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PubMed1981

On the control of the trophoblastic giant-cell transformation in the mouse: homotypic cellular interactions and polyploidy.

Trophoblastic tissues grown under different conditions in vitro display distinct patterns of cellular growth. Thus, trophoblast cultured on 'bacteriological grade' plastic surfaces remained in suspension culture as rounded tissue fragments. Such tissues maintained numerous cell contacts and remained, in turn, largely diploid. Trophoblast explanted on a 'tissue-culture grade' substrate formed monolayers. These contained fewer cell contacts and had more giant nuclei than the rounded tissues. Finally, if trophoblast was dissociated and grown as attached single cells, so that cell contact was minimal or absent, the single-cell preparations contained more giant nuclei than tissues grown either as monolayers or in suspension. These results suggest that changes in tissue shape and the number of cell contacts can modify the growth of mouse trophoblast and alter its ability to become giant.

Animals↗
PubMed1995

Matrix metalloproteinases and their tissue inhibitors at the ovine trophoblast-uterine interface.

Trophoblast invasiveness in ruminants is limited to fusion of migrating binucleate cells with uterine epithelium, but considerable tissue remodelling and angiogenesis occurs within the endometrium at implantation. Such processes are elsewhere associated with an altered balance of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs). ProMMPs-1, -2, -3 are secreted by cultured ovine endometrial stromal, but not epithelial, cells and expression of proMMP-1 and proMMP-3 is inhibited by interferon tau, the dominant preimplantation trophoblast product, independently of its effects on prostaglandin production. Messenger RNA for TIMP-1 and TIMP-2 is expressed in endometrium throughout the oestrous cycle and early pregnancy. Both TIMP-1 mRNA (0.9 kb transcript) and TIMP-2 mRNA (1.0 kb transcript) expression increase at day 12 through to day 20, suggesting a role in preventing trophoblast invasion. Expression of the 3.5 kb transcript for TIMP-2 decreases from day 16 and is undetectable on day 20. Uterine flushings from both nonpregnant and pregnant ewes on day 16 after oestrus contain proMMP-2, possibly transudated from plasma, and proMMP-9, but concentrations are higher in pregnancy. These enzymes are also detected in conditioned medium following culture of trophoblasts at days 16-20. Whether the trophoblast MMPs have a role in implantation in sheep remains to be established. The production of MMPs and TIMPs in the endometrium and the changes associated with implantation events suggest that they contribute to the marked edometrial remodelling associated with early placentation.

Animals↗
PubMed1994

Gestational trophoblastic tumors: refining histologic diagnoses by using DNA flow and image cytometry.

During the past year much effort has been focused on defining the DNA content of gestational trophoblastic tumors. Flow cytometric and image analysis studies of molar pregnancies confirmed that the majority of partial hydatidiform moles were triploid, and, as expected, most complete hydatidiform moles were diploid or diploid/tetraploid. There were rather large intra- and interobserver variations in diagnosing hydropic abortuses and hydatidiform moles when the DNA content had not been assayed. Knowledge of the DNA content increased diagnostic accord. Interphase cytogenetic probes for specific chromosomes and analysis of dinucleotide repeat sequences (microsatellites) allowed determination of DNA ploidy and assignment of parental origin, respectively. Unusual cases of hydatidiform moles complicated by twin pregnancy were associated with delays in clinical diagnosis and increased rates of persistent and metastatic trophoblastic disease. Residual nodules of intermediate trophoblast, an unusual form of persistent trophoblastic disease, were relatively resistant to chemotherapy and required further surgical intervention. Though immunohistochemistry aids in distinguishing placental site trophoblastic tumor from choriocarcinoma, occasional tumors show overlapping immunohistochemical profiles.

Cytodiagnosis↗
PubMed1995

T-helper 1-type immunity to trophoblast in women with recurrent spontaneous abortion.

