocytes and trophoblasts associated with healthy or viable but arresting porcine fetuses. In healthy implantation sites, endometrial gene expression levels differed between anatomic subregions and endometrial lymphocytes showed much greater transcription of angiogenic genes than trophoblasts. In arresting fetal sites, uterine lymphocytes had no angiogenic gene transcription and showed rapid elevation in transcription of proinflammatory cytokines Fas and Fas ligand while trophoblasts showed elevated transcription of IFN-gamma and Fas. This model of experimentally accessible spontaneous fetal loss, involving blocked maternal angiogenesis, should prove valuable for further investigations of peri-implantation failure of normally conceived and surgically transferred embryos in many species, including the human.

  13. ACCRETA COMPLICATING COMPLETE PLACENTA PREVIA IS CHARACTERIZED BY REDUCED SYSTEMIC LEVELS OF VASCULAR ENDOTHELIAL GROWTH FACTOR AND EPITHELIAL-TO-MESENCHYMAL TRANSITION OF THE INVASIVE TROPHOBLAST

    PubMed Central

    Wehrum, Mark J.; Buhimschi, Irina A.; Salafia, Carolyn; Thung, Stephen; Bahtiyar, Mert O.; Werner, Erica F.; Campbell, Katherine H.; Laky, Christine; Sfakianaki, Anna K.; Zhao, Guomao; Funai, Edmund F.; Buhimschi, Catalin S.

    2011-01-01

    OBJECTIVE To characterize serum angiogenic factor profile of women with complete placenta previa and determine if invasive trophoblast differentiation characteristic of accreta, increta or percreta shares features of epitehelial-mesenchymal-transition (EMT). STUDY DESIGN We analyzed gestational age matched serum samples from 90 pregnant women with either complete placenta previa (n=45) or uncomplicated pregnancies (n=45). Vascular-endothelial-growth-factor (VEGF), placental-growth-factor (PlGF) and soluble fms-like-tyrosine-kinase-1 (sFlt-1) were immunoassayed. VEGF and phosphotyrosine (P-Tyr) immunoreactivity was surveyed in histological specimens relative to expression of vimentin and cytokeratin-7. RESULTS Women with previa and invasive placentation [accreta (n=5); increta (n=6); percreta (n=2)] had lower systemic VEGF (invasive previa: median [IQR]: 0.8[0.02–3.4] vs. control: 6.5[2.7–10.5] pg/mL, P=0.02). VEGF and P-Tyr immunostaining predominated in the invasive extravillous trophoblasts (EVT) which co-expressed vimentin and cytokeratin-7, a EMT feature and tumor-like cell phenotype. CONCLUSIONS Lower systemic free VEGF and a switch of the interstitial EVT to a metastable cell phenotype characterize placenta previa with excessive myometrial invasion. PMID:21316642

  14. Group B Streptococcus Induces Trophoblast Death

    PubMed Central

    Kaplan, Amber; Chung, Kathy; Kocak, Hande; Bertolotto, Cristina; Uh, Andy; Hobel, Calvin J; Simmons, Charles F; Doran, Kelly; Liu, George; Equils, Ozlem

    2008-01-01

    Group B streptococcus (GBS) is one of the leading causes of neonatal infection; however the molecular mechanisms involved are not clearly known. Here we used high and low hemolytic GBS isolates and mutant GBS that lacks β-hemolysin expression and showed that GBS infection or exposure to GBS-hemolysin extract induces primary human trophoblast, placental fibroblast and JEG3 trophoblast cell line death, and that GBS-induced trophoblast death was β-hemolysin dependent. The fibroblasts and trophoblasts provide an innate immune barrier between fetal and maternal circulation in the placenta. These data suggest that GBS may disrupt this barrier to invade fetal circulation. PMID:18599257

  15. Endoarterial pulmonary metastasis of malignant trophoblast associated with a term intrauterine pregnancy.

    PubMed

    Carlson, J A; Day, T G; Kuhns, J G; Howell, R S; Masterson, B J

    1984-02-01

    A previously healthy gravida 4, para 3, developed preclampsia and progressive dyspnea at the 37th gestational week and had bilateral pulmonary infiltrates on chest roentgenogram. She delivered a healthy, term, male infant with a normal appearing placenta. Postpartum, her respiratory status gradually worsened. A lung biopsy on the 20th postpartum day revealed intravascular trophoblasts, diffuse arteriolar thrombosis with pulmonary infarction, and subacute interstitial pneumonitis. Combination chemotherapy was instituted, but the patient died from respiratory insufficiency.

  16. Advances in the epidemiology of gestational trophoblastic disease.

    PubMed

    Palmer, J R

    1994-03-01

    Recent reports on the incidence of hydatidiform mole and choriocarcinoma are reviewed, with consideration of the methodologic difficulties of obtaining accurate rates. The incidence of hydatidiform mole appears to be about 1 per 1,000 pregnancies in most parts of the world and perhaps twice as high in Japan. Choriocarcinoma is much less common, and estimates of the incidence are highly variable. Maternal age and a history of hydatidiform mole have been established as strong risk factors for both hydatidiform mole and choriocarcinoma. The evidence for a role of other factors, including diet, ethnicity, endogenous estrogen levels, ABO blood group and environmental toxins, is weaker.

  17. PreImplantation Factor (PIF*) endogenously prevents preeclampsia: Promotes trophoblast invasion and reduces oxidative stress.

    PubMed

    Barnea, E R; Vialard, F; Moindjie, H; Ornaghi, S; Dieudonne, M N; Paidas, M J

    2016-04-01

    Preeclampsia is a unique pregnancy disorder whose patho-physiology is initiated early in gestation, while clinical manifestations typically occur in mid-to-late pregnancy. Thus, prevention should optimally be initiated in early gestation. The intimate interaction between PIF, secreted early by viable embryos, and its host-mother provides insight into putative mechanisms of preeclampsia prevention. PIF is instrumental at the two critical events underlying preeclampsia. At first, shallow implantation leads to impaired placentation, oxidative stress, protein misfolding, and endothelial dysfunction. Later in gestation, hyper-oxygenation due to overflow of maternally derived oxygenated blood compromises the placenta. The first is likely involved in early preeclampsia occurrence due to reduced effectiveness of trophoblast/uterus interaction. The latter is observed with later-onset preeclampsia, caused by a breakdown in placental blood flow regulation. We reported that 1. PIF promotes implantation, endometrium receptivity, trophoblast invasion and increases pro-tolerance trophoblastic HLA-G expression and, 2. PIF protects against oxidative stress and protein misfolding, interacting with specific targets in embryo, 3. PIF regulates systemic immunity to reduce oxidative stress. Using PIF as an early preventative preeclampsia intervention could ameliorate or even prevent the disease, whose current main solution is early delivery. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  18. Gene targeting in primary human trophoblasts

    PubMed Central

    Rosario, Fredrick J; Sadovsky, Yoel; Jansson, Thomas

    2012-01-01

    Studies in primary human trophoblasts provide critical insights into placental function in normal and complicated pregnancies. Mechanistic studies in these cells require experimental tools to modulate gene expression. Lipid-based methods to transfect primary trophoblasts are fairly simple to use and allow for the efficient delivery of nucleic acids, but potential toxic effects limit these methods. Viral vectors are versatile transfection tools of native trophoblastic or foreign cDNAs, providing high transfection efficiency, low toxicity and stable DNA integration into the trophoblast genome. RNA interference (RNAi), using small interfering RNA (siRNA) or microRNA, constitutes a powerful approach to silence trophoblast genes. However, off-target effects, such as regulation of unintended complementary transcripts, inflammatory responses and saturation of the endogenous RNAi machinery, are significant concerns. Strategies to minimize off-target effects include using multiple individual siRNAs, elimination of pro-inflammatory sequences in the siRNA construct and chemical modification of a nucleotide in the guide strand or of the ribose moiety. Tools for efficient gene targeting in primary human trophoblasts are currently available, albeit not yet extensively validated. These methods are critical for exploring the function of human trophoblast genes and may provide a foundation for the future application of gene therapy that targets placental trophoblasts. PMID:22831880

  19. Function of caspase-14 in trophoblast differentiation

    PubMed Central

    White, Lloyd J; Declercq, Wim; Arfuso, Frank; Charles, Adrian K; Dharmarajan, Arun M

    2009-01-01

    Background Within the human placenta, the cytotrophoblast consists of a proliferative pool of progenitor cells which differentiate to replenish the overlying continuous, multi-nucleated syncytiotrophoblast, which forms the barrier between the maternal and fetal tissues. Disruption to trophoblast differentiation and function may result in impaired fetal development and preeclampsia. Caspase-14 expression is limited to barrier forming tissues. It promotes keratinocyte differentiation by cleaving profilaggrin to stabilise keratin intermediate filaments, and indirectly providing hydration and UV protection. However its role in the trophoblast remains unexplored. Methods Using RNA Interference the reaction of control and differentiating trophoblastic BeWo cells to suppressed caspase-14 was examined for genes pertaining to hormonal, cell cycle and cytoskeletal pathways. Results Transcription of hCG, KLF4 and cytokeratin-18 were increased following caspase-14 suppression suggesting a role for caspase-14 in inhibiting their pathways. Furthermore, hCG, KLF4 and cytokeratin-18 protein levels were disrupted. Conclusion Since expression of these molecules is normally increased with trophoblast differentiation, our results imply that caspase-14 inhibits trophoblast differentiation. This is the first functional study of this unusual member of the caspase family in the trophoblast, where it has a different function than in the epidermis. This knowledge of the molecular underpinnings of trophoblast differentiation may instruct future therapies of trophoblast disease. PMID:19747408

  20. Maternal DNA Methylation Regulates Early Trophoblast Development

    PubMed Central

    Branco, Miguel R.; King, Michelle; Perez-Garcia, Vicente; Bogutz, Aaron B.; Caley, Matthew; Fineberg, Elena; Lefebvre, Louis; Cook, Simon J.; Dean, Wendy; Hemberger, Myriam; Reik, Wolf

    2016-01-01

    Summary Critical roles for DNA methylation in embryonic development are well established, but less is known about its roles during trophoblast development, the extraembryonic lineage that gives rise to the placenta. We dissected the role of DNA methylation in trophoblast development by performing mRNA and DNA methylation profiling of Dnmt3a/3b mutants. We find that oocyte-derived methylation plays a major role in regulating trophoblast development but that imprinting of the key placental regulator Ascl2 is only partially responsible for these effects. We have identified several methylation-regulated genes associated with trophoblast differentiation that are involved in cell adhesion and migration, potentially affecting trophoblast invasion. Specifically, trophoblast-specific DNA methylation is linked to the silencing of Scml2, a Polycomb Repressive Complex 1 protein that drives loss of cell adhesion in methylation-deficient trophoblast. Our results reveal that maternal DNA methylation controls multiple differentiation-related and physiological processes in trophoblast via both imprinting-dependent and -independent mechanisms. PMID:26812015

  1. Myometrial tumor necrosis factor-α receptors increase with gestation and labor and modulate gene expression through mitogen-activated kinase and nuclear factor-κB.

    PubMed

    Alexander, Helen A; Sooranna, Suren R; Myatt, Leslie; Johnson, Mark R

    2012-01-01

    Previously, we found that myometrial tumor necrosis factor-α (TNF-α) messenger RNA (mRNA) expression did not increase with preterm or term labor. To further investigate the role of TNF-α in human labor, we studied TNF-α receptor (TNFR1A and B) expression, regulation, and associated intracellular signaling pathways in human myometrial samples obtained both before and after the onset of labor and in primary cultures of uterine smooth muscle cells (USMCs). We found that the mRNA expression of both receptors increased with advancing gestation and labor and protein levels of TNFR1B were significantly higher in term laboring myometrial samples than in nonlabor controls. Tumor necrosis factor- treatment of USMCs activated all mitogen-activated protein kinase (MAPK) subtypes and nuclear factor κ-B (NF-κB). The TNF-α induced increases in the expression of TNFR1B and prostaglandin H synthase type 2 were reduced by inhibitors of NF-κB and MAPKs, respectively. The TNF-α induced increase in interleukin 8 (IL-8) appeared to be independent of MAPK and NF-κB pathway. These data suggest that the uterus may become more sensitive to the action of TNF-α with advancing gestation and labor and that TNF-α acts via MAPK and NF-κB to promote labor-associated gene expression.

  2. Notch signalling in placental development and gestational diseases.

    PubMed

    Haider, S; Pollheimer, J; Knöfler, M

    2017-01-16

    Activation of Notch signalling upon cell-cell contact of neighbouring cells controls a plethora of cellular processes such as stem cell maintenance, cell lineage determination, cell proliferation, and survival. Accumulating evidence suggests that the pathway also critically regulates these events during placental development and differentiation. Herein, we summarize our present knowledge about Notch signalling in murine and human placentation and discuss its potential role in the pathophysiology of gestational disorders. Studies in mice suggest that Notch controls trophectoderm formation, decidualization, placental branching morphogenesis and endovascular trophoblast invasion. In humans, the particular signalling cascade promotes formation of the extravillous trophoblast lineage and regulates trophoblast proliferation, survival and differentiation. Expression patterns as well as functional analyses indicate distinct roles of Notch receptors in different trophoblast subtypes. Altered effects of Notch signalling have been detected in choriocarcinoma cells, consistent with its role in cancer development and progression. Moreover, deregulation of Notch signalling components were observed in pregnancy disorders such as preeclampsia and fetal growth restriction. In summary, Notch plays fundamental roles in different developmental processes of the placenta. Abnormal signalling through this pathway could contribute to the pathogenesis of gestational diseases with aberrant placentation and trophoblast function.

  3. Role of the L-amino acid transporter-1 (LAT-1) in mouse trophoblast cell invasion.

    PubMed

    Chrostowski, M K; McGonnigal, B G; Stabila, J P; Padbury, J F

    2010-06-01

    LAT-1 (L-type amino acid transporter 1) is a system L, Na(+)-independent amino acid transporter responsible for transport of large neutral amino acids. Dysregulated expression of LAT-1 is characteristic of many primary human cancers and it's over expression is related to tumor invasion. LAT-1 is highly expressed in the trophoblast giant cells (TGCs) at the time of implantation. Since trophoblast giant cells are highly invasive during the process of endometrial implantation and placentation, LAT-1 may play a role in the invasive phenotype. Our objectives were to identify the effects of increased and decreased LAT-1 expression on mouse trophoblast invasion. We therefore examined the role of amino acid deprivation, pharmacologic blockade specific to leucine transport and gene silencing (siRNA) on LAT-1 expression and trophoblast cell invasion. We utilized mouse primary trophoblast stem (TS) cells. LAT-1 mRNA expression was quantified by real time qPCR, protein by Western blotting and cell invasion was measured in Transwell plates through Matrigel. Amino acid transport using uptake of tritiated leucine. Under limited leucine availability and/or pharmacologic blockage, LAT-1 gene expression was significantly increased, p<0.05. This was associated with a 3-fold increase in cell invasion, p<0.05. In contrast, following siRNA-mediated gene silencing decreased LAT-1 expression (both mRNA and protein) was associated with decreased cell invasion and decreased leucine uptake, p<0.05. Upregulation of LAT-1 gene expression via limited amino acid availability or following pharmacologic blockade of transport leads to an increase in mouse trophoblast stem cell invasiveness. Downregulation of LAT-1 expression via genetic silencing leads to inhibition of invasiveness. These results demonstrate that LAT-1 plays an important role in trophoblast invasion.

  4. Role of the L- amino acid transporter-1 (LAT-1) in Mouse Trophoblast Cell Invasion*

    PubMed Central

    Chrostowski, Magdalena K.; McGonnigal, Bethany G.; Stabila, Joan P.; Padbury, James F.

    2010-01-01

    LAT-1 (L-type amino acid transporter 1) is a system L, Na+-independent amino acid transporter responsible for transport of large neutral amino acids. Dysregulated expression of LAT-1 is characteristic of many primary human cancers and it’s over expression is related to tumor invasion. LAT-1 is highly expressed in the trophoblast giant cells (TGCs) at the time of implantation. Since trophoblast giant cells are highly invasive during the process of endometrial implantation and placentation, LAT-1 may play a role in the invasive phenotype. Our objectives were to identify the effects of increased and decreased LAT-1 expression on mouse trophoblast invasion. We therefore examined the role of amino acid deprivation, pharmacologic blockade specific to leucine transport and gene silencing (siRNA) on LAT-1 expression and trophoblast cell invasion. We utilized mouse primary trophoblast stem (TS) cells. LAT-1 mRNA expression was quantified by real-time qPCR, protein by Western blotting and cell invasion was measured in Transwell plates through Matrigel. Amino acid transport using uptake of tritiated leucine. Under limited leucine availability and/or pharmacologic blockage, LAT-1 gene expression was significantly increased, p<0.05. This was associated with a 3-fold increase in cell invasion, p<0.05. In contrast, following siRNA-mediated gene silencing decreased LAT-1 expression (both mRNA and protein) was associated with decreased cell invasion and decreased leucine uptake, p<0.05. Upregulation of LAT-1 gene expression via limited amino acid availability or following pharmacologic blockade of transport leads to an increase in mouse trophoblast stem cell invasiveness. Downregulation of LAT-1 expression via genetic silencing leads to inhibition of invasiveness. These results demonstrate that LAT-1 plays an important role in trophoblast invasion. PMID:20421131

  5. A disintegrin and metalloproteinase 12 (ADAM12) localizes to invasive trophoblast, promotes cell invasion and directs column outgrowth in early placental development.

    PubMed

    Aghababaei, M; Perdu, S; Irvine, K; Beristain, A G

    2014-03-01

    During pregnancy, stromal- and vascular-remodeling trophoblasts serve critical roles in directing placental development acquiring pro-invasive characteristics. The A Disintegrin and Metalloproteinase (ADAM) family of multifunctional proteins direct cellular processes across multiple organ systems via their intrinsic catalytic, cell adhesive and intracellular signaling properties. ADAM12, existing as two distinct splice variants (ADAM12L and ADAM12S), is highly expressed in the human placenta and promotes cell migration and invasion in several tumor cell lines; however, its role in trophoblast biology is unknown. In this study, ADAM12 was localized to anchoring trophoblast columns in first trimester placentas and to highly invasive extracellular matrix-degrading trophoblasts in placental villous explants. The importance of ADAM12 in directing trophoblast invasion was tested using loss-of and gain-of-function strategies, where siRNA-directed knockdown of ADAM12 inhibited trophoblast cell invasion while over-expression promoted migration and invasion in two trophoblastic cell models. In placental villous explant cultures, siRNA-directed loss of ADAM12 significantly dampened trophoblast column outgrowth. Additionally, we provide functional evidence for the ADAM12S variant in promoting trophoblast invasion and column outgrowth through a mechanism requiring its catalytic activity. This is the first study to assign a function for ADAM12 in trophoblast biology, where ADAM12 may play a central role regulating the behavior of invasive trophoblast subsets in early pregnancy. This study also underlines the importance of ADAM12L and ADAM12S in directing cell motility in normal developmental processes outside of cancer, specifically highlighting a potentially important function of ADAM12S in directing early placental development.

  6. Human pluripotent stem cells as a model of trophoblast differentiation in both normal development and disease.

    PubMed

    Horii, Mariko; Li, Yingchun; Wakeland, Anna K; Pizzo, Donald P; Nelson, Katharine K; Sabatini, Karen; Laurent, Louise Chang; Liu, Ying; Parast, Mana M

    2016-07-05

    Trophoblast is the primary epithelial cell type in the placenta, a transient organ required for proper fetal growth and development. Different trophoblast subtypes are responsible for gas/nutrient exchange (syncytiotrophoblasts, STBs) and invasion and maternal vascular remodeling (extravillous trophoblasts, EVTs). Studies of early human placental development are severely hampered by the lack of a representative trophoblast stem cell (TSC) model with the capacity for self-renewal and the ability to differentiate into both STBs and EVTs. Primary cytotrophoblasts (CTBs) isolated from early-gestation (6-8 wk) human placentas are bipotential, a phenotype that is lost with increasing gestational age. We have identified a CDX2(+)/p63(+) CTB subpopulation in the early postimplantation human placenta that is significantly reduced later in gestation. We describe a reproducible protocol, using defined medium containing bone morphogenetic protein 4 by which human pluripotent stem cells (hPSCs) can be differentiated into CDX2(+)/p63(+) CTB stem-like cells. These cells can be replated and further differentiated into STB- and EVT-like cells, based on marker expression, hormone secretion, and invasive ability. As in primary CTBs, differentiation of hPSC-derived CTBs in low oxygen leads to reduced human chorionic gonadotropin secretion and STB-associated gene expression, instead promoting differentiation into HLA-G(+) EVTs in an hypoxia-inducible, factor-dependent manner. To validate further the utility of hPSC-derived CTBs, we demonstrated that differentiation of trisomy 21 (T21) hPSCs recapitulates the delayed CTB maturation and blunted STB differentiation seen in T21 placentae. Collectively, our data suggest that hPSCs are a valuable model of human placental development, enabling us to recapitulate processes that result in both normal and diseased pregnancies.

  7. miR-210 Targets Iron-Sulfur Cluster Scaffold Homologue in Human Trophoblast Cell Lines

    PubMed Central

    Lee, Deug-Chan; Romero, Roberto; Kim, Jung-Sun; Tarca, Adi L.; Montenegro, Daniel; Pineles, Beth L.; Kim, Ernest; Lee, JoonHo; Kim, Sun Young; Draghici, Sorin; Mittal, Pooja; Kusanovic, Juan Pedro; Chaiworapongsa, Tinnakorn; Hassan, Sonia S.; Kim, Chong Jai

    2011-01-01

    This study was performed to assess the biological significance of miR-210 in preeclampsia and small-for-gestational-age (SGA) pregnancies. Placental miR-210 expression was evaluated by quantitative RT-PCR (RT-qPCR) in the following groups: i) appropriate-for-gestational-age pregnancies (n = 72), ii) preeclampsia (n = 52), iii) SGA (n = 66), and iv)preeclampsia with SGA (n = 31). The effects of hypoxia (1% O2) on miR-210 and iron-sulfur cluster scaffold homologue (ISCU) expressions and miR-210 binding to ISCU 3′ UTR were examined in Swan 71 and BeWo cell lines. Perls' reaction (n = 229) and electron microscopy (n = 3) were conducted to verify siderosis of trophoblasts. miR-210 expression was increased in preeclampsia and SGA cases and was decreased with birth weight and gestational age. In both cell lines, miR-210 was induced by hypoxia, whereas ISCU expression was decreased. The luciferase assay confirmed miR-210 binding to ISCU mRNA 3′ UTR. RNA interference knockdown of ISCU expression in Swan 71, but not in BeWo, cells resulted in autophagosomal and siderosomal iron accumulation and a fourfold decrease of Matrigel invasion (P = 0.004). Placental ISCU expression was decreased in preeclampsia (P = 0.002) and SGA (P = 0.002) cases. Furthermore, hemosiderin-laden trophoblasts were more frequent in the placental bed of preterm preeclampsia and/or SGA births than in control cases (48.7% versus 17.9%; P = 0.004). Siderosis of interstitial trophoblasts is a novel pathological feature of preeclampsia and SGA. The findings herein suggest that ISCU down-regulation by miR-210 perturbing trophoblast iron metabolism is associated with defective placentation. PMID:21801864

  8. Serum tumor markers.

    PubMed

    Perkins, Greg L; Slater, Evan D; Sanders, Georganne K; Prichard, John G

    2003-09-15

    Monoclonal antibodies are used to detect serum antigens associated with specific malignancies. These tumor markers are most useful for monitoring response to therapy and detecting early relapse. With the exception of prostate-specific antigen (PSA), tumor markers do not have sufficient sensitivity or specificity for use in screening. Cancer antigen (CA) 27.29 most frequently is used to follow response to therapy in patients with metastatic breast cancer. Carcinoembryonic antigen is used to detect relapse of colorectal cancer, and CA 19-9 may be helpful in establishing the nature of pancreatic masses. CA 125 is useful for evaluating pelvic masses in postmenopausal women, monitoring response to therapy in women with ovarian cancer, and detecting recurrence of this malignancy. Alpha-fetoprotein (AFP), a marker for hepatocellular carcinoma, sometimes is used to screen highly selected populations and to assess hepatic masses in patients at particular risk for developing hepatic malignancy. Testing for the beta subunit of human chorionic gonadotropin (beta-hCG) is an integral part of the diagnosis and management of gestational trophoblastic disease. Combined AFP and beta-hCG testing is an essential adjunct in the evaluation and treatment of nonseminomatous germ cell tumors, and in monitoring the response to therapy. AFP and beta-hCG also may be useful in evaluating potential origins of poorly differentiated metastatic cancer. PSA is used to screen for prostate cancer, detect recurrence of the malignancy, and evaluate specific syndromes of adenocarcinoma of unknown primary.

  9. Gestational mutations in radiation carcinogenesis

    NASA Astrophysics Data System (ADS)

    Meza, R.; Luebeck, G.; Moolgavkar, S.

    Mutations in critical genes during gestation could increase substantially the risk of cancer. We examine the consequences of such mutations using the Luebeck-Moolgavkar model for colorectal cancer and the Lea-Coulson modification of the Luria-Delbruck model for the accumulation of mutations during gestation. When gestational mutation rates are high, such mutations make a significant contribution to cancer risk even for adult tumors. Furthermore, gestational mutations ocurring at distinct times during emryonic developmemt lead to substantially different numbers of mutated cells at birth, with early mutations leading to a large number (jackpots) of mutated cells at birth and mutation occurring late leading to only a few mutated cells. Thus gestational mutations could confer considerable heterogeneity of the risk of cancer. If the fetus is exposed to an environmental mutagen, such as ionizing radiation, the gestational mutation rate would be expected to increase. We examine the consequences of such exposures during gestation on the subsequent development of cancer.

  10. [Prediction of complications of I trimester of pregnancy in women with distressed reproductive history by detection of transcervical trophoblastic cells].

    PubMed

    Grabar', V V

    2013-12-01

    The present study investigated the possibility of using trophoblastic (fetal) cells in cervical mucus of pregnant women with complicated reproductive history to predict the course of early I trimester of pregnancy. We examined 86 women at 5-6 weeks of gestation, 56 of them with normal pregnancy, 12 with missed abortion, 18 with tubal pregnancy. As a control we used 21 non-pregnant womеn with primary infertility. Trophoblastic cells we detected by immunohistochemical method and then counted. It was revealed that in the normal course of early I trimester transcervical trophoblastic cells were detected in 4 times more likely than in missed abortion and 5 times more often than in women with tubal pregnancy. In women of the control group, who never had pregnancies, trophoblastic cells were not detected. Thus, the determination of the number of transcervical trophoblastic cells can be used in the complex diagnosis of pathological course of I trimester of pregnancy in women with complicated reproductive history.

  11. Interferon-γ expression in trophoblast cells in pregnant ewes challenged with Chlamydophila abortus.

    PubMed

    Worrall, S; Sammin, D J; Bassett, H F; Reid, C R; Gutierrez, J; Marques, P X; Nally, J E; O'Donovan, J; Williams, E J; Proctor, A; Markey, B K

    2011-08-01

    Pregnant ewes were challenged with Chlamydia abortus at 91-98 days of gestation and euthanised at 14, 21 and 28 days post-challenge. IFNγ mRNA labelling appeared to be co-localised with Chlamydial lipopolysaccharide within trophoblast cells in discrete areas lining the primary villi in the limbus and hilar zone of the placentomes from challenged sheep on days 21 and 28 post-infection. The presence of IFNγ was also demonstrated by immunohistochemistry. No labelling was seen in tissues from the non-infected ewes. The presence of IFNγ in trophoblast cells from infected ewes may indicate an attempt to restrict the replication of the organism and be an important trigger for the inflammatory responses that develop on the fetal side of the placenta in enzootic abortion.

  12. Immortalization of porcine placental trophoblast cells through reconstitution of telomerase activity.

    PubMed

    Zhang, Hongling; Huang, Yong; Wang, Lili; Yu, Tingting; Wang, Zengguo; Chang, Lingling; Zhao, Xiaomin; Luo, Xiaomao; Zhang, Liang; Tong, Dewen

    2016-05-01

    Placental trophoblast cells (PTCs) play a critical role in histotrophic nutrient absorption, gaseous exchange, endocrine activities, and barrier function between the maternal and fetal systems. Establishment of immortalized porcine PTCs will help us to investigate the potential effects of different viruses on porcine trophoblast. In the present study, primary porcine PTCs were isolated from healthy gilts at Day 30 to Day 50 of gestation through collagenase digestion, percoll gradient centrifugation, and anti-CD9 immunomagnetic negative selection. To provide stable and long lifespan cells, primary PTCs were transfected with human telomerase reverse transcriptase (hTERT) gene. One porcine placental trophoblast cell line, named as hTERT-PTCs, was chosen for characterization. Human telomerase reverse transcriptase-PTCs achieved an extended replicative lifespan without exhibiting any neoplastic transformation signs in vivo or in vitro. The morphologic and key physiological characteristics of the immortalized PTCs were similar to primary PTCs. The immortalized PTCs retained original cell polarity and normal karyotype, expressed trophoblast-specific marker cytokeratin 7 and E-cadherin but did not express vimentin and major histocompatibility complex class I antigens as well as primary PTCs. Human telomerase reverse transcriptase-PTCs secreted low levels of chorionic gonadotrophin β-subunit and placental lactogen that were coincident with primary PTCs. Taken together, our results demonstrated that the porcine PTCs could be immortalized through reconstitution of telomerase activity. The immortalized PTCs maintained its original characteristics and can be used as a model cells line to study the pathologic changes of porcine placental trophoblast in viruses infectious diseases. Copyright © 2016 Elsevier Inc. All rights reserved.

  13. Trophoblast lineage cells derived from human induced pluripotent stem cells

    SciTech Connect

    Chen, Ying; Wang, Kai; Chandramouli, Gadisetti V.R.; Knott, Jason G.; Leach, Richard

    2013-07-12

    Highlights: •Epithelial-like phenotype of trophoblast lineage cells derived from human iPS cells. •Trophoblast lineage cells derived from human iPS cells exhibit trophoblast function. •Trophoblasts from iPS cells provides a proof-of-concept in regenerative medicine. -- Abstract: Background: During implantation, the blastocyst trophectoderm attaches to the endometrial epithelium and continues to differentiate into all trophoblast subtypes, which are the major components of a placenta. Aberrant trophoblast proliferation and differentiation are associated with placental diseases. However, due to ethical and practical issues, there is almost no available cell or tissue source to study the molecular mechanism of human trophoblast differentiation, which further becomes a barrier to the study of the pathogenesis of trophoblast-associated diseases of pregnancy. In this study, our goal was to generate a proof-of-concept model for deriving trophoblast lineage cells from induced pluripotency stem (iPS) cells from human fibroblasts. In future studies the generation of trophoblast lineage cells from iPS cells established from patient’s placenta will be extremely useful for studying the pathogenesis of individual trophoblast-associated diseases and for drug testing. Methods and results: Combining iPS cell technology with BMP4 induction, we derived trophoblast lineage cells from human iPS cells. The gene expression profile of these trophoblast lineage cells was distinct from fibroblasts and iPS cells. These cells expressed markers of human trophoblasts. Furthermore, when these cells were differentiated they exhibited invasive capacity and placental hormone secretive capacity, suggesting extravillous trophoblasts and syncytiotrophoblasts. Conclusion: Trophoblast lineage cells can be successfully derived from human iPS cells, which provide a proof-of-concept tool to recapitulate pathogenesis of patient placental trophoblasts in vitro.

  14. Tumors and Proliferative Lesions in Adult Offspring After Maternal Exposure to Methylarsonous Acid During Gestation in CD1 Mice

    EPA Science Inventory

    Developmental exposure to inorganic arsenic is carcinogenic in humans and mice, and adult offspring of mice exposed to inorganic arsenic can develop tumors of the lung, liver, adrenal, uterus, and ovary. It has been suggested that methylarsonous acid (MMA3+), a product of the bi...

  15. Tumors and Proliferative Lesions in Adult Offspring After Maternal Exposure to Methylarsonous Acid During Gestation in CD1 Mice

    EPA Science Inventory

    Developmental exposure to inorganic arsenic is carcinogenic in humans and mice, and adult offspring of mice exposed to inorganic arsenic can develop tumors of the lung, liver, adrenal, uterus, and ovary. It has been suggested that methylarsonous acid (MMA3+), a product of the bi...

  16. Tumors and Proliferative Lesions in Adult Offspring After Maternal Exposure to Methylarsonous Acid During Gestation in CDl Mice.

    EPA Science Inventory

    Inorganic arsenic exposure is carcinogenic in humans and rodents. When pregnant mice are exposed to inorganic arsenic in the drinking water their offspring, when adults, develop tumors and proliferative lesions at several sites, such as lung, liver, adrenal, uterus, ovary and ovi...

  17. Tumors and Proliferative Lesions in Adult Offspring After Maternal Exposure to Methylarsonous Acid During Gestation in CDl Mice.

    EPA Science Inventory

    Inorganic arsenic exposure is carcinogenic in humans and rodents. When pregnant mice are exposed to inorganic arsenic in the drinking water their offspring, when adults, develop tumors and proliferative lesions at several sites, such as lung, liver, adrenal, uterus, ovary and ovi...

  18. The psychoactive compound of Cannabis sativa, Δ(9)-tetrahydrocannabinol (THC) inhibits the human trophoblast cell turnover.

    PubMed

    Costa, M A; Fonseca, B M; Marques, F; Teixeira, N A; Correia-da-Silva, G

    2015-08-06

    The noxious effects of cannabis consumption for fertility and pregnancy outcome are recognized for years. Its consumption during gestation is associated with alterations in foetal growth, low birth weight and preterm labor. The main psychoactive molecule of cannabis, Δ(9)-tetrahydrocannabinol (THC) impairs the production of reproductive hormones and is also able to cross the placenta barrier. However, its effect on the main placental cells, the trophoblasts, are unknown. Actually, the role of THC in cell survival/death of primary human cytotrophoblasts (CTs) and syncytiotrophoblasts (STs) and in the syncytialization process remains to be explored. Here, we show that THC has a dual effect, enhancing MTT metabolism at low concentrations, whereas higher doses decreased cell viability, on both trophoblast phenotypes, though the effects on STs were more evident. THC also diminished the generation of oxidative and nitrative stress and the oxidized form of glutathione, whereas the reduced form of this tripeptide was increased, suggesting that THC prevents ST cell death due to an antioxidant effect. Moreover, this compound enhanced the mitochondrial function of STs, as observed by the increased MTT metabolism and intracellular ATP levels. These effects were independent of cannabinoid receptors activation. Besides, THC impaired CT differentiation into STs, since it decreased the expression of biochemical and morphological biomarkers of syncytialization, through a cannabinoid receptor-dependent mechanism. Together, these results suggest that THC interferes with trophoblast turnover, preventing trophoblast cell death and differentiation, and contribute to disclose the cellular mechanisms that lead to pregnancy complications in women that consume cannabis-derived drugs during gestation.

  19. Collecting Tumor Samples From Patients With Gynecological Tumors

    ClinicalTrials.gov

    2016-10-26

    Borderline Ovarian Clear Cell Tumor; Borderline Ovarian Serous Tumor; Cervical Adenocarcinoma; Cervical Adenosquamous Carcinoma; Cervical Small Cell Carcinoma; Cervical Squamous Cell Carcinoma, Not Otherwise Specified; Childhood Embryonal Rhabdomyosarcoma; Childhood Malignant Ovarian Germ Cell Tumor; Endometrioid Stromal Sarcoma; Gestational Trophoblastic Tumor; Malignant Mesothelioma; Malignant Ovarian Epithelial Tumor; Melanoma; Neoplasm of Uncertain Malignant Potential; Ovarian Brenner Tumor; Ovarian Clear Cell Cystadenocarcinoma; Ovarian Serous Cystadenocarcinoma; Paget Disease of the Vulva; Recurrent Cervical Carcinoma; Recurrent Fallopian Tube Carcinoma; Recurrent Ovarian Carcinoma; Recurrent Ovarian Germ Cell Tumor; Recurrent Primary Peritoneal Carcinoma; Recurrent Uterine Corpus Carcinoma; Recurrent Vaginal Carcinoma; Recurrent Vulvar Carcinoma; Stage I Ovarian Cancer; Stage I Uterine Corpus Cancer; Stage I Vaginal Cancer; Stage I Vulvar Cancer; Stage IA Cervical Cancer; Stage IA Fallopian Tube Cancer; Stage IA Ovarian Cancer; Stage IA Ovarian Germ Cell Tumor; Stage IB Cervical Cancer; Stage IB Fallopian Tube Cancer; Stage IB Ovarian Cancer; Stage IB Ovarian Germ Cell Tumor; Stage IC Fallopian Tube Cancer; Stage IC Ovarian Cancer; Stage IC Ovarian Germ Cell Tumor; Stage II Ovarian Cancer; Stage II Uterine Corpus Cancer; Stage II Vaginal Cancer; Stage II Vulvar Cancer; Stage IIA Cervical Cancer; Stage IIA Fallopian Tube Cancer; Stage IIA Ovarian Cancer; Stage IIA Ovarian Germ Cell Tumor; Stage IIB Cervical Cancer; Stage IIB Fallopian Tube Cancer; Stage IIB Ovarian Cancer; Stage IIB Ovarian Germ Cell Tumor; Stage IIC Fallopian Tube Cancer; Stage IIC Ovarian Cancer; Stage IIC Ovarian Germ Cell Tumor; Stage III Borderline Ovarian Surface Epithelial-Stromal Tumor; Stage III Cervical Cancer; Stage III Uterine Corpus Cancer; Stage III Vaginal Cancer; Stage III Vulvar Cancer; Stage IIIA Fallopian Tube Cancer; Stage IIIA Ovarian Cancer; Stage IIIA Ovarian Germ Cell

  20. Gestational Gigantomastia

    PubMed Central

    Türkan, Halil; Gökgöz, M. Şehsuvar; Taşdelen, İsmet; Dündar, Halit Ziya

    2016-01-01

    Gestational gigantomastia is a rare condition characterized by fast, disproportionate and excessive breast growth, decreased quality of life in pregnancy, and presence of psychologic as well as physical complications. The etiology is not fully understood, although hormonal changes in pregnancy are considered responsible. Prolactin is the most important hormone. To date, 125 cases of gigantomastia have been reported in the literature. In this case presentation, we report a pregnant woman aged 26 years with a 22-week gestational age with gestational gigantomastia and review the diagnosis and treatment of this rare disease in relation with the literature.

