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Abstract Meiotic prophase progression is differently regulated in males and females. In males, pachytene transition during meiotic prophase is accompanied by robust alteration in gene expression. However, how gene expression is regulated differently to ensure meiotic prophase completion in males remains elusive. Herein, we identify HSF5 as a male germ cell-specific heat shock transcription factor (HSF) for meiotic prophase progression. Genetic analyzes and single-cell RNA-sequencing demonstrate that HSF5 is essential for progression beyond the pachytene stage under non-stress conditions rather than heat stress. Chromatin binding analysis in vivo and DNA-binding assays in vitro suggest that HSF5 binds to promoters in a subset of genes associated with chromatin organization. HSF5 recognizes a DNA motif different from typical heat shock elements recognized by other canonical HSFs. This study suggests that HSF5 is an atypical HSF that is required for the gene expression program for pachytene transition during meiotic prophase in males.

Background: The prevalence of cesarean section procedures is on the rise worldwide, necessitating a deeper understanding of the factors driving this trend to mitigate potential adverse consequences associated with unnecessary cesarean section deliveries. Objectives: This study aims to investigate the rate of primary cesarean deliveries (PCD), a potential key indicator of obstetric care quality. Study Design: A national retrospective cohort study was conducted utilizing extensive data from the National Database of Health Insurance Claims and Specific Health Checkups of Japan spanning the years 2012 to 2018. The study examined the temporal trends in PCD rates and the indications for these procedures across different prefectures. Additionally, the study employed the obstetrician disproportionality index, as published by the Ministry of Health, Labour, and Welfare, to assess the influence of obstetrician availability on PCD rates. Results: Throughout the study period from 2012 to 2018, the rate of PCD in Japan remained relatively stable at approximately 14%. The primary indications for PCD in 2018 included labor arrest (18.3%), malpresentation (16.5%), nonreassuring fetal status (6.5%), and macrosomia (6.0%). Substantial regional disparities in PCD rates were observed, ranging from 8.9% to 20.4% among prefectures in 2018. Notably, prefectures categorized in the bottom 10 of the obstetrician disproportionality index exhibited significantly higher PCD rates compared to the top 10 prefectures (P=.0232), with a similar trend noted for PCD due to labor arrest (P=.0288). Furthermore, a negative correlation was identified between the obstetrician disproportionality index and PCD rates at the prefectural level (r=–0.3119, P=.0328). Conclusions: Our study presents a comprehensive analysis of PCD rates in Japan, shedding light on regional disparities and highlighting the notable influence of obstetrician availability on clinical decision-making. This study contributes to the ongoing discourse on the escalating global trend in cesarean sections and the importance of healthcare resource allocation in maternal care.

Objective: To assess the clinical characteristics and endocrinological background of women with vascular retained products of conception (RPOC) after miscarriage or abortion and evaluate the effect of estrogen–progestogen therapy (EPT) as an initial treatment on this population based on their endocrinological background. Materials and methods: Women with vascular RPOC after miscarriage or abortion at less than 20 weeks of pregnancy who were given EPT (conjugated estrogen and norethisterone) were retrospectively reviewed. Their clinical characteristics, hormonal parameters, ultrasonographic findings, and outcomes were evaluated. Results: Of 35 women with vascular RPOC, 30 (86%) presented with vaginal bleeding at a visit, and 6 (17%) required inpatient management due to heavy bleeding. Among women who presented with vaginal bleeding, serum progesterone levels were significantly lower (0.25 vs. 6.5 ng/mL, p = 0.004) than those in women who did not present with vaginal bleeding. There were no differences in serum hCG levels (10.5 vs. 3.1 mIU/mL) or serum estradiol levels (65.4 vs. 162.3 pg/mL). After withdrawal bleeding following the first course of EPT, vaginal bleeding was stopped in 27 of the 30 women (90%), and 23 (66%) of all women had a thin and linear endometrium. All women could be treated by up to two courses of EPT and did not require additional interventions. The median duration to hCG normalization after the initial EPT was 24.5 (9–88) days. Conclusion: Women with vascular RPOC who have no bleeding had significantly higher levels of serum progesterone, indicating that administration of progestogen may have an effect on hemostasis. Endometrial bleeding can be prevented or stopped, and retained tissues can be conservatively expelled by oral administration of EPT, including norethisterone, in women with vascular RPOC.