OBJECTIVE: To test the hypothesis that peripheral blood mononuclear cells in women with unexplained recurrent abortion (URA) produce T-helper 1 (TH1)-type cytokines in response to trophoblast antigens. DESIGN: Cohort study. SETTING: Medical center. PARTICIPANTS: A total of 244 women with URA, 13 reproductively normal parous control women, and 10 men. MAIN OUTCOME MEASURES: Supernatants from trophoblast-activated peripheral blood mononuclear cells from all participants were tested for toxic effects on mouse embryos and by enzyme-linked immunosorbent assay (ELISA) for interferon gamma (IFN-gamma). Supernatants from 20 URA patients with embryotoxic activity and IFN-gamma, 13 reproductively normal parous women, and 10 men were further tested by ELISA for other TH1-type cytokines (interleukin-2 [IL-2], tumor necrosis factor-beta [TNF-beta]), TH2-type cytokines (IL-4, IL-10), and TNF-alpha. RESULTS: Embryotoxic activity was detected in supernatants from 160 of 244 URA patients and in none of the controls. Interferon gamma was detected in supernatants from 125 of 244 URA patients and was significantly associated with embryotoxicity (121 of 160 supernatants with embryotoxicity vs four of 84 supernatants without embryotoxicity [P < .001]). Of 20 supernatants from patients chosen for further study, all were positive for TNF-alpha, 17 for TNF-beta, two for IL-10, and one for IL-4. No cytokines were detected in supernatants from unstimulated or red blood cell membrane-activated cells of women with URA. In contrast, trophoblast-activated lymphocyte supernatants from reproductively normal women and men neither were embryotoxic nor contained TH1-type cytokines, but most contained the TH2-type cytokine IL-10. Three supernatants from reproductively normal women also contained IL-4. CONCLUSION: Whereas TH1-type immunity to trophoblast is associated with URA and may play a role in reproductive failure, TH2-type immunity may be a natural response to trophoblast contributing to successful pregnancy.

Abortion, Habitual↗
PubMed1994

Opioids regulation of human chorionic gonadotropin release from trophoblast tissue is mediated by gonadotropin releasing hormone.

In the hypothalamic-pituitary axis opioid regulation of luteinizing hormone secretion occurs via gonadotropin hormone-releasing hormone (GnRH). Trophoblast gonadotropic hormone human chorionic gonadotropin (hCG) and locally produced GnRH in human placenta are similar in structure and biological functions to luteinizing hormone and GnRH from hypothalamic-pituitary axis. In addition, placental kappa receptors mediate opioid regulation of hCG release from trophoblast tissue in vitro and placental GnRH plays a role in regulation of hCG secretion as well. The purpose of this investigation was to determine whether opioids regulation of hCG release from trophoblast tissue is mediated by GnRH. Opioid agonists at their concentrations causing maximal release of hCG from the tissue also stimulated GnRH secretion. Antagonists inhibited the release of hCG and GnRH and totally reversed the effect of agonists, i.e., their effect is kappa receptor mediated. GnRH antagonist inhibited both opioids and GnRH stimulation of hCG release from trophoblast tissue. Neither GnRH nor its antagonist bind to placental kappa receptors. These data suggest that in vitro opioids regulation of hCG release from term trophoblast tissue is mediated by GnRH.

Chorionic Gonadotropin↗
PubMed1993

Distribution of Fc gamma receptors on trophoblast during human placental development: an immunohistochemical and immunoblotting study.

Expression of Fc gamma receptors on human placental trophoblast was investigated by immunostaining and immunoblotting using a panel of Fc gamma receptor monoclonal antibodies (mAb). Fc gamma receptors typical of other cell types were not detected on syncytiotrophoblast in term placentae when transplacental IgG transport was maximal. Unexpectedly, however, and by contrast with term, all Fc gamma receptor III mAb tested bound to first trimester placental syncytiotrophoblast by immunostaining. Reactivity was relatively restricted and varied between specimens. Fc gamma receptor III products of 41,000-45,000 and 49,000-52,000 MW were consistently detected on first trimester trophoblast membranes by immunoblotting and levels of these products were greatly reduced following treatment with phosphatidylinositol-specific phospholipase C, suggesting that the early trophoblast Fc gamma receptor III is glycosyl-phosphatidylinositol (GPI) linked. The mAb Leu-11b behaved differently to other anti-Fc gamma receptor III mAb examined. By immunostaining, Leu-11b bound to syncytiotrophoblast at term and detected both syncytiotrophoblast and underlying cytotrophoblast in the first trimester. In addition to the GPI-anchored Fc gamma receptor III in first trimester, Leu-11b also detected a 74,000 MW component on both first trimester and term trophoblast membranes by immunoblotting. Thus trophoblast appears to express a GPI-anchored Fc gamma receptor III in first trimester but not term placentae. With the exception of the 74,000 MW Leu-11b-defined product whose function is unclear, currently available Fc gamma receptor mAb appear to be incapable of detecting the protein involved in IgG transport during the later stages of gestation.