  1. Characterization of the invasive and inflammatory traits of oral Campylobacter rectus in a murine model of fetoplacental growth restriction and in trophoblast cultures.

    PubMed

    Arce, R M; Diaz, P I; Barros, S P; Galloway, P; Bobetsis, Y; Threadgill, D; Offenbacher, S

    2010-03-01

    Campylobacter species (C. jejuni, C. fetus) are enteric abortifacient bacteria in humans and ungulates. Campylobacter rectus is a periodontal pathogen associated with human fetal exposure and adverse pregnancy outcomes including preterm delivery. Experiments in pregnant mice have demonstrated that C. rectus can translocate from a distant site of infection to the placenta to induce fetal growth restriction and impair placental development. However, placental tissues from human, small-for-gestational age deliveries have not been reported to harbor C. rectus despite evidence of maternal infection and fetal exposure by fetal IgM response. This investigation examined the temporal relationship between the placental translocation of C. rectus and the effects on fetal growth in mice. BALB/c mice were infected at gestational day E7.5 to examine placental translocation of C. rectus by immunohistology. C. rectus significantly decreased fetoplacental weight at E14.5 and at E16.5. C. rectus was detected in 63% of placentas at E14.5, but not at E16.5. In in vitro trophoblast invasion assays, C. rectus was able to effectively invade human trophoblasts (BeWo) but not murine trophoblasts (SM9-1), and showed a trend for more invasiveness than C. jejuni. C. rectus challenge significantly upregulated both mRNA and protein levels of IL-6 and TNFalpha in a dose-dependent manner in human trophoblasts, but did not increase cytokine expression in murine cells, suggesting a correlation between invasion and cytokine activation. In conclusion, the trophoblast-invasive trait of C. rectus that appears limited to human trophoblasts may play a role in facilitating bacterial translocation and placental inflammation during early gestation. Copyright 2009 Elsevier Ireland Ltd. All rights reserved.

  2. Characterization of the invasive and inflammatory traits of oral Campylobacter rectus in a murine model of fetoplacental growth restriction and in trophoblast cultures

    PubMed Central

    Arce, R.M.; Diaz, P.I.; Barros, S.P.; Galloway, P.; Bobetsis, Y.; Threadgill, D.; Offenbacher, S.

    2010-01-01

    Campylobacter species (C. jejuni, C. fetus) are enteric abortifacient bacteria in humans and ungulates. Campylobacter rectus is a periodontal pathogen associated with human fetal exposure and adverse pregnancy outcomes including preterm delivery. Experiments in pregnant mice have demonstrated that C. rectus can translocate from a distant site of infection to the placenta to induce fetal growth restriction and impair placental development. However, placental tissues from human, small-for-gestational age deliveries have not been reported to harbor C. rectus despite evidence of maternal infection and fetal exposure by fetal IgM response. This investigation examined the temporal relationship between the placental translocation of C. rectus and the effects on fetal growth in mice. BALB/c mice were infected at gestational day E7.5 to examine placental translocation of C. rectus by immunohistology. C. rectus significantly decreased fetoplacental weight at E14.5 and at E16.5. C. rectus was detected in 63% of placentas at E14.5, but not at E16.5. In in vitro trophoblast invasion assays, C. rectus was able to effectively invade human trophoblasts (BeWo) but not murine trophoblasts (SM9-1), and showed a trend for more invasiveness than C. jejuni. C. rectus challenge significantly upregulated both mRNA and protein levels of IL-6 and TNFα in a dose-dependent manner in human trophoblasts, but did not increase cytokine expression in murine cells, suggesting a correlation between invasion and cytokine activation. In conclusion, the trophoblast-invasive trait of C. rectus that appears limited to human trophoblasts may play a role in facilitating bacterial translocation and placental inflammation during early gestation. PMID:20089314

  3. What Is Trophoblast? A Combination of Criteria Define Human First-Trimester Trophoblast

    PubMed Central

    Lee, Cheryl Q.E.; Gardner, Lucy; Turco, Margherita; Zhao, Nancy; Murray, Matthew J.; Coleman, Nicholas; Rossant, Janet; Hemberger, Myriam; Moffett, Ashley

    2016-01-01

    Summary Controversy surrounds reports describing the derivation of human trophoblast cells from placentas and embryonic stem cells (ESC), partly due to the difficulty in identifying markers that define cells as belonging to the trophoblast lineage. We have selected criteria that are characteristic of primary first-trimester trophoblast: a set of protein markers, HLA class I profile, methylation of ELF5, and expression of microRNAs (miRNAs) from the chromosome 19 miRNA cluster (C19MC). We tested these criteria on cells previously reported to show some phenotypic characteristics of trophoblast: bone morphogenetic protein (BMP)-treated human ESC and 2102Ep, an embryonal carcinoma cell line. Both cell types only show some, but not all, of the four trophoblast criteria. Thus, BMP-treated human ESC have not fully differentiated to trophoblast. Our study identifies a robust panel, including both protein and non-protein-coding markers that, in combination, can be used to reliably define cells as characteristic of early trophoblast. PMID:26862703

  4. What Is Trophoblast? A Combination of Criteria Define Human First-Trimester Trophoblast.

    PubMed

    Lee, Cheryl Q E; Gardner, Lucy; Turco, Margherita; Zhao, Nancy; Murray, Matthew J; Coleman, Nicholas; Rossant, Janet; Hemberger, Myriam; Moffett, Ashley

    2016-02-09

    Controversy surrounds reports describing the derivation of human trophoblast cells from placentas and embryonic stem cells (ESC), partly due to the difficulty in identifying markers that define cells as belonging to the trophoblast lineage. We have selected criteria that are characteristic of primary first-trimester trophoblast: a set of protein markers, HLA class I profile, methylation of ELF5, and expression of microRNAs (miRNAs) from the chromosome 19 miRNA cluster (C19MC). We tested these criteria on cells previously reported to show some phenotypic characteristics of trophoblast: bone morphogenetic protein (BMP)-treated human ESC and 2102Ep, an embryonal carcinoma cell line. Both cell types only show some, but not all, of the four trophoblast criteria. Thus, BMP-treated human ESC have not fully differentiated to trophoblast. Our study identifies a robust panel, including both protein and non-protein-coding markers that, in combination, can be used to reliably define cells as characteristic of early trophoblast. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  5. Gal-1 silenced trophoblast tumor cells (BeWo) show decreased syncytium formation and different miRNA production compared to non-target silenced BeWo cells

    PubMed Central

    Hutter, Stefan; Morales-Prieto, Diana M.; Andergassen, Ulrich; Tschakert, Lisa; Kuhn, Christina; Hofmann, Simone; Markert, Udo R.; Jeschke, Udo

    2016-01-01

    ABSTRACT Galectin-1 (gal-1), a member of the mammalian β-galactoside-binding proteins, exerts biological effects by recognition of glycan ligands, including those involved in cell adhesion and growth regulation. In previous studies, we demonstrated that gal-1 induces cell differentiation processes on the membrane of choriocarcinoma cells BeWo, including the receptor tyrosine kinases (RTKs) REarranged during Transfection (RET), Janus Kinase 2 (JAK2) and Vascular endothelial growth factor receptor 3 (VEGFR3). Furthermore, Mitogen-Activated Protein Kinases (MAPK) and serine/threonine kinases were phosphorylated by gal-1. In addition, gal-1 in trophoblast cells in vitro induced syncytium formation especially after concentration dependent stimulation of the cells with this galectin. This is in contrast to MAPK-inhibitor U0126 that reduced syncytium formation of BeWo cells. The aim of this study was to analyze the syncytium formation abilities of BeWo cells that were gal-1 silenced. We found a significantly reduced syncytium formation rate in gal-1 silenced BeWo cells. In addition, these cells show a different miRNA expression profile. In summary, we found that gal-1 is a major trigger for fusion processes in BeWo cells. This function is accompanied by different regulation of miRNA synthesis in the BeWo cell culture model. PMID:26418280

  6. Effect of Fetal Size on Fetal Placental Hyaluronan and Hyaluronoglucosaminidases Throughout Gestation in the Pig

    USDA-ARS?s Scientific Manuscript database

    Previous results indicated that the trophoblast-endometrial epithelial cell bilayer of porcine placenta undergoes microscopic folding during gestation, and the folded bilayer is embedded in placental stroma. We hypothesized that hyaluronan was a component of placental stroma, and that hyaluronidases...

  7. Split Immunological Tolerance to Trophoblast

    PubMed Central

    de Mestre, Amanda; Noronha, Leela; Wagner, Bettina; Antczak, Douglas F.

    2010-01-01

    Split immunological tolerance refers to states in which an individual is capable of mounting certain types of immune responses to a particular antigenic challenge, but is tolerant of the same antigen in other compartments of the immune system. This concept is applicable to the immunological relationship between mother and fetus, and particularly relevant in equine pregnancy. In pregnant mares, antibody responses to paternal foreign Major Histocompatibility Complex class I antigens are robust, while anti-paternal cytotoxic T cell responses are diminished compared to those mounted by non-pregnant mares. Here we compared the distribution of the major lymphocyte subsets, the percentage of lymphocytes expressing Interferon Gamma (IFNG) and Interleukin 4 (IL4) and the level of expression of the immunoregulatory transcription factor FOXP3 between pregnant and non-pregnant mares, and between peripheral blood and the endometrium during pregnancy. In a cohort of mares in which peripheral blood lymphocytes were tested during early pregnancy and in the non-pregnant state, there were only slight changes observed during pregnancy. In contrast, comparison of peripheral blood lymphocytes with lymphocytes isolated from the endometrial cups of pregnant mares revealed striking differences in lymphocyte sub-populations. The endometrial cups contained higher numbers of IFNG+ lymphocytes, and lower numbers of lymphocytes expressing IL4. The endometrial cup lymphocytes also had higher numbers of FOXP3+ cells compared to peripheral blood lymphocytes. Taken together, these results strengthen the evidence for a state of split tolerance to trophoblast, and furthermore define sharp differences in immune reactivity during equine pregnancy between peripheral blood lymphocytes and lymphocytes at the maternal-fetal interface. PMID:19876828

  8. Expression of the orexin system in the porcine uterus, conceptus and trophoblast during early pregnancy.

    PubMed

    Smolinska, N; Kiezun, M; Dobrzyn, K; Szeszko, K; Maleszka, A; Kaminski, T

    2015-11-01

    Orexin A and B are hypothalamic peptides derived from the prepro-orexin (PPO) precursor. Orexins stimulate food intake and arousal. Those peptides bind and activate two G protein-coupled receptors: orexin receptor 1 (OX1R) and orexin receptor 2 (OX2R). Numerous authors have suggested that orexins play an important role in the regulation of the reproductive functions. The objective of the present study was to analyse the presence of and changes in the gene and protein expression pattern of the orexin system in the porcine uterus, conceptus and trophoblast (chorioallantois) during early pregnancy. In the endometrium, the highest PPO and OX1R gene expression was detected on days 15 to 16 of gestation. The OX2R mRNA content in the endometrium was higher on days 10 to 11 and 15 to 16 than on days 12 to 13 and 27 to 28. In the trophoblasts, PPO gene expression was higher on days 30 to 32 than on days 27 to 28. The highest PPO protein content in the endometrium was noted on days 12 to 13. The highest OX1R protein content in the endometrium was detected on days 10 to 11, whereas OX2R protein on days 15 to 16. In the trophoblasts, PPO and OX1R protein levels were more pronounced on days 27 to 28 than on days 30 to 32, but OX2R expression was higher on days 30 to 32. The expression of PPO, OX1R and OX2R was different in the conceptuses and trophoblasts during early pregnancy. Local orexin production and the presence of the specific orexin receptors suggest that the orexin system may participate in the control of porcine reproductive functions by exerting endocrine and auto/paracrine effects on the uterus, conceptuses and trophoblasts during early pregnancy. This study provides the first evidence for the presence of orexins and their receptors in the uteri, conceptuses and trophoblasts in pigs during early pregnancy. The local orexin system is dependent on the stage of pregnancy.

  9. CCN1 (CYR61) and CCN3 (NOV) signaling drives human trophoblast cells into senescence and stimulates migration properties.

    PubMed

    Kipkeew, Friederike; Kirsch, Manuela; Klein, Diana; Wuelling, Manuela; Winterhager, Elke; Gellhaus, Alexandra

    2016-03-03

    During placental development, continuous invasion of trophoblasts into the maternal compartment depends on the support of proliferating extravillous trophoblasts (EVTs). Unlike tumor cells, EVTs escape from the cell cycle before invasion into the decidua and spiral arteries. This study focused on the regulation properties of glycosylated and non-glycosylated matricellular CCN1 and CCN3, primarily for proliferation control in the benign SGHPL-5 trophoblast cell line, which originates from the first-trimester placenta. Treating SGHPL-5 trophoblast cells with the glycosylated forms of recombinant CCN1 and CCN3 decreased cell proliferation by bringing about G0/G1 cell cycle arrest, which was accompanied by the upregulation of activated Notch-1 and its target gene p21. Interestingly, both CCN proteins increased senescence-associated β-galactosidase activity and the expression of the senescence marker p16. The migration capability of SGHPL-5 cells was mostly enhanced in response to CCN1 and CCN3, by the activation of FAK and Akt kinase but not by the activation of ERK1/2. In summary, both CCN proteins play a key role in regulating trophoblast cell differentiation by inducing senescence and enhancing migration properties. Reduced levels of CCN1 and CCN3, as found in early-onset preeclampsia, could contribute to a shift from invasive to proliferative EVTs and may explain their shallow invasion properties in this disease.

  10. BROMODICHLOROMETHANE INHIBITS HUMAN PLACENTAL TROPHOBLAST DIFFERENTIATION

    EPA Science Inventory

    BROMODICHLOROMETHANE INHIBITS HUMAN PLACENTAL
    TROPHOBLAST DIFFERENTIATION
    Jiangang Chen, Twanda L. Thirkill, Peter N. Lohstroh, Susan R. Bielmeier, Michael
    G. Narotsky, Deborah S. Best, Randy A. Harrison, Kala Natarajan, Rex A. Pegram,
    Bill L. Lasley, and Gordon C. Do...

  11. BROMODICHLOROMETHANE INHIBITS HUMAN PLACENTAL TROPHOBLAST DIFFERENTIATION

    EPA Science Inventory

    BROMODICHLOROMETHANE INHIBITS HUMAN PLACENTAL
    TROPHOBLAST DIFFERENTIATION
    Jiangang Chen, Twanda L. Thirkill, Peter N. Lohstroh, Susan R. Bielmeier, Michael
    G. Narotsky, Deborah S. Best, Randy A. Harrison, Kala Natarajan, Rex A. Pegram,
    Bill L. Lasley, and Gordon C. Do...

  12. 8-Iso-prostaglandin f(2alpha) reduces trophoblast invasion and matrix metalloproteinase activity.

    PubMed

    Staff, A C; Ranheim, T; Henriksen, T; Halvorsen, B

    2000-06-01

    Preeclampsia is a common pregnancy complication in the latter half of gestation diagnosed by hypertension and proteinuria. A key feature of preeclampsia is an altered placentation with reduced trophoblast invasion. Normal placentation requires controlled invasion of trophoblasts into the maternal uterine wall, with secretion of specific proteolytic enzymes able to degrade basement membranes and extracellular matrix, such as the matrix metalloproteinases (MMPs). 8-Iso-prostaglandin F(2alpha) (8-iso-PGF(2alpha)) is a marker of oxidative stress in vivo and is biologically active. We have recently reported an elevated content of free 8-iso-PGF(2alpha) in preeclamptic gestational tissue at delivery. Assuming an elevated level of 8-iso-PGF(2alpha) during the invasion period of the pregnancy, we hypothesized that 8-iso-PGF(2alpha) could reduce invasion of JAR cells, a choriocarcinoma cell line. We investigated JAR cell invasion with 2 types of Transwell assays and demonstrated that 8-iso-PGF(2alpha) (10 micromol/L) resulted in reduced cell invasion in both the colorimetric and radioactivity Transwell assays (P<0.01). Zymograms revealed reduced MMP-2 and MMP-9 activity in conditioned media from JAR cells incubated with 8-iso-PGF(2alpha) (10 micromol/L) (P<0.02). 8-Iso-PGF(2alpha) (10 micromol/L) also reduced the collagenase type IV activity in the conditioned media of JAR cells (P=0.04). No effects on MMP-2 and MMP-9 mRNA levels were observed after incubation with 8-iso-PGF(2alpha) (10 micromol/L), whereas protein levels were significantly decreased (P<0.02), suggesting a posttranscriptional regulation. We hypothesize a potential role for 8-iso-PGF(2alpha) in the reduced trophoblast invasion in preeclampsia.

  13. Antenatal retinoic acid administration increases trophoblastic retinol-binding protein dependent retinol transport in the nitrofen model of congenital diaphragmatic hernia.

    PubMed

    Kutasy, Balazs; Friedmacher, Florian; Pes, Lara; Coyle, David; Doi, Takashi; Paradisi, Francesca; Puri, Prem

    2016-04-01

    Low pulmonary retinol levels and disrupted retinoid signaling pathway (RSP) have been implicated in the pathogenesis of congenital diaphragmatic hernia (CDH) and associated pulmonary hypoplasia (PH). It has been demonstrated that nitrofen disturbs the main retinol-binding protein (RBP)-dependent trophoblastic retinol transport. Several studies have demonstrated that prenatal treatment with retinoic acid (RA) can reverse PH in the nitrofen-induced CDH model. We hypothesized that maternal administration of RA can increase trophoblastic RBP-dependent retinol transport in a nitrofen model of CDH. Pregnant rats were treated with nitrofen or vehicle on gestational day 9 (D9) and sacrificed on D21. RA was given i.p. on D18, D19, and D20. Retinol and RA levels were measured using high-performance liquid chromatography. Immunohistochemistry was performed to evaluate trophoblastic expression of RBP. Expression levels of the primary RSP genes were determined using quantitative real-time PCR and immunohistochemistry. Markedly increased trophoblastic RBP immunoreactivity was observed in CDH+RA compared to CDH. Significantly increased serum and pulmonary retinol and RA levels were detected in CDH+RA compared to CDH. Pulmonary expression of RSP genes and proteins were increased in CDH+RA compared to CDH. Increased trophoblastic RBP expression and retinol transport after antenatal administration of RA suggest that retinol-triggered RSP activation may attenuate CDH-associated PH by elevating serum and pulmonary retinol levels.

  14. Increasing quantity of maternal immunoglobulin G in trophoblastic tissue before the onset of normal labor.

    PubMed

    Akin, J W; Conover, W B; DePriest, P D

    1990-05-01

    While levels of maternal immunoglobulin G (IgG) increase in the fetal circulation during the third trimester, actual trophoblastic concentrations have not been extensively studied. To investigate this process, placentas from 71 patients with gestational ages between 26 and 42 weeks were examined by means of a peroxidase-antiperoxidase immunostaining technique specific for IgG. Linear regression revealed a significant increase in antibody with advancing gestational age (r = 0.36, p less than 0.01). In addition, placentas from patients in spontaneous term labor revealed a significantly higher antibody level when compared with those of patients at term delivered electively before the onset of labor (mean +/- SEM 2.6 +/- 0.2 vs 1.7 +/- 0.3, p less than 0.02). Patients in premature labor failed to demonstrate this increase in antibody staining. One possible explanation for these findings is an enhanced recognition of the fetal trophoblastic tissue by the maternal immune system at term. It also suggests immunologic factors may play an important role in the initiation of normal labor.

  15. Cytogenetic features of human trophoblast cell lines SWAN-71 and 3A-subE.

    PubMed

    Reiter, Jill L; Drendel, Holli M; Chakraborty, Sujata; Schellinger, Megan M; Lee, Men-Jean; Mor, Gil

    2017-04-01

    Immortalization of primary cells with telomerase is thought to maintain normal phenotypic properties and avoid chromosomal abnormalities and other cancer-associated changes that occur following simian virus 40 tumor antigen (SV40 Tag) induced immortalization. However, we report that the human telomerase reverse transcriptase (hTERT)-immortalized SWAN-71 trophoblast cell line has a near pentaploid 103∼119,XXXX[cp20] karyotype. Additionally, DNA typing analysis indicated that SWAN-71 cells have acquired microsatellite instability. In comparison, the post-crisis SV40-transformed trophoblast cell line 3A-subE was hypertriploid 69∼81,XX[cp20]. Both cell lines contained multiple specific clonal rearrangements. These findings emphasize the need to monitor for genetic instability in hTERT-immortalized cells. Copyright © 2017 Elsevier Ltd. All rights reserved.

  16. Gestational surrogacy.

    PubMed

    Brinsden, Peter R

    2003-01-01

    Gestational surrogacy is a treatment option available to women with certain clearly defined medical problems, usually an absent uterus, to help them have their own genetic children. IVF allows the creation of embryos from the gametes of the commissioning couple and subsequent transfer of these embryos to the uterus of a surrogate host. The indications for treatment include absent uterus, recurrent miscarriage, repeated failure of IVF and certain medical conditions. Treatment by gestational surrogacy is straightforward and follows routine IVF procedures for the commissioning mother, with the transfer of fresh or frozen-thawed embryos to the surrogate host. The results of treatment are good, as would be expected from the transfer of embryos derived from young women and transferred to fit, fertile women who are also young. Clinical pregnancy rates achieved in large series are up to 40% per transfer and series have reported 60% of hosts achieving live births. The majority of ethical or legal problems that have arisen out of surrogacy have been from natural or partial surrogacy arrangements. The experience of gestational surrogacy has been largely complication-free and early results of the follow-up of children, commissioning couples and surrogates are reassuring. In conclusion, gestational surrogacy arrangements are carried out in a few European countries and in the USA. The results of treatment are satisfactory and the incidence of major ethical or legal complications has been limited. IVF surrogacy is therefore a successful treatment for a small group of women who would otherwise not be able to have their own genetic children.

  17. Gestational anemia.

    PubMed

    Wahed, F; Latif, S A; Nessa, A; Bhuiyan, M R; Hossain, M B; Akther, A; Mahmud, M M

    2010-07-01

    Gestational anemia is a common public health problem in our country. Most anemia during pregnancy results from an increased need for iron as her body is making more blood. Often dietary supplementation does not provide enough iron to meet the extra needs. Also the growing baby takes all the iron it needs from mother, regardless of how much iron is stored in mother's blood. Gestational Anemia contributed significantly to maternal morbidity and mortality, IUGR, preterm delivery and perinatal morbidity and mortality. A high proportion of women in both industrialized and developing countries become anemic during pregnancy. The most important cause of gestational anemia due to iron deficiency, because high iron requirements during pregnancy are not easily fulfilled by dietary intake. Adequate iron stores can help a pregnant women replace lost red blood cells. So, iron supplementation is strongly recommended for all pregnant women in developing countries. Oral iron intake is the treatment of choice and almost all pregnant women can be treated effectively with oral iron preparation during their pregnancy period.

  18. MiR-519d-3p Suppresses Invasion and Migration of Trophoblast Cells via Targeting MMP-2

    PubMed Central

    Weng, Dan; Wu, Chengli; Zhang, Xiaodong; Yao, Yuanqing; Zhu, Xiaoming

    2015-01-01

    Our study was approved by the Medical Ethics Committee of Tang Du Hospital, Fourth Military Medical University and complied strictly with national ethical guidelines. Preeclampsia (PE) is a specific clinical disorder characterized by gestational hypertension and proteinuria and is a leading cause of maternal and perinatal mortality worldwide. The miR-519d-3p is upregulated in the maternal plasma of patients with PE which indicates a possible association between this microRNA and the pathogenesis of PE. No studies to date have addressed the effect of miR-519d-3p on the invasion and migration of trophoblast cells. In our study, we found that miR-519d-3p expression was elevated in placental samples from patients with PE. In vitro, overexpression of miR-519d-3p significantly inhibited trophoblast cell migration and invasion, whereas transfection of a miR-519d-3p inhibitor enhanced trophoblast cell migration and invasion. Luciferase assays confirmed that matrix metalloproteinase-2 (MMP-2) is a direct target of miR-519d-3p. Quantitative real-time PCR and western blot assays showed that overexpression of miR-519d-3p downregulated MMP-2 mRNA and protein expression. Knockdown of MMP-2 using a siRNA attenuated the increased trophoblast migration and invasion promoted by the miR-519d-3p inhibitor. In placentas from patients with PE or normal pregnancies, a negative correlation between the expression of MMP-2 and miR-519d-3p was observed using the Pearson correlation and linear regression analysis. Our present findings suggest that upregulation of miR-519d-3p may contribute to the development of PE by inhibiting trophoblast cell migration and invasion via targeting MMP-2; miR-519d-3p may represent a potential predictive and therapeutic target for PE. PMID:25803859

  19. Chlamydia trachomatis infection modulates trophoblast cytokine/chemokine production1

    PubMed Central

    de la Torre, Eugenia; Mulla, Melissa J.; Yu, Andrew G.; Lee, Seung-Joon; Kavathas, Paula B.; Abrahams, Vikki M.

    2009-01-01

    It is well established that intrauterine infections can pose a threat to pregnancy by gaining access to the placenta and fetus, and clinical studies have strongly linked bacterial infections with preterm labor. While Chlamydia trachomatis (C. trachomatis; Ct) can infect the placenta and decidua, little is known about its effects on trophoblast cell immune function. We have demonstrated that Ct infects trophoblast cells to form inclusions, and completes the life cycle within these cells by generating infectious elementary bodies. Moreover, infection with Ct leads to differential modulation of the trophoblast cell's production of cytokines and chemokines. Using two human first trimester trophoblast cell lines, Sw.71 and H8, the most striking feature we found was that Ct infection results in a strong induction of IL-1β secretion, and a concomitant reduction in MCP-1 (CCL2) production in both cell lines. In addition, we have found that Ct infection of the trophoblast results in the cleavage and degradation of NFκB p65. These findings suggest that the effect of a Chlamydia infection on trophoblast secretion of chemokines and cytokines involves both activation of innate immune receptors expressed by the trophoblast, and virulence factors secreted into the trophoblast by the bacteria. Such altered trophoblast innate immune responses may have a profound impact on the microenvironment of the maternal-fetal interface, and this could influence pregnancy outcome. PMID:19265152

  20. Functions of ectopically transplanted invasive horse trophoblast

    PubMed Central

    de Mestre, Amanda M.; Hanlon, David; Adams, A. Paige; Runcan, Erin; Leadbeater, Jane C.; Erb, Hollis N.; Costa, Christina C.; Miller, Donald; Allen, W. R; Antczak, Douglas F.

    2013-01-01

    The invasive and fully antigenic trophoblast of the chorionic girdle portion of the equine fetal membranes has the capacity to survive and differentiate after transplantation to ectopic sites. The objectives of this study were to determine: (i) the survival time of ectopically transplanted allogeneic trophoblast cells in non-pregnant recipient mares, (ii) whether equine Chorionic Gonadotrophin (eCG) can be delivered systemically by transplanted chorionic girdle cells, and (iii) if eCG delivered by the transplanted cells is biologically active and can suppress behavioral signs associated with estrus. Ectopically transplanted chorionic girdle survived for up to 105 days with a mean lifespan of 75 days (95% CI 55–94), and secreted sufficient eCG for the hormone to be measurable in the recipients’ circulation. Immunohistochemical labeling of serial biopsies of the transplant sites and measurement of eCG profiles demonstrated that graft survival was similar to the lifespan of equine endometrial cups in normal horse pregnancy. The eCG secreted by the transplanted cells induced corpora lutea formation and sustained systemic progesterone levels in the recipient mares, effects that are also observed during pregnancy. This in turn caused suppression of estrus behavior in the recipients for up to three months. Thus, ectopically transplanted equine trophoblast provides an unusual example of sustained viability and function of an immunogenic transplant in a recipient with an intact immune system. This model highlights the importance of innate immunoregulatory capabilities of invasive trophoblast cells and describes a new method to deliver sustained circulating concentrations of eCG in non-pregnant mares. PMID:21389079

  1. [Effects of Brucella phosphoglucomutase on inducing infection of trophoblastic cells].

    PubMed

    Wang, Zhen; Zhang, Hui; Zhang, Yan; Guo, Fei; Zhang, Yu; Chen, Ruihua; Meng, Ru; Li, Zhiqiang; Zhang, Qian; Chen, Chuangfu

    2012-08-04

    We studied the biological function of Brucella phosphoglucomutase (pgm) gene, and detected the changes of human trophoblast cell invaded by the Brucella pgm mutant and PGM protein. Human trophoblast cells were infected by the pgm mutant and PGM protein. The changes of cytokines were detected by enzyme-linked immunosorbent assay, and morphology of cells was identified. PGM protein was purified, and pgm mutant was constructed. The sera of mice immunized by pgm mutant were negative by agglutination test and Standard Tube Agglutination Test for Brucellosis. The cellular morphology of human trophoblast cells infected pgm mutant or PGM protein changed. The adhesion and infection of the pgm mutant reduced more than Brucella vaccine strain M5-90, and human trophoblast cells partially cracked off. The activity of IL-6, TNF-alpha or lactic dehydrogenae increased in human trophoblast cells infected by the pgm mutant more than Brucella vaccine strain M5-90 (P < 0.01), but not for IL-10. Lactic dehydrogenae in human trophoblast cells infected by the PGM Protein increased more than sodium phosphate buffer (P < 0.01), whereas IL-6 and TNF-alpha decreased in human trophoblast cells less than sodium phosphate buffer (P < 0.05). The results suggest that the pgm mutant of brucella and PGM protein had the cytotoxic effect for human trophoblast cells with cellular morphology and changes of cytokines.

  2. Kisspeptins and the placenta: regulation of trophoblast invasion.

    PubMed

    Hiden, Ursula; Bilban, Martin; Knöfler, Martin; Desoye, Gernot

    2007-03-01

    The invasion of extravillous trophoblasts into the uterine wall is of crucial importance for placental and fetal development, and its dysregulation has been implicated in a wide spectrum of abnormal pregnancies. Mechanistically, trophoblast invasion strongly resembles the invasion of tumour cells, but differs from it by tight regulation in time and space. This regulation is accomplished by different factors including cytokines and hormones, which are produced by both fetal as well as maternal tissues i.e., placenta and uterus, respectively. Recently, products of the KiSS-1 gene (kisspeptins) have been identified to not only inhibit metastasis in various tumours, but also to repress trophoblast invasion via binding to the G protein-coupled receptor KiSS-1R. In the placenta, expression levels of kisspeptins and their receptor are highest in the first trimester in humans and at day 12.5 in rats, respectively. This coincides with the time when invasiveness peaks and invasion regulation is of central importance. Human kisspeptins are predominantly produced by the syncytiotrophoblast, whereas KiSS-1R is additionally expressed on the invading extravillous trophoblasts indicating a paracrine regulation of extravillous trophoblast invasion by the syncytiotrophoblast. In the structurally different rat placenta both KiSS-1 and its receptor are predominantly expressed by the invasive trophoblast giant cells, thus establishing an autocrine system in the invasion regulation of this trophoblast subpopulation. Amongst all kisspeptins the highly conserved kisspeptin Kp-10 has strongest invasion inhibiting effects suggesting its major role in regulation of trophoblast invasion.

  3. Downregulation of SPARC Expression Inhibits the Invasion of Human Trophoblast Cells In Vitro

    PubMed Central

    Jiang, Yahong; Zhu, Yan; Shi, Yan; He, Yaping; Kuang, Zhichao; Sun, Zhaogui; Wang, Jian

    2013-01-01

    Successful pregnancy depends on the precise regulation of extravilloustrophoblast (EVT) invasion into the uterine decidua. SPARC (secreted protein acidic and rich in cysteine) is a matricellular glycoprotein that plays critical roles in the pathologies associated with obesity and diabetes, as well as tumorigenesis. The objective of this study was to investigate the role of SPARC in the process of trophoblast invasion which shares many similarities with tumor cell invasion. By Western blot, higher expression of SPARC was observed in mouse brain, ovary and uterus compared to other mouse tissues. Immunohistochemistry analysis revealed a spatio-temporal expression of SPARC in mouse uterus in the periimplantation period. At the implantation site of d8 pregnancy, SPARC mainly accumulated in the secondary decidua zone (SDZ), trophoblast cells and blastocyst. The expression of SPARC was also detected in human placental villi and trophoblast cell lines. In a Matrigel invasion assay, we found SPARC-specific RNA interference significantly reduced the invasion of human extravilloustrophoblast HTR8/SVneo cells. Microarray analysis revealed that SPARC depletion upregulated the expression of interleukin 11 (IL11), KISS1, insulin-like growth factor binding protein 4 (IGFBP4), collagen type I alpha 1 (COLIA1), matrix metallopeptidase 9 (MMP9), and downregulated the expression of the alpha polypeptide of chorionic gonadotropin (CGA), MMP1, gap junction protein alpha 1 (GJA1), et al. The gene array result was further validated by qRT-PCR and Western blot. The present data indicate that SPARC may play an important role in the regulation of normal placentation by promoting the invasion of trophoblast cells into the uterine decidua. PMID:23935929

  4. Proinflammatory Response of Human Trophoblastic Cells to Brucella abortus Infection and upon Interactions with Infected Phagocytes.

    PubMed

    Fernández, Andrea G; Ferrero, Mariana C; Hielpos, M Soledad; Fossati, Carlos A; Baldi, Pablo C

    2016-02-01

    Trophoblasts are targets of infection by Brucella spp. but their role in the pathophysiology of pregnancy complications of brucellosis is unknown. Here we show that Brucella abortus invades and replicates in the human trophoblastic cell line Swan-71 and that the intracellular survival of the bacterium depends on a functional virB operon. The infection elicited significant increments of interleukin 8 (IL8), monocyte chemotactic protein 1 (MCP-1), and IL6 secretion, but levels of IL1beta and tumor necrosis factor-alpha (TNF-alpha) did not vary significantly. Such proinflammatory response was not modified by the absence of the Brucella TIR domain-containing proteins BtpA and BtpB. The stimulation of Swan-71 cells with conditioned medium (CM) from B. abortus-infected human monocytes (THP-1 cells) or macrophages induced a significant increase of IL8, MCP-1 and IL6 as compared to stimulation with CM from non-infected cells. Similar results were obtained when stimulation was performed with CM from infected neutrophils. Neutralization studies showed that IL1beta and/or TNF-alpha mediated the stimulating effects of CM from infected phagocytes. Reciprocally, stimulation of monocytes and neutrophils with CM from Brucella-infected trophoblasts increased IL8 and/or IL6 secretion. These results suggest that human trophoblasts may provide a local inflammatory environment during B. abortus infections either through a direct response to the pathogen or through interactions with monocytes/macrophages or neutrophils, potentially contributing to the pregnancy complications of brucellosis.

  5. Heat-killed Lactobacillus rhamnosus GG modulates urocortin and cytokine release in primary trophoblast cells.

    PubMed

    Bloise, E; Torricelli, M; Novembri, R; Borges, L E; Carrarelli, P; Reis, F M; Petraglia, F

    2010-10-01

    A number of studies are showing that probiotic treatment induces an anti-inflammatory state. Intrauterine infection can lead to preterm delivery by modulating immune function and efforts to prevent this condition are ongoing nowadays. Lactobacillus rhamnosus GG (LGG) is a probiotic known to ameliorate inflammation by increasing local anti-inflammatory mediators in urinary and gastrointestinal tracts. The present study then analyzed the effect of heat-killed LGG over β-hCG, progesterone, interleukins (IL) 4 and 10, tumor necrosis factor-α (TNF-α), corticotropin releasing hormone (CRH) and urocortin (Ucn) release by primary trophoblast cells. Normal human term placentas (n = 6) were collected and purified trophoblast cells were incubated in the presence of LGG, lipopolysaccharide (LPS) or either LGG + LPS during 3 h, after which the target substances were quantified by ELISA and real-time PCR. LGG did not affect β-hCG, progesterone, or CRH secretion. Conversely, LGG increased IL-4 protein and mRNA expression (P < 0.05) while IL-10 and Ucn secretion were increased in a dose dependent manner and the highest dose of LGG increased significantly IL-10 mRNA (P < 0.05). LGG did not alter TNF-α, while LPS exposure increased TNF-α protein (P < 0.001) and mRNA expression (P < 0.01). Conversely, LGG treatment reversed LPS-induced TNF-α release at both protein (P < 0.01) and mRNA levels (P < 0.05) in a dose dependent fashion. In conclusion, LGG stimulates IL-4, IL-10 and Ucn expression and reverses LPS-induced TNF-α release from trophoblast cells, with no change in β-hCG or progesterone release, suggesting that this probiotic may play a role as an immunomodulatory agent in human placenta without altering basic trophoblast functions. Copyright © 2010. Published by Elsevier Ltd.

