Evolutionary histories of breast cancer and related clones.

Recent studies have documented frequent evolution of clones carrying common cancer mutations in apparently normal tissues, which are implicated in cancer development1-3. However, our knowledge is still missing with regard to what additional driver events take place in what order, before one or more of these clones in normal tissues ultimately evolve to cancer. Here, using phylogenetic analyses of multiple microdissected samples from both cancer and non-cancer lesions, we show unique evolutionary histories of breast cancers harbouring der(1;16), a common driver alteration found in roughly 20% of breast cancers. The approximate timing of early evolutionary events was estimated from the mutation rate measured in normal epithelial cells. In der(1;16)(+) cancers, the derivative chromosome was acquired from early puberty to late adolescence, followed by the emergence of a common ancestor by the patient's early 30s, from which both cancer and non-cancer clones evolved. Replacing the pre-existing mammary epithelium in the following years, these clones occupied a large area within the premenopausal breast tissues by the time of cancer diagnosis. Evolution of multiple independent cancer founders from the non-cancer ancestors was common, contributing to intratumour heterogeneity. The number of driver events did not correlate with histology, suggesting the role of local microenvironments and/or epigenetic driver events. A similar evolutionary pattern was also observed in another case evolving from an AKT1-mutated founder. Taken together, our findings provide new insight into how breast cancer evolves.

Shear stress in the intervillous space promotes syncytial formation of iPS cells-derived trophoblasts†.

The intervillous space of human placenta is filled with maternal blood, and villous trophoblasts are constantly exposed to the shear stress generated by maternal blood pressure and flow throughout the entire gestation period. However, the effects of shear stress on villous trophoblasts and their biological significance remain unknown. Here, using our recently established naïve human pluripotent stem cells-derived cytotrophoblast stem cells (nCTs) and a device that can apply arbitrary shear stress to cells, we investigated the impact of shear stress on early-stage trophoblasts. After 72 h of exposure to 10 dyn/cm2 shear stress, nCTs became fused and multinuclear, and mRNA expression of the syncytiotrophoblast (ST) markers, such as glial cell missing 1, endogenous retrovirus group W member 1 envelope, chorionic gonadotropin subunit beta 3, syndecan 1, pregnancy specific beta-1-glycoprotein 3, placental growth factor, and solute carrier family 2 member 1 were significantly upregulated compared to static conditions. Immunohistochemistry showed that shear stress increased fusion index, human chorionic gonadotropin secretion, and human placental lactogen secretion. Increased microvilli formation on the surface of nCTs under flow conditions was detected using scanning electron microscopy. Intracellular cyclic adenosine monophosphate significantly increased under flow conditions. Moreover, transcriptome analysis of nCTs subjected to shear stress revealed that shear stress upregulated ST-specific genes and downregulated CT-specific genes. Collectively, these findings indicate that shear stress promotes the differentiation of nCTs into ST.

Advantages and limitations of estrogen replacement therapy on hypogonadal survivors of childhood cancer.

BACKGROUND: Hypogonadism is a significant late complication in childhood cancer survivors (CCS). The aim of this study was to elucidate the advantages and limitations of estrogen replacement therapy (ERT) for CCS with hypogonadism. METHODS: Seventeen CCS were divided into two groups: gonadal hypogonadism (GH) group (n = 8) and central hypogonadism (CH) group (n = 9). Pearson correlation coefficients were used to investigate the impact of cancer management on final height, bone density, and uterine development. RESULTS: Seven of GH group had hematologic malignancies, and all of them underwent total body irradiation before bone marrow transplantation. The GH group showed significant positive correlations between the onset age of disease treatment and final height (p < 0.05, R = 0.712) and uterine size following ERT (p < 0.05, R = 0.775). All CCS in the CH group had brain tumors, and seven of them received chemotherapy. There were trends towards positive and negative correlations between the onset age of disease treatment and final height (p = 0.09, R = 0.598) or uterine size (p = 0.07, R = - 0.669), respectively. A negative correlation trend was observed between the age at ERT initiation and final height (p = 0.07, R = - 0.769) or bone density (p = 0.18, R = - 0.626) in six CH patients who received growth hormone therapy. Five CCS in both groups experienced osteoporosis, despite receiving ERT. CONCLUSION: Individualized management strategies beyond ERT are essential to reduce long-term complications in CCS with hypogonadism, considering the type and timing of cancer treatment.

Impact of efforts to prevent maternal deaths due to obstetric hemorrhage on trends in epidemiology and management of severe postpartum hemorrhage in Japan: a nationwide retrospective study.