Antibodies, Monoclonal↗
PubMed1993

[Epidermal growth factor regulates trophoblast proliferation and differentiation in an autocrine/paracrine manner].

Effects of epidermal growth factor (EGF) on the expression of trophoblast proliferation and differentiation were investigated in vitro using an organ culture system of human placental tissues. Explants of trophoblastic tissues obtained from each trimester of gestation were cultured with or without EGF (100 ng/ml) in serum-free conditions. In order to determine the possible effect of EGF on the proliferation activity of villous trophoblasts, immunostaining with monoclonal antibody Ki-67 was used. On the other hand, the possible effect of EGF on the differentiated cellular function of villous trophoblasts was assessed by determining the ability to secrete hCG and hPL. In 4-5 week placenta, EGF and EGF receptor were found to be almost exclusively localized in cytotrophoblasts and EGF enhanced the proliferation of cytotrophoblasts without affecting the ability to secrete hCG and hPL, whereas in 6-12 week placenta, EGF and EGF receptor were predominantly localized in syncytiotrophoblasts and EGF stimulated the secretion of hCG and hPL without affecting the proliferation of cytotrophoblasts. These findings suggest that EGF has dual actions which independently affect trophoblast proliferation and differentiation in the first trimester of gestation in an autocrine manner. But, in the second and third trimesters of gestation, EGF mediates the expression of placental function in a paracrine manner.

Cell Differentiation↗
PubMed1995

[The ultrastructure of intermediate type trophoblast cell].

Transmission electron microscopy was used to clarify the detailed morphology of the "intermediate type" trophoblast cell in normal and tumor issue. 67 normal placental villi specimen, 10 placental bed specimens and 10 malignant mole, 10 hydatidiform mole, 5 choriocarcinoma specimen (the last three types taken before chemotherapy) were examined. Results showed that the transitional type trophoblasts of the placenta were developed from cytotrophoblasts through differentiation and fusion to syncytiotrophoblasts which showed features of maturation and aging, having features of cytotrophoblast nuclei and syncytiotrophoblast cytoplasm. The transitional trophoblast of placental bed showed similar morphology as that of transitional type cells of villi. The morphology of transitional type cells of villi. The morphology of transitional type cells of trophoblastic tumors had both normal morphology and cellular hyperplasia, atypia and features of tumor ultrastructure. The prominent feature was the high electron density of the granules and polymorphic cysts crowded in villi, demonstrating that the morphology of "intermediate type" trophoblasts in placental and tumor tissue are similar, whereas heterotype cellular morphology is present in varying degrees in tumor tissue.

Choriocarcinoma↗
PubMed1996

Endothelin-1 stimulates the proliferation and invasion of first trimester trophoblastic cells in vitro--a possible role in the etiology of pre-eclampsia?

BACKGROUND: Endothelin-1 is a potent mitogen and stimulates cell chemokinesis, but these properties have not been investigated in the placenta. Trophoblastic cells from pre-eclamptic pregnancies have a reduced invasive potency and secrete less endothelin-1 than those from normal pregnancies. The present study tested the hypothesis that endothelin-1 affects trophoblast proliferation and invasion. METHODS: Trophoblastic cells were isolated from 37 placentae of normal human pregnancies at week 12 by dispastrypsin digestion and subsequently immunopurified to remove nontrophoblastic components. The effects of 5, 10, and 20 nmol/mL endothelin-1 on proliferation and invasion were determined after 24 and 72 hours, respectively, by fluorescence-activated pulse cytometry (FACS) analysis, by measuring DNA synthesis using two different methods and by a Matrigel invasion assay. RESULTS: All cell preparations uniformly responded to 10 nmol/mL by increased proliferation, owing to a greater proportion of cells in the S-phase of their cell cycle, and invasion. The effects were more pronounced after 24 hours than after 72 hours, by which time cell viability, as measured by the secretion of human chorionic gonadotropin (hCG-beta), had deteriorated. The nonselective receptor antagonist PD 142893 inhibited both endothelin-1 effects. CONCLUSION: Endothelin-1 is a mitogenic stimulus for first trimester trophoblastic cells in vitro. The stimulation of cellular invasion represents a novel effect of endothelin-1. We suggest the implication of endothelin-1 in proliferation and invasion of trophoblast and tumour cells and hypothesize a possible role in the etiology of pre-eclampsia.