  6. Nuclear localisation of the endocannabinoid metabolizing enzyme fatty acid amide hydrolase (FAAH) in invasive trophoblasts and an association with recurrent miscarriage.

    PubMed

    Chamley, L W; Bhalla, A; Stone, P R; Liddell, H; O'Carroll, S; Kearn, C; Glass, M

    2008-11-01

    Endocannabinoids are lipid signalling molecules that are related to the major psychoactive component in marijuana, delta-9-tetrahydrocannabinol and are increasingly recognized as being important in implantation and development of early embryos. The endocannabinoid anandamide, is metabolized by the enzyme fatty acid amide hydrolase (FAAH), and insufficient levels of this enzyme have been implicated in spontaneous miscarriage in women and implantation failure in mice. We screened placental bed biopsies and placental tissue from 45 women with recurrent miscarriage and 17 gestation-matched women with normal pregnancies for the expression of FAAH by immunohistochemistry. Unexpectedly, the enzyme appeared to be localised to the nucleus of trophoblasts and this was confirmed by western blotting of sub-cellular fractions and confocal microscopy. FAAH was expressed in the cytoplasm of large decidual stromal cells and significantly more women with recurrent miscarriage (73%) expressed FAAH in these cells than women with normal pregnancy (31%). FAAH was also expressed in the nucleus of extravillous trophoblasts that had invaded the decidua from 67% of women with recurrent miscarriage but was not expressed by these cells in any women with normal pregnancies. In contrast, FAAH was expressed in extravillous trophoblasts that had migrated out of the villi but that had not yet invaded the decidua in both normal pregnancies and in cases of recurrent miscarriage. FAAH was also present in the nucleus of a small number of villous trophoblasts in some specimens. FAAH appears to be over expressed in trophoblasts that have invaded the decidua, as well as in large decidual stromal cells in many cases of recurrent miscarriage. This may reflect inadequate control of the cannabinoid system in the uterus of women who experience recurrent miscarriages. The functional significance of the unexpected nuclear localisation of FAAH in trophoblasts is not yet clear.

  7. EPHB4 Regulates Human Trophoblast Cell Line HTR-8/SVneo Function: Implications for the Role of EPHB4 in Preeclampsia.

    PubMed

    Liu, Xiaoping; Hu, Ying; Zheng, Yanfang; Liu, Xiaoxia; Luo, Minglian; Liu, Weifang; Zhao, Yin; Zou, Li

    2016-09-01

    Successful pregnancy depends on well-regulated extravillous trophoblast (EVT) invasion into the uterine decidua and moderate uterine spiral artery remodeling. Ephrin receptor B4 (EPHB4) is a membrane-anchored receptor tyrosine kinase that plays an important role in various cellular functions in human normal tissue and tumors. Reportedly, EPHB4 plays important roles during placentation. Still, there is no investigation of EPHB4 modulating trophoblast function. In our study, term placentas of preeclamptic pregnancies showed a significantly increased EPHB4 expression compared to those of uncomplicated pregnancies (n = 15). Exogenous up-regulation of EPHB4 in HTR-8/SVneo cells was performed to investigate the effects of EPHB4 on cell biological behavior. The results showed that EPHB4 enhancement reduced cell proliferation and promoted trophoblast apoptosis; and inhibited cell migration, invasion, and endothelial replacement. Associated factors, such as matrix metalloproteinases, vascular endothelial growth factor, placental growth factor, and soluble Fms-like tyrosine kinase 1 were examined at transcriptional level. Furthermore, cell functional results were confirmed in a placenta-decidua coculture system, showing poor vascular remodeling. Additionally, we detected possible down-stream PI3K-Akt signal pathway involved in EPHB4-mediated function of HTR-8/SVneo cells. Our study demonstrates that EPHB4 overexpression may contribute to trophoblasts dysfunction and impair maternal artery remodeling, as is associated with the pathogenesis of preeclampsia.

  8. Preimplantation factor is an anti-apoptotic effector in human trophoblasts involving p53 signaling pathway

    PubMed Central

    Moindjie, Hadia; Santos, Esther Dos; Gouesse, Rita-Josiane; Swierkowski-Blanchard, Nelly; Serazin, Valérie; Barnea, Eytan R; Vialard, François; Dieudonné, Marie-Noëlle

    2016-01-01

    From the earliest stages of gestation, embryonic–maternal interaction has a key role in a successful pregnancy. Various factors present during gestation may significantly influence this type of juxta/paracrine interaction. PreImplantation Factor (PIF) is a recently identified factor with activity at the fetomaternal interface. PIF is secreted by viable embryos and directly controls placental development by increasing the invasive capacity of human extravillous trophoblasts (EVTs). To further specify PIF's role in the human placenta, we analyzed the genome-wide expression profile of the EVT in the presence of a synthetic PIF analog (sPIF). We found that sPIF exposure altered several pathways related to p53 signaling, survival and the immune response. Functional assays revealed that sPIF acts through the p53 pathway to reduce both early and late trophoblast apoptosis. More precisely, sPIF (i) decreases the phosphorylation of p53 at Ser-15, (ii) enhances the B-cell lymphoma-2 (BCL2) expression and (iii) reduces the BCL2-associated X protein (BAX) and BCL2 homologous antagonist killer (BAK) mRNA expression levels. Furthermore, invalidation experiments of TP53 allowed us to demonstrate that PIF's effects on placental apoptosis seemed to be essentially mediated by this gene. We have clearly shown that p53 and sPIF pathways could interact in human trophoblast and thus promotes cell survival. Furthermore, sPIF was found to regulate a gene network related to immune tolerance in the EVT, which emphasizes the beneficial effect of this peptide on the human placenta. Finally, the PIF protein levels in placentas from pregnancies affected by preeclampsia or intra-uterine growth restriction were significantly lower than in gestational age-matched control placentas. Taken as a whole, our results suggest that sPIF protects the EVT's functional status through a variety of mechanisms. Clinical application of sPIF in the treatment of disorders of early pregnancy can be envisioned

  9. Promoter Methylation Pattern Controls Corticotropin Releasing Hormone Gene Activity in Human Trophoblasts

    PubMed Central

    Pan, Xin; Bowman, Maria; Scott, Rodney J.; Fitter, John; Smith, Roger

    2017-01-01

    Placental CRH production increases with advancing pregnancy in women and its course predicts gestational length. We hypothesized that CRH gene expression in the placenta is epigenetically controlled setting gestational trajectories characteristic of normal and pathological pregnancies. Here we determined histone modification and DNA methylation levels and DNA methylation patterns at the CRH promoter in primary trophoblast cultures by chromatin immunoprecipitation combined with clonal bisulfite sequencing and identified the transcriptionally active epialleles that associate with particular histone modifications and transcription factors during syncytialisation and cAMP-stimulation. CRH gene expression increased during syncytial differentiation and cAMP stimulation, which was associated with increased activating and decreased repressive histone modification levels at the promoter. DNA methylation levels remained unchanged. The nine CpGs of the CRH proximal promoter were partially and allele-independently methylated displaying many (>100) epialleles. RNA-polymerase-II (Pol-II) bound only to three particular epialleles in cAMP-stimulated cells, while phospho-cAMP response element-binding protein (pCREB) bound to only one epiallele, which was different from those selected by Pol-II. Binding of TATA-binding protein increased during syncytial differentiation preferentially at epialleles compatible with Pol-II and pCREB binding. Histone-3 acetylation was detected only at epialleles targeted by Pol-II and pCREB, while gene activating histone-4 acetylation and histone-3-lysine-4 trimethylation occurred at CRH epialleles not associated with Pol-II or pCREB. The suppressive histone-3-lysine-27 trimethyl and–lysine-9 trimethyl modifications showed little or no epiallele preference. The epiallele selectivity of activating histone modifications and transcription factor binding demonstrates the epigenetic and functional diversity of the CRH gene in trophoblasts, which is

  10. Treatment of persistent trophoblastic disease later than 6 months after diagnosis of molar pregnancy

    PubMed Central

    Gillespie, A M; Kumar, S; Hancock, B W

    2000-01-01

    Of 4257 patients with gestational trophoblastic disease (GTD) registered between 1986 and 1996 with the Trophoblastic Screening and Treatment Centre, Sheffield, 231 women required chemotherapy; 28 were treated 24 weeks or more after the initial evacuation of products of conception. In 18 patients late treatment was a result of a predetermined watch and wait policy on the part of the Centre; these patients formed the study group. Patients were identified from the Centre's computer database. The time interval from first evacuation (diagnosis) to start of chemotherapy was calculated for each patient. Hospital records were reviewed when the interval of observation was 24 weeks or greater to determine patient characteristics, treatment and outcome. Eighteen women were treated ‘late’ (according to Centre policy), with a median age of 30 years (range 21–57 years). The interval from diagnosis to treatment ranged from 24 to, in one case, 56 weeks (median 33 weeks). Fourteen of 18 women had complete moles, 3/18 had partial moles and one had unclassified disease. All women had low-risk disease and were treated with single-agent methotrexate; 17 were cured with this regimen, one also required salvage chemotherapy. In conclusion, where a successful surveillance programme is in operation for GTD, a wait and watch policy can be adopted without compromising patients whose definitive treatment is commenced more than 6 months after the initial diagnosis. © 2000 Cancer Research Campaign PMID:10780516

  11. Trophoblasts are the preferential target for human papilloma virus infection in spontaneously aborted products of conception.

    PubMed

    Hermonat, P L; Kechelava, S; Lowery, C L; Korourian, S

    1998-02-01

    In a recent study it has been shown that human papillomavirus (HPV) infection was threefold more prevalent in spontaneous abortion specimens compared with elective specimens (60% [15 of 25] v 20% [3 of 15], respectively) as analyzed by broad-spectrum HPV polymerase chain reaction (PCR) amplification and dot-blot hybridization with an HPV-16 probe. In this study, archival paraffin-embedded tissue from a subset of previously analyzed spontaneous abortion cases were reanalyzed by in situ PCR amplification so that the specific cells infected by HPV could be identified. In the current study, using a new PCR primer set for HPV-16 E6, the status of six previously analyzed cases were verified (five HPV-positive and one negative). Furthermore, syncytiotrophoblasts were identified as the predominant cellular target of HPV (HPV-16 or a related type). Finally, four of four third-trimester placentas similarly analyzed gave no HPV-positive signal. Trophoblasts are the cell type that maintains placental contact with maternal tissue and through which nutrient exchange occurs. This knowledge prompts the hypothesis that HPV-infected trophoblasts may have altered characteristics, which may lead to a compromised gestation.

  12. Altered Biomarkers in Trophoblast Cells Obtained Noninvasively Prior to Clinical Manifestation of Perinatal Disease

    PubMed Central

    Bolnick, Jay M.; Kohan-Ghadr, Hamid-Reza; Fritz, Rani; Bolnick, Alan D.; Kilburn, Brian A.; Diamond, Michael P.; Armant, D. Randall; Drewlo, Sascha

    2016-01-01

    A contributing factor to poor placental perfusion, leading to intrauterine growth restriction and preeclampsia, is the failure of invading extravillous trophoblast (EVT) cells to remodel the maternal uterine arteries during the first and second trimesters of pregnancy. Noninvasive assessment of EVT cells in ongoing pregnancies is possible beginning three weeks after conception, using trophoblast retrieval and isolation from the cervix (TRIC). Seven proteins were semi-quantified by immunofluorescence microscopy in EVT cells obtained between gestational weeks 6 and 20 from pregnancies with normal outcomes (N = 29) and those with intrauterine growth restriction or preeclampsia (N = 12). Significant differences were measured in expression of PAPPA, FLT1, ENG, AFP, PGF, and LGALS14, but not LGALS13 or the lineage marker KRT7. These findings provide for the first time direct evidence of pathology-associated protein dysregulation in EVT cells during early placentation. The TRIC platform provides a novel approach to acquire molecular signatures of EVT cells that can be correlated with pregnancy outcome. PMID:27660926

  13. Scripted Sexual Health Informational Intervention in Improving Sexual Function in Patients With Gynecologic Cancer

    ClinicalTrials.gov

    2016-11-02

    Anxiety Disorder; Cervical Cancer; Endometrial Cancer; Female Reproductive Cancer; Gestational Trophoblastic Tumor; Ovarian Epithelial Cancer; Ovarian Germ Cell Tumor; Sexual Dysfunction; Uterine Sarcoma; Vaginal Cancer; Vulvar Cancer

  14. Biological Therapy Following Chemotherapy and Peripheral Stem Cell Transplantation in Treating Patients With Cancer

    ClinicalTrials.gov

    2013-03-25

    Breast Cancer; Chronic Myeloproliferative Disorders; Gestational Trophoblastic Tumor; Kidney Cancer; Leukemia; Lymphoma; Multiple Myeloma and Plasma Cell Neoplasm; Myelodysplastic Syndromes; Neuroblastoma; Ovarian Cancer; Sarcoma; Testicular Germ Cell Tumor

  15. Lymphocyte Infusion in Treating Patients With Relapsed Cancer After Bone Marrow or Peripheral Stem Cell Transplantation

    ClinicalTrials.gov

    2011-11-28

    Breast Cancer; Chronic Myeloproliferative Disorders; Gestational Trophoblastic Tumor; Kidney Cancer; Leukemia; Lymphoma; Multiple Myeloma and Plasma Cell Neoplasm; Myelodysplastic Syndromes; Neuroblastoma; Ovarian Cancer; Sarcoma; Testicular Germ Cell Tumor

  16. Ethanol cytotoxic effect on trophoblast cells.

    PubMed

    Clave, S; Joya, X; Salat-Batlle, J; Garcia-Algar, O; Vall, O

    2014-03-03

    Prenatal ethanol exposure may cause both, altered fetal neurodevelopment and impaired placental function. These disturbances can lead to growth retardation, which is one of the most prevalent features in Fetal Alcohol Syndrome (FAS). It is not known whether there is a specific pattern of cytotoxicity caused by ethanol that can be extrapolated to other cell types. The aim of this study was to determine the cytotoxic effects caused by sustained exposure of trophoblast cells to ethanol. The cytotoxic effect of sustained exposure to standard doses of ethanol on an in vitro human trophoblast cell line, JEG3, was examined. Viable cell count by exclusion method, total protein concentration, lactate dehydrogenase (LDH) activity and activation of apoptotic markers (P-H2AX, caspase-3 and PARP-1) were determined. Sustained exposure to ethanol decreased viable cell count and total protein concentration. LDH activity did not increased in exposed cells but apoptotic markers were detected. In addition, there was a dose-dependent relationship between ethanol concentration and apoptotic pathways activation. Sustained ethanol exposure causes cellular cytotoxicity by apoptotic pathways induction as a result of DNA damage. This apoptotic induction may partially explain the altered function of placental cells and the damage previously detected in other tissues.

  17. Isolation and manipulation of mouse trophoblast stem cells.

    PubMed

    Hayakawa, Koji; Himeno, Emi; Tanaka, Satoshi; Kunath, Tilo

    2015-02-02

    The isolation of stable trophoblast stem (TS) cell lines from early mouse embryos has provided a useful cell culture model to study trophoblast development. TS cells are derived from pre-implantation blastocysts or from the extraembryonic ectoderm of early post-implantation embryos. The derivation and maintenance of mouse TS cells is dependent upon continuous fibroblast growth factor (FGF) signaling. Gene expression analysis, differentiation in culture, and chimera formation show that TS cells accurately model the mouse trophoblast lineage. This unit describes how to derive, maintain, and manipulate TS cells, including DNA transfection and chimera formation.

  18. [Gestational disorders].

    PubMed

    Ortigosa Corona, E; Carrasco Resendiz, I; González Flores, A; Dámaso Ortiz, M

    1993-09-01

    We present the results of an interview of 375 pregnant women which explores their gestational risk diagnoses, the types and frequencies of complaints. Five groups of 75 patients each were formed from this random sample corresponding to 30, 32, 34, 36 and 38 weeks of pregnancy respectively. We too analyze the patients' opinions about their own morbidity, the repercussion on activities of daily life and self-medication. The interview included the actions taken on their own account to deal with complaints during pregnancy, as well as to establish the relationships between these actions and medical attention they received. A total of 1534 complaints were recorded from the entire group, the mean per patient were four with a range from one to six. The reported from the entire group, the mean per patient were four with a range from one to six. The reported complaints did not caused medical consultation and were totally different with the respective risk diagnoses. Our results show that patients almost always accept their symptoms as a normal part of pregnancy, even when arise from pathology. Almost 70% of the patients view their symptoms as normal despite the fact that they produce difficulties of daily life in 41%, and that they temporarily block these activities in 19%. Around 10% of the patients admit self-medication. Over 50 types of actions were self-initiated, 1371 for the entire group as a whole. Around 95% of the complaints considered abnormal received no medical attention. We presented a series of thoughts on the effectiveness of popular practices and the possibility of integrating some of them into medical practice.(ABSTRACT TRUNCATED AT 250 WORDS)

  19. Increased lectin binding capacity of trophoblastic cells of late day 5 rat blastocysts.

    PubMed Central

    Stein, B A; Shaw, T J; Turner, V F; Murphy, C R

    1994-01-01

    The binding of lectins to the trophoblast of rat blastocysts has been studied using quantitative ultrastructural cytochemistry. Rat blastocysts from early, mid and late d 5 of gestation were stained using biotinylated lectins (Phytolacca americana [Phy am], fucose binding protein [FBP] and soybean agglutinin [SBA]) and a sensitive avidin-ferritin cytochemical method. Electron micrographs of ferritin particles along the membrane were processed to produce images for which grey scale levels could be established and the ferritin particles automatically counted. The ferritin:membrane ratio was then calculated. Increased binding with Phy am (which detects short chain oligosaccharides) was found after midday of d 5, i.e. after hatching. Binding of FBP and SBA did not alter during the period studied. The increased concentration of oligosaccharides on the blastocyst surface membrane after hatching may have important implications for blastocyst attachment to the endometrium. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 PMID:7649802

  20. Human Extravillous Trophoblasts Penetrate Decidual Veins and Lymphatics before Remodeling Spiral Arteries during Early Pregnancy

    PubMed Central

    He, Nannan; van Iperen, Liesbeth; de Jong, Danielle; Szuhai, Karoly; Helmerhorst, Frans M.; van der Westerlaken, Lucette A. J.; Chuva de Sousa Lopes, Susana M.

    2017-01-01

    In humans, the defective invasion of the maternal endometrium by fetal extravillous trophoblasts (EVTs) can lead to insufficient perfusion of the placenta, resulting in pregnancy complications that can put both mother and baby at risk. To study the invasion of maternal endometrium between (W)5.5–12 weeks of gestation by EVTs, we combined fluorescence in situ hybridization, immunofluorescence and immunohistochemistry to determine the presence of (male) EVTs in the vasculature of the maternal decidua. We observed that interstitial mononuclear EVTs directly entered decidual veins and lymphatics from W5.5. This invasion of decidual veins and lymphatics occurred long before endovascular EVTs remodelled decidual spiral arteries. This unexpected early entrance of interstitial mononuclear EVTs in the maternal circulation does not seem to contribute to the materno-placental vascular connection directly, but rather to establish (and expand) the materno-fetal interface through an alternative vascular route. PMID:28081266

  1. Transcriptional Regulators of the Trophoblast Lineage in Mammals with Hemochorial Placentation

    PubMed Central

    Knott, Jason G.; Paul, Soumen

    2014-01-01

    Mammalian reproduction is critically dependent on the trophoblast cell lineage, which assures proper establishment of maternal-fetal interactions during pregnancy. Specification of trophoblast cell lineage begins with the development of the trophectoderm (TE) in preimplantation embryos. Subsequently, other trophoblast cell types arise with progression of pregnancy. Studies with transgenic animal models as well as trophoblast stem/progenitor cells have implicated distinct transcriptional and epigenetic regulators in trophoblast lineage development. This review focuses on our current understanding of transcriptional and epigenetic mechanisms regulating specification, determination, maintenance and differentiation of trophoblast cells. PMID:25190503

  2. Nivolumab and Ipilimumab in Treating Patients With Rare Tumors

    ClinicalTrials.gov

    2017-10-12

    Acinar Cell Carcinoma; Adrenal Cortex Carcinoma; Adrenal Gland Pheochromocytoma; Anal Canal Neuroendocrine Carcinoma; Anal Canal Undifferentiated Carcinoma; Appendix Mucinous Adenocarcinoma; Bartholin Gland Transitional Cell Carcinoma; Bladder Adenocarcinoma; Cervical Adenocarcinoma; Cholangiocarcinoma; Chordoma; Colorectal Squamous Cell Carcinoma; Dermoid Cyst; Endometrial Transitional Cell Carcinoma; Endometrioid Adenocarcinoma; Esophageal Neuroendocrine Carcinoma; Esophageal Undifferentiated Carcinoma; Extrahepatic Bile Duct Carcinoma; Fallopian Tube Adenocarcinoma; Fallopian Tube Transitional Cell Carcinoma; Fibromyxoid Tumor; Gastric Neuroendocrine Carcinoma; Gastric Squamous Cell Carcinoma; Giant Cell Carcinoma; Intestinal Neuroendocrine Carcinoma; Intrahepatic Cholangiocarcinoma; Lung Carcinoid Tumor; Lung Sarcomatoid Carcinoma; Major Salivary Gland Carcinoma; Malignant Odontogenic Neoplasm; Malignant Peripheral Nerve Sheath Tumor; Malignant Testicular Sex Cord-Stromal Tumor; Metastatic Malignant Neoplasm of Unknown Primary Origin; Minimally Invasive Lung Adenocarcinoma; Mixed Mesodermal (Mullerian) Tumor; Mucinous Adenocarcinoma; Mucinous Cystadenocarcinoma; Nasal Cavity Adenocarcinoma; Nasal Cavity Carcinoma; Nasopharyngeal Carcinoma; Nasopharyngeal Papillary Adenocarcinoma; Nasopharyngeal Undifferentiated Carcinoma; Oral Cavity Carcinoma; Oropharyngeal Undifferentiated Carcinoma; Ovarian Adenocarcinoma; Ovarian Germ Cell Tumor; Ovarian Mucinous Adenocarcinoma; Ovarian Squamous Cell Carcinoma; Ovarian Transitional Cell Carcinoma; Pancreatic Acinar Cell Carcinoma; Pancreatic Neuroendocrine Carcinoma; Paraganglioma; Paranasal Sinus Adenocarcinoma; Paranasal Sinus Carcinoma; Parathyroid Gland Carcinoma; Pituitary Gland Carcinoma; Placental Choriocarcinoma; Placental-Site Gestational Trophoblastic Tumor; Primary Peritoneal High Grade Serous Adenocarcinoma; Pseudomyxoma Peritonei; Scrotal Squamous Cell Carcinoma; Seminal Vesicle Adenocarcinoma; Seminoma; Serous

  3. BMP4 regulation of human trophoblast development

    PubMed Central

    Li, Yingchun; Parast, Mana M.

    2017-01-01

    Since derivation of human embryonic stem cells, and subsequent generation of induced pluripotent stem cells, there has been much excitement about the ability to model and evaluate human organ development in vitro. The finding that these cells, when treated with BMP4, are able to generate the extraembryonic cell type, trophoblast, which is the predominant functional epithelium in the placenta, has not been widely accepted. This review evaluates this model, providing comparison to early known events during placentation in both human and mouse and addressing specific challenges. Keeping in mind the ultimate goal of understanding human placental development and pregnancy disorders, our aim here is two-fold: 1) to distinguish gaps in knowledge from mis- or over-interpretation of data, and 2) to recognize the limitations of both mouse and human models, but work within those limitations towards the ultimate goal. PMID:25023690

  4. Trophoblast-specific gene manipulation using lentivirus-based vectors.

    PubMed

    Georgiades, Pantelis; Cox, Brian; Gertsenstein, Marina; Chawengsaksophak, Kallayanee; Rossant, Janet

    2007-03-01

    The trophoblast layers of the mammalian placenta carry out many complex functions required to pattern the developing embryo and maintain its growth and survival in the uterine environment. Genetic disruption of many gene pathways can result in embryonic lethality because of placental failure, potentially confusing the interpretation of mouse knockout phenotypes. Development of tools to specifically and efficiently manipulate gene expression in the trophoblast lineage would greatly aid understanding of the relative roles of different genetic pathways in the trophoblast versus embryonic lineages. We show that short-term lentivirus-mediated infection of mouse blastocysts can lead to rapid expression of a green fluorescent protein (GFP) transgene specifically in the outer trophoblast progenitors and their later placental derivatives. Efficient trophoblast-specific gene knockdown can also be produced by lentivirus-mediated pol III-driven short hairpin RNA (shRNA) and efficient trophoblast-specific gene knockout by pol II-driven Cre recombinase lentiviral vectors. This lentivirus lineage-specific infection system thus facilitates both gain and loss of function studies during placental development in the mouse and potentially other mammalian species.

  5. Glucose metabolism in cultured trophoblasts from human placenta

    SciTech Connect

    Moe, A.J.; Farmer, D.R.; Nelson, D.M.; Smith, C.H. )

    1990-02-26

    The development of appropriate placental trophoblast isolation and culture techniques enables the study of pathways of glucose utilization by this important cell layer in vitro. Trophoblasts from normal term placentas were isolated and cultured 24 hours and 72 hours in uncoated polystyrene culture tubes or tubes previously coated with a fibrin matrix. Trophoblasts cultured on fibrin are morphologically distinct from those cultured on plastic or other matrices and generally resemble in vivo syncytium. Cells were incubated up to 3 hours with {sup 14}C-labeled glucose and reactions were stopped by addition of perchloric acid. {sup 14}CO{sub 2} production by trophoblasts increased linearly with time however the largest accumulation of label was in organic acids. Trophoblasts cultured in absence of fibrin utilized more glucose and accumulated more {sup 14}C in metabolic products compared to cells cultured on fibrin. Glucose oxidation to CO{sub 2} by the phosphogluconate (PG) pathway was estimated from specific yields of {sup 14}CO{sub 2} from (1-{sup 14}C)-D-glucose and (6-{sup 14}C)-D-glucose. Approximately 6% of glucose oxidation was by the PG pathway when cells were cultured on fibrin compared to approximately 1% by cells cultured in the absence of fibrin. The presence of a fibrin growth matrix appears to modulate the metabolism of glucose by trophoblast from human placenta in vitro.

  6. Developmental ability of trophoblast stem cells in uniparental mouse embryos.

    PubMed

    Ogawa, H; Shindo, N; Kumagai, T; Usami, Y; Shikanai, M; Jonwn, K; Fukuda, A; Kawahara, M; Sotomaru, Y; Tanaka, S; Arima, T; Kono, T

    2009-05-01

    Neither parthenogenetic (PG) nor androgenetic (AG) mouse embryos survive after day 9.5 of pregnancy, owing to the inadequate growth of extraembryonic tissues, including the placenta. At day 9.5 of pregnancy, the placental structures are poorly developed in PG embryos, while trophoblast giant cells are abundant at the implantation site in AG embryos. These findings suggest that both parental genomes are required for placental development. To gain further insight into the trophoblast lineage in PG and AG embryos, we attempted to derive trophoblast stem (TS)-like cell lines from uniparental embryos. Furthermore, we sought to assess their ability to differentiate into cells of the trophoblast lineage by using gene expression analysis. Three cell lines that expressed marker genes for undifferentiated TS cells (Cdx2 and Errbeta) were derived from AG embryos. Under differentiation conditions, these cells expressed the trophoblast giant cell-specific genes, but did not express the spongiotrophoblast-specific genes. In contrast, none of the four cell lines from PG embryos expressed marker genes for undifferentiated TS cells, but they expressed Oct3/4, a marker gene for embryonic stem cells. Immunohistochemical analysis indicated that PG blastocysts expressed Oct3/4 and Cdx2 specifically in inner cell mass and the trophectoderm respectively. These results suggest that PG embryos do not possess TS cells, because of the lack of the developmental ability of trophoblast cells.

  7. Triazole fungicide tebuconazole disrupts human placental trophoblast cell functions.

    PubMed

    Zhou, Jinghua; Zhang, Jianyun; Li, Feixue; Liu, Jing

    2016-05-05

    Triazole fungicides are one of the top ten classes of current-use pesticides. Although exposure to triazole fungicides is associated with reproductive toxicity in mammals, limited information is available regarding the effects of triazole fungicides on human placental trophoblast function. Tebuconazole (TEB) is a common triazole fungicide that has been extensively used for fungi control. In this work, we showed that TEB could reduce cell viability, disturb normal cell cycle distribution and induce apoptosis of human placental trophoblast cell line HTR-8/SVneo (HTR-8). Bcl-2 protein expression decreased and the level of Bax protein increased after TEB treatment in HTR-8 cells. The results demonstrated that this fungicide induced apoptosis of trophoblast cells via mitochondrial pathway. Importantly, we found that the invasive and migratory capacities of HTR-8 cells decreased significantly after TEB administration. TEB altered the expression of key regulatory genes involved in the modulation of trophoblast functions. Taken together, TEB suppressed human trophoblast invasion and migration through affecting the expression of protease, hormones, angiogenic factors, growth factors and cytokines. As the invasive and migratory abilities of trophoblast are essential for successful placentation and fetus development, our findings suggest a potential risk of triazole fungicides to human pregnancy. Copyright © 2016 Elsevier B.V. All rights reserved.

  8. Genome wide expression profile in human HTR-8/Svneo trophoblastic cells in response to overexpression of placental alkaline phosphatase gene.

    PubMed

    Bellazi, L; Mornet, E; Meurice, G; Pata-Merci, N; De Mazancourt, P; Dieudonné, M-N

    2011-10-01

    During pregnancy, placental growth allows the adaptation of the feto-maternal unit to fetal requirements. Placental alkaline phosphatase (PLAP) is a phosphomonoesterase produced increasingly until term by the placenta and also ectopically in some tumors. To precise the role of this enzyme in the placenta, we analyzed the genome wide expression profile of HTR-8/Svneo trophoblastic cells after overexpression of the alkaline phosphatase gene (ALPP). We showed that ALPP overexpression mainly altered expression of genes implicated in cellular growth and proliferation. These results were confirmed by the study of cellular effects in HTR-8/Svneo cells overexpressing ALPP and in HTR-8/Svneo cells in which ALPP expression was suppressed by siRNA. We showed that PLAP exerts a positive effect on DNA replication and acts as a proliferative factor in trophoblastic cells.

  9. Cellular and molecular oxidative stress-related effects in uterine myometrial and trophoblast-decidual tissues after perigestational alcohol intake up to early mouse organogenesis.

    PubMed

    Coll, Tamara Anahí; Chaufan, Gabriela; Pérez-Tito, Leticia Gabriela; Ventureira, Martín Ricardo; Ríos de Molina, María Del Carmen; Cebral, Elisa

    2017-08-18

    The placenta plays a major role in embryo-fetal defects and intrauterine growth retardation after maternal alcohol consumption. Our aims were to determine the oxidative status and cellular and molecular oxidative stress effects on uterine myometrium and trophoblast-decidual tissue following perigestational alcohol intake at early organogenesis. CF-1 female mice were administered with 10% alcohol in drinking water for 17 days prior to and up to day 10 of gestation. Control females received ethanol-free water. Treated mice had smaller implantation sites compared to controls (p < 0.05), diminished maternal vascular lumen, and irregular/discontinuous endothelium of decidual vessels. The trophoblast giant cell layer was disorganized and presented increased abnormal nuclear frequency. The myometrium of treated females had reduced nitrite content, increased superoxide dismutase activity, and reduced glutathione (GSH) content (p < 0.05). However, the trophoblast-decidual tissue of treated females had increased nitrite content (p < 0.05), increased GSH level (p < 0.001), increased thiobarbituric acid-reactive substance concentration (p < 0.001), higher 3-nitrotyrosine immunoreaction, and increased apoptotic index (p < 0.05) compared to controls. In summary, perigestational alcohol ingestion at organogenesis induced oxidative stress in the myometrium and trophoblast-decidual tissue, mainly affecting cells and macromolecules of trophoblast and decidual tissues around early organogenesis, in CF-1 mouse, and suggests that oxidative-induced abnormal early placental formation probably leads to risk of prematurity and fetal growth impairment at term.

  10. Experimental Neospora caninum infection modifies trophoblast cell populations and plasma pregnancy-associated glycoprotein 1 and 2 dynamics in pregnant dairy heifers.

    PubMed

    Mur-Novales, R; Serrano-Pérez, B; García-Ispierto, I; de Sousa, N M; Beckers, J F; Almería, S; López-Gatius, F

    2016-01-30

    Neospora caninum is an obligate intracellular protozoan that causes abortion in cattle worldwide. Plasma concentrations of pregnancy-associated glycoprotein 1 (PAG-1), produced by binucleate trophoblast cells, are used for pregnancy diagnosis and as a marker of foetal-placental well-being, while PAG-2, produced by both mono- and binucleate trophoblast cells, may serve as an indicator of abortion risk. In prior work, natural N. caninum infection was found to modify plasma PAG-1 and PAG-2 patterns. The present study examines PAG-1 and PAG-2 dynamics and trophoblast cell populations following experimental infection with N. caninum. The study population was comprised of 17 N. caninum seronegative Holstein-Friesian heifers. On day 110 of gestation, 6 heifers were inoculated intravenously with 10(7) taquyzoites of N. canimum. Plasma samples for PAG-1 and PAG-2 determinations were collected on days 0, 7, 14, 21 and 42 post infection. During the study course, pregnancy was normally expressed in all controls while three infected heifers lost their foetuses. All heifers were euthanised on day 42 post infection and placentome samples from the 14 non-aborting heifers were collected to examine trophoblast cell populations. Plasma PAG-1 and PAG-2 concentrations in non-infected heifers increased until the day of euthanasia while non-aborting infected heifers showed a temporary fall in PAG-1 (P<0.004) and PAG-2 (P<0.002) concentrations from 7 to 14 days post infection (dpi). The two dams aborting at 14 and 21 dpi and a third dam with a mummified foetus upon euthanasia showed dramatic PAG-1 and PAG-2 reductions from 14 dpi to undetectable levels upon euthanasia. A stereological study of placentomes revealed significantly higher relative proportions of mono- (P=0.035) and binucleate (P=0.029) trophoblast cells at 42 dpi in non-infected heifers than infected non-aborting heifers. According to our findings, following experimental N. caninum infection on day 110 of gestation, non

  11. Gestational diabetes - self-care

    MedlinePlus

    Pregnancy - gestational diabetes; Prenatal care - gestational diabetes ... Gestational diabetes is high blood sugar (glucose) that happens during pregnancy. There are no symptoms in most cases. But ...

  12. [A case of a nonseminomatous germ cell tumor responding to MEA therapy].

    PubMed

    Nagai, Yasuharu; Minami, Takafumi; Itami, Yoshitaka; Kobayashi, Yasuyuki; Shimizu, Nobutaka; Yamamoto, Yutaka; Hayashi, Taiji; Nozawa, Masahiro; Yoshimura, Kazuhiro; Ishii, Tokumi; Uemura, Hirotugu

    2013-10-01

    We experienced a case of testicular cancer that was successfully treated by salvage chemotherapy comprised of methotrexate, actinomycin D and etoposide (MEA). A 25-year-old man was admitted to our hospital with a diagnosis of stage III B2 (JUA classification) testicular cancer. The patient had multiple lung metastases, and underwent a left orchiectomy. A histopathological examination revealed a choriocarcinoma, embryonal carcinoma, mature teratoma, and a yolk sac tumor. Tumor marker levels were elevated ; human chorionic gonadotropin β was 46 mIU/ml and alpha fetoprotein was 437 ng/ml. Although he was treated post-operatively with two courses of bleomycin, etoposide and cisplatin therapy, four courses of high-dose carboplatin, etoposide and iphosphamide (VIP) therapy, and two courses of CPT-11+ cisplatin therapy, tumor maker levels remained elevated and lung metastases were stable. Accordingly, he received three courses of MEA therapy. MEA therapy is regimen used to treat gestational trophoblastic neoplasia. After MEA therapy, levels of the tumor markers normalized. He then underwent a partial resection of lung and enucleation of lung metastasis by the video assisted thoracoscopic surgery method. Histopathological examination of the lung metastasis revealed only necrotic tissue. Tumor recurrence has not been observed in the 14 months since the MEA therapy.

