Short tandem repeat polymorphism analysis for primary peritoneal choriocarcinoma: A case report and literature review.

The peritoneum is an extremely rare site for primary choriocarcinoma development. Primary peritoneal choriocarcinoma could be either gestational or nongestational, whereas it is straightforward to ascribe uterine or tubal choriocarcinoma to the gestational origin. Herein, we report a case of primary peritoneal choriocarcinoma that is genetically diagnosed as a gestational subtype originating from an occult complete hydatidiform mole. A 46-year-old female patient with two-time induced abortion histories underwent emergency laparotomy under clinical suspicion of ruptured tubal pregnancy. Laparotomy revealed a hemorrhagic tumor in the left mesosalpinx with apparently intact left ovary and fallopian tube. The excised tumor was pathologically diagnosed as choriocarcinoma. Multiplex short tandem repeat polymorphism analysis revealed an androgenetic/homozygous genotype tumor, identifying its origin as a complete hydatidiform mole. Our literature review of nine primary peritoneal choriocarcinoma cases, including ours, highlighted the importance of tumor genotyping in differentiating between gestational and non-gestational subtypes and identifying the causative pregnancy.

Temporal changes in magnetic resonance imaging appearance of adult granulosa cell tumor.

Granulosa cell tumors (GCTs) can have a wide variety of appearances on magnetic resonance imaging (MRI), ranging from entirely solid to multilocular cystic, suggesting that GCTs undergo remarkable morphological changes during growth. These temporal changes in MRI appearance of individual GCTs have not been documented. A 54-year-old asymptomatic postmenopausal woman was referred to our department for a small ovarian mass. This 3-cm solid mass showed high intensity on diffusion-weighted MRI and low intensity on apparent diffusion coefficient mapping. Close clinical follow-up was recommended, but she did not return to our hospital until the age of 63, when she was referred for a large ovarian tumor. MRI showed a 15-cm multilocular cyst containing a solid component with hemorrhaging. Postoperative diagnosis was adult GCT (AGCT). These temporal changes demonstrate a possible reason why GCTs can have such a wide range of MRI appearance. This knowledge might promote accurate preoperative diagnosis of AGCTs.

Figla promotes secondary follicle growth in mature mice.

The in vitro growth (IVG) of human follicles is a potential fertility option for women for whom cryopreserved ovarian tissues cannot be transplanted due to the risk of cancer cell reintroduction; however, there is currently no established method. Furthermore, optimal IVG conditions may differ between the follicles of adult and pre-pubertal females due to molecular differences suggested by basic research. To systematically identify differences between the secondary follicles of adult and pre-pubertal females, a comparative transcriptomic study using mice was conducted herein. Among differentially expressed genes (DEGs), Figla was up-regulated in mature mice. We successfully down-regulated Figla expression in secondary follicle oocytes by a Figla siRNA microinjection, and the subsequent IVG of follicles showed that the diameter of these follicles was smaller than those of controls in mature mice, whereas no significant difference was observed in premature mice. The canonical pathways of DEGs between control and Figla-reduced secondary follicles suggest that Figla up-regulates VDR/RXR activation and down-regulates stem cell pluripotency as well as estrogen signaling. We demonstrated for the first time that folliculogenesis of the secondary follicles of premature and mature mice may be regulated by different factors, such as Figla with its possible target genes, providing insights into optimal IVG conditions for adult and pre-pubertal females, respectively.

Factors contributing to favourable neonatal outcomes in early-onset severe preeclampsia.

We collected data from all the women with singleton pregnancies complicated by early-onset severe preeclampsia between 2008 and 2018 to identify the factor(s) that contributed to favourable neonatal outcome. Thirty women delivered the neonates with favourable outcome and the remaining 21 women delivered those with unfavourable outcome. Univariate logistic regression analysis revealed that gestational age at diagnosis ≥28 weeks (crude odds ratio [OR], 6.00), protocol-based management (crude OR 5.83), use of magnesium sulphate (crude OR, 6.00), gestational age at delivery ≥32 weeks (crude OR, 31.90), and birthweight ≥1000 g (crude OR, 10.36) were significantly associated with favourable neonatal outcome. Among these five factors, multivariate logistic regression analysis extracted gestational age at delivery ≥32 weeks (adjusted OR, 17.62) as an only independent factor contributing to favourable neonatal outcome. These data suggest that prolongation of pregnancy up to 32 weeks of gestation is a key factor to improve neonatal outcome in the expectant management of early-onset severe preeclampsia.This study was approved by the ethics committee of Otsu Red Cross Hospital (reference number: 363, date of approval: April 28th, 2016).Impact statementWhat is already known on this subject? It has been demonstrated that expectant management for the women with early-onset severe preeclampsia is associated with decreased neonatal morbidity as compared to the aggressive management, suggesting that prolongation of the pregnancy period contributes to improved neonatal outcomes.What do the results of this study add? Among multiple elements composing expectant management for the women with early-onset severe preeclampsia, 'gestational age at delivery ≥32 weeks' was extracted as an only independent factor that significantly contributes to favourable neonatal outcomes. Importantly, small for gestational age was not significantly associated with poor neonatal outcomes.What are the implications of these findings for clinical practice and/or further research? The obstetrician should aim to prolong the pregnancies complicated by early-onset severe preeclampsia up to 32 gestational weeks even in the presence of foetal growth restriction, as far as maternal conditions allow. Such management policy could contribute to improvement of the neonatal outcomes.