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 < 0.0001). The proportion of postpartum hemorrhage in maternal deaths decreased from 21.1% (2013-2015) to 14.1% (2016-2018) per all maternal deaths cases (p = 0.14). Cases with postpartum hemorrhage managed in large referral hospitals was increased (65.9% in 2012 to 70.4% in 2018) during the study period (p < 0.0001). CONCLUSIONS: The efforts by the Societies to prevent maternal mortality due to obstetric hemorrhage resulted in a significant decrease in the frequency of hysterectomies and a downward trend in maternal mortality due to obstetric hemorrhage.

Maternal thrombocytopenia precedes fetal death associated with COVID-19.

Acute coagulopathy, specific placental pathology, and an increased risk of fetal death have been reported in pregnant women with COVID-19; however, the association between coagulopathy and fetal death remains unknown. We report two pregnant women with COVID-19 who showed acute coagulopathy prior to fetal death. Both pregnant women presented with thrombocytopenia after testing positive for SARS-CoV-2 (days 5 and 7). They had mild symptoms, but coagulopathy progressed, and their fetuses died on day 9 at 27 and 22 weeks of pregnancy. Their coagulability improved after delivery. Placental histology in both cases showed intervillous infiltration of histiocytes, necrosis of trophoblasts, and intervillous fibrin deposition, which were consistent with previously reported pathological findings related to SARS-CoV-2. In the management of pregnant women with COVID-19, thrombocytopenia may be a predictive marker of fetal death following coagulopathy and placental inflammatory changes due to SARS-CoV-2 infection.

Fertility-sparing surgery for early-stage cervical cancer: A case series study on the efficacy and feasibility of cervical conization followed by pelvic lymphadenectomy.

OBJECTIVES: To evaluate the oncologic and obstetric outcomes of cervical conization followed by pelvic lymphadenectomy, which is used as a fertility-sparing procedure, in reproductive-aged patients with early-stage cervical cancer. METHODS: We performed a retrospective study of patients with stage IA1-IB1 cervical cancer who underwent cervical conization followed by pelvic lymphadenectomy from 2011 to 2020 at Kumamoto University Hospital. RESULTS: In total, eight patients underwent conization followed by pelvic lymphadenectomy. The median age of the patients was 33 (range: 28-36) years. Four (50.0%) patients were nulliparous. Seven (87.5%) patients were diagnosed with squamous cell carcinoma (87.5%) and one (12.5%) with adenocarcinoma. Five (62.5%), two (25.0%), and one (12.5%) presented with stage IA1, IA2, and IB1 disease, respectively. Five (62.5%) patients had lymphovascular space invasion (LVSI) based on the assessment of specimens obtained via conization. However, none had lymph node metastasis based on pelvic lymphadenectomy. Regarding long-term oncologic outcomes, recurrence was not observed at a median follow-up of 60 (range: 8-107) months. In addition, obstetric outcomes were consistently favorable in terms of achieving pregnancy, preterm delivery, and live birth. During the study period, two patients who actively attempted to conceive had four pregnancies, resulting in full-term deliveries, and one was on her first trimester of pregnancy. CONCLUSION: Cervical conization combined with pelvic lymphadenectomy represents a feasible conservative management for histologically well-selected patients with early-stage cervical cancer. Furthermore, an optimal histopathological evaluation of conization specimens will contribute to decision-making regarding the use of this fertility-sparing procedure.

Fertility preservation of polypoid endometriosis: Case series and literature review.

Polypoid endometriosis (PE) is a rare distinctive variant of endometriosis with morphological features resembling malignant tumors. Although a surgical procedure is usually performed for the treatment and diagnosis of PE, fertility preservation is usually desired in cases of reproductive age. However, there have been no reports of fertility-preserving treatments resulting in live births. In this study, we report three cases of PE that were diagnosed preoperatively or intraoperatively, leading to fertility preservation. Intraoperative pathological diagnosis, hysteroscopy, and hormone therapy before treatment were useful for preoperative diagnosis in the three cases. Two of the three patients got pregnant and the pregnancy progressed to a live birth. We also performed a literature review to identify the clinical characteristics indicative of the preoperative diagnosis of PE.

A Novel Direct Approach to the Deep Uterine Vein in Laparoscopic Radical Hysterectomy.