Objective: Preterm prelabor rupture of fetal membranes (pPROM) is a leading cause of preterm birth. When pPROM occurs around the pre- and periviable period, the perinatal outcome is unfavorable. However, there have been a few cases in which the leakage of amniotic fluid ceases and the ruptured fetal membranes are spontaneously sealed. Materials and methods: The prognosis of 38 cases of pPROM at less than 27 weeks of gestation in Kyoto University Hospital were studied. The clinical factors related to the sealing of fetal membranes were investigated. Results: Spontaneous sealing was confirmed in five patients (13%), and sealing occurred within 14 days of pPROM. Women in the no sealing group delivered at 26.3 ± 0.5 weeks of gestation, whereas women in the sealing group delivered at term at 38.8 ± 0.4 weeks (p

Objective: We aimed to elucidate the pathogenesis of ovarian cancer through the loss of mismatch repair (MMR) proteins in women with Lynch syndrome (LS) in this report. Case report: Two women with LS underwent surgery for synchronous endometrial cancer and ovarian cancer. In both cases, immunohistochemical examination showed concomitant MMR protein deficiency in endometrial cancer, ovarian cancer, and contiguous ovarian endometriosis. In Case 1, the macroscopically normal ovary included multiple endometrioses with MSH2 and MSH6 expression, and FIGO grade 1 endometrioid carcinoma and contiguous endometriosis without MSH2 and MSH6 expression. In Case 2, all endometriotic cells contiguous with carcinoma in the lumen of the ovarian cyst showed loss of the expression of MSH2 and MSH6. Conclusion: Ovarian endometriosis with MMR protein deficiency may progress to endometriosis-associated ovarian cancer in women with LS. Diagnosing endometriosis in women with LS during surveillance is important.

Abstract Background The Japan Society of Obstetrics and Gynecology and the Japan Association of Obstetricians and Gynecologists have issued the guidelines and recommendations on postpartum hemorrhage since 2010 and have been conducted widespread educational activities from 2012. The aim of this study was to investigate the impact of these efforts by the Societies to prevent maternal deaths due to obstetric hemorrhage on trends in epidemiology and management of severe postpartum hemorrhage in Japan. Methods A national retrospective cohort study was conducted using the national database of health insurance claims for the period 2012 and 2018. The subjects were all insured women who received a blood transfusion for postpartum hemorrhage. The primary endpoints of this study were hysterectomy and maternal mortality. The etiology of hemorrhage, treatment facility, type of procedure, and blood transfusion volume were tabulated. Results Women with postpartum hemorrhage that underwent transfusion increased from 3.5 to 5.5 per 1000 deliveries between 2012 and 2018. The most common cause of postpartum hemorrhage was atonic hemorrhage. After insurance coverage in 2013, the intrauterine balloon tamponade use increased to 20.3% of postpartum hemorrhages treated with transfusion in 2018, while the proportion of hysterectomy was decreased from 7.6% (2013–2015) to 6.4% (2016–2018) (p

Abstract Placental dysfunction is related to the pathogenesis of preeclampsia and fetal growth restriction, but there is no effective treatment for it. Recently, various functional three-dimensional organs have been generated from human induced-pluripotent cells (iPSCs), and the transplantation of these iPSCs-derived organs has alleviated liver failure or diabetes mellitus in mouse models. Here we successfully generated a three-dimensional placental organ bud from human iPSCs. The iPSCs differentiated into various lineages of trophoblasts such as cytotrophoblast-like, syncytiotrophoblast-like, and extravillous trophoblast-like cells, forming organized layers in the bud. Placental buds were transplanted to the murine uterus, where 22% of the buds were successfully engrafted. These iPSC-derived placental organ buds could serve as a new model for the study of placental function and pathology.

Abstract 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.

Radical hysterectomy is a standard operation for invasive cervical cancers. However, if the invasion to the parametrium is more advanced than estimation in the operation, it is difficult to perform usual radical hysterectomy. Superradical hysterectomy was developed by Prof. Ryukichi Mibayashi of Kyoto University and was published in 1941, and has been performed for the limited cases by a part of Japanese gynecologic surgeons. Superradical hysterectomy is a procedure in which the soft tissues in the pelvis are removed en bloc by sequential processing of the internal iliac vessels, which leads to a complete dissection of the lymphatic tissue in the pelvis to the pelvic wall.

