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.

Placental functional assessment and its relationship to adverse pregnancy outcome: comparison of intravoxel incoherent motion (IVIM) MRI, T2-relaxation time, and umbilical artery Doppler ultrasound.

BACKGROUND: Early identification of placental insufficiency can lead to appropriate treatment selections and can improve neonates' outcomes. Possible contributions of magnetic resonance imaging (MRI) have been suggested. PURPOSE: To evaluate the prognostic capabilities of placental intravoxel incoherent motion (IVIM) parameters and T2-relaxation time, and their correlation with fetal growth and adverse outcomes, comparing umbilical artery (UmA) pulsatility index (PI). MATERIAL AND METHODS: A total of 68 singleton pregnancies at 24-40 weeks of gestation underwent placental MRI and were reviewed retrospectively. UmA-PI was measured using Doppler ultrasound by obstetricians. IVIM parameters (Dfast, Dslow, and f) were calculated with a Bayesian model fitting. First, the associations between gestational age (GA) with placental IVIM parameters, T2-relaxation time, and placental thickness (PT) were evaluated. Second, IVIM parameters, T2 value (Z-score), PT (Z-score), and UmA-PI (Z-score) were compared between ( 1) those delivering small for gestational age (SGA) and appropriate for gestational age (AGA) neonates, ( 2) emergency cesarean section (ECS), and non-ECS, and ( 3) preterm birth and full-term birth. RESULTS: Low birth weight was observed in 15/68 cases (22%). GA was significantly associated only with T2-relaxation time and PT. SGA was significantly associated with T2 value (Z-score), f, and UmA-PI (Z-score). In the ECS groups, T2 value (Z-score), f, and Dfast were significantly lower than those in non-ECS groups. All IVIM parameters and T2 values (Z-score) showed significantly lower scores in the preterm birth group. CONCLUSION: Placental f and T2 value (Z-score) had significant associations with low birth weight and clinical adverse outcomes and could be potential imaging biomarkers of placental insufficiency.

The prognosis of neonatal respiratory status within three years after birth in chronic abruption-oligohydramnios sequence.

AIM: Chronic abruption-oligohydramnios sequence (CAOS), which is characterized by vaginal bleeding and oligohydramnios, adversely affects the lungs of fetuses due to bloody amniotic fluid and oligohydramnios. The criteria for termination of pregnancy remain controversial. This study aimed to examine respiratory function in infants within 3 years after birth and risk factors for respiratory prognosis, and to clarify the management of CAOS. METHODS: This study is a case series of patients with CAOS managed at our institution between 2010 and 2020. The clinical data of the patients and their infants within 3 years after birth were reviewed. The amniotic fluid volume was measured using the maximum vertical pocket (MVP). RESULTS: Six of 17 neonates (35.3%) used inhaled nitric oxide (iNO) to improve oxygenation. Women with longer periods of MVP <1 cm delivered more neonates using iNO; however, periods of MVP <2 cm were not associated with iNO use. Almost half of the infants required home oxygen therapy when discharged, regardless of amniotic fluid volume. At 18 months corrected age, only one child needed respiratory support, and the others discontinued. Two neonates, both born at 23 weeks of gestational age, died within 1 month after birth because of extremely preterm birth. CONCLUSIONS: The amniotic fluid volume could predict the use of iNO in neonates, but it did not affect the child's respiratory function after the newborn period. Almost all children born to women with CAOS can improve their respiratory function as they grow up.

High-grade vaginal intraepithelial neoplasia after hysterectomy for high-grade cervical intraepithelial neoplasia: Is hysterectomy a "definitive" treatment compared to conization?

AIM: We investigated the frequency of early recurrence of vaginal intraepithelial neoplasia grade 2/3 (VaIN 2/3) (within 2 years) after hysterectomy for cervical intraepithelial neoplasia grade 3 (CIN3). The characteristics of the clinicopathological factors common to them were explored including different surgical methods. METHODS: As a retrospective observational study, a total of 647 CIN3 patients were divided into a conization and hysterectomy group (C group, n = 492; H group, n = 155), and HSIL (CIN2/3 or VaIN2/3) recurrence within 2 years after surgery was evaluated. A stratified analyses was performed. Surgical methods were divided into trans-abdominal, trans-vaginal, and laparoscopic. RESULTS: The recurrence of VaIN3 was detected in four cases (2.6%) in the H group, which was similar to that of CIN2/3 in the C group, 12 out of 491 patients (2.4%). The patients who developed VaIN3 were significantly older than those who did not (median, VaIN3: 71.0; VaIN1 and less: 48.0; p < 0.0001). All VaIN3 cases were detected within 5 months, although majority of cases were negative in the margin (3/4 cases; margin negative). The method of hysterectomy was not related to the VaIN3 recurrence. CONCLUSION: For CIN3 patients for whom hysterectomy is the main treatment, VaIN3 can develop in 2.6% within very shortly after operation even if surgical margin was negative. The elder the age, the higher the risk of early recurrence could be. Laparoscopic surgery is considered to be acceptable methods of hysterectomy.