Cell Division↗
PubMed1977

An experimental study of trophoblast growth in the lung.

Trophoblast can be grown from blastocysts or ectoplacental cones of the mouse in a variety of extrauterine sites. An attempt was made to grow trophoblast in the lung under various conditions. In 94 mice, blastocysts, or cones, were introduced into the lung through the vascular system. Trophoblast growth never occurred. However, when blastocysts, or cones, were introduced directly into the lung, trophoblast grew in 30-50% of mice, depending on technique. Failure to grow from the intravascular position does not appear to be due to liberation of common products of ischemia because blastocysts produced normal trophoblast in the liver when implanted via the portal system, even in the presence of extensive necrosis. The inhibiting factor, which is apparently produced in the lung, is being investigated.

Animals↗
PubMed1997

Antigen processing and presentation by human trophoblast-derived cell lines.

The trophoblast-derived choriocarcinoma cell lines JEG-3 and JAR express the nonclassical MHC class I molecules HLA-G (JEG-3) or, at a low level, HLA-E (JAR), but lack expression of the classical MHC class I molecules HLA-A and HLA-B. Expression of these nonclassical MHC class I genes was found to coincide with expression of the genes encoding the peptide transporter associated with Ag processing (TAP). In immunoprecipitation studies, a physical interaction between the TAP complex and HLA-G or HLA-E could be demonstrated. To investigate whether trophoblast-derived cell lines were capable of peptide processing, transport, and loading of MHC class I molecules, HLA-A*0201-expressing transfectants of JEG-3 and JAR were used for functional studies. These transfectants were recognized by both allospecific cytotoxic T cell clones and, after viral infection, by an influenza A matrix peptide-specific cytotoxic T cell clone, indicating that these trophoblast-derived cell lines were capable of presenting endogenously derived peptides in the context of HLA-A*0201. From these observations, it can be inferred that the TAP complex and other molecules involved in Ag processing and presentation by MHC class I molecules are functionally active in these trophoblast-derived cell lines. This implies that trophoblasts are able to provide antigenic peptides for presentation by nonclassical MHC class I molecules that are naturally expressed by this cell type.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1996

Influence of uterine growth factors on blastocyst expansion and trophoblast knob formation in the rabbit.

The effects of insulin-like growth factors (IGF-1 and IGF-2) on blastocyst expansion, and of basic fibroblast growth (FGF-2) on trophoblast knob formation were studied by in vitro culture of rabbit blastocysts. Both growth factors are present in the uterine secretions. Embryo culture was carried out in Ham's F10 supplemented with polyvinylpyrrolidone in the presence or absence of human recombinant growth factors in concentrations ranging from 1 to 100 ng/ml. IGF-1 stimulated expansion of late preimplantation blastocysts to levels found in vivo; after addition of 10 ng/ml, day-6.0 blastocysts increased their diameter within 24 h to 103% of that of day-7.0 blastocysts expanded in vivo (in comparison to 84% without growth factor), and day-7.0 blastocysts expanded to 108% (in comparison to 76% without growth factor). IGF-1 suppressed the synthesis of a pH 6.3/35-kDa protein. Addition of IGF-2 had no effects. FGF-2 effected formation of trophoblast knobs in day-7.0 blastocysts. After addition of 10 ng/ml, the trophoblast knobs appeared within 12 h of culture. The controls without FGF-2 were negative. The striking increase of FGF-2 concentration in the uterine secretion at day 7.0 is perhaps connected with the formation of trophoblast knobs in vivo. FGF receptor-1 was localized in the trophoblast knobs of day-7.5 blastocysts by the use of immunostaining.

Animals↗
PubMed1995

Insulin-like growth factor-I as a local regulator of proliferation and differentiated function of the human trophoblast in early pregnancy.