  13. Tumor

    MedlinePlus

    ... excessively in the body. Normally, the body controls cell growth and division. New cells are created to replace ... room for healthy replacements. If the balance of cell growth and death is disturbed, a tumor may form. ...

  14. Placental steroids in cattle: hormones, placental growth factors or by-products of trophoblast giant cell differentiation?

    PubMed

    Schuler, G; Greven, H; Kowalewski, M P; Döring, B; Ozalp, G R; Hoffmann, B

    2008-07-01

    The bovine placenta produces large amounts of steroids, mainly estrone (E1) and progesterone (P4). Specific features of bovine placental steroidogenesis are 1) the expression of all enzymes needed for the production of estrogens from cholesterol in the trophoblast 2) an only marginal and temporal contribution to peripheral maternal P4 levels restricted to a period between approx. days 150 - 240 of gestation 3) the predominance of sulfoconjugated over free E1 and 4) a complementary setting of steroidogenic enzymes in the two morphologically discriminable trophoblast cell types, the uninucleated trophoblast cells (UTC) and the trophoblast giant cells (TGC). In cattle so far no definite information is available on the specific biological roles of placental estrogens and P4. However, the detection of estrogen receptors and progesterone receptors in the placentomes suggests a role primarily as local regulators of caruncular growth, differentiation and functions. Inconsistent with a function as a caruncular growth factor is the strong evidence that in cattle placental estrogens enter the maternal compartment almost completely as estrone sulfate (E1S), which is not active at classical nuclear receptors. On the other hand, E1S may be converted locally to free active estrogens via the action of steroid sulfatase (StS), which has been detected in specific parts of the bovine caruncular epithelium. Alternatively or in addition, StS expression in the caruncular epithelium may serve the utilization of sulfated neutral steroid precursors (e.g. pregnenolone sulfate or cholesterol sulfate) supplied with maternal blood, thus providing free substrates for further metabolization in the adjacent trophoblast. The down-regulation of P450scc and P450c17 and the up-regulation of 3beta-HSD and aromatase during the differentiation of TGC from UTC in parallel with the up-regulation of ER beta and estrogen sulfotransferase in maturing TGC suggests a function of placental estrogens primarily

  15. Gestational Diabetes and Pregnancy

    MedlinePlus

    ... Arrives Trouble Getting Pregnant Avoiding Pregnancy Articles Gestational Diabetes and Pregnancy Language: English Español (Spanish) Recommend ... diabetes must also take insulin. Problems of Gestational Diabetes in Pregnancy Blood sugar that is not well ...

  16. Iodine Affects Differentiation and Migration Process in Trophoblastic Cells.

    PubMed

    Olivo-Vidal, Zendy Evelyn; Rodríguez, Roció Coutiño; Arroyo-Helguera, Omar

    2016-02-01

    Iodine deficiency is associated with oxidative stress increase and preeclampsia during gestation, suggesting that iodine concentration plays an important role in the normal placenta physiology. The question raised is to analyze the effect of iodine deficiency on oxidative stress, viability, differentiation, and migration process and changes in the expression of differentiation and migration markers. Iodine deprivation was done using potassium perchlorate (KCLO4) to block sodium iodide symporter (NIS) transporter and 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid DIDS to inhibit pendrine (PEN) transport for 3-48 h. Then trophoblast cells were treated with low iodine doses of 5-500 μM and high iodine doses of 100-5000 μM. Oxidative stress, viability, and human chorionic gonadotropin (hGC) were measured by colorimetric methods. Migration throphoblast cells were evaluated by both wound healing and Boyden chamber assays. Changes in mRNA expression were analyzed by real-time RT-PCR. Iodine deprivation induces a significant increase of reactive oxygen species (ROS), viability, and migration process vs control cells. We found a significant overregulation in the mRNA's peroxisome proliferator-activated receptor (PPAR-gamma), Snail, and matrix metalloproteinase-9 (MMP-9) mRNA's in cells deprived of iodine, as well as a down glial cell missing-1 (GCM-1) regulation, hGC, pregnancy-associated plasma protein-A (PAPP-A), and E-cadherin mRNA expression. The expression of hypoxic induction factor alpha (HIFα) mRNA does not change with iodine deprivation. In cells deprived of iodine, supplementing low iodine doses (5-500 μM) does not induce any significant changes in viability. However, ROS and migration process were decreased, although we found an increased human chorionic gonadotropin (hCG) secretion as a differentiation marker. In addition, we found that PPAR-gamma, Snail, and MPP-9 mRNAs expression are downregulated with low iodine doses, in contrast with GCM-1, PAPP

  17. Effect of Immortalization-Upregulated Protein-2 (IMUP-2) on Cell Death of Trophoblast

    PubMed Central

    Jung, Ran; Choi, Jong Ho; Lee, Hyun Jung; Kim, Jin Kyeoung; Kim, Gi Jin

    2013-01-01

    Trophoblasts, in the placenta, play a role for placental development as well as implantation in the early pregnancy. The characteristics and functions of trophoblast are identified by their localization and potency for proliferation, differentiation, and invasion. Thus, inadequate trophoblast cell death induces trophoblast dysfunction resulting in abnormal placental development and several gynecological diseases. Recently, it was reported that increased immortalization-upregulated protein-2 (IMUP-2) by hypoxia influences trophoblast apoptosis. However, IMUP-2 function on autophagy, which is type II programmed cell death remains unclear. In this study, we analyzed IMUP-2 expression in trophoblast cells (HTR8-SVneo) and compared IMUP-2 effects on cell death including apoptosis and autophagy in trophoblast regardless of IMUP-2 expression. Increased IMUP-2 in trophoblast by IMUP-2 gene transfection induces cell death, especially, apoptosis increases more than autophagy (p<0.05). However, the decreased IMUP-2 in trophoblasts after siRNA treatment decreased apoptosis with the decreased activities of caspase 3 and 7. The expressions of LC3 and MDC as an autophagosome makers and phosphorylated mTOR, which is a negative regulator for autophagy, increased. In addition, the S phase of cell cycle increased in trophoblasts when IMUP-2 expression decreased. Taken together, the alteration of IMUP-2 can control the balance between apoptosis and autophagy of trophoblasts resulting in functional involvement in placental development and in gynecological diseases by regulating the function of trophoblasts. PMID:25949126

  18. A comparative study of proliferative activity and tumor stage of pregnancy-associated melanoma (PAM) and non-PAM in gestational age women.

    PubMed

    Merkel, Emily A; Martini, Mary C; Amin, Sapna M; Yélamos, Oriol; Lee, Christina Y; Sholl, Lauren M; Rademaker, Alfred W; Guitart, Joan; Gerami, Pedram

    2016-01-01

    The influence of pregnancy on the development, progression, and prognosis of melanoma is controversial. We sought to compare clinical characteristics, histologic features, and proliferative activity in pregnancy-associated melanoma (PAM) and melanoma in nonpregnant women of reproductive age (non-PAM). In this retrospective cohort study, we reviewed medical records and pathology reports from women given a diagnosis of melanoma between 2006 and 2015. We also examined tumor proliferation rates using mitotic count and 2 immunohistochemical markers of proliferation, phosphohistone H3 and Ki-67. In 50 PAM and 122 non-PAM cases, a diagnosis of melanoma in situ was associated with PAM. Among invasive melanomas, there was no difference in proliferative activity between groups. Pregnancy status was also not associated with age at diagnosis, tumor site, Breslow depth, Clark level, ulceration, or overall stage. This was a retrospective study with a small sample size of mostly patients with early-stage melanoma. In our study of primarily early-stage melanoma, pregnancy did not have a significant impact on tumor proliferation. Particularly for patients given a diagnosis of stage I melanoma who are undergoing close surveillance, a history of PAM should not outweigh traditional factors, such as advanced maternal age, in planning future pregnancies. Copyright © 2015 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.

  19. Recurrence of gestational diabetes.

    PubMed

    Coelingh Bennink, H J

    1977-01-01

    The recurrence rate of gestational diabetes in 58 patients who had had the foregoing pregnancy complicated by diabetes was estimated to be 30% if our former criteria for abnormal glucose tolerance were strictly applied and 25% if our new, more stringent criteria were used. The recurrence rate is not influenced by prophylactic administration of pyridoxine. The perinatal morbidity complicating the 'second' pregnancy of former gestational diabetics was not increased in those patients who were not treated again, as compared with those who were. Recurrent gestational diabetes is associated with a degree of overdiagnosis in an attempt to detect all gestational diabetics. It is suggested that recurrent gestational diabetes occurs mainly in prediabetic patients.

  20. Mechanisms of trophoblast migration, endometrial angiogenesis in preeclampsia: The role of decorin

    PubMed Central

    Lala, Peeyush K.; Nandi, Pinki

    2016-01-01

    abstract The objective of the present review is to synthesize the information on the cellular and molecular players responsible for maintaining a homeostatic balance between a naturally invasive human placenta and the maternal uterus in pregnancy; to review the roles of decorin (DCN) as a molecular player in this homeostasis; to list the common maladies associated with a break-down in this homeostasis, resulting from a hypo-invasive or hyper-invasive placenta, and their underlying mechanisms. We show that both the fetal components of the placenta, represented primarily by the extravillous trophoblast, and the maternal component represented primarily by the decidual tissue and the endometrial arterioles, participate actively in this balance. We discuss the process of uterine angiogenesis in the context of uterine arterial changes during normal pregnancy and preeclampsia. We compare and contrast trophoblast growth and invasion with the processes involved in tumorigenesis with special emphasis on the roles of DCN and raise important questions that remain to be addressed. Decorin (DCN) is a small leucine-rich proteoglycan produced by stromal cells, including dermal fibroblasts, chondrocytes, chorionic villus mesenchymal cells and decidual cells of the pregnant endometrium. It contains a 40 kDa protein core having 10 leucine-rich repeats covalently linked with a glycosaminoglycan chain. Biological functions of DCN include: collagen assembly, myogenesis, tissue repair and regulation of cell adhesion and migration by binding to ECM molecules or antagonising multiple tyrosine kinase receptors (TKR) including EGFR, IGF-IR, HGFR and VEGFR-2. DCN restrains angiogenesis by binding to thrombospondin-1, TGFβ, VEGFR-2 and possibly IGF-IR. DCN can halt tumor growth by antagonising oncogenic TKRs and restraining angiogenesis. DCN actions at the fetal-maternal interface include restraint of trophoblast migration, invasion and uterine angiogenesis. We demonstrate that DCN

  1. Mechanisms of trophoblast migration, endometrial angiogenesis in preeclampsia: The role of decorin.

    PubMed

    Lala, Peeyush K; Nandi, Pinki

    2016-03-03

    The objective of the present review is to synthesize the information on the cellular and molecular players responsible for maintaining a homeostatic balance between a naturally invasive human placenta and the maternal uterus in pregnancy; to review the roles of decorin (DCN) as a molecular player in this homeostasis; to list the common maladies associated with a break-down in this homeostasis, resulting from a hypo-invasive or hyper-invasive placenta, and their underlying mechanisms. We show that both the fetal components of the placenta, represented primarily by the extravillous trophoblast, and the maternal component represented primarily by the decidual tissue and the endometrial arterioles, participate actively in this balance. We discuss the process of uterine angiogenesis in the context of uterine arterial changes during normal pregnancy and preeclampsia. We compare and contrast trophoblast growth and invasion with the processes involved in tumorigenesis with special emphasis on the roles of DCN and raise important questions that remain to be addressed. Decorin (DCN) is a small leucine-rich proteoglycan produced by stromal cells, including dermal fibroblasts, chondrocytes, chorionic villus mesenchymal cells and decidual cells of the pregnant endometrium. It contains a 40 kDa protein core having 10 leucine-rich repeats covalently linked with a glycosaminoglycan chain. Biological functions of DCN include: collagen assembly, myogenesis, tissue repair and regulation of cell adhesion and migration by binding to ECM molecules or antagonising multiple tyrosine kinase receptors (TKR) including EGFR, IGF-IR, HGFR and VEGFR-2. DCN restrains angiogenesis by binding to thrombospondin-1, TGFβ, VEGFR-2 and possibly IGF-IR. DCN can halt tumor growth by antagonising oncogenic TKRs and restraining angiogenesis. DCN actions at the fetal-maternal interface include restraint of trophoblast migration, invasion and uterine angiogenesis. We demonstrate that DCN overexpression in

  2. Characterization of Choline Transporters in the Human Placenta over Gestation

    PubMed Central

    Baumgartner, Heidi K.; Trinder, Kinsey M.; Galimanis, Carly E.; Post, Annalisa; Phang, Tzu; Ross, Randal G.; Winn, Virginia D.

    2015-01-01

    INTRODUCTION The developing fetus relies on the maternal blood supply to provide the choline it requires for making membrane lipids, synthesizing acetylcholine, and performing important methylation reactions. It is vital, therefore, that the placenta is efficient at transporting choline from maternal to fetal circulation. Although choline transporters have been found in term placenta samples, little is known about what cell types express specific choline transporters and how expression of the transporters may change over gestation. The objective of this study was to characterize choline transporter expression levels and localization in the human placenta throughout placental development. METHODS We analyzed CTL1 and −2 expression over gestation in human placental biopsies from 6 to 40 weeks gestation (n=6–10 per gestational window) by immunoblot analysis. To determine the cellular expression pattern of the choline transporters throughout gestation, immunofluorescence analysis was then performed. RESULTS Both CTL1 and CTL2 were expressed in the chorionic villi from 6 weeks gestation to term. Labor did not alter expression levels of either transporter. CTL1 localized to the syncytial trophoblasts and the endothelium of the fetal vasculature within the chorionic villous structure. CTL2 localized mainly to the stroma early in gestation and by the second trimester co-localized with CTL1 at the fetal vasculature. DISCUSSION The differential expression pattern of CTL1 and CTL2 suggests that CTL1 is the key transporter involved in choline transport from maternal circulation and both transporters are likely involved in stromal and endothelial cell choline transport. PMID:26601765

  3. Characterization of choline transporters in the human placenta over gestation.

    PubMed

    Baumgartner, Heidi K; Trinder, Kinsey M; Galimanis, Carly E; Post, Annalisa; Phang, Tzu; Ross, Randal G; Winn, Virginia D

    2015-12-01

    The developing fetus relies on the maternal blood supply to provide the choline it requires for making membrane lipids, synthesizing acetylcholine, and performing important methylation reactions. It is vital, therefore, that the placenta is efficient at transporting choline from the maternal to the fetal circulation. Although choline transporters have been found in term placenta samples, little is known about what cell types express specific choline transporters and how expression of the transporters may change over gestation. The objective of this study was to characterize choline transporter expression levels and localization in the human placenta throughout placental development. We analyzed CTL1 and -2 expression over gestation in human placental biopsies from 6 to 40 weeks gestation (n = 6-10 per gestational window) by immunoblot analysis. To determine the cellular expression pattern of the choline transporters throughout gestation, immunofluorescence analysis was then performed. Both CTL1 and CTL2 were expressed in the chorionic villi from 6 weeks gestation to term. Labor did not alter expression levels of either transporter. CTL1 localized to the syncytial trophoblasts and the endothelium of the fetal vasculature within the chorionic villous structure. CTL2 localized mainly to the stroma early in gestation and by the second trimester co-localized with CTL1 at the fetal vasculature. The differential expression pattern of CTL1 and CTL2 suggests that CTL1 is the key transporter involved in choline transport from maternal circulation and both transporters are likely involved in stromal and endothelial cell choline transport. Copyright © 2015 Elsevier Ltd. All rights reserved.

  4. The invasive phenotype of placenta accreta extravillous trophoblasts associates with loss of E-cadherin.

    PubMed

    Duzyj, C M; Buhimschi, I A; Motawea, H; Laky, C A; Cozzini, G; Zhao, G; Funai, E F; Buhimschi, C S

    2015-06-01

    Epithelial-to-mesenchymal transition (EMT) is a process of molecular and phenotypic epithelial cell alteration promoting invasiveness. Loss of E-cadherin (E-CAD), a transmembrane protein involved in cell adhesion, is a marker of EMT. Proteolysis into N- and C-terminus fragments by ADAM10 and presenilin-1 (PSEN-1) generates soluble (sE-CAD) and transcriptionally active forms. We studied the protein expression patterns of E-CAD in the serum and placenta of women with histologically-confirmed over-invasive placentation. The patterns of expression and levels of sE-CAD were analyzed by Western blot, immunoassay, and immunoprecipitation. Tissue immunostaining for E-CAD, cytokeratin-7 (epithelial marker), vimentin (mesenchymal marker), ADAM10, PSEN-1 and β-catenin expression were investigated in parallel. N-terminus cleaved 80 kDa sE-CAD fragments were present in serum of pregnant women with gestational age regulation of the circulatory levels. Women with advanced trophoblast invasion did not display circulatory levels of sE-CAD different from those of women with normal placentation. Histologically, extravillous trophoblasts (EVT) closer to the placental-myometrial interface demonstrated less E-CAD staining than those found deeper in the myometrium. These cells expressed both vimentin and cytokeratin, an additional feature of EMT. EVT of placentas with advanced invasion displayed intracellular E-CAD C-terminus immunoreactivity predominating over that of the extracellular N-terminus, a pattern consistent with preferential PSEN-1 processing. Local processing of E-CAD may be an important molecular mechanism controlling the invasive phenotype of accreta EVT. Copyright © 2015 Elsevier Ltd. All rights reserved.

  5. Extravillous trophoblast invasion of venous as well as lymphatic vessels is altered in idiopathic, recurrent, spontaneous abortions.

    PubMed

    Windsperger, Karin; Dekan, Sabine; Pils, Sophie; Golletz, Carsten; Kunihs, Victoria; Fiala, Christian; Kristiansen, Glen; Knöfler, Martin; Pollheimer, Jürgen

    2017-06-01

    Do extravillous trophoblasts (EVTs) invade non-arterial decidual vessels in healthy and pathological pregnancies? Our results reveal that trophoblast invasion of venous and lymphatic vessels is a frequent event during the first trimester of pregnancy and is compromised in  recurrent spontaneous abortion (RSA). In addition, the present data suggest that EVTs populate regional lymph nodes during pregnancy. Human trophoblasts remodel and invade decidual spiral arteries. In addition, a recent report demonstrates that trophoblasts contact and invade decidual veins. Tissue samples of human first trimester deciduae basalis (n = 54, 6th-13th weeks of gestation) obtained from elective pregnancy terminations were used to study trophoblast invasion into veins and lymphatics, in comparison to arteries. Age-matched cases of idiopathic, recurrent spontaneous abortions tissue samples (n = 23) were assessed for cell numbers of EVTs in these decidual vessels. In addition, lymph nodes of four pregnant women were analysed for the presence of EVTs. Localization, frequency and EVT-mediated targeting and invasion of arterial, venous as well as lymphatic vessels were determined in first trimester decidua basalis tissue sections using immunofluorescence staining with antibodies against CD31, CD34, ephrin B2 (EFNB2), ephrin receptor B4 (EPHB4), HLA-G, podoplanin, prospero-related homeobox 1 (Prox-1), alpha-smooth muscle actin 2 (ATCTA2), von willebrand factor (vWF) and proteoglycan 2 (PRG2). Arterial, venous and lymphatic-associated EVTs were further characterized according to their position in the vascular structure and classified as intramural (im) or intraluminal (il). EVTs, specifically expressing PRG2, target and invade veins and lymphatics in first trimester decidua basalis since HLA-G+ trophoblast were detected in the vascular wall (intramural EVT, imEVTs) and in the lumen of these vessels (intraluminal EVT, ilEVTs). In total, 276 arteries, 793 veins and 113 lymphatics were

  6. The contribution of SNAT1 to system A amino acid transporter activity in human placental trophoblast

    SciTech Connect

    Desforges, M.; Greenwood, S.L.; Glazier, J.D.; Westwood, M.; Sibley, C.P.

    2010-07-16

    Research highlights: {yields} mRNA levels for SNAT1 are higher than other system A subtype mRNAs in primary human cytotrophoblast. {yields} SNAT1 knockdown in cytotrophoblast cells significantly reduces system A activity. {yields} SNAT1 is a key contributor to system A-mediated amino acid transport in human placenta. -- Abstract: System A-mediated amino acid transport across the placenta is important for the supply of neutral amino acids needed for fetal growth. All three system A subtypes (SNAT1, 2, and 4) are expressed in human placental trophoblast suggesting there is an important biological role for each. Placental system A activity increases as pregnancy progresses, coinciding with increased fetal nutrient demands. We have previously shown SNAT4-mediated system A activity is higher in first trimester than at term, suggesting that SNAT1 and/or SNAT2 are responsible for the increased system A activity later in gestation. However, the relative contribution of each subtype to transporter activity in trophoblast at term has yet to be evaluated. The purpose of this study was to identify the predominant subtype of system A in cytotrophoblast cells isolated from term placenta, maintained in culture for 66 h, by: (1) measuring mRNA expression of the three subtypes and determining the Michaelis-Menten constants for uptake of the system A-specific substrate, {sup 14}C-MeAIB, (2) investigating the contribution of SNAT1 to total system A activity using siRNA. Results: mRNA expression was highest for the SNAT1 subtype of system A. Kinetic analysis of {sup 14}C-MeAIB uptake revealed two distinct transport systems; system 1: K{sub m} = 0.38 {+-} 0.12 mM, V{sub max} = 27.8 {+-} 9.0 pmol/mg protein/20 min, which resembles that reported for SNAT1 and SNAT2 in other cell types, and system 2: K{sub m} = 45.4 {+-} 25.0 mM, V{sub max} = 1190 {+-} 291 pmol/mg protein/20 min, which potentially represents SNAT4. Successful knockdown of SNAT1 mRNA using target-specific si

  7. Stem cell insights into human trophoblast lineage differentiation.

    PubMed

    Gamage, Teena Kjb; Chamley, Lawrence W; James, Joanna L

    2016-12-01

    The human placenta is vital for fetal development, yet little is understood about how it forms successfully to ensure a healthy pregnancy or why this process is inadequate in 1 in 10 pregnancies, leading to miscarriage, intrauterine growth restriction or preeclampsia. Trophoblasts are placenta-specific epithelial cells that maximize nutrient exchange. All trophoblast lineages are thought to arise from a population of trophoblast stem cells (TSCs). However, whilst the isolation of murine TSC has led to an explosion in understanding murine placentation, the isolation of an analogous human TSC has proved more difficult. Consequently, alternative methods of studying human trophoblast lineage development have been employed, including human embryonic stem cells (hESCs), induced pluripotent stem cells (iPS) and transformed cell lines; but what do these proxy models tell us about what is happening during early placental development? In this systematic review, we evaluate current approaches to understanding human trophoblast lineage development in order to collate and refine these models and inform future approaches aimed at establishing human TSC lines. To ensure all relevant articles were analysed, an unfiltered search of Pubmed, Embase, Scopus and Web of Science was conducted for 25 key terms on the 13th May 2016. In total, 47 313 articles were retrieved and manually filtered based on non-human, non-English, non-full text, non-original article and off-topic subject matter. This resulted in a total of 71 articles deemed relevant for review in this article. Candidate human TSC populations have been identified in, and isolated from, both the chorionic membrane and villous tissue of the placenta, but further investigation is required to validate these as 'true' human TSCs. Isolating human TSCs from blastocyst trophectoderm has not been successful in humans as it was in mice, although recently the first reported TSC line (USFB6) was isolated from an eight-cell morula. In lieu

  8. Markedly elevated beta-hCG levels in a normal singleton gestation with hyperreactio luteinalis.

    PubMed

    Bidus, Michael A; Ries, Andrea; Magann, Everett F; Martin, James N

    2002-05-01

    Human chorionic gonadotropin (hCG) is produced by the trophoblast early in pregnancy and peaks at a level of approximately 100,000 IU/liter around the ninth week of gestation. Abnormally high levels are usually noted in association with multiple gestation, molar gestation, and specific ovarian or gestational malignancies. A multiparous patient in the second trimester was referred for evaluation after a maternal triple marker screen was incalculable due to a beta-hCG level of 2.1 million IU/L. Targeted sonography revealed bilateral complex adnexal masses with a solid component of the left ovary, a normal fetus, and normal placenta. The patient underwent an exploratory laparotomy at 18 weeks' gestational age. A left oophorectomy was performed. Pathology confirmed hyperreactio luteinalis. The remainder of the pregnancy was remarkable for preterm labor and delivery at 35 weeks' gestational age. At delivery, the hCG level was noted to be 24,210 IU/L, and the fetus and placenta were normal. Markedly elevated hCG levels rarely occur in normal singleton pregnancy and can be associated with hyperreactio luteinalis. When noted, a work-up to evaluate possible malignancy, molar gestation, and multiple gestation should be pursued.

  9. 2005 Trophoblast Research Award Lecture: Defects in the keratin cytoskeleton disrupt normal murine placental development and trophoblast cell function.

    PubMed

    Watson, E D

    2007-04-01

    The keratin cytoskeleton is present in all trophoblast cell subtypes of the mouse and human placenta and is required to maintain the structural integrity of these cells. Recently, various genetic mouse models have shown that a normal keratin network is necessary for placental development. Keratin-deficiency leads to trophoblast giant cell fragility, breaking the barrier between the conceptus and the maternal blood circulation. Alternatively, keratin aggregation prevents chorioallantoic attachment, a key developmental milestone required for the formation of the labyrinth within the mouse placenta. These models give us insight into cytokeratin function in human trophoblast cell subtypes and suggest that defects in the keratin cytoskeleton may result in intrauterine growth restriction or miscarriage.

  10. Accreta complicating complete placenta previa is characterized by reduced systemic levels of vascular endothelial growth factor and by epithelial-to-mesenchymal transition of the invasive trophoblast.

    PubMed

    Wehrum, Mark J; Buhimschi, Irina A; Salafia, Carolyn; Thung, Stephen; Bahtiyar, Mert O; Werner, Erica F; Campbell, Katherine H; Laky, Christine; Sfakianaki, Anna K; Zhao, Guomao; Funai, Edmund F; Buhimschi, Catalin S

    2011-05-01

    We sought to characterize serum angiogenic factor profile of women with complete placenta previa and determine if invasive trophoblast differentiation characteristic of accreta, increta, or percreta shares features of epithelial-to-mesenchymal transition. We analyzed gestational age-matched serum samples from 90 pregnant women with either complete placenta previa (n = 45) or uncomplicated pregnancies (n = 45). Vascular endothelial growth factor (VEGF), placental growth factor, and soluble form of fms-like-tyrosine-kinase-1 were immunoassayed. VEGF and phosphotyrosine immunoreactivity was surveyed in histological specimens relative to expression of vimentin and cytokeratin-7. Women with previa and invasive placentation (accreta, n = 5; increta, n = 6; percreta, n = 2) had lower systemic VEGF (invasive previa: median 0.8 [0.02-3.4] vs control 6.5 [2.7-10.5] pg/mL, P = .02). VEGF and phosphotyrosine immunostaining predominated in the invasive extravillous trophoblasts that coexpressed vimentin and cytokeratin-7, an epithelial-to-mesenchymal transition feature and tumorlike cell phenotype. Lower systemic free VEGF and a switch of the interstitial extravillous trophoblasts to a metastable cell phenotype characterize placenta previa with excessive myometrial invasion. Published by Mosby, Inc.

  11. Gestational Hyperandrogenism in Developmental Programming.

    PubMed

    Hakim, Christopher; Padmanabhan, Vasantha; Vyas, Arpita K

    2017-02-01

    Androgen excess (hyperandrogenism) is a common endocrine disorder affecting women of reproductive age. The potential causes of androgen excess in women include polycystic ovary syndrome, congenital adrenal hyperplasia (CAH), adrenal tumors, and racial disparity among many others. During pregnancy, luteoma, placental aromatase deficiency, and fetal CAH are additional causes of gestational hyperandrogenism. The present report reviews the various phenotypes of hyperandrogenism during pregnancy and its origin, pathophysiology, and the effect of hyperandrogenism on the fetal developmental trajectory and offspring consequences. Copyright © 2017 by the Endocrine Society.

  12. Production of interferons in human placental trophoblast subpopulations and their possible roles in pregnancy.

    PubMed Central

    Aboagye-Mathiesen, G; Tóth, F D; Zdravkovic, M; Ebbesen, P

    1994-01-01

    The human cytotrophoblasts are the first fetal cells to arise during embryogenesis and are the progenitor cells to villous (noninvasive), syncytiotrophoblast (noninvasive), "intermediate" extravillous (invasive), and "anchoring" extravillous (invasive) trophoblast subpopulations. These trophoblast subpopulations were isolated from first- and third-trimester placentae and were stimulated with Sendai virus, granulocyte-macrophage colony-stimulating factors (GM-CSF), and platelet-derived growth factor (PDGF) to produce interferons (IFNs). GM-CSF and PDGF induced very low levels of IFN in first-trimester extravillous and villous trophoblast subpopulations. Highly proliferating and invasive intermediate extravillous trophoblast cultures produced five- to eightfold more IFNs than villous trophoblast cultures and two- to fivefold more IFN than the syncytiotrophoblast cultures when stimulated with Sendai virus. Syncytiotrophoblast cultures produced higher levels of IFNs (up to twofold) than villous trophoblast cultures when stimulated with the same virus. Pretreatment of first-trimester extravillous and villous trophoblast cultures with GM-CSF and PDGF followed by infection with Sendai virus resulted in greater IFN production than when the cultures were stimulated with virus alone. The levels of IFN produced were dependent on the type of trophoblast, the type of inducer, and the stage of differentiation of the trophoblasts. The purified trophoblast IFNs have potent antiviral activities when assayed on human amniotic WISH cells, and they inhibited proliferation of normal trophoblasts and trophoblast-derived malignant cells in vitro without any toxicity. Furthermore, the trophoblast IFNs activated NK cell activity and suppressed mitogen-stimulated lymphocyte proliferation at concentrations of between 10 and 1,000 IU/ml. The possible functions of the trophoblast IFNs during pregnancy are discussed with respect to human placental and fetal protection and development. Images

  13. [Clinic characteristics of patients with trophoblastic gestational disease complicate with hypertension].

    PubMed

    Tovar-Rodríguez, José María; Medel-Lagunes, Irais del Carmen; Acosta-Altamirano, Gustavo; Vargas-Hernández, Víctor Manuel

    2013-10-01

    The molar pregnancy is complicated with hypertension before 20 weeks, divided into complete mole and partial mole, and in diploid and triploid hydatidiform mola depending on the fetal chromosomes. To determine clinical and laboratory characteristics of patients with hydatidiform mole with and without hypertension, and choriocarcinoma, correlate serum chorionic gonadotropin (hCG) and hypertension. We reviewed 55 cases with histopathologically proven mole, separately analyzed clinical, laboratory and hCG. The prevalence of mole with hypertension was 1:7; with the choriocarcinoma is 1:11. The age and sexual initiation of mole with hypertension was higher (p = .004 and .002 respectively), liver transaminase AST (p =. 004) and lactate dehydrogenase are higher in the group with hypertension (p =. 000). Positive correlation was obtained r = .246 p =. 044 statistically significant between mean arterial pressure and hCG. We reviewed 31 cases of 28 national and international articles, in patients with diploid hydatidiform the product is allowed to live normal and high blood pressure is showing mild preeclampsia, while partial moles are triploid, malformed products, incompatible with life and with hypertension severe like severe pre-eclampsia. The molar pregnancy is partially diagnosed with hypertension in our environment, is not properly analyzed and that most of the products of curettage were not performed genetic testing. The hCG probably participate in the hypertensive disorders of pregnancy.

  14. Identification of genes dysregulated by elevation of microRNA-210 levels in human trophoblasts cell line, Swan 71.

    PubMed

    Ahn, Sejin; Jeong, Eunbee; Min, Jae Woong; Kim, Eunhee; Choi, Sun Shim; Kim, Chong Jae; Lee, Deug-Chan

    2017-06-27

    Preeclampsia is a serious pregnancy disorder characterized by gestational hypertension and proteinuria. miR-210 is significantly overexpressed in the placentas of preeclampsia patients. Swan 71 cells, first-trimester human trophoblastic cell line, were transfected with hsa-miR-210-3p oligonucleotides by electroporation. Altered transcriptome was analyzed using microarray technique. Differentially expressed genes (DEGs) were clustered into Gene Ontology annotation biological processes. The extent of physical interaction between miR-210 and IGFBP3 mRNA was assessed via ribonucleoprotein immunoprecipitation. Microarray analysis showed 408 DEGs by elevated levels of miR-210 in Swan 71 cells. These genes were enriched in several biological processes involved in the pathogenesis of preeclampsia. IGFBP3, a gene associated with preeclampsia pathophysiology, was validated as a target gene of miR-210. We have demonstrated that elevated miR-210 levels in human trophoblast alter the expression profile of known preeclampsia-associated genes, and of gene targets involved in various biological processes essential to preeclampsia progression. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  15. Failure of physiologic transformation of spiral arteries, endothelial and trophoblast cell activation, and acute atherosis in the basal plate of the placenta.

    PubMed

    Labarrere, Carlos A; DiCarlo, Hector L; Bammerlin, Elaine; Hardin, James W; Kim, Yeon M; Chaemsaithong, Piya; Haas, David M; Kassab, Ghassan S; Romero, Roberto

    2017-03-01

    Failure of physiologic transformation of spiral arteries has been reported in preeclampsia, fetal growth restriction, fetal death, and spontaneous preterm labor with intact or ruptured membranes. Spiral arteries with failure of physiologic transformation are prone to develop atherosclerotic-like lesions of atherosis. There are striking parallels between preeclampsia and atherosclerotic disease, and between lesions of atherosis and atherosclerosis. Endothelial activation, identified by intercellular adhesion molecule-1 expression, is present in atherosclerotic-like lesions of heart transplantation, and is considered a manifestation of rejection. Similarly, endothelial activation/dysfunction has been implicated in the pathophysiology of atherosclerosis and preeclampsia. Intercellular adhesion molecule-1-overexpressing-activated endothelial cells are more resistant to trophoblast displacement than nonactivated endothelium, and may contribute to shallow spiral artery trophoblastic invasion in obstetrical syndromes having failure of physiologic transformation. We sought to determine whether failure of spiral artery physiologic transformation was associated with activation of interstitial extravillous trophoblasts and/or spiral artery endothelium and presence of acute atherosis in the placental basal plate. A cross-sectional study of 123 placentas (19-42 weeks' gestation) obtained from normal pregnancies (n = 22), preterm prelabor rupture of membranes (n = 26), preterm labor (n = 23), preeclampsia (n = 27), intrauterine fetal death (n = 15), and small for gestational age (n = 10) was performed. Failure of spiral artery physiologic transformation and presence of cell activation was determined using immunohistochemistry of placental basal plates containing a median of 4 (minimum: 1; maximum: 9) vessels per placenta. Endothelial/trophoblast cell activation was defined by the expression of intercellular adhesion molecule-1. Investigators examining microscopic sections

  16. mTOR mediates human trophoblast invasion through regulation of matrix-remodeling enzymes and is associated with serine phosphorylation of STAT3

    SciTech Connect

    Busch, Susann; Renaud, Stephen J.; Schleussner, Ekkehard; Graham, Charles H.; Markert, Udo R.

    2009-06-10

    The intracellular signaling molecule mammalian target of rapamycin (mTOR) is essential for cell growth and proliferation. It is involved in mouse embryogenesis, murine trophoblast outgrowth and linked to tumor cell invasiveness. In order to assess the role of mTOR in human trophoblast invasion we analyzed the in vitro invasiveness of HTR-8/SVneo immortalized first-trimester trophoblast cells in conjunction with enzyme secretion upon mTOR inhibition and knockdown of mTOR protein expression. Additionally, we also tested the capability of mTOR to trigger signal transducer and activator of transcription (STAT)-3 by its phosphorylation status. Rapamycin inhibited mTOR kinase activity as demonstrated with a lower phosphorylation level of the mTOR substrate p70 S6 kinase (S6K). With the use of rapamycin and siRNA-mediated mTOR knockdown we could show that cell proliferation, invasion and secretion of matrix-metalloproteinases (MMP)-2 and -9, urokinase-like plasminogen activator (uPA) and its major physiological uPA inhibitor (PAI)-1 were inhibited. While tyrosine phosphorylation of STAT3 was unaffected by mTOR inhibition and knockdown, serine phosphorylation was diminished. We conclude that mTOR signaling is one major mechanism in a tightly regulated network of intracellular signal pathways including the JAK/STAT system to regulate invasion in human trophoblast cells by secretion of enzymes that remodel the extra-cellular matrix (ECM) such as MMP-2, -9, uPA and PAI-1. Dysregulation of mTOR may contribute to pregnancy-related pathologies caused through impaired trophoblast invasion.

  17. EFFECT OF BROMODICHLOROMETHANE ON HUMAN TROPHOBLAST CHORIONIC GONADOTROPHIN SECRETION

    EPA Science Inventory

    Effect of Bromodichloromethane on Human Trophoblast Chorionic Gonadotrophin Secretion

    Jiangang Chen1, Twanda L. Thirkill1, Peter N. Lohstroh1, Susan R. Bielmeier2, Michael G. Narotsky3, Deborah S. Best3, Randy A. Harrison3, Kala Natarajan1, Rex A. Pegram3, Gordon C. Dougla...