Promoting Roles of Embryonic Signals in Embryo Implantation and Placentation in Cooperation with Endocrine and Immune Systems.

Embryo implantation in the uterus is an essential process for successful pregnancy in mammals. In general, the endocrine system induces sufficient embryo receptivity in the endometrium, where adhesion-promoting molecules increase and adhesion-inhibitory molecules decrease. Although the precise mechanisms remain unknown, it is widely accepted that maternal-embryo communications, including embryonic signals, improve the receptive ability of the sex steroid hormone-primed endometrium. The embryo may utilize repulsive forces produced by an Eph-ephrin system for its timely attachment to and subsequent invasion through the endometrial epithelial layer. Importantly, the embryonic signals are considered to act on maternal immune cells to induce immune tolerance. They also elicit local inflammation that promotes endometrial differentiation and maternal tissue remodeling during embryo implantation and placentation. Additional clarification of the immune control mechanisms by embryonic signals, such as human chorionic gonadotropin, pre-implantation factor, zona pellucida degradation products, and laeverin, will aid in the further development of immunotherapy to minimize implantation failure in the future.

Endovascular trophoblast and spiral artery remodeling.

Spiral artery remodeling, which is indispensable for successful pregnancy, is accomplished by endovascular trophoblasts that move upstream along the arterial wall, replace the endothelium, and disrupt the muscular lining. This review outlines the possible factors that could regulate endovascular trophoblast differentiation and invasion. First, high oxygen tension in the spiral artery could initiate endovascular trophoblast invasion. Second, activation of maternal decidual natural killer (dNK) cells could support perivascular invasion of interstitial trophoblasts and consequently could facilitate the endovascular trophoblast invasion. Third, maternal platelets trapped by the endovascular trophoblasts could enhance endovascular trophoblast invasion, which is in part mediated by chemokine CCL5 (C-C motif ligand 5) released from the activated platelets and chemokine receptor CCR1 (C-C chemokine receptor type 1) expressed specifically on the endovascular trophoblasts. The rat, in which trophoblast cells exhibit extensive interstitial and endovascular invasion, could be a suitable model animal for the study of human spiral artery remodeling. Apparently paradoxical results came from the rat study, i.e., exposure to hypoxia or depletion of dNK cells resulted in acceleration of the endovascular trophoblast invasion. This implies the presence of as-yet-undetermined regulator(s) whose effects on endovascular trophoblast invasion surpass the effects of surrounding oxygen tension or maternal dNK cells. In the future, clarification of the molecular differences between human interstitial and endovascular trophoblasts as well as establishment of the pregnant rat model exhibiting shallow endovascular trophoblast invasion and preeclamptic symptoms will contribute to elucidating the mechanism of spiral artery remodeling.

Placenta Accreta in a Woman with Childhood Uterine Irradiation: A Case Report and Literature Review.

The pregnancies of childhood cancer survivors who have received uterine irradiation are associated with a high risk of several obstetrical complications, including placenta accreta. The present case was a 26-year-old pregnant woman with a history of myelodysplastic syndrome treated with umbilical cord blood transplantation following chemotherapy and total body irradiation at the age of 10. Despite every possible measure to prevent preterm labor, uterine contractions became uncontrollable and a female infant weighing 892 g was vaginally delivered at 27+4 weeks of gestation. Under the postpartum ultrasonographic diagnosis of placenta accreta, we selected to leave the placenta in situ. Although emergency bilateral uterine artery embolization was required, complete resorption of the residual placenta was accomplished on the 115th day postpartum. Our experience highlighted the following points. (1) The expectant management of placenta accreta arising in an irradiated uterus may not only fulfill fertility preservation, but may also reduce possible risks associated with cesarean hysterectomy. (2) Due to extreme thinning of and a poor blood supply to the myometrium, reaching an antepartum diagnosis of placenta accreta in an irradiated uterus is difficult. (3) The recurrence of placenta accreta in subsequent pregnancies needs to be considered after successful preservation of the uterus.