Tuft cell-like carcinomas: novel cancer subsets present in multiple organs sharing a unique gene expression signature.

BACKGROUND: Tuft cells are chemosensory epithelial cells playing a role in innate immunity. Recent studies revealed cancers with a tuft cell-like gene expression signature in the thorax. We wondered whether this signature might also occur in extrathoracic cancers. METHODS: We examined mRNA expression of tuft cell markers (POU2F3, GFI1B, TRPM5, SOX9, CHAT, and AVIL) in 19 different types of cancers in multiple extrathoracic organs with The Cancer Genome Atlas (TCGA) (N = 6322). Four different extrathoracic cancers in our local archives (N = 909) were analysed by immunohistochemistry. RESULTS: Twenty-two (0.35%) extrathoracic tumours with co-expression of POU2F3 and other tuft cell markers were identified in various TCGA datasets. Twelve of the 22 "tuft cell-like tumours" shared poor differentiation and a gene expression pattern, including KIT, anti-apoptotic BCL2, and ionocyte-associated genes. In our archival cases, eleven (1.21%) tumours co-expressing POU2F3, KIT, and BCL2 on immunohistochemistry, i.e., were presumable tuft cell-like cancers. In three among five TCGA cohorts, the tuft cell-like cancer subsets expressed SLFN11, a promising biomarker of PARP inhibitor susceptibility. CONCLUSIONS: Tuft cell-like carcinomas form distinct subsets in cancers of many organs. It appears warranted to investigate their shared gene expression signature as a predictive biomarker for novel therapeutic strategies.

Risk Stratification for Pregnancies Diagnosed With Fetal Growth Restriction Based on Placental MRI.

BACKGROUND: Diagnosis of fetal growth restriction (FGR) entails difficulties with differentiating fetuses not fulfilling their growth potential because of pathologic conditions, such as placental insufficiency, from constitutionally small fetuses. The feasibility of placental MRI for risk stratification among pregnancies diagnosed with FGR remains unexplored. PURPOSE: To explore quantitative MRI features useful to identify pregnancies with unfavorable outcomes and to assess the diagnostic performance of visual analysis of MRI to detect pregnancies with unfavorable outcomes, among pregnancies diagnosed with FGR. STUDY TYPE: Retrospective. POPULATION: Thirteen pregnancies with unfavorable outcomes (preterm emergency cesarean section or intrauterine fetal death) and 11 pregnancies with favorable outcomes performed MRI at gestational weeks 21-36. FIELD STRENGTH/SEQUENCE: A 5-T, half-Fourier-acquired single-shot turbo spin echo (HASTE), spin-echo echo-planar imaging (SE-EPI) and T2 map derived from SE-EPI. ASSESSMENT: Placental size on HASTE sequences and T2 mapping-based histogram features were extracted. Three radiologists qualitatively evaluated the visibility of maternal cotyledon on HASTE and SE-EPI sequences with echo times (TEs) = 60, 90, and 120 msec using 3-point Likert scales: 0, absent; 1, equivocal; and 2, present. STATISTICAL TESTS: Welch's t-test or Mann-Whitney U test for quantitative features between the favorable and unfavorable outcome groups. Areas under the receiver operating curves (AUCs) of the three readers' visual analyses to detect pregnancies with unfavorable outcomes. A P value of <0.05 was inferred as statistically significant. RESULTS: Placental size (major and minor axis, estimated area of placental bed, and volume of placenta) and T2 mapping-based histogram features (mean, skewness, and kurtosis) were statistically significantly different between the two groups. Visual analysis of HASTE and SE-EPI with TE = 60 msec showed AUCs of 0.80-0.86 to detect pregnancies with unfavorable outcomes. DATA CONCLUSION: Placental size, histogram features, and visual analysis of placental MRI may allow for risk stratification regarding outcomes among pregnancies diagnosed with FGR. EVIDENCE LEVEL: 3 TECHNICAL EFFICACY: Stage 5.

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.

Association between non-anemic iron deficiency in early pregnancy and perinatal mental health: A retrospective pilot study.