Placenta accreta spectrum (PAS) disorder is a potentially life-threatening complication. The incidence of PAS has increased over the past few decades, mainly due to the increased cesarean section rate. While cesarean hysterectomy remains the most standard treatment for the management of PAS, expectant management is becoming increasingly prevalent to avoid serious maternal morbidity and maintain future fertility. Expectant management is defined as leaving the placenta either partially or fully in situ, and waiting for its spontaneous resorption or expulsion. The success rate of expectant management is high, but intraoperative uncontrolled hemorrhage results in hysterectomy. Moreover, some individuals fail expectant management and require delayed hysterectomy due to complications such as secondary postpartum hemorrhage, sepsis, uterine necrosis, and vesicouterine fistula. As a result of the very limited data currently available, there is no consensus on the optimal strategy for the expectant management of PAS. However, it is clear that a multidisciplinary team approach in tertiary centers is essential for women with PAS. In addition, meticulous preparation is the key to successful expectant management. Here, we describe a surgical strategy designed to reduce perioperative blood loss, which is a minimum requirement to ensure maternal safety. This article also addresses practical issues in expectant management of PAS, based on the published literature and our own experience.

Abstract Purpose To investigate the role of beta‐human chorionic gonadotropin (HCG) level and its change prior to methotrexate (MTX) treatment as predictors of treatment success and to access the posttreatment observation period for ectopic tubal pregnancy. Methods Clinical data of 41 females treated with MTX for tubal pregnancies were reviewed and analyzed retrospectively. Results Among 41 patients, 34 achieved complete resolution without surgery. No statistically significant difference was observed in the presence of hemorrhagic ascites, serum progesterone levels, or diameters of adnexal mass between the MTX success and failure groups. Serum HCG levels on the day of MTX administration (day 1) were significantly lower in the MTX success group. Moreover, % HCG change per day, which represents the increment ratio of HCG prior to MTX treatment, was significantly lower in the MTX success group. Receiver operating characteristic (ROC) curves demonstrated that the treatment success was predicted by % HCG change per day less than +12.6% per day with a sensitivity of 87% and a specificity of 71%. The duration from treatment to complete recovery was strongly correlated with day 1 HCG levels. Conclusions Pretreatment HCG change is a significant predictor of therapeutic success of MTX treatment, and the treatment period may be predicted from initial HCG levels.

Aim: To ascertain the actual outcomes of oncofertility care in young women to provide more appropriate care. Materials & methods: We analyzed the data of 67 female patients under 43 years of age who underwent oncofertility care between January 2015 and September 2019. Results: There were 28 patients with breast cancer, 19 patients with hematologic cancer and 20 patients with other cancer diagnoses. Breast cancer patients tended to take longer than hematologic cancer patients to initiate oncofertility treatment. Despite undergoing oncofertility care, seven of nine pregnant patients did not choose assisted reproductive technology (ART). Conclusion: As spontaneous pregnancies were more common than ART pregnancies in our study, pregnancy by not only ART but also non-ART method is a viable option for young cancer survivors.

Ovarian tumors can get extremely giant to occupy the whole abdominal cavity. We report a case of 36 kg solid ovarian tumor, which was the largest ovarian solid tumor that have been ever reported. A 54-year-old woman presented to our hospital with a chief complaint of markedly distended abdominal wall. Preoperative imaging examinations revealed that most of the tumor was uniform and its density was like that of subcutaneous fat. Pleural effusion was detected in the right thoracic region. We organized a multidisciplinary team and successfully resected the right adnexa. The patient had an uneventful postoperative course, and she was discharged on the 7th postoperative day and diagnosed with a fibroma of the ovary with Meigs syndrome. A comprehensive literature search revealed 48 cases of extremely giant ovarian tumor in these 20 years. Six out of 48 cases are solid. Twelve out of 48 cases are malignant or borderline malignant, and patients’ age and tumor size/weight were not related to the frequency of malignancy/borderline malignancy. As many as 4 out of 48 patients died before their first hospital visit or early after surgery. Clinicians should consider a considerable high mortality and frequency of severe surgical complications when planning the treatment strategy for extremely giant ovarian tumors.

We report a case of torsion in an otherwise-normal ovary with a giant hematosalpinx. A 23-year-old woman presented with complaints of abdominal pain and nausea. At initial visit, there was few abnormal findings of imaging tests, and we made a diagnosis of ovarian hemorrhage. Three days later, she came back with increased symptoms, and we detected the mass of a complex solid cystic structure with a unilocular cyst much larger than solid component. A diagnostic laparoscopy was performed immediately, and we could make a diagnosis of torsion in an otherwise-normal ovary with a giant hematosalpinx. We performed a salpingectomy and could preserve her ovary. This is the first case of torsion in an otherwise-normal ovary with a giant hematosalpinx which enlarged to a greater extent than the ovary.