Impact of the recommendation for embryo transfer limitation on multiple pregnancy: A population-based study in Japan.

OBJECTIVE: Limitations on the number of embryos transferred have been recommended worldwide to reduce the number of medically assisted multiple births. Our aim was to evaluate the impact of this recommendation for embryo transfer limitation on perinatal outcomes of multiple births. STUDY DESIGN: A retrospective and population-based study compared all multiple births in Shiga prefecture of Japan in 2014-2015 (2015 group) with those in 2007-2008 (2008 group). The perinatal background and neonatal outcomes of multiple births were compared. RESULTS: The number of multiple pregnancies in the 2015 group (n = 251) was almost the same as in the 2008 group (n = 245). The proportion of multiple pregnancies conceived through assisted reproductive technology significantly decreased to 23% in the 2015 group compared to 31% in the 2008 group. In contrast, the rate of ovulation induction significantly increased to 24% in the 2015 group from 15% in the 2008 group. There was no significant difference in the outcome of multiple-birth infants between the two groups. CONCLUSION: The method of conception in multiple pregnancies markedly shifted from in vitro fertilization to non-in vitro fertilization after the issuance of a recommendation for limits on embryo transfer. It should be necessary for the assessment of the impact of this recommendation to monitor closely multiple pregnancies via non-in vitro fertilization as well as via in vitro fertilization.

Endovascular trophoblast expresses CD59 to evade complement-dependent cytotoxicity.

In the human placenta, extravillous trophoblasts (EVTs) invade maternal decidual tissues (interstitial trophoblasts) and maternal spiral arteries (endovascular trophoblasts). Although endovascular trophoblasts are directly exposed to maternal blood containing complement components, they are not eliminated by complement-dependent cytotoxicity (CDC). In this study, we investigated the expression and possible function of CD59, one of the membrane-bound complement regulators, in EVTs. Immunohistochemistry of early embryo implantation sites revealed that CD59 was hardly expressed on interstitial trophoblasts, whereas it was intensely expressed on endovascular trophoblasts. Using the human EVT-like cell line Swan71, we established CD59-silencing Swan71 cells (Sw_CD59sh) and non-silencing control Swan71 cells (Sw_CTRsh). In vitro cell apoptosis assay showed that Sw_CD59sh cells were significantly more susceptible to CDC as compared to Sw_CTRsh. Our results suggest that CD59 confers some protection against maternal complement attack to the endovascular trophoblasts.

Versican V1 in human endometrial epithelial cells promotes BeWo spheroid adhesion in vitro.

The endometrium extracellular matrix (ECM) is essential for embryo implantation. Versican, a large chondroitin sulfate proteoglycan that binds hyaluronan and forms large ECM aggregates, can influence fundamental physiological phenomena, such as cell proliferation, adhesion and migration. The present study investigated the possible role of versican in human embryo implantation. Versican V1 expression and secretion in human endometrial epithelial cells (EECs) was most prominent in the mid-secretory phase. Versican expression in EECs significantly increased after treatment with estrogen and progesterone, but not by estrogen alone. We also established versican V1-overexpressing Ishikawa (endometrial cancer cell line) cells (ISKW-V1), versican V3-overexpressing (ISKW-V3) and control GFP-overexpressing (ISKW-GFP) Ishikawa cells. By the in vitro implantation model, the attachment ratio of BeWo (choriocarcinoma cell line) spheroids to the monolayer of ISKW-V1, but not of ISKW-V3, was found significantly enhanced compared with attachment to the ISKW-GFP monolayer. The conditioned medium derived from ISKW-V1 (V1-CM) also promoted the attachment of BeWo spheroids to the ISKW monolayer. However, this attachment-promoting effect was abolished when V1-CM was pretreated with chondroitinase ABC, which degrades chondroitin sulfate. Therefore, out of the ECM components, versican V1 may facilitate human embryo implantation.

Factors Regulating Human Extravillous Trophoblast Invasion: Chemokine-peptidase and CD9-integrin Systems.