  18. EFFECT OF BROMODICHLOROMETHANE ON HUMAN TROPHOBLAST CHORIONIC GONADOTROPHIN SECRETION

    EPA Science Inventory

    Effect of Bromodichloromethane on Human Trophoblast Chorionic Gonadotrophin Secretion

    Jiangang Chen1, Twanda L. Thirkill1, Peter N. Lohstroh1, Susan R. Bielmeier2, Michael G. Narotsky3, Deborah S. Best3, Randy A. Harrison3, Kala Natarajan1, Rex A. Pegram3, Gordon C. Dougla...

  19. HCV Sensing by Human Trophoblasts Induces Innate Immune Responses and Recruitment of Maternal NK Cells: Potential Implications for Limiting Vertical Transmission

    PubMed Central

    Giugliano, Silvia; Petroff, Margaret G; Warren, Bryce D; Jasti, Susmita; Linscheid, Caitlin; Ward, Ashley; Kramer, Anita; Dobrinskikh, Evgenia; Sheiko, Melissa A; Gale, Michael; Golden-Mason, Lucy; Winn, Virginia D; Rosen, Hugo R

    2015-01-01

    Hepatitis C virus (HCV) is the world’s most common blood-borne viral infection for which there is no vaccine. The rates of vertical transmission range between 3–6% with odds 90% higher in the presence of HIV co-infection. Prevention of vertical transmission is not possible due to lack of an approved therapy for use in pregnancy or an effective vaccine. Recently, HCV has been identified as an independent risk factor for pre-term delivery, perinatal mortality and other complications. In this study, we characterized the immune responses that contribute to the control of viral infection at the maternal-fetal interface (MFI) in the early gestational stages. Here we show that primary human trophoblast cells and an extravillous trophoblast cell line (HTR8), from first and second trimester of pregnancy, express receptors relevant for HCV binding/entry and are permissive for HCV-uptake. We found that HCV-RNA sensing by human trophoblast cells induces robust up-regulation of Type I/III IFNs and secretion of multiple chemokines that elicit recruitment and activation of decidual NK cells. Furthermore, we observed that HCV-RNA transfection induces a pro-apoptotic response within HTR8 that could affect the morphology of the placenta. For the first time, we demonstrate that HCV-RNA sensing by human trophoblast cells elicits a strong antiviral response that alters the recruitment and activation of innate immune cells at the MFI. This work provides a paradigm shift in our understanding of HCV-specific immunity at the MFI, as well as novel insights into mechanisms that limit vertical transmission, but may paradoxically lead to virus-related pregnancy complications. PMID:26342030

  20. Discrepancy in Insulin Regulation between Gestational Diabetes Mellitus (GDM) Platelets and Placenta.

    PubMed

    Li, Yicong; Cooper, Anthonya; Odibo, Imelda N; Ahmed, Asli; Murphy, Pamela; Koonce, Ruston; Dajani, Nafisa K; Lowery, Curtis L; Roberts, Drucilla J; Maroteaux, Luc; Kilic, Fusun

    2016-04-29

    Earlier findings have identified the requirement of insulin signaling on maturation and the translocation of serotonin (5-HT) transporter, SERT to the plasma membrane of the trophoblast in placenta. Because of the defect on insulin receptor (IR) in the trophoblast of the gestational diabetes mellitus (GDM)-associated placenta, SERT is found entrapped in the cytoplasm of the GDM-trophoblast. SERT is encoded by the same gene expressed in trophoblast and platelets. Additionally, alteration in plasma 5-HT levels and the 5-HT uptake rates are associated with the aggregation rates of platelets. Therefore, here, we investigated a novel hypothesis that GDM-associated defects in platelet IR should change their 5-HT uptake rates, and this should be a leading factor for thrombosis in GDM maternal blood. The maternal blood and the placentas were obtained at the time of cesarean section from the GDM and non-diabetic subjects (n = 6 for each group), and the platelets and trophoblasts were isolated to determine the IR activity, surface level of SERT, and their 5-HT uptake rates.Interestingly, no significant differences were evident in IR tyrosine phosphorylation or the downstream elements, AKT and S6K in platelets and their aggregation rates in both groups. Furthermore, insulin stimulation up-regulated 5-HT uptake rates of GDM-platelets as it does in the control group. However, the phosphorylation of IR and the downstream elements were significantly lower in GDM-trophoblast and showed no response to the insulin stimulation while they showed 4-fold increase to insulin stimulation in control group. Similarly, the 5-HT uptake rates of GDM-trophoblast and the SERT expression on their surface were severalfold lower compared with control subjects. IR is expressed in all tissues, but it is not known if diabetes affects IR in all tissues equally. Here, for the first time, our findings with clinical samples show that in GDM-associated defect on IR is tissue type-dependent. While IR is

  1. Polyglucosan Bodies in Placental Extravillious Trophoblast for the Diagnosis of Fatal Perinatal Neuromuscular Type Glycogen Storage Disease Type IV.

    PubMed

    Yu, Weiming; Brundler, Marie-Anne; Wright, James R

    2017-01-01

    The fatal infantile neuromuscular type is the most severe form of glycogen storage disease type IV. We report a case of a 22-day-old female neonate born at 34 weeks gestation with polyhyramnios, fetal hydrops, and severe hypotonia. Placental examination revealed numerous periodic acid schiff (PAS)-positive diastase-resistant polyglucosan bodies in the cytoplasm of extravillous trophoblast predominantly in the placental basal plate. Muscle biopsy and autopsy findings supported a diagnosis of neuromuscular-type glycogen storage disease IV with extensive involvement of skeletal muscle, heart, and liver. The diagnosis was confirmed by molecular genetic testing. We could only find one prior report in the English literature that describes placental pathological changes. Our findings suggest that placental examination can be a useful adjunct for early diagnosis, as placentas are often received for pathological examination shortly after birth and usually before a diagnostic muscle biopsy can be performed. Pathologists need to be aware of characteristic placental features.

  2. Insulin Exhibits an Antiproliferative and Hypertrophic Effect in First Trimester Human Extravillous Trophoblasts.

    PubMed

    Silva, Cláudia; Nunes, Catarina; Correia-Branco, Ana; Araújo, João R; Martel, Fátima

    2017-04-01

    Our aim was to investigate the effect of high levels of glucose, insulin, leptin, and tumor necrosis factor alpha, biomarkers of diabetes in pregnancy, in the process of placentation, using as a cell model a first trimester extravillous human trophoblast cell line (HTR8/SVneo cells). Exposure of HTR8/SVneo cells for 24 hours to either glucose (20 mmol/L) or leptin (25-100 ng/mL) did not cause significant changes in cell proliferation and viability. Tumor necrosis factor alpha (24 hours; 10-100 ng/L) caused a small decrease (10%) in cell proliferation and an increase (9%) in cell viability; however, both effects disappeared when exposure time was increased. Insulin (24 hours; 1-10 nmol/L) caused a concentration- and time-dependent decrease (10%-20%) in cell proliferation; the effect of insulin (10 nmol/L) was more pronounced after a 48 hours exposure (35%). In contrast, exposure to insulin (10 nmol/L; 48 hours) showed no significant effect on cell viability, apoptosis, and migration capacity. Insulin appears to cause hypertrophy of HTR8/SVneo cells as it reduces the cell mitotic index while increasing the culture protein content. The antiproliferative effect of insulin seems to involve activation of mammalian target of rapamycin, phosphoinositide 3-kinase, and p38 mitogen-activated protein kinase. Finally, simvastatin and the polyphenol quercetin potentiated the antiproliferative effect of insulin; on the contrary, the polyphenol resveratrol, the polyunsaturated fatty acids eicosapentaenoic and docosahexaenoic acids, and folic acid were not able to change it. In conclusion, we show that insulin has an antiproliferative and hypertrophic effect on a first trimester extravillous human trophoblast cell line. So insulin might affect the process of placentation.

  3. Suppression of trophoblast uterine spiral artery remodeling by estrogen during baboon pregnancy: impact on uterine and fetal blood flow dynamics

    PubMed Central

    Aberdeen, Graham W.; Bonagura, Thomas W.; Harman, Chris R.; Pepe, Gerald J.

    2012-01-01

    The present study was conducted to determine the impact of suppressing trophoblast remodeling of the uterine spiral arteries by prematurely elevating estrogen levels in the first trimester of baboon pregnancy on uterine and umbilical blood flow dynamics. Uteroplacental blood flow was assessed by Doppler ultrasonography after acute administration of saline (basal state) and serotonin on days 60, 100, and 160 of gestation (term: 184 days) to baboons in which uterine spiral artery remodeling had been suppressed by the administration of estradiol on days 25–59 of gestation. Maternal blood pressure in the basal state was increased (P < 0.01), and uterine artery diastolic notching and the umbilical artery pulsatility index and systolic-to-diastolic ratio, reflecting downstream flow impedance, were increased (P < 0.01) after serotonin administration on day 160, but not earlier, in baboons treated with estradiol in early gestation. These changes in uteroplacental flow dynamics in serotonin-infused, estradiol-treated animals were accompanied by a decrease (P < 0.05) in uterine and umbilical artery volume flow and fetal bradycardia. The results of this study show that suppression of uterine artery remodeling by advancing the rise in estrogen from the second trimester to the first trimester disrupted uteroplacental blood flow dynamics and fetal homeostasis after vasochallenge late in primate pregnancy. PMID:22427518

  4. Trisomy 21- affected placentas highlight prerequisite factors for human trophoblast fusion and differentiation.

    PubMed

    Malassiné, André; Frendo, Jean-Louis; Evain-Brion, Danièle

    2010-01-01

    Trophoblastic cell fusion is one essential step of the human trophoblast differentiation pathway and is a multifactorial and dynamic process finely regulated and still poorly known. Disturbances of syncytiotrophoblast formation are observed in numerous pathological clinical conditions such as preeclampsia, intrauterine growth retardation and trisomy 21. In this review, we summarize current knowledge of the different membrane proteins directly involved in trophoblastic cell fusion, which we identified by using the physiological model of primary culture of villous trophoblastic cells. Connexin 43 and gap junctional intercellular communication point to the role of molecular exchanges through connexin channels preceding membrane fusion. Zona occludens-1, which can interact with connexin 43, is also directly involved in trophoblast fusion. The recently identified fusogenic membrane retroviral envelop glycoproteins syncytin 1 (encoded by the HERV-W gene) and syncytin 2 (encoded by the FRD gene) and their receptors are major factors involved in human placental development . We describe the increasing number of factors promoting or inhibiting trophoblast fusion and differentiation and emphasize the role of human chorionic gonadotropin (hCG) and its receptor. Indeed, in trisomy 21 the dynamic process leading to membrane fusion is impaired due to an abnormal hCG signaling. This abnormal trophoblast fusion and differentiation in trisomy 21-affected placenta is reversible in vitro. Trisomy 21 trophoblastic cell culture may therefore be useful to identify the possible large number of prerequisite factors involved in trophoblast fusion, the limiting step of trophoblast differentiation.

  5. Nanoparticles can cross mouse placenta and induce trophoblast apoptosis.

    PubMed

    Huang, Jian-Pei; Hsieh, Patrick C H; Chen, Chen-Yu; Wang, Tao-Yeuan; Chen, Pei-Chun; Liu, Chang-Ching; Chen, Chen-Chun; Chen, Chie-Pein

    2015-12-01

    The effects of nanoparticles on pregnancy remain unclear. In this study, we investigate whether nanoparticles of a specific size can cross the placenta and affect trophoblast function. Fluorescently labelled carboxylate-modified polystyrene beads with diameters of 20, 40, 100, 200, and 500 nm were chosen as model particles. In vitro, trophoblast cell line (3A-Sub-E) or primary culture of term trophoblasts was used for nanoparticle uptake analysis using flow cytometry, confocal microscopy, BrdU proliferation assay and analysis of cell apoptosis using Western blot. Intravenous injection of nanoparticles into pregnant mice at embryonic day 17 was used to study whether nanoparticles can cross the placenta. The mouse placentas were collected and quantitatively analyzed using high-performance liquid chromatography for nanoparticle uptake. Fluorescent polystyrene particles with diameters of up to 500 nm were taken up by the placenta and were able to cross the placental barrier. The fluorescent polystyrene particles were observed in various organs of fetuses after 4 h of administration to pregnant mice. The nanoparticle uptake by placental tissue was significantly increased in nanoparticles with a diameter of 40 nm. No linear association was evident between nanoparticle size and uptake. Nanoparticles with diameters of 20 nm (200 μg/ml) and 40 nm (500 μg/ml) could induce trophoblast cell apoptosis with increased cleaved caspase 3 and reduced cell proliferation. Our findings suggest that nanoparticles can cross the placenta and be taken up by fetal organs. Certain concentrations of carboxylate-modified polystyrene nanoparticles may be cytotoxic to trophoblasts, which could alter placental function. Copyright © 2015 Elsevier Ltd. All rights reserved.

  6. Minor Histocompatibility Antigens Are Expressed in Syncytiotrophoblast and Trophoblast Debris

    PubMed Central

    Holland, Olivia J.; Linscheid, Caitlin; Hodes, Herbert C.; Nauser, Traci L.; Gilliam, Melissa; Stone, Peter; Chamley, Larry W.; Petroff, Margaret G.

    2012-01-01

    The fetal semi-allograft can induce expansion and tolerance of antigen-specific maternal T and B cells through paternally inherited major histocompatibility complex and minor histocompatibility antigens (mHAgs). The effects of these antigens have important consequences on the maternal immune system both during and long after pregnancy. Herein, we investigate the possibility that the placental syncytiotrophoblast and deported trophoblastic debris serve as sources of fetal mHAgs. We mapped the expression of four mHAgs (human mHAg 1, pumilio domain-containing protein KIAA0020, B-cell lymphoma 2–related protein A1, and ribosomal protein S4, Y linked) in the placenta. Each of these proteins was expressed in several placental cell types, including the syncytiotrophoblast. These antigens and two additional Y chromosome–encoded antigens [DEAD box polypeptide 3, Y linked (DDX3Y), and lysine demethylase5D] were also identified by RT-PCR in the placenta, purified trophoblast cells, and cord blood cells. Finally, we used a proteomic approach to investigate the presence of mHAgs in the syncytiotrophoblast and trophoblast debris shed from first-trimester placenta. By this method, four antigens (DDX3Y; ribosomal protein S4, Y linked; solute carrier 1A5; and signal sequence receptor 1) were found in the syncytiotrophoblast, and one antigen (DDX3Y) was found in shed trophoblast debris. The finding of mHAgs in the placenta and in trophoblast debris provides the first direct evidence that fetal antigens are present in debris shed from the human placenta. The data, thus, suggest a mechanism by which the maternal immune system is exposed to fetal alloantigens, possibly explaining the relationship between parity and graft-versus-host disease. PMID:22079431

  7. Vulnerability of primitive human placental trophoblast to Zika virus

    PubMed Central

    Sheridan, Megan A.; Yunusov, Dinar; Balaraman, Velmurugan; Alexenko, Andrei P.; Yabe, Shinichiro; Verjovski-Almeida, Sergio; Schust, Danny J.; Franz, Alexander W.; Ezashi, Toshihiko; Roberts, R. Michael

    2017-01-01

    Infection of pregnant women by Asian lineage strains of Zika virus (ZIKV) has been linked to brain abnormalities in their infants, yet it is uncertain when during pregnancy the human conceptus is most vulnerable to the virus. We have examined two models to study susceptibility of human placental trophoblast to ZIKV: cytotrophoblast and syncytiotrophoblast derived from placental villi at term and colonies of trophoblast differentiated from embryonic stem cells (ESC). The latter appear to be analogous to the primitive placenta formed during implantation. The cells from term placentas, which resist infection, do not express genes encoding most attachment factors implicated in ZIKV entry but do express many genes associated with antiviral defense. By contrast, the ESC-derived trophoblasts possess a wide range of attachment factors for ZIKV entry and lack components of a robust antiviral response system. These cells, particularly areas of syncytiotrophoblast within the colonies, quickly become infected, produce infectious virus and undergo lysis within 48 h after exposure to low titers (multiplicity of infection > 0.07) of an African lineage strain (MR766 Uganda: ZIKVU) considered to be benign with regards to effects on fetal development. Unexpectedly, lytic effects required significantly higher titers of the presumed more virulent FSS13025 Cambodia (ZIKVC). Our data suggest that the developing fetus might be most vulnerable to ZIKV early in the first trimester before a protective zone of mature villous trophoblast has been established. Additionally, MR766 is highly trophic toward primitive trophoblast, which may put the early conceptus of an infected mother at high risk for destruction. PMID:28193876

  8. Adrenomedullin Promotes Rat Trophoblast Stem Cell Differentiation1

    PubMed Central

    Gao, Haijun; Liebenthal, Daniel A.; Yallampalli, Uma; Yallampalli, Chandra

    2014-01-01

    ABSTRACT Accumulating data suggest that adrenomedullin (ADM) regulates the trophoblast cell growth, migration, and invasion. However, the effect of ADM on trophoblast differentiation is poorly understood. In this study, we hypothesized that ADM promotes the differentiation of trophoblast stem cells (TSCs) into trophoblast giant cells (TGCs). Using rat TSCs, Rcho-1 cells, we investigated the effect of ADM on TSC differentiation into TGCs in differentiation or stem cell media, respectively, and explored the effect of ADM on the mechanistic target of rapamycin (MTOR) signaling in trophoblast cell differentiation. The results include: 1) in the presence of differentiation medium, 10−7 M ADM, but not lower doses, elevated (P < 0.05) Prl3b1/Esrrb (i.e., the ratio of mRNA levels) by 1.7-fold compared to that in control; 2) the supplementation of ADM antagonist, regardless of the concentration of ADM, reduced (P < 0.05) Prl3b1/Esrrb by 2-fold, compared to control group, while the supplementation of CGRP antagonist, regardless of the concentration of ADM, did not change Prl3b1/Esrrb; 3) in the presence of stem cell medium, ADM did not alter the expression of TSC and TGC marker genes, however, the ratio of Prl3b1/Esrrb was reduced (P < 0.05) by ADM antagonist compared to that in control; and 4) ADM increased (P < 0.05) phosphorylated MTOR proteins and the ratio of phosphorylated to total MTOR proteins by 2.0- and 1.7-fold, respectively. The results indicate that ADM promotes but does not induce the differentiation of TSCs to TGCs in a dose-dependent manner and MTOR signaling may play a role in this process. PMID:25061099

  9. Evidence for Differential Glycosylation of Trophoblast Cell Types*

    PubMed Central

    Chen, Qiushi; Pang, Poh-Choo; Cohen, Marie E.; Longtine, Mark S.; Schust, Danny J.; Haslam, Stuart M.; Blois, Sandra M.; Dell, Anne; Clark, Gary F.

    2016-01-01

    Human placental villi are surfaced by the syncytiotrophoblast (STB), with a layer of cytotrophoblasts (CTB) positioned just beneath the STB. STB in normal term pregnancies is exposed to maternal immune cells in the placental intervillous space. Extravillous cytotrophoblasts (EVT) invade the decidua and spiral arteries, where they act in conjunction with natural killer (NK) cells to convert the spiral arteries into flaccid conduits for maternal blood that support a 3–4 fold increase in the rate of maternal blood flow into the placental intervillous space. The functional roles of these distinct trophoblast subtypes during pregnancy suggested that they could be differentially glycosylated. Glycomic analysis of these trophoblasts has revealed the expression of elevated levels of biantennary N-glycans in STB and CTB, with the majority of them bearing a bisecting GlcNAc. N-glycans terminated with polylactosamine extensions were also detected at low levels. A subset of the N-glycans linked to these trophoblasts were sialylated, primarily with terminal NeuAcα2–3Gal sequences. EVT were decorated with the same N-glycans as STB and CTB, except in different proportions. The level of bisecting type N-glycans was reduced, but the level of N-glycans decorated with polylactosamine sequences were substantially elevated compared with the other types of trophoblasts. The level of triantennary and tetraantennary N-glycans was also elevated in EVT. The sialylated N-glycans derived from EVT were completely susceptible to an α2–3 specific neuraminidase (sialidase S). The possibility exists that the N-glycans associated with these different trophoblast subpopulations could act as functional groups. These potential relationships will be considered. PMID:26929217

  10. Vulnerability of primitive human placental trophoblast to Zika virus.

    PubMed

    Sheridan, Megan A; Yunusov, Dinar; Balaraman, Velmurugan; Alexenko, Andrei P; Yabe, Shinichiro; Verjovski-Almeida, Sergio; Schust, Danny J; Franz, Alexander W; Sadovsky, Yoel; Ezashi, Toshihiko; Roberts, R Michael

    2017-02-28

    Infection of pregnant women by Asian lineage strains of Zika virus (ZIKV) has been linked to brain abnormalities in their infants, yet it is uncertain when during pregnancy the human conceptus is most vulnerable to the virus. We have examined two models to study susceptibility of human placental trophoblast to ZIKV: cytotrophoblast and syncytiotrophoblast derived from placental villi at term and colonies of trophoblast differentiated from embryonic stem cells (ESC). The latter appear to be analogous to the primitive placenta formed during implantation. The cells from term placentas, which resist infection, do not express genes encoding most attachment factors implicated in ZIKV entry but do express many genes associated with antiviral defense. By contrast, the ESC-derived trophoblasts possess a wide range of attachment factors for ZIKV entry and lack components of a robust antiviral response system. These cells, particularly areas of syncytiotrophoblast within the colonies, quickly become infected, produce infectious virus and undergo lysis within 48 h after exposure to low titers (multiplicity of infection > 0.07) of an African lineage strain (MR766 Uganda: ZIKV(U)) considered to be benign with regards to effects on fetal development. Unexpectedly, lytic effects required significantly higher titers of the presumed more virulent FSS13025 Cambodia (ZIKV(C)). Our data suggest that the developing fetus might be most vulnerable to ZIKV early in the first trimester before a protective zone of mature villous trophoblast has been established. Additionally, MR766 is highly trophic toward primitive trophoblast, which may put the early conceptus of an infected mother at high risk for destruction.

  11. Preeclampsia: novel insights from global RNA profiling of trophoblast subpopulations.

    PubMed

    Gormley, Matthew; Ona, Katherine; Kapidzic, Mirhan; Garrido-Gomez, Tamara; Zdravkovic, Tamara; Fisher, Susan J

    2017-08-01

    The maternal signs of preeclampsia, which include the new onset of high blood pressure, can occur because of faulty placentation. We theorized that transcriptomic analyses of trophoblast subpopulations in situ would lend new insights into the role of these cells in preeclampsia pathogenesis. Our goal was to enrich syncytiotrophoblasts, invasive cytotrophoblasts, or endovascular cytotrophoblasts from the placentas of severe preeclampsia cases. Total RNA was subjected to global transcriptional profiling to identify RNAs that were misexpressed compared with controls. This was a cross-sectional analysis of placentas from women who had been diagnosed with severe preeclampsia. Gestational age-matched controls were placentas from women who had a preterm birth with no signs of infection. Laser microdissection enabled enrichment of syncytiotrophoblasts, invasive cytotrophoblasts, or endovascular cytotrophoblasts. After RNA isolation, a microarray approach was used for global transcriptional profiling. Immunolocalization identified changes in messenger RNA expression that carried over to the protein level. Differential expression of non-protein-coding RNAs was confirmed by in situ hybridization. A 2-way analysis of variance of non-coding RNA expression identified particular classes that distinguished trophoblasts in cases vs controls. Cajal body foci were visualized by coilin immunolocalization. Comparison of the trophoblast subtype data within each group (severe preeclampsia or noninfected preterm birth) identified many highly differentially expressed genes. They included molecules that are known to be expressed by each subpopulation, which is evidence that the method worked. Genes that were expressed differentially between the 2 groups, in a cell-type-specific manner, encoded a combination of molecules that previous studies associated with severe preeclampsia and those that were not known to be dysregulated in this pregnancy complication. Gene ontology analysis of the

  12. Elsevier Trophoblast Research Award lecture: Molecular mechanisms underlying estrogen functions in trophoblastic cells--focus on leptin expression.

    PubMed

    Gambino, Y P; Maymó, J L; Pérez Pérez, A; Calvo, J C; Sánchez-Margalet, V; Varone, C L

    2012-02-01

    The steroid hormone 17β-estradiol is an estrogen that influences multiple aspects of placental function and fetal development in humans. During early pregnancy it plays a role in the regulation of blastocyst implantation, trophoblast differentiation and invasiveness, remodeling of uterine arteries, immunology and trophoblast production of hormones such as leptin. Estradiol exerts some effects through the action of classical estrogen receptors ERα and ERβ, which act as ligand-activated transcription factors and regulate gene expression. In addition, estradiol can elicit rapid responses from membrane-associated receptors, like activation of protein-kinase pathways. Thus, the cellular effects of estradiol will depend on the specific receptors expressed and the integration of their signaling events. Leptin, the 16,000MW protein product of the obese gene, was originally considered an adipocyte-derived signaling molecule for the central control of metabolism. However, pleiotropic effects of leptin have been identified in reproduction and pregnancy. The leptin gene is expressed in placenta, where leptin promotes proliferation and survival of trophoblastic cells. Expression of leptin in placenta is highly regulated by key pregnancy molecules as hCG and estradiol. The aim of this paper is to review the molecular mechanisms underlying estrogen functions in trophoblastic cells; focusing on mechanisms involved in estradiol regulation of placental leptin expression. Copyright © 2012 Elsevier Ltd. All rights reserved.

  13. How to Treat Gestational Diabetes

    MedlinePlus

    ... A Listen En Español How to Treat Gestational Diabetes Be sure to see the latest Diabetes Forecast ... and a healthy start for your baby. Gestational Diabetes – Looking Ahead Gestational diabetes usually goes away after ...

  14. Expression of serum amyloid A4 in human trophoblast-like choriocarcinoma cell lines and human first trimester/term trophoblast cells

    PubMed Central

    Rossmann, C.; Hammer, A.; Koyani, C.N.; Kovacevic, A.; Siwetz, M.; Desoye, G.; Poehlmann, T.G.; Markert, U.R.; Huppertz, B.; Sattler, W.; Malle, E.

    2014-01-01

    Trophoblast invasion into uterine tissues represents a hallmark of first trimester placental development. As expression of serum amyloid A4 (SAA4) occurs in tumorigenic and invasive tissues we here investigated whether SAA4 is present in trophoblast-like human AC1-M59/Jeg-3 cells and trophoblast preparations of human first trimester and term placenta. SAA4 mRNA was expressed in non-stimulated and cytokine-treated AC1-M59/Jeg-3 cells. In purified trophoblast cells SAA4 mRNA expression was upregulated at weeks 10 and 12 of pregnancy. Western-blot and immunohistochemical staining of first trimester placental tissue revealed pronounced SAA4 expression in invasive trophoblast cells indicating a potential role of SAA4 during invasion. PMID:24951172

  15. MTA3 regulates CGB5 and Snail genes in trophoblast

    SciTech Connect

    Chen, Ying; Miyazaki, Jun; Nishizawa, Haruki; Kurahashi, Hiroki; Leach, Richard; Wang, Kai

    2013-04-19

    Highlights: •Impaired MTA3, raised CGB5 and Snail expression are associated with preeclampsia. •Knock-down of MTA3 causes up-regulation of CGB5 and Snail genes in BeWo cells. •MTA3 occupies CGB5 and Snail gene promoters in BeWo cells. -- Abstract: Secreted by the placental trophoblast, human chorionic gonadotropin (hCG) is an important hormone during pregnancy and is required for the maintenance of pregnancy. Previous studies have shown that dys-regulation of hCG expression is associated with preeclampsia. However, the exact relationship between altered hCG levels and development of preeclampsia is unknown. Metastasis associated protein 3 (MTA3), a chromatin remodeling protein, is abundantly expressed in the placental trophoblasts, but its function is unknown. In breast cancer, MTA3 has been shown to repress the expression of Snail and cell migration. However, whether MTA3 acts similarly in the trophoblast has not been investigated. In the present study, we examined the role of MTA3 in regulating the hCG β-subunit gene (gene name: CGB5) and Snail expression in the trophoblast cell line, BeWo, as well as its relevance to the high hCG expression levels seen in preeclampsia. First, we investigated MTA3 expression in preeclamptic placenta as compared to normal control placenta via gene expression microarray and qRT-PCR and found that MTA3 was significantly down-regulated, whereas both CGB5 and Snail were up-regulated in preeclamptic placenta. Secondly, we knocked down MTA3 gene in trophoblast cell line BeWo and found Snail and hCG were both up-regulated, suggesting that MTA3 represses Snail and hCG gene expression in trophoblasts. Next, we cloned the CGB5 and Snail promoters into the pGL3-basic vector individually and found that silencing of MTA3 by siRNA resulted in an increase of both CGB5 and Snail promoter activities. To confirm that this MTA3 inhibition is a direct effect, we performed a chromatin immune-precipitation (ChIP) assay and found that MTA3

  16. Differential Receptor for Advanced Glycation End Products Expression in Preeclamptic, Intrauterine Growth Restricted, and Gestational Diabetic Placentas.

    PubMed

    Alexander, Kristen L; Mejia, Camilo A; Jordan, Clinton; Nelson, Michael B; Howell, Brian M; Jones, Cameron M; Reynolds, Paul R; Arroyo, Juan A

    2016-02-01

    Receptor for advanced glycation end products (RAGE) is a receptor implicated in the modulation of inflammation. Inflammation has been associated with pregnancy pathologies including preeclampsia (PE), intrauterine growth restriction (IUGR), and gestational diabetes mellitus (GDM). Our objective was to examine placental RAGE expression in PE, IUGR, and GDM complications. Human placental tissues were obtained for RAGE determination using Q-PCR, immunohistochemistry, and Western blot. Invasive trophoblast cells were cultured and treated with AGES for RAGE activation studies. Compared to control placenta, we observed: (i) decreased RAGE gene expression during GDM, (ii) increased RAGE protein in the PE placenta, and (iii) decreased RAGE protein in the IUGR placenta. In trophoblast cells exposed AGEs, we observed: (i) decreased trophoblast invasion, (ii) increased c-Jun N-terminal kinases (JNK) and Extracellular signal-regulated kinases (ERK), and (iii) increased TNF-α and IL-1β secretion. We conclude that placental RAGE is activated during PE and that RAGE-mediated inflammation in the trophoblast involves increased pro-inflammatory cytokine secretion. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  17. Insulin-like growth factor binding protein 7 modulates estrogen-induced trophoblast proliferation and invasion in HTR-8 and JEG-3 cells.

    PubMed

    Liu, Zhen-Kun; Liu, Hai-Yan; Fang, Wen-Ning; Yang, Ying; Wang, Hong-Mei; Peng, Jing-Pian

    2012-05-01

    Previous research has reported that IGFBP7 functions as a tumor suppressor gene in different tumors, but its role in the trophoblast has not been elucidated. In this research, we studied the regulation mechanism of IGFBP7 in trophoblast proliferation and invasion in HTR-8 and JEG-3 cell lines. We found that IGFBP7 was abundantly expressed in normal human syncytiotrophoblast tissue samples but that this was lacking in hydatidiform moles. The proliferation and invasion capacities of HTR-8 and JEG-3 cells were significantly inhibited by recombinant IGFBP7. Estrogen (E2) stimulated the expression of IGFBP7 at a concentration of 5-10 ng/mL. This stimulation was inhibited by the estrogen receptor antagonist Fulvestrant (ICI182.780) and a TGFβ-neutralizing antibody. In conclusion, our data reveals that estrogen stimulates the expression of IGFBP7 through estrogen receptors and TGFβ. The expression of IGFBP7 could be stimulated by TGFβ in a dose-dependent manner and inhibited by IFNγ in HTR-8 and JEG-3 cells. IGFBP7 could also inhibit the phosphorylation of ERK and the expression of PCNA, MMP2 and MMP9 in HTR-8 and JEG-3 cells. These findings suggest that IGFBP7 is a key regulator of E2-induced trophoblast proliferation and invasion.

  18. Regulation of gap junctional communication during human trophoblast differentiation.

    PubMed

    Cronier, L; Hervé, J C; Délèze, J; Malassiné, A

    During pregnancy, the trophoblast, supporting the main functions of the placenta, develops from the fusion of cytotrophoblastic cells into a syncytiotrophoblast. Gap junction channels consisting of connexins link the cytosols of cells in contact. Gap junctional communication has been involved in the control of cell and tissue differentiation. Recently, a gap junctional communication was demonstrated in trophoblast cell culture by means of the fluorescence recovery after photobleaching (gap-FRAP) technique. This gap junctional communication appeared to be stimulated by human chorionic gonadotropin (hCG). Therefore, the specificity of hCG action and the signalling mechanisms implicated in gap junctional communication were investigated by means of gap-FRAP. In culture, cytotrophoblastic cells develop into cellular aggregates, then into a syncytium, within 1-2 days after plating. During this in vitro differentiation, gap junctional communication was measured, and the maximum percentage of coupling between adjacent cells occurred on the fourth day. In the presence of 500 mIU/ml hCG, the percentage of coupled cells was increased at all stages of culture, and the highest proportion of coupled cells was observed after 2 days instead of 4 days in control conditions. The hCG action was specific, since the addition of heat-inactivated hCG of oFSH or of bTSH did not affect gap junctional communication in trophoblastic cells. The addition of a polyclonal hCG antibody decreased basal gap junctional communication as well as the response to exogenous hCG. Moreover, the presence of 8Br-cAMP (0.5 or 1 mM) mimicked the stimulation by hCG. Interestingly, H89 (2 microM), a specific protein kinase-A inhibitor, dramatically decreased the responses to hCG (500 mIU/ml) and the 8Br-cAMP (0.5 mM) stimulation of trophoblastic gap junctional communication. Calphostin (1 or 2 microM), a specific protein kinase-C inhibitor, strongly stimulated gap junctional communication. In conclusion, the

  19. Roles of CDX2 and EOMES in human induced trophoblast progenitor cells

    SciTech Connect

    Chen, Ying; Wang, Kai; Gong, Yun Guo; Khoo, Sok Kean; Leach, Richard

    2013-02-08

    Highlights: ► CDX2 and EOMES play critical roles in human induced trophoblast progenitors (iTP). ► iTP cells directly transformed from fibroblasts. ► Differentiation of iTP cells into extravillous trophoblasts and syncytiotrophoblasts. -- Abstract: Abnormal trophoblast lineage proliferation and differentiation in early pregnancy have been associated with the pathogenesis of placenta diseases of pregnancy. However, there is still a gap in understanding the molecular mechanisms of early placental development due to the limited primary trophoblast cultures and fidelity of immortalized trophoblast lines. Trophoblasts stem (TS) cells, an in vitro model of trophectoderm that can differentiate into syncytiotrophoblasts and extravillous trophoblasts, can be an attractive tool for early pregnancy research. TS cells are well established in mouse but not in humans due to insufficient knowledge of which trophoblast lineage-specific transcription factors are involved in human trophectoderm (TE) proliferation and differentiation. Here, we applied induced pluripotent stem cell technique to investigate the human trophoblast lineage-specific transcription factors. We established human induced trophoblast progenitor (iTP) cells by direct reprogramming the fibroblasts with a pool of mouse trophoblast lineage-specific transcription factors consisting of CDX2, EOMES, and ELF5. The human iTP cells exhibit epithelial morphology and can be maintained in vitro for more than 2 months. Gene expression profile of these cells was tightly clustered with human trophectoderm but not with human neuron progenitor cells, mesenchymal stem cells, or endoderm cells. These cells are capable of differentiating into cells with an invasive capacity, suggesting extravillous trophoblasts. They also form multi-nucleated cells which secrete human chorionic gonadotropin and estradiol, consistent with a syncytiotrophoblast phenotype. Our results provide the evidence that transcription factors CDX2 and

  20. Restraint of Trophoblast Invasion of the Uterus by Decorin: Role in Pre-eclampsia.

    PubMed

    Nandi, Pinki; Siddiqui, Mohammad Fyyaz; Lala, Peeyush K

    2016-03-01

    Decorin (DCN) is a leucine-rich, TGF-β binding proteoglycan produced by mesenchymal cells including chondrocytes, dermal fibroblasts, and uterine decidual cells. It exerts multiple physiological functions including collagen fibrillogenesis, myogenesis, angiostasis, and restraining placental invasiveness. We discovered that decidua-derived DCN restrains proliferation, migration, and invasion of extravillous trophoblast (EVT) cells of the human placenta in a TGF-β-independent manner. These functions were differentially mediated by binding of DCN to multiple tyrosine kinase receptors (TKR) including EGFR, IGFR1, and VEGFR2. DCN blocked VEGFR-2 dependent EVT cell migration and endovascular differentiation by inhibiting P38MAPK and ERK1/2 pathways.We identified the avid VEGFR2 binding site in DCN protein as a 12 amino acids (LGTNPLKSSGIE) span in the Leucine-rich-repeat (LRR) 5 region of domain III. A single amino acid mutation (substitution of K to A) of DCN at this site abrogated VEGFR-2- dependent DCN actions. Also, DCN mRNA expression, measured with in situ hybridization, was selectively upregulated in decidual cells in placentas from mothers suffering from pre-eclampsia (PE), whereas the expression levels remained unchanged in chorionic villus mesenchymal cells. This difference between PE and control placentas was present at all gestational ages, indicating the pathogenic role of DCN in PE. We hypothesize that increased blood DCN levels could be a candidate biomarker for PE. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  1. Current trends in follow-up of trophoblastic function in ruminant species.