AIM: Postpartum anemia and iron deficiency are reportedly involved in postpartum depression, but the association between perinatal depression and iron deficiency with or without anemia is poorly documented. This pilot study retrospectively investigated the relationship between non-anemic iron deficiency (NAID) in early pregnancy and perinatal depressive symptoms. METHODS: This study included 31 non-anemic women among patients who received perinatal care with preserved residual serum from routine antenatal checkups in Kyoto University Hospital. All participants gave informed consent for research. The ferritin concentration in their preserved serum was measured. The hemoglobin (Hb) and ferritin in early pregnancy, as well as the Edinburgh Postpartum Depression Scale (EPDS) at mid-pregnancy and 1 month after childbirth were analyzed. Iron deficiency was defined as a serum ferritin concentration < 30 ng/mL. RESULTS: Based on the ferritin level in early pregnancy, 13 women (41.9%) had NAID, whereas 18 were normal. The mean Hb and ferritin were 12.7 ± 0.6 g/dL and 18.5 ± 5.8 ng/mL in the NAID group and 12.8 ± 0.9 g/dL and 74.7 ± 39.2 ng/mL in the normal group, respectively. The median EPDS scores at mid-pregnancy and 1 month postpartum, respectively, were 2.0 (2.0-3.3) and 5.0 (4.0-6.6) in the NAID group and 4.5 (2.3-7.3) and 4.5 (2.3-5.7) in the normal group. EPDS scores increased significantly from mid-pregnancy to 1 month postpartum in the NAID group only. CONCLUSION: NAID in early pregnancy was highly prevalent and was suggested to reduce resilience to depression during the perinatal period.

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.

Diagnostic Accuracy of Magnetic Resonance Imaging for International Federation of Gynecology and Obstetrics 2018 IB to IIB Cervical Cancer Staging: Comparison Among Magnetic Resonance Sequences and Pathologies.

OBJECTIVE: This study aimed to investigate the most accurate magnetic resonance (MR) sequence for tumor detection, maximal tumor diameter, and parametrial invasion compared with histopathologic diagnoses. METHODS: Fifty-one patients with International Federation of Gynecology and Obstetrics 2018 IB1 to IIB cervical cancer underwent preoperative MR imaging and surgical resection. Two radiologists independently evaluated the tumor detection, parametrial invasion, and tumor size in each of T2-weighted image, diffusion-weighted image, and contrast-enhanced T1-weighted image. Results obtained for squamous cell carcinoma (SCC) and adenocarcinoma were also compared. RESULTS: Neither the tumor detection rate nor parametrial invasion was found to be significantly different among sequences. Tumor size assessment using MR imaging with pathology showed good correlation: r = 0.63-0.72. The adenocarcinoma size tended to be more underestimated than SCC in comparison with the pathologic specimen. CONCLUSIONS: Cervical cancer staging by MR images showed no significant difference among T2-weighted image, diffusion-weighted image, and contrast-enhanced T1-weighted image. Adenocarcinoma was prone to be measured as smaller than the pathologic specimen compared with SCC.

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.

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.

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.

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.

Pregnancy outcomes in liver transplant recipients: A 15-year single-center experience.

AIM: There are an increasing number of reports of pregnancy following liver transplantation, but many questions remain regarding preconception counseling and management of the pregnancy. The aim of this study was to report pregnancy outcomes in women who had undergone liver transplants and to gain insight into these issues. METHODS: We conducted a retrospective review of liver transplant recipients who had received prenatal care at Kyoto University Hospital between January 2001 and December 2015. RESULTS: Twenty-six consecutive pregnancies in 17 liver transplant recipients were identified during the period. The most common indication for liver transplantation was biliary atresia (65%). The median age at transplantation was 19 years (range, 2-38). The median age at conception was 28 years (range, 20-41) with a median time between transplantation and conception of 8 years (range, 0-22). A tacrolimus-based immunosuppressive regimen (n = 21, 81%) was the most common at the time of conception. There were 13 live births (50%), four spontaneous miscarriages (15%), and nine induced abortions (35%). Median gestational age at delivery was 38 weeks (range, 32-42), and the median birthweight was 2858 g (range, 1815-3864 g). Pregnancy and maternal complications included preterm deliveries (23%), intrauterine growth restriction (23%), pre-eclampsia (8%), cesarean delivery (23%), bacterial infection (15%), and biopsy-proven acute cellular rejection (15%). Two infants had congenital anomalies (tetralogy of Fallot and hydronephrosis). CONCLUSION: Pregnancy after liver transplantation can achieve relatively favorable outcomes. Obstetricians should be involved in the contraceptive and fertility counseling of female transplant recipients to prevent unintended pregnancies.

Simvastatin inhibits oxidative stress via the activation of nuclear factor erythroid 2-related factor 2 signaling in trophoblast cells.