The invasion of an extravillous trophoblast (EVT) into maternal decidual tissues, especially towards maternal spiral arteries, is an essential process in the human placental formation and subsequent normal fetal development. However, the precise regulatory mechanisms to induce EVT invasion towards arteries and/or to protect EVT from further invasion are not well understood. We found that a chemokine receptor, CCR1, was specifically expressed on EVT migrating towards maternal arteries. Using EVT isolated from a primary villous explant culture, RANTES, which is one of the ligands for CCR1, was shown to enhance EVT invasion. Furthermore, we observed that the platelets were deposited among intravascular EVT and platelet-derived soluble factors, which contained RANTES, enhanced EVT invasion. On the one hand, dipeptidyl peptidase IV (DPPIV), which can metabolize RANTES on the cell surface, was expressed on non-invading EVT and was demonstrated to suppress EVT invasion. In contrast, laeverin/aminopeptidase Q, which is specifically expressed on EVT, was shown to induce EVT invasion. Also, CD9 which is a cell surface marker of platelets and a regulator of integrin function was expressed on EVT and gene knockdown of the CD9 molecule enhanced EVT invasion. These findings suggest that the chemokine-chemokine receptor, chemokine-peptidase, and CD9-integrin systems play important roles in the regulation of EVT invasion during early human placental formation.

Power morcellation-induced dissemination of sarcomatous component arising in leiomyoma.

In 2014, the US Food and Drug Administration issued a safety communication warning against the use of power morcellators during laparoscopic hysterectomy or myomectomy. We report a case of peritoneal leiomyosarcomatosis attributable to power morcellation. A 49-year-old nulligravid woman presented with a huge uterine tumor measuring 15 × 8 cm that was diagnosed as benign leiomyoma on magnetic resonance imaging. The uterine tumor had shrunk to 13 × 7 cm after five treatment courses with a gonadotropin-releasing hormone agonist. She underwent laparoscopic hysterectomy using power morcellation; postoperative pathological diagnosis was benign leiomyoma. After 6 months, urinary ascites developed because of right ureteral rupture. She underwent laparotomy and was diagnosed with peritoneal leiomyosarcomatosis. Meticulous and thorough reevaluation of the morcellated specimens revealed a small component of leiomyosarcoma. Use of power morcellation should be minimized until the advent of novel methods that can perfectly differentiate benign from malignant uterine tumors preoperatively.

Positive vaginal culture at rescue cerclage predicts subsequent preterm delivery.

PURPOSE: This retrospective case-control study is aimed to extract predictors of preterm delivery after rescue cerclage. MATERIALS AND METHODS: We collected the data from all the pregnant women who underwent rescue cerclage before 26+0 gestational weeks at our facility between July 2006 and July 2016. These women were divided into "delivery at <34 weeks" group (n = 12) and "delivery at ≥34 weeks" group (n = 12). Multiple factors that had been detected at the time of cerclage were compared between these two groups. RESULTS: "Gestational weeks at cerclage ≥23" and "positive vaginal culture at cerclage" were significantly more prevalent in the "delivery at <34 weeks" group than in the "delivery at ≥34 weeks" group. "Prolapsed membranes at cerclage" tended to be more prevalent in the "delivery at <34 weeks" group than in the "delivery at ≥34 weeks" group. "Positive vaginal culture at cerclage" was the only independent risk factor associated with eventual preterm delivery before 34 gestational weeks. CONCLUSIONS: Simple aerobic bacterial culture of the vaginal swab sampled at the time of cerclage could be used as a reliable test to predict subsequent preterm delivery before 34 gestational weeks.

Introduction of management protocol for early-onset severe pre-eclampsia.

AIM: This quality Improvement study evaluated the applicability of our protocol for early-onset severe pre-eclampsia, prepared in April 2013. METHODS: We collected data from all women with early-onset severe pre-eclampsia treated at our hospital between March 2008 and August 2015. Neonatal and maternal outcomes were compared between protocol-based (n = 17) and non-protocol-based management groups (n = 28). RESULTS: The latency period was significantly longer in the protocol-based than in the non-protocol-based group (21.9 ± 3.7 vs 11.0 ± 2.9 days). Gestational age at delivery was significantly more advanced in the protocol-based than in the non-protocol-based group (31.4 ± 0.6 vs 29.8 ± 0.4 weeks). Serious neonatal complications were significantly less prevalent in the protocol-based than in the non-protocol-based group (26% vs 79%). Among the protocol components, magnesium sulfate use was the only independent factor contributing to the absence of serious neonatal complications. The percentages of women exhibiting persistent proteinuria or hypertension at one, two and three months post-partum were similar between the groups. CONCLUSIONS: Strict adherence to our protocol improved neonatal outcomes without affecting maternal prognosis. Routine use of magnesium sulfate could be the most important component of the protocol.