In order to elucidate the role of insulin-like growth factor-I (IGF-I) in human placental growth and function, the effects of IGF-I on the proliferation and differentiation of trophoblasts were investigated using an organ culture system of early placental tissues. Explants of trophoblastic tissues obtained from 4-5-week or 6-12-week placentae were, respectively, cultured with or without IGF-I, in a serum-free condition. The effect of IGF-I on the proliferative activity of trophoblasts was examined by immunocytochemical techniques with a monoclonal antibody to proliferating cell nuclear antigen (PCNA), while the effect of IGF-I on the differentiated function of trophoblasts was assessed by determining the ability to secrete human chorionic gonadotropin (hCG) and human placental lactogen (hPL). In 4-5-week placentae, IGF-I and IGF-I receptor were almost exclusively localized in cytotrophoblasts and IGF-I augmented the proliferative activity of cytotrophoblasts without affecting the ability to secrete hCG and hPL. By contrast, in 6-12-week placentae, IGF-I and IGF-I receptor were localized in both cytotrophoblasts and syncytiotrophoblasts and IGF-I stimulated the secretion of hCG and hPL following the enhancement of the proliferative activity of trophoblasts. In column chromatography of the serum-free medium obtained following 5-day culture of early placental tissues, an elution peak of immunoreactive IGF-I was found in the fractions similar to the elution region of [125I]IGF-I. These findings suggest that IGF-I acts as an autocrine/paracrine factor in regulating early placental growth and function.

Cell Differentiation↗
PubMed1998

Differential expression of p57kip2, a maternally imprinted cdk inhibitor, in normal human placenta and gestational trophoblastic disease.

Evidence has recently been provided to support a role for genomic imprinting in the regulation of embryonic implantation and development and placental growth, as well as in the pathogenesis of proliferative trophoblastic diseases. The cyclin-dependent kinase inhibitor p57KIP2 has recently been recognized as a maternally imprinted gene. We investigated p57KIP2 expression in first-trimester normal placentas from interrupted pregnancy, spontaneous abortions, and different types of proliferative trophoblastic diseases using single- and double-marker immunohistochemical techniques. In normal placenta, nuclear p57KIP2 expression was observed at high frequency (up to 100%) in extravillous trophoblast, cytotrophoblast, and implantation-site interstitial trophoblast, but was absent in syncytiotrophoblast. p57KIP2 was also expressed in the stromal cells of maternal decidua, which was one of the few adult tissues retaining p57KIP2 expression (most other adult tissues investigated were negative). p57KIP2 expression was either absent or low in all cases of diploid/tetraploid complete moles (20 cases) and in three cases of gestational choriocarcinoma. On the other hand, all spontaneous abortions (12 cases) and triploid partial moles (19 cases) showed p57KIP2 levels comparable to those observed in normal placenta. These findings are in line with the hypothesis that deregulation of genomic imprinting, particularly the loss of cell-cycle inhibitors such as p57KIP2, is involved in the abnormal development of androgenetic trophoblastic proliferations. In addition, this simple immunohistochemical analysis could provide a useful diagnostic marker in difficult cases.

Choriocarcinoma↗
PubMed1998

Transduction of human trophoblastic cells by replication-deficient recombinant viral vectors. Promoting cellular differentiation affects virus entry.

We investigated the transfer of the lacZ reporter gene into human trophoblastic cells using herpes simplex virus and adeno-associated virus vectors. We used an established choriocarcinoma cell line (BeWo cells) that can be induced to terminally differentiate after treatment with cyclic-AMP. Our results demonstrate that transduction of trophoblastic cells by the herpes simplex virus vector, HSV.CMVlac, and the adeno-associated virus vector, AAV.CMVlac, is affected by cellular differentiation. Treatment of BeWo cells with cyclic-AMP reduced transduction by HSV.CMVlac but increased transduction by the AAV vector. In contrast, when BeWo cells were transfected with herpes simplex virus and adeno-associated virus plasmids, lacZ expression was not affected by treatment with cyclic-AMP. Southern blot analysis demonstrated 2.75 times less herpes simplex virus DNA in cyclic-AMP treated BeWo cells, but 2.0 to 7.4 times more adeno-associated virus DNA in treated cells. We conclude that inefficient transduction of differentiated trophoblastic cells with HSV.CMVlac is because of diminished viral entry, whereas cellular differentiation is associated with increased entry of AAV.CMVlac. These observations suggest that adeno-associated virus vectors may be used to modify trophoblast function and study placental physiology. Additionally, trophoblast differentiation leads to alterations in the mechanisms of virus uptake that may affect maternal-to-fetus transmission.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1996

Transvaginal sonohysterography: a new aid in the diagnosis of residual trophoblastic tissue.