Intrauterine bleeding during pregnancy is a major risk factor for preterm birth. Thrombin, the most abundant coagulation factor in blood, is associated with uterine myometrial contraction. Here, we investigated the molecular mechanism and signaling of thrombin-induced myometrial contraction. First, histologic studies of placental abruption, as a representative intrauterine bleeding, revealed that thrombin was expressed within the infiltrating hemorrhage and that thrombin receptor (protease-activated receptor 1, PAR1) was highly expressed in myometrial cells surrounding the hemorrhage. Treatment of human myometrial cells with thrombin resulted in augmented contraction via PAR1. Thrombin-induced signaling to myosin was then mediated by activation of myosin light chain kinase- and Rho-induced phosphorylation of myosin light chain-2. In addition, thrombin increased prostaglandin-endoperoxidase synthase-2 (PTGS2 or COX2) mRNA and prostaglandin E2 and F2α synthesis in human myometrial cells. Thrombin significantly increased the mRNA level of interleukine-1β, whereas it decreased the expressions of prostaglandin EP3 and F2α receptors. Progesterone partially blocked thrombin-induced myometrial contractions, which was accompanied by suppression of the thrombin-induced increase of PTGS2 and IL1B mRNA expressions as well as suppression of PAR1 expression. Collectively, thrombin induces myometrial contractions by two mechanisms, including direct activation of myosin and indirect increases in prostaglandin synthesis. The results suggest a therapeutic potential of progesterone for preterm labor complicated by intrauterine bleeding.

A well-known typical feature of ectopic pregnancy is an evident gestational sac structure outside of the uterus. However, some cases show atypical appearance that is described as a heterogeneous hypervascular mass. We report two cases of ectopic pregnancy that presented heterogeneous findings mimicking gestational trophoblastic diseases but were correctly diagnosed as ectopic pregnancies on MRI. The first case was an interstitial pregnancy in which the patient underwent surgical treatment. The second case was a cesarean scar pregnancy that was treated conservatively but showed spurious enlargement of pregnancy-related lesions after the treatment. Both cases lacked myometrial invasion on MRI, and the patients were diagnosed with ectopic pregnancies. Invasive findings on MRI may discriminate ectopic pregnancy from trophoblastic tumors and avoid unnecessary hysterectomy.

Abstract Background The Cancer Genome Atlas Research Network reported that high-grade serous carcinoma (HGSC) can be classified based on gene expression profiles into four subtypes, termed “immunoreactive,” “differentiated,” “proliferative,” and “mesenchymal.” We previously established a novel histopathological classification of HGSC, corresponding to the gene expression subtypes: immune reactive (IR), papillo-glandular (PG), solid and proliferative (SP), and mesenchymal transition (MT). The purpose of this study is to identify distinct clinical findings among the four pathological subtypes of HGSC, as well as to predict pathological subtype based on preoperative images. Methods We retrospectively assessed 65 HGSC cases (IR: 17, PG: 7, SP: 14, MT: 27) and analyzed preoperative images. Results All IR cases originated from either the ovary or fallopian tube (P = 0.0269). Significantly more IR cases were diagnosed at earlier stages (P = 0.0013), and IR cases displayed lower levels of ascites (P = 0.0014), fewer peritoneal lesions (P = 0.0080), a sporadic pattern of peritoneal lesions (P = 0.0016), a lower incidence of omental cake (P = 0.0416), and fewer distant metastases (P = 0.0146) compared with the other subtypes. MT cases were more likely to be of peritoneal origin (P = 0.0202), presented at advanced stages with higher levels of ascites (P = 0.0008, 0.0052, respectively), and more frequently had a diffuse pattern of peritoneal lesions (P = 0.0059), omental cake (P = 0.0179), and distant metastasis (P = 0.0053). A decision tree analysis estimated the histopathological subtypes based on preoperative images, with a sensitivity of 67.3%. Conclusions Pathological subtypes of HGSC have distinct clinical behaviors, and preoperative images enable better prediction of pathological subtype. These findings may lead to individualized treatment plans if the effect of treatment based on the HGSC subtype is elucidated.

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.

Esophageal cancer rarely coincides with pregnancy, and only five cases have been reported thus far. The management of esophageal cancer during pregnancy is extremely challenging due to its aggressive nature. We herein report a case of recurrent esophageal cancer in pregnancy. A 41-year-old multigravida with a history of esophageal squamous cell cancer treated with esophagectomy and perioperative chemotherapy was diagnosed with local recurrent carcinoma of the residual esophagus at 16 weeks of gestation. The patient strongly desired to continue the pregnancy, and concurrent chemoradiation therapy (CRT) consisting of 50.4 Gy of radiation, cisplatin, and 5-fluorouracil was carried out from 19 weeks of gestation. CRT was dramatically effective, and the recurrent lesion disappeared. At 38 weeks of gestation, she underwent cesarean section and delivered a healthy female baby. Both maternal and fetal courses were satisfactory, and the patient has been free of disease for 12 months. This is the first case of recurrent esophageal cancer in pregnancy in which CRT was completed without reducing treatment intensity and led to a complete response. Nevertheless, little is known regarding the safety and possible adverse effects of CRT on the fetus. Therefore, deliberate selection of patients and long-term follow-up of the child are necessary.