STUDY OBJECTIVE: To describe a direct approach to the deep uterine vein in laparoscopic radical hysterectomy. DESIGN: Demonstration of the laparoscopic technique with narrated video footage. SETTING: Securing sufficient radicality is extremely important when performing a radical hysterectomy for cervical cancer, either by laparotomy or by minimally invasive surgery. The nerve-sparing Okabayashi radical hysterectomy (NS-RH) was originally aimed at achieving both radical resection and function preservation [1-3]. A key procedure when performing NS-RH is intraoperative identification of the relationship between the deep uterine vein and pelvic splanchnic nerve fibers [4]. With this in mind, a safe and easy method for identifying the crossing point of the deep uterine vein and pelvic splanchnic nerve in the initial phase of the surgery may greatly improve the safety and efficacy of functional preservation in NS-RH. Herein, we describe a minimally invasive "direct approach" to the deep uterine vein. INTERVENTIONS: Before undergoing the pelvic lymphadenectomy, all steps of laparoscopic radical hysterectomy were performed. First, we identified the ureter on the posterior peritoneum, and the peritoneum was dissected just above the ureter. By continuously exploring the pelvic cavity along the ureter, especially through the opening of the space below the ureter in a cranial to caudal direction, we could easily identify the deep uterine vein. This procedure also exposed the fibers of the hypogastric nerve, clarifying the relationship of these structures. CONCLUSION: Because the relationship between the deep uterine vein and nerve fibers is the most important guidepost of this surgery, their identification in the early phase of the surgery enables us to perform the subsequent procedure precisely and securely. This direct approach to the deep uterine vein can be easily and safely performed.

Conservative management for retained products of conception after less than 22 weeks of gestation.

AIM: The aim of the study was to investigate the efficacy of conservative treatment in cases of retained products of conception (RPOC) with a preceding pregnancy of less than 22 weeks and to assess whether serum beta-human chorionic gonadotropin (hCG) levels could be a useful index to monitor the progress of treatment. METHODS: This is a case series of patients with RPOC developed after less than 22 weeks of gestation and managed expectantly with serial serum hCG measurement between 2011 and 2017. The clinical data of subjects were reviewed retrospectively. Cases that did not require invasive treatment such as surgery were designated as conservative management success. RESULTS: A total of 19 cases were eligible: 14 miscarriages and 5 induced abortions. Eleven patients underwent dilatation and curettage. The diagnosis of RPOC was made 35 (8-80) days after abortion. All patients were successfully treated with conservative management. Serum hCG levels at diagnosis were 29.6 (3.2-1585) mIU/mL. Serial measurement of serum hCG was continued until the levels became lower than the cutoff value, and the mean duration to hCG disappearance was 67.5 (6-183) days. In all cases, RPOC vanished spontaneously 77 (27-184) days after diagnosis. The disappearance of RPOC in the uterine cavity was subsequent to a significant decrease in serum hCG. Once serum hCG levels reached the cutoff value, no bleeding episodes were observed. CONCLUSION: Conservative management for RPOC might be acceptable and effective. Furthermore, serial serum hCG levels reflect the activity of RPOC, and hCG may be a reliable index to monitor the progress of treatment.

Trial of labor after cesarean delivery (TOLAC) in Japan: rates and complications.

PURPOSE: To determine the rates of trial of labor after cesarean delivery (TOLAC) and complications in Japan. METHODS: We conducted a descriptive study of pregnant women with one prior cesarean section registered between January 2013 and December 2015 in the perinatal database of the Japan Society of Obstetrics and Gynecology. This database is a nationwide institution-based registry in Japan. This study included women who had undergone one prior cesarean delivery and who delivered a singleton by cephalic presentation between 37 and 41 weeks of gestation. We collected data on delivery method, particularly with regard to the involvement of TOLAC or elective repeated cesarean deliveries (ERCD). Rates of TOLAC were investigated by facility type, and we calculated the rates of maternal and perinatal complications including uterine rupture in TOLAC. RESULTS: During the study period, 647,098 births were registered. Among the 34,460 women who met the inclusion criteria, 1730 (5.0%) and 32,730 (95.0%) underwent TOLAC and ERCD, respectively. In total, 76.4% of hospitals did not perform TOLAC at all. Generally in perinatal medical centers, which are better equipped with facilities, 58.7% women did not perform TOLAC. With regard to complications, we identified eight cases (0.46%) of uterine rupture with TOLAC. TOLAC births did not include maternal death and perinatal death. Among women attempting TOLAC, 1532 (88.6%) had successful vaginal births. CONCLUSION: The TOLAC rate in Japan was considerably lower than that reported in other countries, despite comparable complication rates.

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.

Novel intrauterine balloon tamponade systems for postpartum hemorrhage.