    PubMed

    Sousa, N M; Beckers, J F; Gajewski, Z

    2008-12-01

    During the pregnancy of ruminants, different hormones and proteins are secreted by placenta or corpus luteum allowing the follow up of gestation. Among them, progesterone (P4) and pregnancy-associated glycoproteins (PAG) were proposed as laboratory tools to establish or to confirm pregnancy diagnosis. In last years, PAG assay also provided useful information for researchers working in programs focused on the follow up of trophoblastic function. Concentrations of PAG appeared as altered after the use of embryo biotechnology (in vitro fertilization, cloning by nuclear transfer, inter-specific pregnancies), according to nutritional status of pregnant females (overnourished or undernourished), or consecutive to infectious diseases leading to pathologies affecting the pregnancy in cows (Actynomyces pyogenes and Neospora caninum) and goats (Toxoplasma gondii, Listeria monocytogenes and Trypanosoma congolense). As well, in numerous studies, the association of repeated ultrasound examinations with P4 and PAG determinations allowed a better understanding of mechanisms related to embryonic and fetal mortalities: failure after artificial insemination or embryo transfer techniques, large offspring syndrome after in vitro fecundation and cloning.

  2. Early trophoblast determination and stem cell maintenance in the mouse--a review.

    PubMed

    Kunath, T; Strumpf, D; Rossant, J

    2004-04-01

    The first priority of a mammalian embryo is to establish an intimate relationship with its mother. This is accomplished by precocious differentiation of the trophoblast lineage, which mediates uterine implantation and initiates the process of placentation. Surprisingly little is known about the molecular mechanisms that drive trophectoderm differentiation from the equipotent blastomeres of the morula. Somewhat more is known about the maintenance of trophoblast stem cells, once this lineage has been established. The first half of this review will focus on determination of the mouse trophoblast lineage and the second half will discuss the maintenance of trophoblast stem cells.

  3. Osmotic water permeability diversification in primary trophoblast cultures from aquaporin 1-deficient pregnant mice.

    PubMed

    Sha, Xiao-Yan; Liu, Hui-Shu; Ma, Tong-Hui

    2015-09-01

    Aquaporins (AQP) are water channel proteins, and some play an important role in maternal-fetal fluid exchange. The present study aimed to measure the osmotic water permeability in primary cultures of trophoblast cells from AQP1-deficient (AQP1(-/-) ) pregnant mice and to define the quantitative role of AQP1 in water transport across the trophoblast plasma membrane. Trophoblast cells were obtained from placental tissue cell culture of AQP1(-/-) pregnant mice and were characterized by cytokeratin 7 immunostaining. The expression of the AQP1 gene in trophoblast cells of wild-type (AQP1(+/+) ) mice was confirmed by immunofluorescence. The osmotic water permeability of trophoblast plasma membranes was measured by a calcein fluorescence quenching method in response to osmotic gradients. A primary cell culture system for trophoblasts was successfully established. Immunofluorescence showed the expression of AQP1 in the trophoblast cell membrane of AQP1(+/+) mice. The osmotic water permeability of AQP1(-/-) trophoblast cells was significantly lower than that in AQP1(+/+) trophoblast cells, in response to both hypotonic and hypertonic challenges. The results suggest an important role of AQP1-mediated plasma membrane water permeability in maternal-fetal fluid balance and also provide a potential direction for the identification of therapeutic targets for the treatment of abnormalities in amniotic fluid volume. © 2015 Japan Society of Obstetrics and Gynecology.

  4. Beta-human chorionic gonadotropin expression in recurrent and metastatic giant cell tumors of bone: a potential mimicker of germ cell tumor.

    PubMed

    Lawless, Margaret E; Jour, George; Hoch, Benjamin L; Rendi, Mara H

    2014-10-01

    Giant cell tumors of bone (GCTs) are generally benign, locally aggressive neoplasms that rarely metastasize. The beta subunit of human chorionic gonadotropin (beta-hCG) is expressed in syncytiotrophoblasts and several nongynecologic neoplasms but has not been described in GCT. At our institution, we observed cases of elevated beta-hCG in patients with GCT leading to diagnostic difficulty and in one case, concern for metastatic choriocarcinoma. This study aims to determine the frequency of beta-hCG expression in GCT and any relationship to clinical aggressiveness. We evaluated tissue expression of beta-hCG by immunohistochemistry with 58% of cases staining for beta-hCG. Additionally, 2 of 11 patients with available serum and/or urine beta-hCG measurements demonstrated elevated beta-hCG due to tumor. It is important to be aware of beta-hCG expression by GCT and the potential for elevated urine and serum beta-hCG levels in patients with GCT so as to avoid misdiagnosis of pregnancy or gestational trophoblastic disease.

  5. Immunohistochemical distribution of heat shock protein 70 and proliferating cell nuclear antigen in mouse placenta at different gestational stages.

    PubMed

    Ozaydin, Tugba; Sur, Emrah; Oznurlu, Yasemin; Celik, Ilhami; Uluisik, Deniz

    2016-04-01

    The aim of the present study was to investigate immunohistochemical distribution of heat shock protein 70 (Hsp70) and proliferating cell nuclear antigen (PCNA) in the mouse placenta at different gestational stages. For this purpose a total of 18 Swiss albino female mice at 12-14 weeks of age were used. Females were sacrificed on days 3 (early), 10 (mid-), and 17 (late) of pregnancy and the implantation sites of the pregnant uterus were sampled. The sections were made transversely through the central region of the implantation site and stained with hematoxylin and eosin for histological examination. PCNA and Hsp70 was stained immunohistochemically. Since the definitive placenta was not still formed on day 3 of pregnancy, Hsp70 and PCNA positivity were evaluated in only luminal epithelium and decidual-stromal cells. On days 10 and 17 of pregnancy, Hsp70 and PCNA positivity were evaluated in labyrinth zone, junctional zone and decidual layer of placenta. Hsp70 expression was observed trophoblast cells and decidual cells and was relatively constant throughout the pregnancy. This protein was strongly labeled in the trophoblast cells; while decidual cells were displayed moderate staining. In early pregnant mouse uteri, PCNA was mainly localized in decidual-stromal cells. The trophoblast cells and decidual cells displayed highly proliferative activity at the midgestational period. However there was a significant decrease in the percentage of PCNA positive cells in late gestation.

  6. MSX2 Induces Trophoblast Invasion in Human Placenta

    PubMed Central

    Lu, Junjie; Yang, Genling; Tian, Na; Wang, Xiaojie; Tan, Yi; Tan, Dongmei

    2016-01-01

    Normal implantation depends on appropriate trophoblast growth and invasion. Inadequate trophoblast invasion results in pregnancy-related disorders, such as early miscarriage and pre-eclampsia, which are dangerous to both the mother and fetus. Msh Homeobox 2 (MSX2), a member of the MSX family of homeobox proteins, plays a significant role in the proliferation and differentiation of various cells and tissues, including ectodermal organs, teeth, and chondrocytes. Recently, MSX2 was found to play important roles in the invasion of cancer cells into adjacent tissues via the epithelial-mesenchymal transition (EMT). However, the role of MSX2 in trophoblastic invasion during placental development has yet to be explored. In the present study, we detected MSX2 expression in cytotrophoblast, syncytiotrophoblast, and extravillous cytotrophoblast cells of first or third trimester human placentas via immunohistochemistry analysis. Furthermore, we found that the in vitro invasive ability of HTR8/SVneo cells was enhanced by exogenous overexpression of MSX2, and that this effect was accompanied by increased protein expression of matrix metalloproteinase-2 (MMP-2), vimentin, and β-catenin. Conversely, treatment of HTR8/SVneo cells with MSX2-specific siRNAs resulted in decreased protein expression of MMP-2, vimentin, and β-catenin, and reduced invasion levels in a Matrigel invasion test. Notably, however, treatment with the MSX2 overexpression plasmid and the MSX2 siRNAs had no effect on the mRNA expression levels of β-catenin. Meanwhile, overexpression of MSX2 and treatment with the MSX2-specific siRNA resulted in decreased and increased E-cadherin expression, respectively, in JEG-3 cells. Lastly, the protein expression levels of MSX2 were significantly lower in human pre-eclamptic placental villi than in the matched control placentas. Collectively, our results suggest that MSX2 may induce human trophoblast cell invasion, and dysregulation of MSX2 expression may be associated

  7. The Elsevier Trophoblast Research Award Lecture: Importance of metzincin proteases in trophoblast biology and placental development: a focus on ADAM12.

    PubMed

    Aghababaei, Mahroo; Beristain, Alexander G

    2015-04-01

    Placental development is a highly regulated process requiring signals from both fetal and maternal uterine compartments. Within this complex system, trophoblasts, placental cells of epithelial lineage, form the maternal-fetal interface controlling nutrient, gas and waste exchange. The commitment of progenitor villous cytotrophoblasts to differentiate into diverse trophoblast subsets is a fundamental process in placental development. Differentiation of trophoblasts into invasive stromal- and vascular-remodeling subtypes is essential for uterine arterial remodeling and placental function. Inadequate placentation, characterized by defects in trophoblast differentiation, may underlie the earliest cellular events driving pregnancy disorders such as preeclampsia and fetal growth restriction. Molecularly, invasive trophoblasts acquire characteristics defined by profound alterations in cell-cell and cell-matrix adhesion, cytoskeletal reorganization and production of proteolytic factors. To date, most studies have investigated the importance of the matrix metalloproteinases (MMPs) and their ability to efficiently remodel components of the extracellular matrix (ECM). However, it is now becoming clear that besides MMPs, other related proteases regulate trophoblast invasion via mechanisms other than ECM turnover. In this review, we will summarize the current knowledge on the regulation of trophoblast invasion by members of the metzincin family of metalloproteinases. Specifically, we will discuss the emerging roles that A Disintegrin and Metalloproteinases (ADAMs) play in placental development, with a particular focus on the ADAM subtype, ADAM12. Copyright © 2015 Elsevier Ltd. All rights reserved.

  8. NLRP7 affects trophoblast lineage differentiation, binds to overexpressed YY1 and alters CpG methylation

    USDA-ARS?s Scientific Manuscript database

    Maternal-effect mutations in NLRP7 cause rare biparentally inherited hydatidiform moles (BiHMs), abnormal pregnancies containing hypertrophic vesicular trophoblast but no embryo. BiHM trophoblasts display abnormal DNA methylation patterns affecting maternally methylated germline differentially methy...

  9. Effect of epigenetic modification of maspin on extravillous trophoblastic function.

    PubMed

    Shi, Xinwei; Wu, Yuanyuan; Liu, Haiyi; Gong, Xun; Du, Hui; Li, Yuqi; Zhao, Jun; Chen, Ping; Tang, Guiju; Qiao, Fuyuan

    2012-12-01

    This study investigated the effect of epigenetic modification of maspin on extravillous trophoblastic function. The mRNA expression of maspin in placentae from normotensive and preeclamptic pregnant women was detected by RT-PCR. TEV-1 cells, a human first-trimester extravillous trophoblast cell line, were cultured and treated with CoCl(2) (300 μmol/L) to induce chemical hypoxia and with 5-aza (500 nmol/L) to induce demethylation. The mRNA expression of maspin in TEV-1 cells subjected to different treatments was determined by RT-PCR, and the proliferative and migratory abilities of TEV-1 cells were assessed by cell counting kit-8 (CCK-8) and Transwell assays. Our results showed that the maspin mRNA expression level in placentae from preeclamptic women was much higher than that from normotensive women. CoCl(2) or 5-aza could up-regulate the mRNA expression of maspin and significantly suppress the proliferation and migration of TEV-1 cells. It was concluded that the epigenetic modification in promoter region of maspin contributes to incomplete trophoblast invasion, which offers a novel approach for predicting and treating placental dysfunction.

  10. Pericellular oxygen concentration of cultured primary human trophoblasts

    PubMed Central

    Chen, Baosheng; Longtine, Mark S.; Nelson, D. Michael

    2012-01-01

    Introduction Oxygen is pivotal in placental development and function. In vitro culture of human trophoblasts provides a useful model to study this phenomenon, but a hotly debated issue is whether or not the oxygen tension of the culture conditions mimics in vivo conditions. We tested the hypothesis that ambient oxygen tensions in culture reflect the pericellular oxygen levels. Methods We used a microelectrode oxygen sensor to measure the concentration of dissolved oxygen in the culture medium equilibrated with 21%, 8% or <0.5% oxygen. Results The concentration of oxygen in medium without cells resembled that in the ambient atmosphere. The oxygen concentration present in medium bathing trophoblasts was remarkably dependent on the depth within the medium where sampling occurred, and the oxygen concentration within the overlying atmosphere was not reflected in medium immediately adjacent to the cells. Indeed, the pericellular oxygen concentration was in a range that most would consider severe hypoxia, at ≤ 0.6% oxygen or about 4.6 mm Hg, when the overlying atmosphere was 21% oxygen. Conclusions We conclude that culture conditions of 21% oxygen are unable to replicate the pO2 of 40–60 mm Hg commonly attributed to the maternal blood in the intervillous space in the second and third trimesters of pregnancy. We further surmise that oxygen atmospheres in culture conditions between 0.5% and 21% provide different oxygen fluxes in the immediate pericellular environment yet can still yield insights into the responses of human trophoblast to different oxygen conditions. PMID:23211472

  11. Kisspeptin Regulation of Genes Involved in Cell Invasion and Angiogenesis in First Trimester Human Trophoblast Cells

    PubMed Central

    Matjila, Mushi; Millar, Robert P.; Katz, Arieh A.

    2014-01-01

    The precise regulation of extravillous trophoblast invasion of the uterine wall is a key process in successful pregnancies. Kisspeptin (KP) has been shown to inhibit cancer cell metastasis and placental trophoblast cell migration. In this study primary cultures of first trimester human trophoblast cells have been utilized in order to study the regulation of invasion and angiogenesis-related genes by KP. Trophoblast cells were isolated from first trimester placenta and their identity was confirmed by immunostaining for cytokeratin-7. Real-time quantitative RT-PCR demonstrated that primary trophoblast cells express higher levels of GPR54 (KP receptor) and KP mRNA than the trophoblast cell line HTR8Svneo. Furthermore, trophoblast cells also expressed higher GPR54 and KP protein levels. Treating primary trophoblast cells with KP induced ERK1/2 phosphorylation, while co-treating the cells with a KP antagonist almost completely blocked the activation of ERK1/2 and demonstrated that KP through its cognate GPR54 receptor can activate ERK1/2 in trophoblast cells. KP reduced the migratory capability of trophoblast cells in a scratch-migration assay. Real-time quantitative RT-PCR demonstrated that KP treatment reduced the expression of matrix metalloproteinase 1, 2, 3, 7, 9, 10, 14 and VEGF-A, and increased the expression of tissue inhibitors of metalloproteinases 1 and 3. These results suggest that KP can inhibit first trimester trophoblast cells invasion via inhibition of cell migration and down regulation of the metalloproteinase system and VEGF-A. PMID:24923321

  12. Kisspeptin regulation of genes involved in cell invasion and angiogenesis in first trimester human trophoblast cells.

    PubMed

    Francis, Víctor A; Abera, Aron B; Matjila, Mushi; Millar, Robert P; Katz, Arieh A

    2014-01-01

    The precise regulation of extravillous trophoblast invasion of the uterine wall is a key process in successful pregnancies. Kisspeptin (KP) has been shown to inhibit cancer cell metastasis and placental trophoblast cell migration. In this study primary cultures of first trimester human trophoblast cells have been utilized in order to study the regulation of invasion and angiogenesis-related genes by KP. Trophoblast cells were isolated from first trimester placenta and their identity was confirmed by immunostaining for cytokeratin-7. Real-time quantitative RT-PCR demonstrated that primary trophoblast cells express higher levels of GPR54 (KP receptor) and KP mRNA than the trophoblast cell line HTR8Svneo. Furthermore, trophoblast cells also expressed higher GPR54 and KP protein levels. Treating primary trophoblast cells with KP induced ERK1/2 phosphorylation, while co-treating the cells with a KP antagonist almost completely blocked the activation of ERK1/2 and demonstrated that KP through its cognate GPR54 receptor can activate ERK1/2 in trophoblast cells. KP reduced the migratory capability of trophoblast cells in a scratch-migration assay. Real-time quantitative RT-PCR demonstrated that KP treatment reduced the expression of matrix metalloproteinase 1, 2, 3, 7, 9, 10, 14 and VEGF-A, and increased the expression of tissue inhibitors of metalloproteinases 1 and 3. These results suggest that KP can inhibit first trimester trophoblast cells invasion via inhibition of cell migration and down regulation of the metalloproteinase system and VEGF-A.

  13. Gestational age in twins.

    PubMed Central

    James, W H

    1980-01-01

    Dubowitz et al. have offered a scoring system for estimating the gestational age of newborn babies. If the system is applied to twin pairs, the heavier twin is generally estimated to have a greater gestational age than the lighter one. Previously this has been interpreted as a flaw in the scoring system. However, it may well be that in some twin pairs the gestational ages are slightly different and that therefore, the heavier twin would be expected to have a greater gestational age. Such cases would arise through superfecundation (the formation of two zygotes from different coitions). Superfecundation can be proved only in rare case (those with two fathers). It can be argued that the rarity of such cases is accounted for by the rarity with which women expose themselves to the risk of bearing such twins (and by the improbability of detection), rather than by the rarity of superfecundation. It is inferred that superfecundation by the same man is relatively common and that therefore dizygotic twins quite often have different gestational ages. The scoring system of Dubowitz can be tested for bias by submitting monozygotic pairs to it: the association between weight and estimated gestational age should be absent in such pairs. If the system proves free of such bias, then a finding first reported here will assume some interest: it is that in opposite-sexed twin pairs, the male is significantly more often assessed as having the greater gestational age. It is suggested that this finding should be provisionally accepted as evidence for the hyopthesis that male zygotes are formed earlier than females. PMID:7191240

  14. New insights for Ets2 function in trophoblast using lentivirus-mediated gene knockdown in trophoblast stem cells.

    PubMed

    Odiatis, C; Georgiades, P

    2010-07-01

    Mouse trophoblast stem (TS) cells represent a unique in vitro system that provides an unlimited supply of TS cells for the study of trophoblast differentiation and TS cell self-renewal. Although the mouse transcription factor Ets2 is required for TS cell self-renewal, its role in this and in TS cell differentiation has not been explored fully, partly due to the early lethality of Ets2 null mice. To address this, we developed a novel lentivirus-based system that resulted in efficient Ets2 knockdown in the overwhelming majority of TS cells. This system enables functional studies in TS cells, especially for genes required for TS cell self-renewal because TS cell derivation using gene-knockout embryos for such genes depends on TS cell self-renewal. Using morphological/morphometric criteria and gene expression analysis, we show that the requirement for Ets2 in self-renewal of TS cells cultured in 'stem cell medium' (SCM) involves maintenance of the expression of genes that inhibit TS cell differentiation in SCM, such as Cdx2 and Esrrb, and preservation of the undifferentiated TS cell morphology. During TS cell differentiation caused by Cdx2/Esrrb downregulation, due to either Ets2 knockdown in SCM or culture in differentiation medium (DM), Ets2 is also required for the promotion of trophoblast giant cell (TGC) and junctional zone trophoblast (JZT) differentiation. This TGC differentiation involves Ets2-dependent expression of Hand1, a gene required for the differentiation of all TGC types. This study uncovers new roles for Ets2 in TS cell self-renewal and differentiation and demonstrates the usefulness of this lentivirus system for gene function studies in TS cells.

  15. Impact of aspirin on trophoblastic invasion in women with abnormal uterine artery Doppler at 11-14 weeks: a randomized controlled study.

    PubMed

    Scazzocchio, E; Oros, D; Diaz, D; Ramirez, J C; Ricart, M; Meler, E; González de Agüero, R; Gratacos, E; Figueras, F

    2017-04-01

    Defective trophoblastic invasion is a key feature in many cases of pre-eclampsia (PE). Uterine artery (UtA) Doppler is a validated non-invasive proxy for trophoblastic invasion. The aim of this study was to explore whether low-dose aspirin, administered from the first trimester, improves trophoblastic invasion, evaluated by UtA Doppler during the second and third trimesters in women defined as high risk by abnormal first-trimester UtA Doppler. This randomized Phase-II study had a triple-blind, parallel-arm, controlled design. Singleton pregnancies with abnormal mean UtA Doppler at 11-14 weeks and absence of other major risk factors for PE received 150 mg extended-release aspirin or identical-appearing placebo tablets from study inclusion to 28 weeks. Main outcome measure was UtA pulsatility index (PI) at 28 weeks' gestation. Secondary outcomes included frequency of development of PE and growth restriction/small-for-gestational age (SGA). A total of 155 women completed the follow-up and were analyzed. No difference in mean UtA-PI was found between women in the aspirin and placebo groups at 28 weeks (mean UtA-PI Z-score (mean ± SD), 0.99 ± 1.48 vs 0.85 ± 1.25; P = 0.52). Seven women developed PE: four (5%) in the aspirin group and three (4%) in the placebo group. There was a trend toward lower incidence of SGA in the aspirin group (8.8% vs 17.3%; P = 0.11). In women with defective trophoblastic invasion, as reflected by abnormal UtA Doppler, low-dose aspirin started in the first trimester does not have a significant effect on UtA impedance as pregnancy progresses; however, the study was underpowered to detect potential small effects . Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

  16. [Cells of immune system of mother and trophoblast cells: constructive cooperation for the sake of achievement of the joint purpose].

    PubMed

    Aĭlamazian, E K; Stepanova, O I; Sel'kov, S A; Sokolov, D I

    2013-01-01

    In the present review modern data about change of morfo-functional properties of a trophoblast during pregnancy, and also about influence of the cytokines produced by cells of a microenvironment, including leucocytes of mother, on a functional state of trophoblast is cited. Features of interaction between trophoblast and immune cells of mother are described within physiological pregnancy and within pregnancy complicated by preeclampsia.

  17. Clinical Presentation of Complete Hydatidiform Mole and Partial Hydatidiform Mole at a Regional Trophoblastic Disease Center in the United States Over the Past 2 Decades.

    PubMed

    Sun, Sue Yazaki; Melamed, Alexander; Joseph, Naima T; Gockley, Allison Ann; Goldstein, Donald Peter; Bernstein, Marilyn R; Horowitz, Neil S; Berkowitz, Ross Stuart

    2016-02-01

    The aim of this study was to compare the clinical presentation and incidence of postmolar gestational trophoblastic neoplasia (GTN) among cases of complete mole (CM) and partial mole (PM) from 1994 to 2013. This study included all cases of patients with CM and PM from our trophoblastic disease center between 1994 and 2013. Their clinical and pathologic reports were reviewed. Gestational age at evacuation, features of clinical presentation, human chorionic gonadotropin levels, and the rate of progression to GTN were compared. The median gestational age at evacuation was 9 weeks for CM and 12 weeks for PM (P < 0.001). Patients with PM had lower pre-evacuation serum human chorionic gonadotropin levels (P < 0.001), and they were also less likely to present with vaginal bleeding (P < 0.001), biochemical hyperthyroidism (P < 0.001), anemia (P < 0.001), uterine size greater than dates (P < 0.001), and hyperemesis (P = 0.002). Consequently, patients with PM were less likely to have been clinically diagnosed as moles compared with CM prior to uterine evacuation (P < 0.001). The development of GTN occurred in 17.7% (33/186) and 4.1% (7/169) of patients with CM and PM, respectively (P < 0.001). This study indicates that, at our center over the past 20 years, both CM and PM were usually evacuated in the first trimester of pregnancy. Because CM more commonly presents with the signs and symptoms of molar disease than PM, CM is more commonly diagnosed prior to evacuation.

  18. Requirement of gap junctional intercellular communication for human villous trophoblast differentiation.

    PubMed

    Cronier, Laurent; Frendo, Jean-Louis; Defamie, Norah; Pidoux, Guillaume; Bertin, Gladys; Guibourdenche, Jean; Pointis, Georges; Malassine, Andre

    2003-11-01

    During pregnancy, the villous trophoblast develops from the fusion of cytotrophoblastic cells (CT) into a syncytiotrophoblast (ST), supporting the main physiological functions of the human placenta. Connexin43 (Cx43) is demonstrated in situ and in vitro in the villous trophoblast between CT and between CT and ST. Moreover, the presence of a gap junctional intercellular communication (GJIC) during in vitro trophoblast differentiation was previously demonstrated. Because the exchange of molecules through gap junctions is considered to play a major role in the control of cell and tissue differentiation, we studied the effects of a gap junctional uncoupler, heptanol, on morphological and functional trophoblast differentiation and on GJIC measured by the fluorescence recovery after photobleaching method. We found that when the GJIC was interrupted, CT still aggregated but fused poorly. This morphological effect was associated with a significant decrease of trophoblastic-specific gene expression (beta human chorionic gonadotropin and human chorionic somatomammotropin). This blocking action was reversible as demonstrated by recovery of GJIC and trophoblast differentiation process after heptanol removal. Moreover, the inhibition of the trophoblast differentiation did not affect Cx43 transcript expression and Cx43 protein expression. These data suggest that the molecular exchanges through gap junctions preceding cellular fusion are essential for trophoblast differentiation generating the multifunctional syncytiotrophoblast.

  19. Nik-related kinase regulates trophoblast proliferation and placental development by modulating AKT phosphorylation.

    PubMed

    Morioka, Yuka; Nam, Jin-Min; Ohashi, Takashi

    2017-01-01

    Nik-related kinase (Nrk) is a Ser/Thr kinase and was initially discovered as a molecule that was predominantly detected in skeletal muscles during development. A recent study using Nrk-null mice suggested the importance of Nrk in proper placental development; however, the molecular mechanism remains unknown. In this study, we demonstrated that differentiated trophoblasts from murine embryonic stem cells (ESCs) endogenously expressed Nrk and that Nrk disruption led to the enhanced proliferation of differentiated trophoblasts. This phenomenon may reflect the overproliferation of trophoblasts that has been reported in enlarged placentas of Nrk-null mice. Furthermore, we demonstrated that AKT phosphorylation at Ser473 was upregulated in Nrk-null trophoblasts and that inhibition of AKT phosphorylation cancelled the enhanced proliferation observed in differentiated Nrk-null trophoblasts. These results indicated that the upregulation of AKT phosphorylation was the possible cause of enhanced proliferation observed in Nrk-null trophoblasts. The upregulation of AKT phosphorylation was also confirmed in enlarged Nrk-null placentas in vivo, suggesting that proper regulation of AKT by Nrk was important for normal placental development. In addition, our detailed analysis on phosphorylation status of AKT isoforms in newly established trophoblast stem cells (TSCs) revealed that different levels of upregulation of AKT phosphorylation were occurred in Nrk-null TSCs depending on AKT isoforms. These results further support the importance of Nrk in proper development of trophoblast lineage cells and indicate the possible application of TSCs for the analysis of differently regulated activation mechanisms of AKT isoforms.

  20. Lipid Raft- and Src Family Kinase-Dependent Entry of Coxsackievirus B into Human Placental Trophoblasts

    PubMed Central

    Delorme-Axford, Elizabeth; Sadovsky, Yoel

    2013-01-01

    Maternal-fetal transmission of group B coxsackieviruses (CVB) during pregnancy has been associated with a number of diverse pathological outcomes, including hydrops fetalis, fetal myocarditis, meningoencephalitis, neurodevelopmental delays, congenital skin lesions, miscarriage, and/or stillbirth. Throughout pregnancy, the placenta forms a critical antimicrobial protective barrier at the maternal-fetal interface. Despite the severity of diseases accompanying fetal CVB infections, little is known regarding the strategies used by CVB to gain entry into placental trophoblasts. Here we used both a trophoblast cell line and primary human trophoblasts to demonstrate the mechanism by which CVB gains entry into polarized placental trophoblasts. Our studies revealed that the kinetics of CVB entry into placental trophoblasts are similar to those previously described for polarized intestinal epithelial cells. Likewise, CVB entry into placental trophoblasts requires decay-accelerating factor (DAF) binding and involves relocalization of the virus from the apical surface to intercellular tight junctions. In contrast, we have identified a divergent mechanism for CVB entry into polarized trophoblasts that is clathrin, caveolin-1, and dynamin II independent but requires intact lipid rafts. In addition, we found that members of the Src family of tyrosine kinases were required for CVB entry. Our studies highlight the complexity of viral entry into human placental trophoblasts and may serve as a model for mechanisms used by diverse pathogens to penetrate the placental barrier. PMID:23720726

  1. Placental lipases in pregnancies complicated by gestational diabetes mellitus (GDM).

    PubMed

    Barrett, Helen L; Kubala, Marta H; Scholz Romero, Katherin; Denny, Kerina J; Woodruff, Trent M; McIntyre, H David; Callaway, Leonie K; Nitert, Marloes Dekker

    2014-01-01

    Infants of women with gestational diabetes mellitus (GDM) are more likely to be born large for gestational age with a higher percentage body fat. Elevated maternal lipids may contribute to this. Placental lipases such as lipoprotein lipase (LPL), endothelial lipase (EL) and hormone sensitive lipase (HSL) are involved in transferring lipids from mother to fetus. Previous studies of expression of these lipases in placentae in women with diabetes in pregnancy have reported divergent results. Intracellular lipases such as adipose triglyceride lipase (ATGL), and HSL are central to lipid droplet metabolism. The activities of these lipases are both influenced by Perilipin 1, and ATGL is also activated by a co-factor comparative gene identification-58 (CGI-58) and inhibited by G0/G1 switch gene 2 (GS02). None of these modifying factors or ATGL have been examined previously in placenta. The purpose of this study was therefore to examine the expression of ATGL, HSL, LPL, EL, as well as Perilipin 1, GS02 and CGI-58 in term pregnancies complicated by GDM. mRNA and protein expression of the lipases were measured in placentae from 17 women with GDM and 17 normoglycaemic pregnancies, matched for maternal BMI and gestational age of delivery. ATGL mRNA expression was increased and HSL mRNA expression reduced in placentae from GDM although there was no differences in protein expression of any of the lipases. All lipases were localised to trophoblasts and endothelial cells. The expression of Perilipin 1 and CGI-58 mRNA was increased and GS02 not altered in GDM. These results suggest that there is no difference in expression in these four lipases between GDM and normoglycaemic placentae, and therefore altered lipid transfer via these lipases does not contribute to large for gestational age in infants of women with GDM.

  2. Human trophoblast in trisomy 21: a model for cell-cell fusion dynamic investigation.

    PubMed

    Malassiné, André; Pidoux, Guillaume; Gerbaud, Pascale; Frendo, Jean Louis; Evain-Brion, Danièle

    2011-01-01

    Trophoblastic cell fusion is one essential step of the human trophoblast differentiation leading to formation of the syncytiotrophoblast, site of the numerous placental functions. This process is multifactorial and finely regulated. Using the physiological model of primary culture of trophoblastic cells isolated from human placenta, we have identified different membrane proteins directly involved in trophoblastic cell fusion: connexin 43, ZO-1 and recently syncytins. These fusogenic membrane retroviral envelop glycoproteins: syncytin-1 (encoded by the HERV-W gene) and syncytin-2 (encoded by the FRD gene) and their receptors are major factors involved in human placental development. Disturbances of syncytiotrophoblast formation are observed in trisomy 21-affected placentas. Overexpression of the copper/zinc superoxide dismutase (SOD-1), encoded by chromosome 21 as well as an abnormal hCG signaling are implicated in the defect of syncytiotrophoblast formation. This abnormal trophoblast fusion and differentiation in trisomy 21-affected placenta is reversible in vitro by different ways.

  3. IFPA meeting 2016 workshop report III: Decidua-trophoblast interactions; trophoblast implantation and invasion; immunology at the maternal-fetal interface; placental inflammation.

    PubMed

    Aplin, John D; Beristain, Alexander; DaSilva-Arnold, Sonia; Dunk, Caroline; Duzyj, Christina; Golos, Thaddeus G; Kemmerling, Ulrike; Knöfler, Martin; Mitchell, Murray D; Olson, David M; Petroff, Margaret; Pollheimer, Jürgen; Reyes, Leticia; Schedin, Pepper; Soares, Michael J; Stencel-Baerenwald, Jennifer; Thornburg, Kent L; Lash, Gendie E

    2017-04-25

    Workshops are an important part of the IFPA annual meeting as they allow for discussion of specialised topics. At IFPA meeting 2016 there were twelve themed workshops, four of which are summarized in this report. These workshops related to various aspects of placental biology but collectively covered areas of decidual-trophoblast interaction, regulation of trophoblast invasion, immune cells at the maternal-fetal interface, and placental inflammation. Copyright © 2017 Elsevier Ltd. All rights reserved.

  4. Gestational Choriocarcinoma Presenting with Lacrimal Gland Metastasis: A First Reported Case

    PubMed Central

    Sait, Khalid; Anfnan, Nisreen; Farwan, Khader; Nizamuddin, S. H. M.

    2015-01-01

    Background. Gestational choriocarcinoma (GC) is a recognized clinicopathological subtype of gestational trophoblastic neoplasia that usually metastasizes hematogenously to highly vascular organs like the lung, liver, and brain. However, orbital metastasis to the choroid and lacrimal gland is a rare occurrence. Case Presentation. A 21-year-old female presented with headache and left orbital swelling one year after resection of a complete hydatidiform mole followed by adjuvant methotrexate chemotherapy. A metastatic imaging screening revealed multiple metastases in the lungs, brain, and adrenal gland, in addition to the choroid and lacrimal gland. Based on her modified WHO risk factors scoring she was started on chemotherapy and whole brain radiotherapy, which resulted in a complete response. At two-year follow-up, serum b-HCG level was with normal limits; imaging surveillance was uneventful. Conclusion. We present the first case of lacrimal gland metastasis in a young girl from GC relapse. PMID:26075121

  5. Assessing the risk of gestational diabetes in twin gestation.

    PubMed Central

    Henderson, C. E.; Scarpelli, S.; LaRosa, D.; Divon, M. Y.

    1995-01-01

    This study examines the hypothesis that twin gestation is a risk factor for gestational diabetes. In a retrospective analysis, the incidence of gestational diabetes in twin and singleton pregnancies was determined in groups matched for maternal age, weight, and parity. One-hour oral glucose challenge tests (50 g) were used to screen 9185 pregnant women. Gestational diabetes was diagnosed when abnormal screens (> or = 130 mg/dL) were followed by two or more abnormal values on a 3-hour (100 g) glucose tolerance test using National Diabetes Data Group (NDDG) criteria. A twin gestation was identified in 1.5% (138/9185) of the pregnancies. Gestational diabetes was diagnosed in 5.8% (8/138) and 5.4% (439/9047) of the twin and singleton pregnancies, respectively. The incidence of gestational diabetes is similar for singleton and twin gestations. PMID:7473851

  6. Trophoblast stem cell derivation, cross-species comparison and use of nuclear transfer: new tools to study trophoblast growth and differentiation.

    PubMed

    Rielland, Maite; Hue, Isabelle; Renard, Jean-Paul; Alice, Jouneau

    2008-10-01

    The trophoblast is a supportive tissue in mammals that plays key roles in embryonic patterning, foetal growth and nutrition. It shows an extensive growth up to the formation of the placenta. This growth is believed to be fed by trophoblast stem cells able to self-renew and to give rise to the differentiated derivatives present in the placenta. In this review, we summarize recent data on the molecular regulation of the trophoblast in vivo and in vitro. Most data have been obtained in the mouse, however, whenever relevant, we compare this model to other mammals. In ungulates, the growth of the trophoblast displays some striking features that make these species interesting alternative models for the study of trophoblast development. After the transfer of somatic nuclei into oocytes, studies in the mouse and the cow have both underlined that the trophoblast may be a direct target of reprogramming defects and that its growth seems specifically affected. We propose that the study of TS cells derived from nuclear transfer embryos may help to unravel some of the epigenetic abnormalities which occur therein.