Pulmonary edema caused by severe preeclampsia can be an indication for pregnancy termination. We aimed to investigate whether noninvasive positive-pressure ventilation (NPPV) was useful for preeclampsia-induced pulmonary edema. Three cases of preeclampsia-induced pulmonary edema managed with NPPV in our institute were reviewed retrospectively. A literature review was conducted regarding NPPV usage during pregnancy. NPPV was initiated at 30, 20, and 24 weeks of gestation in the 3 cases. In all cases, NPPV slowed the progression of pulmonary edema and succeeded in delaying pregnancy termination by 17 days on average. Maternal outcomes were positive, and no intubation was required. Between 1994 and 2017, there were 11 articles describing 12 cases in which NPPV was applied for pulmonary edema during pregnancy. However, there has been no case of NPPV management of preeclampsia-induced pulmonary edema thus far. Maternal and fetal outcomes were positive in these 12 cases. NPPV may contribute to prolonging pregnancy in patients with poor oxygenation due to preeclampsia-induced pulmonary edema. However, patients should be closely monitored, and the decision to intubate or terminate the pregnancy should be made without delay when the maternal or fetal condition worsens.

Pneumonia in pregnancy is associated with adverse maternal and foetal outcomes, and intensive treatment with appropriate antibiotics is essential. However, cases caused by pathogens that are resistant to antibiotics suitable for the developing foetus are challenging. We herein report a case of macrolide-refractory Mycoplasma pneumoniae pneumonia in pregnancy. A 40-year-old multigravida with twin pregnancy complained of cough and fever at 13 weeks of gestation and was diagnosed with pneumonia. Even though empiric treatment with ceftriaxone and oral azithromycin was started, her condition deteriorated rapidly. The findings of chest computed tomography suggested Mycoplasma pneumoniae pneumonia. Since azithromycin did not work, this strain was considered to be macrolide-refractory. Garenoxacin, an oral quinolone, was selected and was dramatically effective. The use of quinolone could be justified with the emergence of drug-resistant bacterial/atypical pneumonia and in the maternal life-threatening condition.

Pneumocystis pneumonia (PCP) is a life-threatening opportunistic infection that sometimes occurs in immunocompromised patients with human immunodeficiency virus (HIV). Here, we report two extremely rare cases of PCP in non-HIV pregnant women who underwent chemotherapy for malignant lymphoma. Case 1 is a 34-year-old primigravida who was diagnosed with Hodgkin’s lymphoma. She received ABVD chemotherapy and developed PCP at 37 weeks of gestation. After the onset of PCP, emergent cesarean section was performed due to a nonreassuring fetal status. Case 2 is a 31-year-old multigravida with diffuse large B-cell lymphoma who was administered R-CHOP chemotherapy. At 34 weeks of gestation, she complained of dyspnea and developed PCP. She delivered her baby vaginally immediately after the onset of symptoms. Both patients were treated with sulfamethoxazole-trimethoprim (ST) and recovered shortly thereafter. The babies’ courses were also uneventful. PCP remains a serious cause of death, especially in non-HIV patients, and, therefore, appropriate prophylaxis and a prompt diagnosis are imperative.

Woman-centered antenatal care necessitates Electronic Medical Record (EMR) systems that respect women’s preferences. However, women’s preferences regarding EMR systems in antenatal care remain unknown. This work aims to understand the EMR-related experiences that pregnant Japanese women want. First, we conducted a field-based observational study at an antenatal care clinic at a Japanese university hospital. We analyzed the data following a thematic analysis approach and found multiple EMR-related experiences that pregnant women encounter during antenatal care. Based on the observations’ findings, we administered a web survey to 413 recently pregnant Japanese women to understand their attitudes regarding the EMR-related experiences. Our results show that pregnant Japanese women want accessible, exchangeable, and biopsychosocial EMRs. They also want EMR-enabled explanations and summaries. Interestingly, differences in their demographics and stages of pregnancy affected their attitudes towards some EMR-related experiences. To respect their preferences, we propose amplifying the roles of EMR systems as tools that promote communication and woman-centeredness in antenatal care. We also propose expanding the EMR design mindset from a biomedical to a biopsychosocial-oriented one. Finally, to accommodate the differences in individual needs and preferences, we propose the design of adaptable person-centered EMR systems.