INTRODUCTION: Postpartum hemorrhage is the most common cause of maternal death worldwide. Although intrauterine balloon tamponade has been widely used as an effective procedure to control atonic postpartum hemorrhage, intrauterine balloon tamponade fails to control postpartum hemorrhage in approximately one-fifth of cases. The aim of this study was to evaluate the efficacy of novel intrauterine balloon tamponade systems for postpartum hemorrhage. MATERIAL AND METHODS: We have developed two novel intrauterine balloon tamponade systems to maintain proper balloon placement. One was a shaft cover with its fixture system and the other was "the Kyoto balloon system" designed to provide direct pressure onto the upper uterine cavity. The efficacy of the intrauterine balloon tamponade systems was evaluated using a silicone three-dimensionally printed postpartum uterine cavity model. RESULTS: Measurements of balloon displacement during inflation showed that the shaft cover significantly prevented the Bakri balloon from being displaced. The residual fluid volume in the upper uterine cavity was significantly less with the Kyoto balloon system than with the Bakri balloon system, indicating the effectiveness of the Kyoto balloon for upper uterine cavity tamponade. CONCLUSIONS: These innovative intrauterine balloon tamponade systems were effective for prevention of balloon displacement and for balloon tamponade of the upper uterine cavity in a 3D-printed postpartum-specific uterine cavity model.

National survey of uterine rupture in Japan: Annual report of Perinatology Committee, Japan Society of Obstetrics and Gynecology, 2018.

AIM: To clarify the frequency of occurrence of uterine rupture and its prognosis, a nationwide survey was performed. METHODS: Cases of uterine rupture recorded for a period of 5 years were included. RESULTS: There were 152 cases of uterine rupture with an incidence rate of 0.015%. The scarred uterine rupture cases were found to have a significantly earlier occurrence of uterine ruptures in comparison to the unscarred cases: unscarred 39.0 weeks, cesarean section 37.0 weeks, myomectomy 32 weeks and adenomyomectomy 30-32 weeks. And it became apparent that the frequency of hysterectomy, cerebral palsy and neonatal death were higher in the cases of uterine rupture during labor than before delivery. Among the cases of scarred uterine rupture, neonatal prognosis was poorer in cases of pregnancy after myomectomy or adenomyomectomy in comparison with postcesarean section cases. CONCLUSION: This survey revealed the current incidence of uterine rupture in Japan.

Mucinous adenocarcinoma, gastric type of the uterine cervix: clinical features and HER2 amplification.

Mucinous adenocarcinoma, gastric type (GAS) is difficult to diagnose and shows poor prognosis. Trastuzumab, an anti-human epidermal growth factor type 2 (HER2) monoclonal antibody, is effective in HER2-positive stomach cancer. The objectives of this study were to identify the clinicopathological characteristics of GAS and to evaluate HER2 expression in GAS. We retrospectively reviewed 322 cervical cancer cases diagnosed at the Kyoto University Hospital from 2010 to 2016. The incidence, clinical factors including age, stage, and lymph node status, tumor markers, immunoreactive expression of MUC6, HIK1083, and HER2, and HER2 amplification were evaluated. Of the 322 cases of cervical cancer, 13 cases of the adenocarcinoma cases were diagnosed as GAS. Watery discharge, lower abdominal pain, CA19-9 elevation, and lymph node metastasis were frequently observed in GAS (p = 0.0226, p = 0.0400, p = 0.0346, and p = 0.0274, respectively). Immunohistochemistry showed positive MUC6 status in all 13 cases and positive HIK1083 status in 8 cases. The HER2 expression status was equivocal in six cases by immunohistochemistry and HER2 amplification was identified in one case. GAS exhibits frequent lymph node metastasis and clinical symptoms such as watery discharge and lower abdominal pain, high levels of CA19-9. In addition, some parts of GAS exhibit HER2 amplification.

Enoxaparin administration within 24 hours of caesarean section: a 6-year single-centre experience and patient outcomes.