  7. Dynamic changes in gene expression during human trophoblast differentiation.

    PubMed

    Handwerger, Stuart; Aronow, Bruce

    2003-01-01

    The genetic program that directs human placental differentiation is poorly understood. In a recent study, we used DNA microarray analyses to determine genes that are dynamically regulated during human placental development in an in vitro model system in which highly purified cytotrophoblast cells aggregate spontaneously and fuse to form a multinucleated syncytium that expresses placental lactogen, human chorionic gonadotropin, and other proteins normally expressed by fully differentiated syncytiotrophoblast cells. Of the 6918 genes present on the Incyte Human GEM V microarray that we analyzed over a 9-day period, 141 were induced and 256 were downregulated by more than 2-fold. The dynamically regulated genes fell into nine distinct kinetic patterns of induction or repression, as detected by the K-means algorithm. Classifying the genes according to functional characteristics, the regulated genes could be divided into six overall categories: cell and tissue structural dynamics, cell cycle and apoptosis, intercellular communication, metabolism, regulation of gene expression, and expressed sequence tags and function unknown. Gene expression changes within key functional categories were tightly coupled to the morphological changes that occurred during trophoblast differentiation. Within several key gene categories (e.g., cell and tissue structure), many genes were strongly activated, while others with related function were strongly repressed. These findings suggest that trophoblast differentiation is augmented by "categorical reprogramming" in which the ability of induced genes to function is enhanced by diminished synthesis of other genes within the same category. We also observed categorical reprogramming in human decidual fibroblasts decidualized in vitro in response to progesterone, estradiol, and cyclic AMP. While there was little overlap between genes that are dynamically regulated during trophoblast differentiation versus decidualization, many of the categories

  8. Bradykinin promotes migration and invasion of human immortalized trophoblasts

    PubMed Central

    2011-01-01

    Having demonstrated that the bradykinin B2 receptor (B2R) is expressed in cells that participate in trophoblast invasion in humans and guinea-pigs, we investigated the role of bradykinin (BK) on cell migration and invasion in the HTR-8/SVneo trophoblast cell line using wound healing and invasion assays. First, we documented that HTR-8/SVneo cells expressed kallikrein, B2R, B1R, MMP-2 and MMP-9 using immunocytochemistry. Incubation with BK (10.0 microMol/L) for 18 hours increased the migration index 3-fold in comparison to controls or to cells preincubated with the B2R antagonist HOE-140. BK (10.0 microMol/L) incubation yielded a similar number of proliferating and viable cells as controls, therefore the enhanced closure of the wound cannot be attributed to proliferating cells. Incubation with BK (10.0 microMol/L) for 18 hours increased the invasion index 2-fold in comparison to controls or to cells preincubated with the antagonist of the B2R. Neither the B1R ligand Lys-des-Arg9 BK, nor its antagonist Lys-(des-Arg9-Leu8), modified migration and invasion. Further support for the stimulatory effect of B2R activation on migration and invasion is provided by the 3-fold increase in the number of filopodia per cell versus controls or cells preincubated with the B2R antagonist. Bradykinin had no effect on the cellular protein content of the B2R, nor the MMP-9 and MMP-2 gelatinase activity in the culture media varied after incubation with BK. This study adds bradykinin-acting on the B2R-to the stimuli of trophoblast migration and invasion, an effect that should be integrated to other modifications of the kallikrein-kinin system in normal and pathological pregnancies. PMID:21729302

  9. Diagnosing gestational diabetes

    PubMed Central

    2011-01-01

    The newly proposed criteria for diagnosing gestational diabetes will result in a gestational diabetes prevalence of 17.8%, doubling the numbers of pregnant women currently diagnosed. These new diagnostic criteria are based primarily on the levels of glucose associated with a 1.75-fold increased risk of giving birth to large-for-gestational age infants (LGA) in the Hyperglycemia Adverse Pregnancy Outcome (HAPO) study; they use a single OGTT. Thus, of 23,316 pregnancies, gestational diabetes would be diagnosed in 4,150 women rather than in 2,448 women if a twofold increased risk of LGA were used. It should be recognised that the majority of women with LGA have normal glucose levels during pregnancy by these proposed criteria and that maternal obesity is a stronger predictor of LGA. The expected benefit of a diagnosis of gestational diabetes in these 1,702 additional women would be the prevention of 140 cases of LGA, 21 cases of shoulder dystocia and 16 cases of birth injury. The reproducibility of an OGTT for diagnosing mild hyperglycaemia is poor. Given that (1) glucose is a weak predictor of LGA, (2) treating these extra numbers has a modest outcome benefit and (3) the diagnosis may be based on a single raised OGTT value, further debate should occur before resources are allocated to implementing this change. Electronic supplementary material The online version of this article (doi:10.1007/s00125-010-2005-4) contains supplementary material, which is available to authorised users. PMID:21203743

  10. Large for gestational age (LGA)

    MedlinePlus

    ... gov/ency/article/002248.htm Large for gestational age (LGA) To use the sharing features on this page, please enable JavaScript. Large for gestational age means that a fetus or infant is larger ...

  11. Immunomodulator expression in trophoblasts from the feline immunodeficiency virus (FIV)-infected cat

    PubMed Central

    2011-01-01

    Background FIV infection frequently compromises pregnancy under experimental conditions and is accompanied by aberrant expression of some placental cytokines. Trophoblasts produce numerous immunomodulators that play a role in placental development and pregnancy maintenance. We hypothesized that FIV infection may cause dysregulation of trophoblast immunomodulator expression, and aberrant expression of these molecules may potentiate inflammation and compromise pregnancy. The purpose of this project was to evaluate the expression of representative pro-(TNF-α, IFN-γ, IL-1β, IL-2, IL-6, IL-12p35, IL-12p40, IL-18, and GM-CSF) and anti-inflammatory cytokines (IL-4, IL-5, and IL-10); CD134, a secondary co-stimulatory molecule expressed on activated T cells (FIV primary receptor); the chemokine receptor CXCR4 (FIV co-receptor); SDF-1α, the chemokine ligand to CXCR4; and FIV gag in trophoblasts from early-and late-term pregnancy. Methods We used an anti-cytokeratin antibody in immunohistochemistry to identify trophoblasts selectively, collected these cells using laser capture microdissection, and extracted total RNA from the captured cell populations. Real time, reverse transcription-PCR was used to quantify gene expression. Results We detected IL-4, IL-5, IL-6, IL-1β, IL-12p35, IL-12p40, and CXCR4 in trophoblasts from early-and late-term pregnancy. Expression of cytokines increased from early to late pregnancy in normal tissues. A clear, pro-inflammatory microenvironment was not evident in trophoblasts from FIV-infected queens at either stage of pregnancy. Reproductive failure was accompanied by down-regulation of both pro-and anti-inflammatory cytokines. CD134 was not detected in trophoblasts, and FIV gag was detected in only one of ten trophoblast specimens collected from FIV-infected queens. Conclusion Feline trophoblasts express an array of pro-and anti-inflammatory immunomodulators whose expression increases from early to late pregnancy in normal tissues. Non

  12. Quantifying trophoblast migration: In vitro approaches to address in vivo situations.

    PubMed

    James, Joanna; Tun, Win; Clark, Alys

    2016-03-03

    When trophoblasts migrate and invade in vivo, they do so by interacting with a range of other cell types, extracellular matrix proteins, chemotactic factors and physical forces such as fluid shear stress. These factors combine to influence overall trophoblast migration and invasion into the decidua, which in turn determines the success of spiral artery remodelling, and pregnancy itself. Our understanding of these important but complex processes is limited by the simplified conditions in which we often study cell migration in vitro, and many discrepancies are observed between different in vitro models in the literature. On top of these experimental considerations, the migration of individual trophoblasts can vary widely. While time-lapse microscopy provides a wealth of information on trophoblast migration, manual tracking of individual cell migration is a time consuming task that ultimately restricts the numbers of cells quantified, and thus the ability to extract meaningful information from the data. However, the development of automated imaging algorithms is likely to aid our ability to accurately interpret trophoblast migration in vitro, and better allow us to relate these observations to in vivo scenarios. This commentary discusses the advantages and disadvantages of techniques commonly used to quantify trophoblast migration and invasion, both from a cell biology and a mathematical perspective, and examines how such techniques could be improved to help us relate trophoblast migration more accurately to in vivo function in the future.

  13. Trypanosoma cruzi induces trophoblast differentiation: a potential local antiparasitic mechanism of the human placenta?

    PubMed

    Liempi, A; Castillo, C; Duaso, J; Droguett, D; Sandoval, A; Barahona, K; Hernández, A; Galanti, N; Maya, J D; Kemmerling, U

    2014-12-01

    The congenital transmission of Trypanosoma cruzi (T. cruzi) is responsible for one-third of new Chagas disease cases each year. During congenital transmission, the parasite breaks down the placental barrier formed by the trophoblast, basal laminae and villous stroma. The observation that only 5% of infected mothers transmit the parasite to the fetus implies that the placenta may impair parasite transmission. The trophoblast undergoes continuous epithelial turnover, which is considered part of innate immunity. Therefore, we propose that T. cruzi induces differentiation in the trophoblast as part of a local antiparasitic mechanism of the placenta. We analyzed β-human chorionic gonadotropin (β-hCG) and syncytin protein expression in HPCVE and BeWo cells using immunofluorescence and western blotting. Additionally, β-hCG secretion into the culture medium was measured by ELISA. We assessed the differentiation of trophoblastic cells in BeWo cells using the two-color fusion assay and by determining desmoplakin re-distribution. T. cruzi trypomastigotes induce β-hCG secretion and protein expression as well as syncytin protein expression in HPCVE and BeWo cells. Additionally, the parasite induces the trophoblast fusion of BeWo cells. T. cruzi induces differentiation of the trophoblast, which may contribute to increase the trophoblast turnover. The turnover could be a component of local antiparasitic mechanisms in the human placenta. Copyright © 2014 Elsevier Ltd. All rights reserved.

  14. Effect of microcystin-LR on human placental villous trophoblast differentiation in vitro.

    PubMed

    Douglas, Gordon C; Thirkill, Twanda L; Kumar, Priyadarsini; Loi, Minerva; Hilborn, Elizabeth D

    2016-04-01

    Microcystin-LR is a cyanobacterial toxin found in surface and recreational waters that inhibits protein phosphatases and may disrupt the cytoskeleton. Microcystins induce apoptosis in hepatocytes at ≤ 2.0 µM. Nothing is known about the effects of microcystins on human placental trophoblast differentiation and function. The differentiation of villous trophoblasts to form syncytiotrophoblast occurs throughout pregnancy and is essential for normal placental and fetal development. To investigate the effects of microcystin, villous cytotrophoblasts were isolated from term placentas using an established method and exposed to microcystin-LR. Microcystin-LR below the cytotoxic dose of 25 µM did not cause cell rounding or detachment, had no effect on apoptosis, and no effect on the morphological differentiation of mononucleated cytotrophoblasts to multinucleated syncytiotrophoblast. However, secretion of human chorionic gonadotropin (hCG) increased in a microcystin-LR dose-dependent manner. When incubated with l-buthionine sulphoximine (BSO) to deplete glutathione levels, trophoblast morphological differentiation proceeded normally in the presence of microcystin-LR. Microcystin-LR did not disrupt the trophoblast microtubule cytoskeleton, which is known to play a role in trophoblast differentiation. Immunofluorescence studies showed that trophoblasts express organic anion transport protein 1B3 (OATP1B3), a known microcystin transport protein. In comparison to hepatocytes, trophoblasts appear to be more resistant to the toxic effects of microcystin-LR. The physiological implications of increased hCG secretion in response to microcystin-LR exposure remain to be determined.

  15. Derivation of Induced Trophoblast Cell Lines in Cattle by Doxycycline-Inducible piggyBac Vectors

    PubMed Central

    Hayashi, Masafumi; Tsukiyama, Tomoyuki; Kimura, Koji; Matsuyama, Shuichi; Minami, Naojiro; Yamada, Masayasu; Imai, Hiroshi

    2016-01-01

    Trophectoderm lineage specification is one of the earliest differentiation events in mammalian development. The trophoblast lineage, which is derived from the trophectoderm, mediates implantation and placental formation. However, the processes involved in trophoblastic differentiation and placental formation in cattle remain unclear due to interspecies differences when compared with other model systems and the small repertoire of available trophoblast cell lines. Here, we describe the generation of trophoblast cell lines (biTBCs) from bovine amnion-derived cells (bADCs) using an induced pluripotent stem cell technique. bADCs were introduced with piggyBac vectors containing doxycycline (Dox)-inducible transcription factors (Oct3⁄4(POU5F1), Sox2, Klf4, and c-Myc). Colonies that appeared showed a flattened epithelial-like morphology similar to cobblestones, had a more definite cell boundary between cells, and frequently formed balloon-like spheroids similar to trophoblastic vesicles (TVs). biTBCs were propagated for over 60 passages and expressed trophoblast-related (CDX2, ELF5, ERRβ, and IFN-τ) and pluripotency-related genes (endogenous OCT3/4, SOX2, KLF4, and c-MYC). Furthermore, when biTBCs were induced to differentiate by removing Dox from culture, they formed binucleate cells and began to express pregnancy-related genes (PL, PRP1, and PAG1). This is the first report demonstrating that the induction of pluripotency in bovine amniotic cells allows the generation of trophoblastic cell lines that possess trophoblast stem cell-like characteristics and have the potential to differentiate into the extra-embryonic cell lineage. These cell lines can be a new cell source as a model for studying trophoblast cell lineages and implantation processes in cattle. PMID:27907214

  16. Schistosome egg antigens elicit a proinflammatory response by trophoblast cells of the human placenta.

    PubMed

    McDonald, Emily A; Kurtis, Jonathan D; Acosta, Luz; Gundogan, Fusun; Sharma, Surendra; Pond-Tor, Sunthorn; Wu, Hai-Wei; Friedman, Jennifer F

    2013-03-01

    Schistosomiasis affects nearly 40 million women of reproductive age. Many of these women are infected while pregnant and lactating. Several studies have demonstrated transplacental trafficking of schistosome antigens; however, little is known regarding how these antigens affect the developing fetus and placenta. To evaluate the impact of schistosomiasis on trophoblasts of the human placenta, we isolated primary trophoblast cells from healthy placentas delivered at term. These trophoblasts were placed in culture and treated with Schistosoma japonicum soluble egg antigens (SEA) or plasma from S. japonicum-infected pregnant women. Outcomes measured included cytokine production and activation of signal transduction pathways. Treatment of primary human trophoblast cells with SEA resulted in upregulation of the proinflammatory cytokines interleukin 6 (IL-6) and IL-8 and the chemokine macrophage inflammatory protein 1α (MIP-1α). Cytokine production in response to SEA was dose dependent and reminiscent of production in response to other proinflammatory stimuli, such as Toll-like receptor 2 (TLR2) and TLR4 agonists. In addition, the signaling pathways extracellular signal-regulated kinase 1/2 (ERK1/2), Jun N-terminal protein kinase (JNK), p38, and NF-κB were all activated by SEA in primary trophoblasts. These effects appeared to be mediated through both carbohydrate and protein epitopes of SEA. Finally, primary trophoblasts cocultured with plasma from S. japonicum-infected pregnant women produced increased levels of IL-8 compared to trophoblasts cocultured with plasma from uninfected pregnant women. We report here a direct impact of SEA on primary human trophoblast cells, which are critical for many aspects of a healthy pregnancy. Our data indicate that schistosome antigens can activate proinflammatory responses in trophoblasts, which might compromise maternal-fetal health in pregnancies complicated by schistosomiasis.

  17. [Gestational diabetes mellitus].

    PubMed

    Senat, M-V; Deruelle, P

    2016-04-01

    While the prevalence of gestational diabetes mellitus (GDM) was estimated between 5 and 10% in 2010, the application of new thresholds recommended by IADPSG and adopted in 2010 by CNGOF seems to significantly increase the number of patients affected by this pathology. A prospective single-center French study estimated in 2014 the prevalence of gestational diabetes at 14% with these criteria, making it one of the most frequent complications during pregnancy. However, to date, there is no published study using these criteria to show a benefit to the health of women and children. If a diagnosis of GDM or type 2 diabetes during pregnancy is definitively an important risk factor for maternal as well as newborn and child complications, it is probably not the case for moderate hyperglycemia discovered during pregnancy. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  18. [Secretion of inflammatory cytokines and prostaglandins by fetal trophoblast cells induces uterine contraction and labor onset].

    PubMed

    Steinbron, A; Günes, H; Lechner, B; Halberstadt, E

    1995-01-01

    Induce infection-associated cytokines intrauterine secretion of prostaglandins and term labor? Concentrations of Il-6, Il-1 beta, TNF-alpha, PGF2 and PGF2 alpha were determined in cervical secretions and amniotic fluid during spontaneous term labor. The supernatant of amnion-, chorion-, decidua- and trophoblast cells, cultured after elective cesarean section or spontaneous delivery, was analysed for cytokine- and prostaglandin activity. Term labor always is associated with intrauterine cytokine- and prostaglandin release. Increased production of cytokines and prostaglandins in case of normal term labor only was found by fetal trophoblast cells. Signal for parturition is of trophoblast and therefore of fetal origin.

  19. Vitamin D Reduces Oxidative Stress-Induced Procaspase-3/ROCK1 Activation and MP Release by Placental Trophoblasts.

    PubMed

    Xu, Jie; Jia, Xiuyue; Gu, Yang; Lewis, David F; Gu, Xin; Wang, Yuping

    2017-06-01

    Increased microparticle (MP) shedding by placental trophoblasts contributes to maternal vascular inflammatory response and endothelial dysfunction in preeclampsia. Vitamin D has beneficial effects in pregnancy; however, its effect on trophoblast MP release has not been investigated. To investigate if vitamin D could protect trophoblasts from oxidative stress-induced MP release. Placental trophoblasts were isolated from uncomplicated and preeclamptic placentas. Effects of vitamin D on MP release induced by oxidative stress inducer CoCl2 were studied. Annexin V+ MPs were assessed by flow cytometry. Expression of caveolin-1, endothelial nitric oxide synthase (eNOS), procaspase-3, cleaved caspase-3, and Rho-associated coiled-coil protein kinase 1 (ROCK1) in trophoblasts and trophoblast-derived MPs were determined by Western blot. Trophoblasts from preeclamptic pregnancies released significantly more MPs than cells from uncomplicated pregnancies (P < 0.01). CoCl2-induced increase in MP release was associated with upregulation of caveolin-1 and downregulation of eNOS expression in trophoblasts (P < 0.05), which could be attenuated by 1,25(OH)2D3. Moreover, 1,25(OH)2D3 could also inhibit CoCl2-induced procaspase-3 cleavage and ROCK1 activation in trophoblasts. Consistently, CoCl2-induced upregulation of procaspase-3, cleaved caspase-3, and ROCK1 expression in trophoblast-derived MPs were also reduced in cells treated with 1,25(OH)2D3. Placental trophoblasts from preeclamptic pregnancies released more MP than cells from uncomplicated pregnancies. Oxidative stress-induced increase in MP shedding is associated with upregulation of caveolin-1 and downregulation of eNOS expression in placental trophoblasts. Inhibition of caspase-3 cleavage and ROCK1 activation, together with upregulation of eNOS expression, could be the potential cellular/molecular mechanism(s) of vitamin D protective effects on placental trophoblasts.

  20. Interaction of human trophoblast cells with gland-like endometrial spheroids: a model system for trophoblast invasion.

    PubMed

    Buck, V U; Gellersen, B; Leube, R E; Classen-Linke, I

    2015-04-01

    Do maternal endometrial epithelial cell (EEC) differentiation and polarity impact the invasive capacity of extravillous trophoblast (EVT) cells during early human implantation? In a three dimensional (3D) confrontation co-culture the invasiveness of the human trophoblast cell line AC-1M88 was inversely correlated with the degree of differentiation and polarization of human endometrial adenocarcinoma cell spheroids. In a previous study desmosomal and adherens junction proteins were shown to spread from a subapically restricted lateral position to the entire lateral membrane in human glandular EECs during the implantation window of the menstrual cycle. Whether this change in EEC junction localization has an impact on the interaction of EVT cells with glandular EECs during early human implantation is not known. A new 3D cell culture system was developed in order to mimic early implantation events in humans. As a model for the invasion of endometrial glands by EVT cells, spheroids of three differently differentiated and polarized endometrial adenocarcinoma cell lines were confronted with an EVT cell line in co-culture experiments. Three human adenocarcinoma EEC lines were chosen for this study because of their differences in differentiation and polarization: HEC-1-A, which is well differentiated and highly polarized, Ishikawa, which is well differentiated and moderately polarized, and RL95-2, which is moderately differentiated and poorly polarized. When the cell lines were grown in reconstituted basement membrane, they formed gland-like, multicellular spheroids. The degree of polarization within the different EEC spheroids was assessed by 3D confocal immunofluorescence microscopy detecting the basal membrane protein integrin α6, the apical tight junction-associated protein ZO-1 and the desmosomal plaque protein desmoplakin 1/2 (Dsp). Cells of the human EVT cell line AC-1M88, which is a fusion cell line of primary EVT cells and choriocarcinoma-derived JEG-3 cells, were

  1. Immunomodulator expression in trophoblasts from the feline immunodeficiency virus FIV infected cat

    USDA-ARS?s Scientific Manuscript database

    FIV infection frequently compromises pregnancy under experimental conditions and is accompanied by aberrant expression of some placental cytokines. Trophoblasts produce numerous immunomodulators that play a role in placental development and pregnancy maintenance. We hypothesized that FIV infection m...

  2. The in vitro immunoregulatory properties of cultured murine trophoblast are not unique to this tissue.

    PubMed Central

    Drake, B L; Rodger, J C

    1985-01-01

    Primary cultures of murine trophoblast (ectoplacental cone and mid-term placenta) and their supernatants were found to inhibit in vitro lymphocyte proliferative responses to concanavalin A (77-87%) and allo-antigen (52-84%). However, cultures and cell-conditioned media from non-trophoblastic tissues (embryonic sac, adult lung and liver, and B16 melanoma line) produced similar results. In all cases, the inhibitory effects were not due to reduced cell viability. Addition of anti-progesterone serum to the ectoplacental cone-lymphocyte co-cultures, at a concentration known to bind the available trophoblast-derived progesterone, did not overcome the observed suppression. The results clearly demonstrate that a range of cultured cell types, and their conditioned media, will suppress immune responses in vitro. We conclude that cultured trophoblast is not an appropriate model for studies of placental immunoregulation. PMID:3159651

  3. Comparative experimental infection of Listeria monocytogenes and Listeria ivanovii in bovine trophoblasts.

    PubMed

    Rocha, Cláudia E; Mol, Juliana P S; Garcia, Luize N N; Costa, Luciana F; Santos, Renato L; Paixão, Tatiane A

    2017-01-01

    Listeria monocytogenes is a Gram-positive, facultative intracellular and invasive bacterium that has tropism to the placenta, and causes fetal morbidity and mortality in several mammalian species. While infection with L. monocytogenes and L. ivanovii are known as important causes of abortion and reproductive failure in cattle, the pathogenesis of maternal-fetal listeriosis in this species is poorly known. This study used the bovine chorioallantoic membrane explant model to investigate the kinetics of L. monocytogenes, L. ivanovii, and L. innocua infections in bovine trophoblastic cells for up to 8 h post infection. L. monocytogenes and L. ivanovii were able to invade and multiply in trophoblastic cells without causing cell death or inducing expression of pro-inflammatory genes. Although L. innocua was unable to multiply in bovine trophoblastic cells, it induced transcription of the pro-inflammatory mediator CXCL6. This study demonstrated for the first time the susceptibility of bovine trophoblastic cells to L. monocytogenes and L. ivanovii infection.

  4. Genetic-epigenetic intersection in trophoblast differentiation: implications for extraembryonic tissue function.

    PubMed

    Hemberger, Myriam

    2010-01-01

    Recent years have seen considerable advances in our understanding of early mammalian development leading up to the establishment of the first cell lineages, with important implications for the behavior of stem cells derived from the early embryo. Dramatic new insights have also propelled the field of epigenetics with the identification of 5-hydroxymethylcytosine as an additional base modification and the pervasiveness of asymmetrical non-CG DNA methylation specifically in ES cells. Prompted by our findings on the role of DNA methylation in cell lineage commitment, this review highlights recent insights into the genetic-epigenetic intersection in the establishment of the placental trophoblast lineage that is essential for embryo implantation, nutrition and survival. The unique trophoblast epigenotype is instrumental for normal trophoblast differentiation and placental function, and consequently trophoblast is particularly susceptible to regrogramming failures.

  5. Significance of trophoblastic infiltration into the tubal wall in ampullary pregnancy.

    PubMed

    Erol, Onur; Suren, Dinc; Unal, Betul; Ozel, Deniz; Kumru, Selahattin; Sezer, Cem

    2015-06-01

    A total of 81 patients with an ampullary ectopic pregnancy undergoing salpingectomy were enrolled in the study. The ampullary pregnancies were classified according to the depth of trophoblastic infiltration into tubal wall as follows: Stage I, limited to mucosa; Stage II, extension to the tubal muscularis; Stage III, complete tubal wall infiltration up to the serosa. An association was observed between serum β-human chorionic gonadotropin (β-hCG) levels and the depth of trophoblastic infiltration. Significantly higher severe ischemic changes and rupture of tubal wall were observed in patients with stage III infiltration compared with the other groups. A significant association was found between the absolute depth of trophoblastic invasion and severe ischemic changes, and also rupture of serosa. In conclusion, serum β-hCG levels are associated with depth of trophoblastic invasion into the tubal wall, severe ischemic changes, and rupture of the tubal wall.

  6. [Gestational Diabetes Mellitus].

    PubMed

    Krejčí, Hana

    2016-01-01

    The present generation of women of childbearing age more frequently suffer from overweight, obesity, initial as well as fully established metabolic syndrome, which together with postponing motherhood until the third decade in life plays an important role in the increasing incidence of gestational diabetes (GDM) that currently affects about 1/5 of pregnant women. However the causal link between diabetes during pregnancy and metabolic diseases in the whole population is mutual. By way of epigenetic changes, maternal diabetes unfavourably programmes metabolism of the offspring, who tend to transfer the disorder to the next generations. Gestational diabetes is therefore an important link fitting into the accumulation curve of the incidence of overweight, obesity, metabolic syndrome and consequently also T2DM among the whole population. Genetic as well as epigenetic factors play a great role in the GDM pathogenesis, which is shown by the fact that this complication also affects women with normal BMI. When it comes to diagnosing GDM, we will need to manage also in future with establishing fasting glycemia and glycemia following glucose challenge (OGTT) that may include a considerable degree of measurement inaccuracy. It is therefore necessary to observe pre-analytical and analytical conditions of measurements in order to obtain a reliable result. It is a positive sign that the Czech professional associations have adopted new international criteria for diagnosing GDM which, as opposed to those valid earlier, better reflect the risk of pregnancy-related and perinatal complications.The care for gestational patients with diabetes at a low risk (due to satisfactory glycemic control through a diet or small pharmacotherapeutic doses, with an eutrophic fetus and without associated complications) is provided by an outpatient gynecologist and a diabetes specialist, they can give birth in standard maternity hospitals. The care for gestational patients with diabetes at a higher risk

  7. Nik-related kinase regulates trophoblast proliferation and placental development by modulating AKT phosphorylation

    PubMed Central

    Morioka, Yuka; Nam, Jin-Min; Ohashi, Takashi

    2017-01-01

    Nik-related kinase (Nrk) is a Ser/Thr kinase and was initially discovered as a molecule that was predominantly detected in skeletal muscles during development. A recent study using Nrk-null mice suggested the importance of Nrk in proper placental development; however, the molecular mechanism remains unknown. In this study, we demonstrated that differentiated trophoblasts from murine embryonic stem cells (ESCs) endogenously expressed Nrk and that Nrk disruption led to the enhanced proliferation of differentiated trophoblasts. This phenomenon may reflect the overproliferation of trophoblasts that has been reported in enlarged placentas of Nrk-null mice. Furthermore, we demonstrated that AKT phosphorylation at Ser473 was upregulated in Nrk-null trophoblasts and that inhibition of AKT phosphorylation cancelled the enhanced proliferation observed in differentiated Nrk-null trophoblasts. These results indicated that the upregulation of AKT phosphorylation was the possible cause of enhanced proliferation observed in Nrk-null trophoblasts. The upregulation of AKT phosphorylation was also confirmed in enlarged Nrk-null placentas in vivo, suggesting that proper regulation of AKT by Nrk was important for normal placental development. In addition, our detailed analysis on phosphorylation status of AKT isoforms in newly established trophoblast stem cells (TSCs) revealed that different levels of upregulation of AKT phosphorylation were occurred in Nrk-null TSCs depending on AKT isoforms. These results further support the importance of Nrk in proper development of trophoblast lineage cells and indicate the possible application of TSCs for the analysis of differently regulated activation mechanisms of AKT isoforms. PMID:28152035

  8. Signaling pathways in mouse and human trophoblast differentiation: a comparative review

    PubMed Central

    Soncin, Francesca; Natale, David; Parast, Mana M.

    2014-01-01

    The mouse is often used as a model for understanding human placentation and offers multiple advantages, including the ability to manipulate gene expression in specific compartments and to derive trophoblast stem cells, which can be maintained or differentiated in vitro. Nevertheless, there are numerous differences between the mouse and human placentas, only the least of which are structural. This review aims to compare mouse and human placentation, with a focus on signaling pathways involved in trophoblast lineage-specific differentiation. PMID:25430479

  9. ADAM12-directed ectodomain shedding of E-cadherin potentiates trophoblast fusion.

    PubMed

    Aghababaei, M; Hogg, K; Perdu, S; Robinson, W P; Beristain, A G

    2015-12-01

    Trophoblasts, placental cells of epithelial lineage, undergo extensive differentiation to form the cellular components of the placenta. Trophoblast progenitor cell differentiation into the multinucleated syncytiotrophoblast is a key developmental process required for placental function, where defects in syncytiotrophoblast formation and turnover associate with placental pathologies and link to poor pregnancy outcomes. The cellular and molecular processes governing syncytiotrophoblast formation are poorly understood, but require the activation of pathways that direct cell fusion. The protease, A Disintegrin and Metalloproteinase 12 (ADAM12), controls cell fusion in myoblasts and is highly expressed in the placenta localizing to multiple trophoblast populations. However, the importance of ADAM12 in regulating trophoblast fusion is unknown. Here, we describe a function for ADAM12 in regulating trophoblast fusion. Using two distinct trophoblast models of cell fusion, we show that ADAM12 is dynamically upregulated and is under the transcriptional control of protein kinase A. siRNA-directed loss of ADAM12 impedes spontaneous fusion of primary cytotrophoblasts, whereas overexpression of the secreted variant, ADAM12S, potentiates cell fusion in the Bewo trophoblast cell line. Mechanistically, both ectopic and endogenous levels of ADAM12 were shown to control trophoblast fusion through E-cadherin ectodomain shedding and remodeling of intercellular boundaries. This study describes a novel role for ADAM12 in placental development, specifically highlighting its importance in controlling the differentiation of villous cytotrophoblasts into multinucleated cellular structures. Moreover, this work identifies E-cadherin as a novel ADAM12 substrate, and highlights the significance that cell adhesion molecule ectodomain shedding has in normal development.

  10. The expression and post-transcriptional regulation of FSTL1 transcripts in placental trophoblasts

    PubMed Central

    Mouillet, Jean-Francois; Mishima, Takuya; Paffaro, Andrea Mollica do Amarante; Parks, Tony W.; Ziegler, Judy A.; Chu, Tianjiao; Sadovsky, Yoel

    2015-01-01

    Introduction Follistatin-like-1 (FSTL1) is a widely expressed secreted protein with diverse but poorly understood functions. Originally described as a pro-inflammatory molecule, it has recently been reported to play a role in signaling pathways that regulate development and homeostasis. Distinctively, FSTL1 harbors within its 3′-UTR the sequence encoding microRNA-198 (miR-198), shown to be inversely regulated relative to FSTL1 expression and to exhibit opposite actions on cellular processes such as cell migration. We sought to investigate the expression of FSTL1 and to assess its interplay with miR-198 in human trophoblasts. Methods We used a combination of northern blot analyses, quantitative PCR, small RNA sequencing, western blot and immunohistochemistry to characterize FSTL1 and miR-198 expression in placental trophoblasts. We also used reporter assays to examine the post-transcriptional regulation of FSTL1 and assess its putative regulation by miR-198. Results We detected the expression of FSTL1 transcript in both the human extravillous trophoblast line HTR-8/SVneo and in primary term human villous trophoblasts. We also found that the expression of FSTL1 was largely restricted to extravillous trophoblasts. Hypoxia enhanced the expression of FSTL1 protein in cultured primary villous trophoblasts. Interestingly, we did not detect any evidence for expression or function of mature miR-198 in human trophoblasts. Discussion Our data indicate that placental FSTL1 is expressed particularly in extravillous trophoblasts. We also found no evidence for placental expression of miR-198, or for its regulation of FSTL1, implying that the post-transcriptional regulation of FSTL1 by miR-198 is tissue specific. PMID:26386648

  11. Pleiotropic actions of forskolin result in phosphatidylserine exposure in primary trophoblasts.

    PubMed

    Riddell, Meghan R; Winkler-Lowen, Bonnie; Jiang, Yanyan; Davidge, Sandra T; Guilbert, Larry J

    2013-01-01

    Forskolin is an extract of the Coleus forskholii plant that is widely used in cell physiology to raise intracellular cAMP levels. In the field of trophoblast biology, forskolin is one of the primary treatments used to induce trophoblastic cellular fusion. The syncytiotrophoblast (ST) is a continuous multinucleated cell in the human placenta that separates maternal from fetal circulations and can only expand by fusion with its stem cell, the cytotrophoblast (CT). Functional investigation of any aspect of ST physiology requires in vitro differentiation of CT and de novo ST formation, thus selecting the most appropriate differentiation agent for the hypothesis being investigated is necessary as well as addressing potential off-target effects. Previous studies, using forskolin to induce fusion in trophoblastic cell lines, identified phosphatidylserine (PS) externalization to be essential for trophoblast fusion and showed that widespread PS externalization is present even after fusion has been achieved. PS is a membrane phospholipid that is primarily localized to the inner-membrane leaflet. Externalization of PS is a hallmark of early apoptosis and is involved in cellular fusion of myocytes and macrophages. We were interested to examine whether PS externalization was also involved in primary trophoblast fusion. We show widespread PS externalization occurs after 72 hours when fusion was stimulated with forskolin, but not when stimulated with the cell permeant cAMP analog Br-cAMP. Using a forskolin analog, 1,9-dideoxyforskolin, which stimulates membrane transporters but not adenylate cyclase, we found that widespread PS externalization required both increased intracellular cAMP levels and stimulation of membrane transporters. Treatment of primary trophoblasts with Br-cAMP alone did not result in widespread PS externalization despite high levels of cellular fusion. Thus, we concluded that widespread PS externalization is independent of trophoblast fusion and, importantly

  12. VIP modulates the pro-inflammatory maternal response, inducing tolerance to trophoblast cells

    PubMed Central

    Fraccaroli, Laura; Alfieri, Julio; Larocca, Luciana; Calafat, Mario; Roca, Valeria; Lombardi, Eduardo; Ramhorst, Rosanna; Leirós, Claudia Pérez

    2009-01-01

    Background and purpose Successful embryo implantation is followed by a local pro-inflammatory and Th1 response, subsequently controlled by a Th2 response. Vasoactive intestinal peptide (VIP) has anti-inflammatory effects and promotes tolerogenic/Th2 responses while favouring embryonic development. We investigated the potential regulatory role of VIP on human trophoblast cells, maternal pro-inflammatory responses and trophoblast-maternal leukocyte interactions. Experimental approach We tested VIP effects directly on a trophoblast cell line (Swan 71 cells) and after co-culture with maternal peripheral blood mononuclear cells (PBMCs) as models of the feto-maternal dialogue. We also co-cultured maternal and paternal PBMCs to test effects of endogenous VIP on maternal alloresponses. Key results Swan 71 cells express VPAC1 receptors and VIP induced their proliferation and the expression of leukaemia inhibitor factor, a pro-implantatory marker. After interaction with trophoblast cells, VIP increased Foxp3, the proportion of CD4+CD25+Foxp3+ cells within maternal PBMCs and transforming growth factor β expression. Also, during the trophoblast-maternal PBMCs interaction, VIP reduced pro-inflammatory mediators [interleukin (IL)-6, monocyte chemoattractant protein 1, nitric oxide], while increasing IL-10. Trophoblast cells produced VIP which dose-dependently suppressed allomaternal responses, accompanied by reduced expression of the T cell transcription factor, T-bet. Conclusions and implications Vasoactive intestinal peptide induced pro-implantatory markers and trophoblast cell proliferation, while controlling the initial pro-inflammatory response, by increasing maternal regulatory T cells and anti-inflammatory cytokines. As an autocrine regulatory peptide VIP might contribute to fetal survival through two mechanisms; a direct trophic effect on trophoblast cells and an immunomodulatory effect that favours tolerance to fetal antigens. PMID:19133995

  13. Expression of AT1R, AT2R and AT4R and their roles in extravillous trophoblast invasion in the human.

    PubMed

    Williams, P J; Mistry, H D; Innes, B A; Bulmer, J N; Broughton Pipkin, F

    2010-05-01

    The placental renin-angiotensin system (RAS) is active from early pregnancy and may have a role in placentation. Angiotensin II (AngII) acts via binding to receptor types AT1R and AT2R. Recently smaller peptide members of the angiotensin family have been recognised as having biological relevance. Angiotensin (3-8) (AngIV) has a specific receptor (AT4R) and evokes hypertrophy, vasodilatation and vascular inflammatory response. The aim of this study was to characterise placental expression of AT1R, AT2R and AT4R, and to determine whether AngII and AngIV regulate extravillous trophoblast (EVT) invasion, apoptosis and proliferation. Placental samples were obtained from women undergoing elective surgical termination of pregnancy (TOP) at 8-10 weeks gestation (early TOP), 12-14 weeks gestation (mid TOP) or at delivery following normal pregnancy or with pre-eclampsia (PE). Immunohistochemistry and qRT-PCR were performed to determine placental mRNA and protein expression of AT1R, AT2R and AT4R at all gestational ages. EVT invasion following culture with AngII or AngIV was assessed in early placental tissue using Matrigel invasion assays. Invasion was assessed on day 6 of culture and placental explants were harvested for immunohistochemical analysis of apoptosis and proliferation. The results from qRT-PCR and immunohistochemistry showed placental AT1R expression which did not vary with gestation. The highest levels of expression of AT2R were found in early and mid TOP placentae compared to term pregnancy. Expression of AT4R was increased in term placentae, with a significant reduction in PE placentae. Moreover, culture with AngIV or AngII increased EVT invasion from placental explants, which showed increased trophoblast proliferation and reduced apoptosis. This study has characterised expression of AT4R and AT1R and AT2R in human placenta throughout normal pregnancy and in PE. Both AngIV and AngII may play an important role in normal pregnancy.