AIM: Nuclear factor erythroid 2-related factor 2 (Nrf2) is a key transcriptional regulator against oxidative stress through the induction of antioxidant and cytoprotective genes, such as heme oxygenase 1 (HO-1), glutamyl cysteine ligase catalytic (GCLC), and glutamyl cysteine ligase modulatory (GCLM). Nrf2 signaling is disrupted in pre-eclamptic placentas, although increased oxidative stress is implicated in pre-eclampsia. The aims of the study were: (i) to investigate the mechanism that underlies the impaired Nrf2 signaling in pre-eclamptic placentas, and (ii) to examine the potential therapeutic role of statin for pre-eclampsia. MATERIAL AND METHODS: Human choriocarcinoma JAR cells were cultured under normoxia (20% O2 ) or hypoxia (1% O2 ). Small-interfering ribonucleic acids were used to knockdown Nrf2. Real-time quantitative reverse transcriptase polymerase chain reaction and Western blotting were used to evaluate the influence of oxidative stress (H2O2 100 µM) and simvastatin (50 µM) on Nrf2 and its target genes. Reactive oxygen species levels were analyzed by flow cytometry in immortalized human trophoblast TCL1 cells treated with or without H2O2 (100 µM) ± simvastatin (50 µM). RESULTS: Nuclear factor erythroid 2-related factor 2 activation was significantly suppressed under hypoxic conditions. Nrf2 knockdown resulted in insufficient enhancement of HO-1, GCLC and GCLM expression under oxidative stress. In contrast, Nrf2 signaling was augmented by simvastatin, which suppressed the induction of oxidative stress in trophoblasts. CONCLUSION: Hypoxia is one of the important negative regulators of Nrf2 activation, and simvastatin inhibits oxidative stress through the activation of Nrf2 signaling in trophoblasts, indicating the potential therapeutic role of statin for pre-eclampsia.

Live-born diploid fetus complicated with partial molar pregnancy presenting with pre-eclampsia, maternal anemia, and seemingly huge placenta: A rare case of confined placental mosaicism and literature review.

A partial molar pregnancy almost always ends in miscarriage due to a triploid fetus. We describe a rare case of a singleton, partial molar pregnancy with a seemingly huge placenta, which continued to delivery of a live-born diploid baby. A 27-year-old primigravida suffered from severe pre-eclampsia and progressive anemia. The uterus was enormously enlarged for the gestational age. A cesarean section was performed because of deterioration of maternal status at 25 weeks' gestation, when more than 3000 mL blood spouted concurrently with the delivery of the placenta. The histological examination showed congestion in the decidua, which indicated disturbance of maternal venous return from the intervillous space. The chromosome complement of the placenta and the neonate were 69,XXX and 46,XX, respectively. We also reviewed all published cases of a singleton, partial molar pregnancy. A literature search yielded 18 cases of a singleton, diploid fetus with partial molar pregnancy. The mean gestational age at delivery was 24.5 ± 6.2 weeks, and fetuses survived outside the uterus in only four cases (22.2%). Intriguingly, previous reports numbered 10 cases with diploid placenta as well as five cases with no karyotyping of the placenta, indicating that they may have included a complete mole in a twin pregnancy or placental mesenchymal dysplasia. In conclusion, this was the first case of placentomegaly that presented manifestations of excessive abdominal distension and maternal severe anemia, and the second case of a singleton, partial molar pregnancy confirmed by chromosome analysis resulting in a diploid living baby.

Reliable pre-eclampsia pathways based on multiple independent microarray data sets.

Pre-eclampsia is a multifactorial disorder characterized by heterogeneous clinical manifestations. Gene expression profiling of preeclamptic placenta have provided different and even opposite results, partly due to data compromised by various experimental artefacts. Here we aimed to identify reliable pre-eclampsia-specific pathways using multiple independent microarray data sets. Gene expression data of control and preeclamptic placentas were obtained from Gene Expression Omnibus. Single-sample gene-set enrichment analysis was performed to generate gene-set activation scores of 9707 pathways obtained from the Molecular Signatures Database. Candidate pathways were identified by t-test-based screening using data sets, GSE10588, GSE14722 and GSE25906. Additionally, recursive feature elimination was applied to arrive at a further reduced set of pathways. To assess the validity of the pre-eclampsia pathways, a statistically-validated protocol was executed using five data sets including two independent other validation data sets, GSE30186, GSE44711. Quantitative real-time PCR was performed for genes in a panel of potential pre-eclampsia pathways using placentas of 20 women with normal or severe preeclamptic singleton pregnancies (n = 10, respectively). A panel of ten pathways were found to discriminate women with pre-eclampsia from controls with high accuracy. Among these were pathways not previously associated with pre-eclampsia, such as the GABA receptor pathway, as well as pathways that have already been linked to pre-eclampsia, such as the glutathione and CDKN1C pathways. mRNA expression of GABRA3 (GABA receptor pathway), GCLC and GCLM (glutathione metabolic pathway), and CDKN1C was significantly reduced in the preeclamptic placentas. In conclusion, ten accurate and reliable pre-eclampsia pathways were identified based on multiple independent microarray data sets. A pathway-based classification may be a worthwhile approach to elucidate the pathogenesis of pre-eclampsia.