OBJECTIVE: The study was undertaken to evaluate the diagnostic accuracy of transvaginal sonohysterography in postabortion and postpartum patients suspected of having residual trophoblastic tissue. METHODS: Twenty two women with late postabortion and postpartum bleeding were evaluated by transvaginal sonography and transvaginal sonohysterography. The patients were prospectively divided into two groups according to the sonohysterographic findings. Women with an empty uterine cavity or with free-floating masses received conservative treatment. Those with suspected attached residual trophoblastic tissue underwent curettage. RESULTS: Sonohysterography confirmed the findings of two-dimensional sonography of an empty uterus in 8 patients; however, a free floating endometrial mass was found in 4 patients and that of an empty uterine cavity in another 2 of 14 patients suspected of having residual trophoblastic tissue by the two-dimensional ultrasound. All 14 patients who were treated conservatively ceased bleeding. The 4 patients with a free-floating mass reported ejection of a vaginal mass within 6 days of treatment. Eight patients underwent curettage. Residual trophoblastic tissue was found in all of them. CONCLUSION: Transvaginal sonohysterography is a simple and effective method for the evaluation of residual trophoblastic tissue in patients with postpartum and post-abortion bleeding. Its use may eliminate unnecessary curettage procedures.

Abortion, Incomplete↗
PubMed2002

Expression of c-erbB2 in gestational trophoblastic disease and its clinical significance.

In order to explore a potential indicator of predicting the occurrence and development of gestational trophoblastic tumor, the expression of c-erbB2 oncogene in human normal placenta, hydatidiform mole and choriocarcinoma was investigated. The expression of c-erbB2 was detected immunohistochemically by monoclonal antibody against the gene on the formalin-fixed paraffin sections of 21 hydatidiform moles, 21 invasive moles, 20 choriocarcinomas and 30 normal placentas. Results showed that the expression level of c-erbB2 was significantly higher in gestational trophoblastic tumor than in hydatidiform mole and normal placenta of midterm and term pregnancy (P < 0.05), while there was no significant difference between patients with gestational trophoblastic tumor of stage III, IV and those of stage I, II. It was demonstrated that overexpression of c-erbB2 may closely associated with malignant transformation of hydatidiform mole, not only providing important insight into pathogenesis of gestational trophoblastic tumor, but also having an important significance for the early diagnosis and early treatment of gestational trophoblastic tumor.

Biomarkers, Tumor↗
PubMed1995

Single-agent methotrexate chemotherapy for the treatment of nonmetastatic gestational trophoblastic tumors.

OBJECTIVE: Our purpose was to evaluate the efficacy and toxicity of single-agent methotrexate chemotherapy and to identify factors associated with chemotherapy resistance in patients with nonmetastatic gestational trophoblastic tumors. STUDY DESIGN: A total of 337 patients with nonmetastatic gestational trophoblastic tumors (choriocarcinoma and invasive mole) received treatment at the Brewer Trophoblastic Disease Center of Northwestern University Medical School from 1962 through 1990. Of the 337 patients, 253 (75.0%) were treated initially with single-agent methotrexate 0.4 mg/kg intravenously daily for 5 days per treatment course repeated every 14 days. RESULTS: All 337 patients with nonmetastatic gestational trophoblastic tumors were cured. Of the 253 patients initially treated with methotrexate, resistance developed in 27 (10.7%), 22 (8.7%) required a second agent (actinomycin D), 3 (1.2%) required multiagent chemotherapy, and 2 (0.8%) had a hysterectomy to achieve complete remission. Factors associated with the development of resistance were pretreatment human chorionic gonadotropin level > or = 50,000 mlU/ml (36%, p < 0.001), nonmolar antecedent pregnancy (26%, p < 0.02), and clinicopathologic diagnosis of choriocarcinoma (20.5%, p = 0.02). Significant methotrexate toxicity requiring a change to a second agent occurred in only 12 patients (4.7%), the most common side effect being severe stomatitis. CONCLUSIONS: In a large series of patients with nonmetastatic gestational trophoblastic disease, single-agent methotrexate chemotherapy proved to be an extremely well-tolerated and effective treatment.

Choriocarcinoma↗