Platelet-derived microparticles and soluble factors differentially regulate human endometrial epithelial cell movement.

PROBLEM: We previously proposed that platelets promote re-epithelialization during menstruation. As cell movement is one of the important cell behaviors in the process of tissue remodeling, we examined the effects of platelets on endometrial epithelial cell invasion. METHOD OF STUDY: The platelets were isolated from healthy women. Using a human endometrial epithelial cell-derived immortalized cell line, EM-E6/E7/hTERT cells, we examined the effects of platelets and platelet-derived condition media with or without microparticles on the morphological and invasive properties of EM-E6/E7/hTERT cells. RESULTS: Platelets and microparticle-containing conditioned media inhibited Matrigel invasion by EM-E6/E7/hTERT cells along with an increase in cortical ring formation, whereas microparticle-depleted conditioned media promoted their invasion without any significant changes of cortical ring formation. CONCLUSION: These results support our previous proposal and newly suggest the dual roles of platelets: platelet-derived soluble factors that promote cell movement in the distant area, and microparticles that induce re-epithelialization by endometrial epithelial cells in the proximal area.

Planned vaginal delivery versus planned cesarean delivery in cases of low-lying placenta.

OBJECTIVE: To assess the applicability of trial of labor in cases of low-lying placenta. METHODS: In this observational cohort study, we collected data from the women with low-lying placenta delivered at our hospital between April 2012 and December 2015. Low-lying placenta was diagnosed when the length from the placental lowest edge to the internal cervical os (placenta-os distance) was 0-20 mm at 36 gestational weeks. Planned mode of delivery for each case was determined by patient's preference. Maternal and neonatal outcomes were compared between the planned vaginal delivery group (N = 11) and the planned cesarean delivery group (N = 7). RESULTS: All the women in the planned cesarean delivery group underwent scheduled cesarean section at 37-38 gestational weeks. Three cases in the planned vaginal delivery group required emergency cesarean section for uncontrollable antepartum bleeding. The intrapartum blood loss was significantly smaller in the planned vaginal delivery group than in the planned cesarean delivery group (946 ± 204 g vs. 1649 ± 256 g, p = 0.047). Umbilical arterial blood pH was similar between the two groups. All the women requiring emergency cesarean section were accompanied by marginal sinus. CONCLUSIONS: Trial of labor can be offered to all the women with low-lying placenta except for those accompanied by marginal sinus.

Expectant management for abdominal pregnancy.

This is the first English language report describing the expectant management for abdominal pregnancy. The patient was a 31-year-old multiparous woman who was transferred to our hospital on suspicion of ectopic pregnancy. Her serum human chorionic gonadotropin was positive, and a poorly-vascularized mass measuring about 4 cm was visualized in the Douglas pouch by transvaginal ultrasonography, as well as by pelvic magnetic resonance imaging. Because the bilateral adnexa were apparently intact, she was diagnosed with abdominal pregnancy, and expectant management was commenced. Unexpectedly, the mass remained in situ for nearly 3 years after her serum human chorionic gonadotropin tested negative. Laparoscopic removal of the mass was finally required because of persistent defecation pain. This case illustrates that some abdominal pregnancies can be managed expectantly, as is the case with tubal pregnancies. During the expectant management, however, it should be considered that the abdominal pregnancy mass may persist for a longer period and cause moderate symptoms necessitating surgical removal.

Platelets are a possible regulator of human endometrial re-epithelialization during menstruation.

PROBLEM: The human endometrium periodically breaks down and regenerates. As platelets have been reported to contribute to the tissue remodeling process, we examined the possible involvement of platelets in endometrial regeneration. METHOD OF STUDY: The distribution of extravasating platelets throughout the menstrual cycle was immunohistochemically examined using human endometrial tissues. EM-E6/E7/hTERT cells, a human endometrial epithelial cell-derived immortalized cell line, were co-cultured with platelets, and the effects of platelets on the epithelialization response of EM-E6/E7/hTERT cells were investigated by attachment and permeability assays, immunohistochemical staining, and Western blot analysis. RESULTS: Immunohistochemical study showed numerous extravasated platelets in the subluminar stroma during the menstrual phase. The platelets promoted the cell-to-matrigel attachment of EM-E6/E7/hTERT cells concomitantly with the phosphorylation of focal adhesion kinase. They also promoted cell-to-cell contact among EM-E6/E7/hTERT cells in parallel with E-cadherin expression. CONCLUSION: These results indicate the possible involvement of platelets in the endometrial epithelial re-epithelialization process.