A caesarean section (CS) is a major risk factor for a venous thromboembolism, and enoxaparin, a low-molecular-weight heparin, has been widely used for thromboprophylaxis. However, it remains unclear whether an enoxaparin thromboprophylaxis has an acceptable safety profile when given early after CS compared to delayed administration, especially in the presence of an epidural catheter. This study aimed to survey cases in which enoxaparin administration was performed within 24 hours of CS and to evaluate patient outcomes with or without epidural anaesthesia. The number of eligible cases were 578: 328 patients received an epidural anaesthesia (epidural group), and 250 did not (non-epidural group). In both groups, no patient developed a spinal epidural haematoma. A wound or a subcutaneous bleeding occurred in 22 (6.7%) and 20 (8.0%) cases in the epidural and non-epidural groups, respectively. One patient developed a mild pulmonary embolism, and one case of asymptomatic deep vein thrombosis was detected. An enoxaparin administration within 24 hours of CS appears to be reasonable, regardless of an epidural anaesthesia. Impact statement What is already known on this subject? A venous thromboembolism (VTE) after a caesarean section (CS) remains a significant cause of maternal morbidity and mortality. Therefore, a thromboprophylaxis using enoxaparin, a low-molecular-weight heparin, has been widely recommended and accepted. However, there is no consensus regarding the optimal timing to initiate an enoxaparin administration after CS in the presence of an epidural catheter. What do the results of this study add? This is the largest study that has collected cases receiving enoxaparin within 24 hours of a CS. Irrespective of the presence of an epidural catheter, no patient developed a spinal epidural haematoma after an early administration of enoxaparin. Furthermore, the incidence of haemorrhagic complications did not increase. What are the implications of these findings for clinical practice and/or further research? Given the significant incidence of VTE after CS and the extremely low frequency of spinal epidural haematomas, it can be justified to initiate thromboprophylaxis with enoxaparin soon after CS. However, appropriately designed, large clinical trials are necessary to examine the safety and efficacy of an early enoxaparin administration after CS. Based on such studies, the starting time of thromboprophylaxis after a CS should be decided.

Human chorionic gonadotropin value and its change prior to methotrexate treatment can predict the prognosis in ectopic tubal pregnancies.

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.

Distinct preoperative clinical features predict four histopathological subtypes of high-grade serous carcinoma of the ovary, fallopian tube, and peritoneum.

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.

Differential expression of thioredoxin binding protein-2/Txnip in human placenta: Possible involvement of hypoxia in its suppression during early pregnancy.

AIM: Thioredoxin binding protein-2 (TBP-2), which is identical to thioredoxin interacting protein (Txnip), controls cellular proliferation and differentiation. The aim of the present study was to compare TBP-2 protein and mRNA expression in human placenta during the three trimesters of pregnancy and to investigate the role of hypoxia in the change of these expressions in placental tissue. A secondary objective was to determine the gene expression of peroxisome proliferator-activated receptors (PPARs) in TBP-2 deficient placenta using TBP-2 gene disrupted mice (TBP-2-/- ). METHODS: Protein and mRNA expression of TBP-2 in human placenta from each trimester were analyzed by immunohistochemistry, Western blots, and by quantitative reverse-transcriptase-polymerase chain reaction. The effect of hypoxia on TBP-2 expression was tested using an explant culture of human placenta. In TBP-2-/- mouse placenta, we detected PPAR mRNA expression. RESULTS: TBP-2 was located in syncytiotrophoblasts and cytotrophoblasts, and also in the endothelium in human placenta. Its expression in the placenta was low in the first trimester, and increased in the second and third trimesters. Hypoxia decreased TBP-2 mRNA and protein expression in human placental explant culture. In TBP-2-/- mice, placental mRNA levels of PPARα and γ were significantly suppressed compared with those in wild-type mice. CONCLUSION: Hypoxia suppresses TBP-2 gene expression, which may ultimately alter placental development.

Vaginal delivery after placental abruption with intrauterine fetal death: A 20-year single-center experience.

AIM: The aim of this study was to elucidate the feasibility and safety of vaginal delivery (VD) when placental abruption causes fetal demise. METHODS: We conducted a retrospective study of women who were managed for placental abruption with intrauterine fetal death at Kyoto University Hospital during the period from 1995 to 2015. RESULTS: Sixteen cases were identified during the study period. VD was attempted in 15 cases and was accomplished in 14 (93.3%) cases. The median gestational age was 36 (24-39) weeks, and there were eight primiparas. The median Bishop score on admission was 2.5 (1-9). Eight pregnancies were complicated with pregnancy-induced hypertension. The median duration of labor was 5 h and 18 min (30 min-12 h 43 min), and the median amount of hemorrhage was 2503 (445-6808) mL. Fresh frozen plasma (≥ 20 U) and red cell concentrate (≥ 10 U) were administered in 10 (71%) and 9 (64%) cases, respectively. Two cases required uterine artery embolization for post-partum hemorrhage, while there was no case of maternal death or hysterectomy. Patients with Bishop score > 3 (n = 6) experienced shorter-duration deliveries (P = 0.020) and had significantly larger blood loss volume (P = 0.020) compared to patients with Bishop score ≤ 3. The duration of labor was negatively correlated with the amount of blood loss (R2 = -0.56, P = 0.039). CONCLUSION: After placental abruption with intrauterine fetal death, VD is feasible and safe regardless of gestational age, parity, cervical maturity, and duration of labor when intensive medical resources are available.