  14. Vessel remodelling, pregnancy hormones and extravillous trophoblast function.

    PubMed

    Chen, Jessie Z-J; Sheehan, Penelope M; Brennecke, Shaun P; Keogh, Rosemary J

    2012-02-26

    During early human pregnancy, extravillous trophoblast (EVT) cells from the placenta invade the uterine decidual spiral arterioles and mediate the remodelling of these vessels such that a low pressure, high blood flow can be supplied to the placenta. This is essential to facilitate normal growth and development of the foetus. Defects in remodelling can manifest as the serious pregnancy complication pre-eclampsia. During the period of vessel remodelling three key pregnancy-associated hormones, human chorionic gonadotrophin (hCG), progesterone (P(4)) and oestradiol (E(2)), are found in high concentrations at the maternal-foetal interface. Potentially these hormones may control EVT movement and thus act as regulators of vessel remodelling. This review will discuss what is known about how these hormones affect EVT proliferation, migration and invasion during vascular remodelling and the potential relationship between hCG, P(4), E(2) and the development of pre-eclampsia.

  15. B-cell lymphoma 6 promotes proliferation and survival of trophoblastic cells

    PubMed Central

    Muschol-Steinmetz, Cornelia; Jasmer, Britta; Kreis, Nina-Naomi; Steinhäuser, Kerstin; Ritter, Andreas; Rolle, Udo; Yuan, Juping; Louwen, Frank

    2016-01-01

    ABSTRACT Preeclampsia is one of the leading causes of maternal and perinatal mortality and morbidity and its pathogenesis is not fully understood. B-cell lymphoma 6 (BCL6), a key regulator of B-lymphocyte development, is altered in preeclamptic placentas. We show here that BCL6 is present in all 3 studied trophoblast cell lines and it is predominantly expressed in trophoblastic HTR-8/SVneo cells derived from a 1st trimester placenta, suggestive of its involvement in trophoblast expansion in the early stage of placental development. BCL6 is strongly stabilized upon stress stimulation. Inhibition of BCL6, by administrating either small interfering RNA or a specific small molecule inhibitor 79–6, reduces proliferation and induces apoptosis in trophoblastic cells. Intriguingly, depletion of BCL6 in HTR-8/SVneo cells results in a mitotic arrest associated with mitotic defects in centrosome integrity, indicative of its involvement in mitotic progression. Thus, like in haematopoietic cells and breast cancer cells, BCL6 promotes proliferation and facilitates survival of trophoblasts under stress situation. Further studies are required to decipher its molecular roles in differentiation, migration and the fusion process of trophoblasts. Whether increased BCL6 observed in preeclamptic placentas is one of the causes or the consequences of preeclampsia warrants further investigations in vivo and in vitro. PMID:27029530

  16. Taurine transport in human placental trophoblast is important for regulation of cell differentiation and survival.

    PubMed

    Desforges, M; Parsons, L; Westwood, M; Sibley, C P; Greenwood, S L

    2013-03-21

    The outer epithelial cell layer of human placenta, the syncytiotrophoblast, is a specialised terminally differentiated multinucleate tissue. It is generated and renewed from underlying cytotrophoblast cells that undergo proliferation, differentiation and fusion with syncytiotrophoblast. Acquisition of fresh cellular components is thought to be balanced by apoptosis and shedding of aged nuclei. This process of trophoblast cell turnover maintains a functional syncytiotrophoblast, capable of sufficient nutrient transfer from mother to foetus. Foetal growth restriction (FGR) is a pregnancy complication associated with aberrant trophoblast turnover and reduced activity of certain amino acid transporters, including the taurine transporter (TauT). Taurine is the most abundant amino acid in human placenta implying an important physiological role within this tissue. Unlike other amino acids, taurine is not incorporated into proteins and in non-placental cell types represents an important osmolyte involved in cell volume regulation, and is also cytoprotective. Here, we investigated the role of taurine in trophoblast turnover using RNA interference to deplete primary human trophoblast cells of TauT and reduce intracellular taurine content. Trophoblast differentiation was compromised in TauT-deficient cells, and susceptibility of these cells to an inflammatory cytokine that is elevated in FGR was increased, evidenced by elevated levels of apoptosis. These data suggest an important role for taurine in trophoblast turnover and cytoprotection.

  17. Taurine transport in human placental trophoblast is important for regulation of cell differentiation and survival

    PubMed Central

    Desforges, M; Parsons, L; Westwood, M; Sibley, C P; Greenwood, S L

    2013-01-01

    The outer epithelial cell layer of human placenta, the syncytiotrophoblast, is a specialised terminally differentiated multinucleate tissue. It is generated and renewed from underlying cytotrophoblast cells that undergo proliferation, differentiation and fusion with syncytiotrophoblast. Acquisition of fresh cellular components is thought to be balanced by apoptosis and shedding of aged nuclei. This process of trophoblast cell turnover maintains a functional syncytiotrophoblast, capable of sufficient nutrient transfer from mother to foetus. Foetal growth restriction (FGR) is a pregnancy complication associated with aberrant trophoblast turnover and reduced activity of certain amino acid transporters, including the taurine transporter (TauT). Taurine is the most abundant amino acid in human placenta implying an important physiological role within this tissue. Unlike other amino acids, taurine is not incorporated into proteins and in non-placental cell types represents an important osmolyte involved in cell volume regulation, and is also cytoprotective. Here, we investigated the role of taurine in trophoblast turnover using RNA interference to deplete primary human trophoblast cells of TauT and reduce intracellular taurine content. Trophoblast differentiation was compromised in TauT-deficient cells, and susceptibility of these cells to an inflammatory cytokine that is elevated in FGR was increased, evidenced by elevated levels of apoptosis. These data suggest an important role for taurine in trophoblast turnover and cytoprotection. PMID:23519128

  18. The NR4A receptors Nurr1 and Nur77 are increased in human placenta from women with gestational diabetes.

    PubMed

    Lappas, M

    2014-11-01

    Members of the NR4A subfamily are involved in a wide range of diseases including obesity and diabetes. The aim of this study was to determine the effect of maternal obesity and gestational diabetes mellitus (GDM) on the expression of the NR4A receptors Nurr1, Nur77 and NOR1. Human placenta was obtained at the time of term Caesarean section from (i) lean and obese and normal glucose tolerant (NGT) pregnant women; and (ii) women with GDM and BMI-matched NGT women (n = 16 patients). Primary trophoblast cells, isolated from human term placenta, were used to determine the effect of pro-inflammatory cytokines on NR4A protein expression. Primary trophoblast cells were also used to assess the effect of Nurr1, Nur77 and NOR1 siRNA knockdown on pro-inflammatory cytokines. There was no effect of pre-existing maternal obesity on Nurr1, Nur77 or NOR1 expression. Nurr1 and Nur77 expression were significantly higher in GDM placenta compared to NGT placenta, and in the presence of the pro-inflammatory cytokines TNF-α and IL-β in primary trophoblast cells. Knockdown of Nurr1 and Nur77 in human primary trophoblast cells significantly decreased TNF-α induced expression and secretion of IL-6 and IL-8. Nurr1 and Nur77, which were increased in human placenta from women with GDM, are involved in TNF-α induced-expression of pro-inflammatory cytokines. Pro-inflammatory cytokines are known to play a role in placental nutrient transport. Thus, the regulation of pro-inflammatory cytokines by Nurr1 and Nur77 suggest that these proteins may play a role in placental function and transport mechanisms. Copyright © 2014 Elsevier Ltd. All rights reserved.

  19. Glycogen Storage Disease Type IV and Early Implantation Defect: Early Trophoblastic Involvement Associated with a New GBE1 Mutation.

    PubMed

    Dainese, Linda; Adam, Nicolas; Boudjemaa, Sabah; Hadid, Kamel; Rosenblatt, Jonathan; Jouannic, Jean-Marie; Heron, Delphine; Froissart, Roseline; Coulomb, Aurore

    A 29-year-old primigravida presented with a spontaneous miscarriage at 8 weeks of gestation. There was no consanguinity in the family. Aspiration was performed. Pathological examination showed immature villi with numerous slightly yellow intracytoplasmic inclusions within the early implantation stage cytotrophoblastic cells. Inclusions were periodic acid-Schiff and Alcian blue positive and partially positive with periodic acid-Schiff with amylase. Diagnosis of Glycogen storage disease type IV (GSD IV) was made. Genetic analysis of glycogen branching enzyme 1 gene (GBE1) was performed in parents and showed a novel deletion of 1 nucleotide, c.1937delT, affecting the mother and a mutation affecting a consensus splice site, c.691+2T>C, in the father. At time of subsequent pregnancy, genetic counseling with GBE1 gene analysis was performed on throphoblastic biopsy and showed a mutated allele, c.1937delT, inherited from the mother. The mother gave birth to a healthy, unaffected female newborn. Our findings demonstrate that GSD IV may affect early pregnancies, leading to trophoblastic damage and early fetal loss. Diagnosis can accurately be made on pathological examination and should be further documented by genetic analysis.

  20. [Gestational and non-gestational factors for perinatal programming of insulin resistance].

    PubMed

    Varadinova, M; Metodieva, R; Boyadjieva, N

    2014-01-01

    Insulin resistance is well known problem in type 2 diabetes mellitus (T2DM). Various factors play roles in the mechanisms of prenatal programming of insulin resistance. Gestational or non-gestational factors are illustrated in the present paper. Adipocytes (fat cells) produce at least 50 proteins (adipokines; peptides, cytokines, etc.), and a large part of them are involved in prenatal development of insulin resistance. The role of pro-inflammatory cytokines as the tumor necrosis factor 1 (TNF alpha), interleukin-6 (IL-6) and interleukin-1 beta (IL-1 beta) is documented. Leptin from adipocytes as well as from the placenta is involved in pathology of metabolism and plays a role as a gestational factor for the prenatal insulin resistance and the risk for T2DM. Epigenetic mechanisms as the methylation of DNA and histones, the acetylation of histones are documented for prenatal development of insulin resistance. Epigenetic modulations may explain the risk of T2DM for generations. New data indicated that the placenta does not produce adiponectin and it is also one of the important factors for the development of gestational diabetes and risk for the fetus. Taken together all factors documented in the present paper may predict the risk for prenatal T2DM.

  1. Plet1 is an epigenetically regulated cell surface protein that provides essential cues to direct trophoblast stem cell differentiation

    PubMed Central

    Murray, Alexander; Sienerth, Arnold R.; Hemberger, Myriam

    2016-01-01

    Gene loci that are hypermethylated and repressed in embryonic (ESCs) but hypomethylated and expressed in trophoblast (TSCs) stem cells are very rare and may have particularly important roles in early developmental cell fate decisions, as previously shown for Elf5. Here, we assessed another member of this small group of genes, Placenta Expressed Transcript 1 (Plet1), for its function in establishing trophoblast lineage identity and modulating trophoblast differentiation. We find that Plet1 is tightly repressed by DNA methylation in ESCs but expressed on the cell surface of TSCs and trophoblast giant cells. In hypomethylated ESCs that are prone to acquire some trophoblast characteristics, Plet1 is required to confer a trophoblast-specific gene expression pattern, including up-regulation of Elf5. Plet1 displays an unusual biphasic expression profile during TSC differentiation and thus may be pivotal in balancing trophoblast self-renewal and differentiation. Furthermore, overexpression and CRISPR/Cas9-mediated knockout in TSCs showed that high Plet1 levels favour differentiation towards the trophoblast giant cell lineage, whereas lack of Plet1 preferentially induces syncytiotrophoblast formation. Thus, the endogenous dynamics of Plet1 expression establish important patterning cues within the trophoblast compartment by promoting differentiation towards the syncytiotrophoblast or giant cell pathway in Plet1-low and Plet1-high cells, respectively. PMID:27121762

  2. Aprepitant, Granisetron, & Dexamethasone in Preventing Nausea & Vomiting in Pts. Receiving Cyclophosphamide Before a Stem Cell Transplant

    ClinicalTrials.gov

    2016-02-12

    Breast Cancer; Chronic Myeloproliferative Disorders; Gestational Trophoblastic Tumor; Leukemia; Lymphoma; Multiple Myeloma and Plasma Cell Neoplasm; Myelodysplastic Syndromes; Myelodysplastic/Myeloproliferative Neoplasms; Nausea and Vomiting; Neuroblastoma; Ovarian Cancer; Testicular Germ Cell Tumor

  3. Moxifloxacin in Preventing Bacterial Infections in Patients Who Have Undergone Donor Stem Cell Transplant

    ClinicalTrials.gov

    2017-05-07

    Breast Cancer; Chronic Myeloproliferative Disorders; Gestational Trophoblastic Tumor; Infection; Leukemia; Lymphoma; Multiple Myeloma and Plasma Cell Neoplasm; Myelodysplastic Syndromes; Myelodysplastic/Myeloproliferative Neoplasms; Neuroblastoma; Ovarian Cancer; Testicular Germ Cell Tumor

  4. Blood Samples From Patients With Cancer Treated on a Clinical Trial to Control Nausea and Vomiting During Donor Stem Cell Transplant

    ClinicalTrials.gov

    2016-02-11

    Breast Cancer; Chronic Myeloproliferative Disorders; Gestational Trophoblastic Tumor; Leukemia; Lymphoma; Multiple Myeloma and Plasma Cell Neoplasm; Myelodysplastic Syndromes; Myelodysplastic/Myeloproliferative Neoplasms; Nausea and Vomiting; Neuroblastoma; Ovarian Cancer; Testicular Germ Cell Tumor

  5. Beclomethasone in Treating Patients With Graft-Versus-Host Disease of the Esophagus, Stomach, Small Intestine, or Colon

    ClinicalTrials.gov

    2010-03-31

    Breast Cancer; Chronic Myeloproliferative Disorders; Gestational Trophoblastic Tumor; Graft Versus Host Disease; Kidney Cancer; Leukemia; Lymphoma; Multiple Myeloma and Plasma Cell Neoplasm; Myelodysplastic Syndromes; Neuroblastoma; Ovarian Cancer; Testicular Germ Cell Tumor

  6. Ravuconazole in Preventing Fungal Infections in Patients Undergoing Allogeneic Stem Cell Transplantation

    ClinicalTrials.gov

    2012-03-07

    Breast Cancer; Chronic Myeloproliferative Disorders; Gestational Trophoblastic Tumor; Infection; Leukemia; Lymphoma; Multiple Myeloma and Plasma Cell Neoplasm; Myelodysplastic Syndromes; Myelodysplastic/Myeloproliferative Neoplasms; Neuroblastoma; Ovarian Cancer; Testicular Germ Cell Tumor

  7. Alemtuzumab and Glucocorticoids in Treating Newly Diagnosed Acute Graft-Versus-Host Disease in Patients Who Have Undergone a Donor Stem Cell Transplant

    ClinicalTrials.gov

    2010-05-12

    Breast Cancer; Chronic Myeloproliferative Disorders; Gestational Trophoblastic Tumor; Graft Versus Host Disease; Leukemia; Lymphoma; Multiple Myeloma and Plasma Cell Neoplasm; Myelodysplastic Syndromes; Myelodysplastic/Myeloproliferative Diseases; Neuroblastoma; Ovarian Cancer; Testicular Germ Cell Tumor

  8. Campath-1H + FK506 and Methylprednisolone for GVHD

    ClinicalTrials.gov

    2010-06-10

    Breast Cancer; Chronic Myeloproliferative Disorders; Gestational Trophoblastic Tumor; Graft Versus Host Disease; Leukemia; Lymphoma; Multiple Myeloma and Plasma Cell Neoplasm; Myelodysplastic Syndromes; Myelodysplastic/Myeloproliferative Diseases; Neuroblastoma; Ovarian Cancer; Testicular Germ Cell Tumor

  9. T Cells in Predicting Acute Graft-Versus-Host Disease in Patients Undergoing Donor Stem Cell Transplant

    ClinicalTrials.gov

    2017-06-26

    Breast Cancer; Chronic Myeloproliferative Disorders; Gestational Trophoblastic Tumor; Leukemia; Lymphoma; Multiple Myeloma and Plasma Cell Neoplasm; Myelodysplastic Syndromes; Myelodysplastic/Myeloproliferative Neoplasms; Neuroblastoma; Ovarian Cancer; Testicular Germ Cell Tumor

  10. Study of the Emotional Needs of Caregivers of Stem Cell Transplantation Patients

    ClinicalTrials.gov

    2010-09-17

    Breast Cancer; Chronic Myeloproliferative Disorders; Gestational Trophoblastic Tumor; Leukemia; Lymphoma; Multiple Myeloma and Plasma Cell Neoplasm; Myelodysplastic Syndromes; Myelodysplastic/Myeloproliferative Diseases; Neuroblastoma; Ovarian Cancer; Psychosocial Effects of Cancer and Its Treatment; Testicular Germ Cell Tumor

  11. Collecting and Storing Tissue and DNA Samples From Patients Undergoing a Donor Stem Cell Transplant

    ClinicalTrials.gov

    2012-11-04

    Breast Cancer; Chronic Myeloproliferative Disorders; Gestational Trophoblastic Tumor; Graft Versus Host Disease; Leukemia; Lymphoma; Multiple Myeloma and Plasma Cell Neoplasm; Myelodysplastic Syndromes; Myelodysplastic/Myeloproliferative Neoplasms; Neuroblastoma; Ovarian Cancer; Testicular Germ Cell Tumor

  12. [Gestational diabetes mellitus].

    PubMed

    Kautzky-Willer, Alexandra; Bancher-Todesca, Dagmar; Pollak, Arnold; Repa, Andreas; Lechleitner, Monika; Weitgasser, Raimund

    2012-12-01

    Gestational diabetes (GDM) is defined as any degree of glucose intolerance with onset during pregnancy and is associated with increased feto-maternal morbidity as well as long-term complications in mothers and offspring. Women detected to have diabetes early in pregnancy receive the diagnosis of overt, non-gestational, diabetes. GDM is diagnosed by an oral glucose tolerance test (OGTT) or fasting glucose concentrations (> 92 mg/dl). Screening for undiagnosed type 2 diabetes at the first prenatal visit (Evidence level B) is recommended in women at increased risk using standard diagnostic criteria (high risk: history of GDM or pre-diabetes (impaired fasting glucose or impaired glucose tolerance); malformation, stillbirth, successive abortions or birthweight > 4,500 g in previous pregnancies; obesity, metabolic syndrome, age > 45 years, vascular disease; clinical symptoms of diabetes (e.g. glucosuria). Performance of the OGTT (120 min; 75 g glucose) may already be indicated in the first trimester in some women but is mandatory between 24 and 28 gestational weeks in all pregnant women with previous non-pathological glucose metabolism (Evidence level B). Based on the results of the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study GDM is defined, if fasting venous plasma glucose exceeds 92 mg/dl or 1 h 180 mg/dl or 2 h 153 mg/dl after glucose loading (OGTT; international consensus criteria). In case of one pathological value a strict metabolic control is mandatory. All women should receive nutritional counseling and be instructed in blood glucose self-monitoring. If blood glucose levels cannot be maintained in the normal range (fasting < 95 mg/dl and 1 h after meals < 140 mg/dl) insulin therapy should be initiated. Maternal and fetal monitoring is required in order to minimize maternal and fetal/neonatal morbidity and perinatal mortality. After delivery all women with GDM have to be reevaluated as to their glucose tolerance by a 75 g OGTT (WHO criteria) 6

  13. The Tnfrh1 (Tnfrsf23) gene is weakly imprinted in several organs and expressed at the trophoblast-decidua interface

    PubMed Central

    Clark, Lorraine; Wei, Michelle; Cattoretti, Giorgio; Mendelsohn, Cathy; Tycko, Benjamin

    2002-01-01

    Background The Tnfrh1 gene (gene symbol Tnfrsf23) is located near one end of a megabase-scale imprinted region on mouse distal chromosome 7, about 350 kb distant from the nearest known imprinting control element. Within 20 kb of Tnfrh1 is a related gene called Tnfrh2 (Tnfrsf22) These duplicated genes encode putative decoy receptors in the tumor necrosis factor (TNF) receptor family. Although other genes in this chromosomal region show conserved synteny with genes on human Chr11p15.5, there are no obvious human orthologues of Tnfrh1 or Tnfrh2. Results We analyzed Tnfrh1 for evidence of parental imprinting, and characterized its tissue-specific expression. Tnfrh1 mRNA is detectable in multiple adult and fetal tissues, with highest expression in placenta, where in situ hybridization reveals a distinctive population of Tnfrh1-positive cells in maternal decidua, directly beneath the trophoblast giant cells. In offspring of interspecific mouse crosses, Tnfrh1 shows a consistent parent-of-origin-dependent allelic expression bias, with relative repression, but not silencing, of the paternal allele in several organs including fetal liver and adult spleen. Conclusions Genes preferentially expressed in the placenta are predicted to evolve rapidly, and Tnfrh1 appears to be an example of this phenomenon. In view of its strong expression in cells at the fetal-maternal boundary, Tnfrh1 warrants further study as a gene that might modulate immune or trophic interactions between the invasive placental trophoblast and the maternal decidua. The preferential expression of Tnfrh1 from the maternal allele indicates weak functional imprinting of this locus in some tissues. PMID:12102730

  14. Immunohistochemical evidence for ubiquitous distribution of metalloendoprotease insulin-degrading enzyme (IDE; insulysin) in human non-malignant tissues and tumor cell lines

    PubMed Central

    Weirich, Gregor; Mengele, Karin; Yfanti, Christina; Gkazepis, Apostolos; Hellmann, Daniela; Welk, Anita; Giersig, Cecylia; Kuo, Wen-Liang; Rosner, Marsha Rich; Tang, Wei-Jen; Schmitt, Manfred

    2013-01-01

    Immunohistochemical evidence for ubiquitous distribution of metalloprotease insulin-degrading enzyme (IDE; insulysin) in human non-malignant tissues and tumor cells is presented. Immunohistochemical staining was performed on a multi-organ tissue microarray (pancreas, lung, kidney, central/peripheral nervous system, liver, breast, placenta, myocardium, striated muscle, bone marrow, thymus, spleen) and on a cell microarray encompassing 31 tumor cell lines of different origin plus trophoblast cells, and normal blood lymphocytes and granulocytes. IDE protein is expressed by all of the tissues assessed and in all of the tumor cell lines except Raji and HL-60; trophoblast cells and granulocytes but not normal lymphocytes are also IDE-positive. PMID:18783335

  15. Gestational diabetes mellitus.

    PubMed

    Landon, Mark B; Gabbe, Steven G

    2011-12-01

    Gestational diabetes mellitus (GDM) represents a heterogeneous group of metabolic disorders, which result in varying degrees of maternal hyperglycemia and pregnancy-associated risk. The frequency of GDM is rising globally and may also increase further as less-stringent criteria for the diagnosis are potentially adopted. The additional burden placed on the health care system by increasing cases of GDM requires consideration of diagnostic approaches and currently used treatment strategies. Debate continues to surround both the diagnosis and treatment of GDM despite several recent large-scale studies addressing these controversial issues. As many now have come to reassess their approach to the management of GDM, we provide information in this review to help guide this process. The goal for each health care practitioner should continue to be to provide optimum care for women discovered to have carbohydrate intolerance during pregnancy.

  16. Gestational diabetes mellitus

    PubMed Central

    Alfadhli, Eman M.

    2015-01-01

    Gestational diabetes mellitus (GDM) is the most common medical complication of pregnancy. It is associated with maternal and neonatal adverse outcomes. Maintaining adequate blood glucose levels in GDM reduces morbidity for both mother and baby. There is a lack of uniform strategies for screening and diagnosing GDM globally. This review covers the latest update in the diagnosis and management of GDM. The initial treatment of GDM consists of diet and exercise. If these measures fail to achieve glycemic goals, insulin should be initiated. Insulin analogs are more physiological than human insulin, and are associated with less risk of hypoglycemia, and may provide better glycemic control. Insulin lispro, aspart, and detemir are approved to be used in pregnancy. Insulin glargine is not approved in pregnancy, but the existing studies did not show any contraindications. The use of oral hypoglycemic agents; glyburide and metformin seems to be safe and effective in pregnancy. PMID:25828275

  17. [Gestational diabetes mellitus].

    PubMed

    Kautzky-Willer, Alexandra; Harreiter, Jürgen; Bancher-Todesca, Dagmar; Berger, Angelika; Repa, Andreas; Lechleitner, Monika; Weitgasser, Raimund

    2016-04-01

    Gestational diabetes (GDM) is defined as any degree of glucose intolerance with onset during pregnancy and is associated with increased feto-maternal morbidity as well as long-term complications in mothers and offspring. Women detected to have diabetes early in pregnancy receive the diagnosis of overt, non-gestational, diabetes (glucose: fasting > 126 mg/dl, spontaneous > 200 mg/dl or HbA1c > 6.5 % before 20 weeks of gestation). GDM is diagnosed by an oral glucose tolerance test (OGTT) or fasting glucose concentrations (> 92 mg/dl). Screening for undiagnosed type 2 diabetes at the first prenatal visit (Evidence level B) is recommended in women at increased risk using standard diagnostic criteria (high risk: history of GDM or pre-diabetes (impaired fasting glucose or impaired glucose tolerance); malformation, stillbirth, successive abortions or birth weight > 4,500 g in previous pregnancies; obesity, metabolic syndrome, age > 45 years, vascular disease; clinical symptoms of diabetes (e. g. glucosuria)). Performance of the OGTT (120 min; 75 g glucose) may already be indicated in the first trimester in some women but is mandatory between 24 and 28 gestational weeks in all pregnant women with previous non-pathological glucose metabolism (Evidence level B). Based on the results of the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study GDM is defined, if fasting venous plasma glucose exceeds 92 mg/dl or 1 h 180 mg/dl or 2 h 153 mg/dl after glucose loading (OGTT; international consensus criteria). In case of one pathological value a strict metabolic control is mandatory. This diagnostic approach was recently also recommended by the WHO. All women should receive nutritional counseling and be instructed in blood glucose self-monitoring and to increase physical activity to moderate intensity levels- if not contraindicated. If blood glucose levels cannot be maintained in the normal range (fasting < 95 mg/dl and 1 h after meals < 140 mg/dl) insulin

  18. [Gestational diabetes mellitus].

    PubMed

    Kautzky-Willer, Alexandra; Bancher-Todesca, Dagmar; Birnbacher, Robert

    2004-01-01

    Gestational diabetes (GDM) is defined as any degree of glucose intolerance with onset or first recognition during pregnancy and is associated with increased feto-maternal morbidity as well as long-term complications in mothers and offspring. GDM is diagnosed by an oral glucose tolerance test (OGTT) or fasting glucose concentrations in the diabetic range. In case of a high risk for GDM/type 2 diabetes (history of GDM or prediabetes [impaired fasting glucose or impaired glucose tolerance]; malformation, stillbirth, successive abortions or birth-weight > 4500 g in previous pregnancies) performance of the OGTT (120 min; 75 g glucose) is recommended already in the first trimester and--if normal--the OGTT should be repeated in the second/third trimester. In case of clinical symptoms of diabetes (glucosuria, macrosomia) the test has to be performed immediately. All other women should undergo a diagnostic test between 24 and 28 gestational weeks. If fasting plasma glucose exceeds 95 mg/dl, 1 h 180 mg/dl and 2 hrs 155 mg/dl after glucose loading (OGTT) the woman is classified as GDM (one pathological value is sufficient). In this case a strict metabolic control is mandatory. All women should receive nutritional counseling and be instructed in blood glucose self-monitoring. If blood glucose levels cannot be maintained in the normal range (fasting < 95 mg/dl and 1 h after meals < 130 mg/dl) insulin therapy should be initiated. Maternal and fetal monitoring is required in order to minimize maternal and fetal/neonatal morbidity and perinatal mortality. After delivery all women with GDM have to be reevaluated as to their glucose tolerance by a 75 g OGTT (WHO criteria).

  19. Gestation length in farmed reindeer.

    PubMed

    Shipka, M P; Rowell, J E

    2010-01-01

    Reindeer (Rangifer tarandus tarundus) are the only cervids indigenous to the arctic environment. In Alaska, reindeer are a recognized agricultural species and an economic mainstay for many native populations. Traditionally raised in extensive free-ranging systems, a recent trend toward intensive farming requires a more in-depth knowledge of reproductive management. Reported gestation length in reindeer varies, ranging from 198 to 229 d in studies performed at the University of Alaska Fairbanks. A switchback study that manipulated only breeding date demonstrated a mean increase in gestation length of 8.5 d among females bred early in the season. The negative correlation between conception date and gestation length is consistent with reindeer research at other locations and reports of variable gestation length in a growing number of domestic and non-domestic species. This paper reviews the phenomenon in reindeer and discusses some of the factors known to affect gestation length as well as possible areas for future research.

  20. Pre-evacuation hCG glycoforms in uneventful complete hydatidiform mole and persistent trophoblastic disease.

    PubMed

    Thomas, Chris M G; Kerkmeijer, Linda G W; Ariaens, Henk J W; van der Steen, Rob C B M; Massuger, Leon F A G; Sweep, Fred C G J

    2010-04-01

    To investigate whether the glycoform distribution patterns of human chorionic gonadotropin (hCG) obtained by chromatofocusing in pre-evacuation serum are different for patients who will eventually develop into persistent trophoblastic disease in case of complete hydatidiform mole pregnancy as compared to those patients for whom trophoblastic tissue will regress uneventfully. Pre-evacuation blood samples were collected from women with complete hydatidiform mole with uneventful spontaneous regression after molar evacuation (n=32), from women with complete hydatidiform mole who developed persistent trophoblastic disease after evacuation of their mole (n=28) and, as a control group, from women during the first trimester of normal pregnancy (n=22). The serum specimens were subjected to chromatofocusing, and hCG was determined in the fractions collected in the pH range 7.0-3.0. Receiver operating characteristics (ROC) analysis revealed that 36% of complete hydatidiform mole patients with post-molar persistent trophoblastic disease development had different hCG glycoform profiles at 97% specificity (pH interval 6.3-5.1, hCG cutoff 9.9%). There was a significant difference between complete hydatidiform mole with and without persistent trophoblastic disease for the cumulative percent amounts of hCG in the pH interval 6.3-5.1 (p<0.0003). In 36% of the patients with complete hydatidiform mole with subsequent development of persistent trophoblastic disease, typical glycoform profiles for hCG are observed in pre-evacuation serum samples. This result suggests that hCG glycoform profiles are of potential use in the prediction of persistent trophoblastic disease. Copyright 2010 Elsevier Inc. All rights reserved.

  1. Human cytomegalovirus infection interferes with the maintenance and differentiation of trophoblast progenitor cells of the human placenta.

    PubMed

    Tabata, Takako; Petitt, Matthew; Zydek, Martin; Fang-Hoover, June; Larocque, Nicholas; Tsuge, Mitsuru; Gormley, Matthew; Kauvar, Lawrence M; Pereira, Lenore

    2015-05-01

    impairment, and pregnancy complications, including intrauterine growth restriction, preterm delivery, and stillbirth. Currently, there is neither a vaccine nor any approved treatment for congenital HCMV infection during gestation. The molecular mechanisms underlying structural deficiencies in the placenta that undermine fetal development are poorly understood. Here we report that HCMV replicates in trophoblast progenitor cells (TBPCs)-precursors of the mature placental cells, syncytiotrophoblasts and cytotrophoblasts, in chorionic villi-in clinical cases of congenital infection. Virus replication in TBPCs in vitro dysregulates key proteins required for self-renewal and differentiation and inhibits normal division and development into mature placental cells. Our findings provide insights into the underlying molecular mechanisms by which HCMV replication interferes with placental maturation and transport functions. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

  2. Human Cytomegalovirus Infection Interferes with the Maintenance and Differentiation of Trophoblast Progenitor Cells of the Human Placenta

    PubMed Central

    Tabata, Takako; Petitt, Matthew; Zydek, Martin; Fang-Hoover, June; Larocque, Nicholas; Tsuge, Mitsuru; Gormley, Matthew; Kauvar, Lawrence M.

    2015-01-01

    , hearing loss, visual impairment, and pregnancy complications, including intrauterine growth restriction, preterm delivery, and stillbirth. Currently, there is neither a vaccine nor any approved treatment for congenital HCMV infection during gestation. The molecular mechanisms underlying structural deficiencies in the placenta that undermine fetal development are poorly understood. Here we report that HCMV replicates in trophoblast progenitor cells (TBPCs)—precursors of the mature placental cells, syncytiotrophoblasts and cytotrophoblasts, in chorionic villi—in clinical cases of congenital infection. Virus replication in TBPCs in vitro dysregulates key proteins required for self-renewal and differentiation and inhibits normal division and development into mature placental cells. Our findings provide insights into the underlying molecular mechanisms by which HCMV replication interferes with placental maturation and transport functions. PMID:25741001

  3. Labor patterns in twin gestations

    PubMed Central

    Leftwich, Heidi K.; Zaki, Mary N.; Wilkins, Isabelle; Hibbard, Judith U.

    2014-01-01

    Objective To compare labor progression in twin vs singleton gestations. Study Design Retrospective review of electronic database created by Consortium on Safe Labor, reflecting labor and delivery information from 12 clinical centers 2002-2008. Women with twin gestations, cephalic presentation of presenting twin, gestational age ≥34 weeks, with ≥2 cervical examinations were included. Exclusion criteria were fetal anomalies or demise. Singleton controls were selected by the same criteria. Categorical variables were analyzed by χ2; continuous by Student t test. Interval censored regression was used to determine distribution for time of cervical dilation in centimeters, or “traverse times,” and controlled for confounding factors. Repeated-measures analysis constructed mean labor curves by parity and number of fetuses. Results A total of 891 twin gestations were compared with 100,513 singleton controls. Twin gestations were more often older, white or African American, earlier gestational age, increased prepregnancy body mass index, and with lower birthweight. There was no difference in number of prior cesarean deliveries, induction, or augmentation, or epidural use. Median traverse times increased at every centimeter interval in nulliparous twins, in both unadjusted and adjusted analysis (P < .01). A similar pattern was noted for multiparas in both analyses. Labor curves demonstrated a delayed inflection point in the labor pattern for nulliparous and multiparous twin gestations. Conclusion Both nulliparous and multiparous women have slower progression of active phase labor with twins even when controlling for confounding factors. PMID:23871795

  4. Effects of vitamin C, vitamin E, and molecular hydrogen on the placental function in trophoblast cells.

    PubMed

    Guan, Zhong; Li, Huai-Fang; Guo, Li-Li; Yang, Xiang

    2015-08-01

    This study aimed to investigate the effects of three different antioxidants, namely vitamin C, vitamin E, and molecular hydrogen, on cytotrophoblasts in vitro. Two trophoblast cell lines, JAR and JEG-3, were exposed to different concentrations of vitamin C (0, 25, 50, 100, 500, 1,000, 5,000 μmol/L), vitamin E (0, 25, 50, 100, 500, 1,000, 5,000 μmol/L), and molecular hydrogen (0, 25, 50, 100, 500 μmol/L) for 48 h. The cell viability was detected using the MTS assay. The secretion of human chorionic gonadotropin (hCG) and the tumor necrosis factor-α (TNF-α) were assessed and the expression of TNF-α mRNA was observed by real-time RT-PCR. Cell viability was significantly suppressed by 500 μmol/L vitamins C and E (P < 0.05), but not by 500 μmol/L molecular hydrogen (P > 0.05). The expression of TNF-α was increased by 100 μmol/L vitamin C and 50 μmol/L vitamins E, separately or combined (P < 0.05), but not by molecular hydrogen (0-500 μmol/L), as validated by real-time RT-PCR. But the secretion of hCG was both inhibited by 50-500 μmol/L molecular hydrogen and high levels of vitamin C and E, separately or combined. High levels of antioxidant vitamins C and E may have significant detrimental effects on placental function, as reflected by decreased cell viability and secretion of hCG; and placental immunity, as reflected by increased production of TNF-a. Meanwhile hydrogen showed no such effects on cell proliferation and TNF-α expression, but it could affect the level of hCG, indicating hydrogen as a potential candidate of antioxidant in the management of preeclampsia (PE) s