Pregnancy outcomes following radical trachelectomy for early-stage cervical cancer: A retrospective observational study in the Kanto area, Japan.

OBJECTIVE: The authors aimed to investigate the prevalence of pregnancy and obstetric outcomes in patients who underwent radical trachelectomy (RT) for early-stage cervical cancer in the Kanto area, Japan. METHOD: A survey among 113 perinatal centers affiliated with the Kanto Society of Obstetrics and Gynecology was conducted to investigate their experience in managing pregnancies following RT, between 2010 and 2020. The association between preterm delivery (before 34 gestational weeks) and a midtrimester short cervix (<13 mm) was evaluated. RESULTS: The authors retrospectively collected maternal and perinatal data from 13 hospitals. There were 135 pregnancies among 115 women following RT. Of the 135 pregnancies, 32 were miscarriages (<12 gestational weeks: n = 22; >12 gestational weeks: n = 10), and 103 were delivered after 22 gestational weeks. The incidences of preterm delivery before 28 and 34 gestational weeks were 8.7% and 30.1%, respectively. A midtrimester short residual cervix was associated with preterm delivery (P = 0.046). CONCLUSION: Since more than 100 pregnancies were recorded after RT in the Kanto area, many physicians had more opportunities to manage pregnancy after RT. Pregnancy following RT is associated with increased risk of preterm delivery, and midtrimester short residual cervix is a good predictor of preterm delivery.

Factors associated with low birthweight among late preterm singletons in Japan using pregnancy birth registry data.

Late preterm (LP, born between 34 0/7 and 36 6/7 weeks of gestation) infants may experience several adverse outcomes, similar to those experienced by low birthweight (LBW, birthweight <2500 g) infants. However, while LP infants are often born with LBW, the association between LP and LBW remains unknown. This study aimed to investigate LBW rate and independent risk factors for LBW in LP singleton neonates. We retrospectively analyzed data of LP singleton neonates, born between 2013 and 2017, from the Japan Society of Obstetrics and Gynecology Successive Pregnancy Birth Registry System. The exclusion criteria included stillbirths and infants with missing data. Logistic regression analyses were performed to investigate maternal and perinatal factors associated with LBW in LP singletons. LBW was observed in 62.5% (n = 35,113) of 56,160 LP singleton births. In the multiple logistic regression analysis, LBW in LP neonates was independently associated with modifiable maternal factors, including pre-pregnancy underweight, inadequate gestational weight gain, and smoking during pregnancy, as well as non-modifiable factors, including younger maternal age, nulliparity, hypertensive disorder of pregnancy, preeclampsia, cesarean section delivery, and female offspring. According to the Japanese pregnancy birth registry data, more than half of LP neonates were LBW. We previously discussed the issue of LBW regarding infants with different backgrounds, as there are many different causes of LBW. Several risk factors should be subdivided and considered for the risk of LP and LBW.

Drosophila innate immunity suppresses the survival of xenografted mammalian tumor cells.

Patient-derived xenograft (PDX) is an emerging tool established in immunodeficient vertebrate models to assess individualized treatments for cancer patients. Current xenograft models are deficient in adaptive immune systems. However, the precise role of the innate immunity in the xenograft models is unknown. With conserved signaling pathways and established genetic tools, Drosophila has contributed to the understanding of the mechanism of tumor growth as well as tumor-host interactions for decades, making it a promising candidate model for studying whether or not the hosts' innate immunity can accommodate transplanted human tumor cells. Here we show initial observations that assess the behavior and impact of several human tumor cell lines when transplanted into Drosophila. We found that some injected cell lines persisted for a longer duration and reduced hosts' lifespan. In particular, the human lung cancer cell line A549 were observed adjacent to the fly host tissues. We examined two factors that affect the survivability of cancer cells: (1) the optimal temperature of each cell line and (2) the innate immunity of Drosophila hosts. Especially, transplanted human tumor cells survived longer in immunodeficient flies, suggesting that the host innate immune system impedes the growth of xenografted cells. Our attempts for xenografting fly models thus provide necessary steps to overcome for establishing PDX cancer models using invertebrates.

A capture methyl-seq protocol with improved efficiency and cost-effectiveness using pre-pooling and enzymatic conversion.

OBJECTIVE: The opportunities for sequencing-based methylome analysis of clinical samples are increasing. To reduce its cost and the amount of genomic DNA required for library preparation, we aimed to establish a capture methyl-seq protocol, which adopts pre-pooling of multiple libraries before hybridization capture and TET2/APOBEC-mediated conversion of unmethylated cytosine to thymine. RESULTS: We compared a publicly available dataset generated by the standard Agilent protocol of SureSelect XT Human Methyl-Seq Kit and our dataset obtained by our modified protocol, EMCap, that adopted sample pre-pooling and enzymatic conversion. We confirmed that the quality of DNA methylation data was comparable between the two datasets. As our protocol, EMCap, is more cost-effective and reduces the amount of input genomic DNA, it would serve as a better choice for clinical methylome sequencing.

Genome-wide association study of preterm birth and gestational age in a Japanese population.

Preterm birth (PTB), defined as the birth of a baby at <37 weeks of gestation, is known to be the main cause of neonatal morbidity and mortality. Here, we report genetic associations between preterm birth and gestational age in a Japanese population. We conducted a genome-wide association study (GWAS) of 384 cases who delivered prematurely and 644 controls and considered gestational age as a quantitative trait in 1028 Japanese women. Unfortunately, we were unable to identify any significant variants associated with PTB or gestational age using the current sample. We also examined genetic associations previously reported in European populations and identified no associations, even with the genome-wide subthreshold (p value < 10-6). This data report aims to provide summary statistics of current GWASs on PTB in a Japanese population for future meta-analyses of genetics and PTB with larger sample sizes.

Ultrasonographic Prediction of Placental Invasion in Placenta Previa by Placenta Accreta Index.

This study aimed to investigate the diagnostic accuracy of the placenta accreta index (PAI) for predicting placenta accreta spectrum (PAS) in women with placenta previa. We analyzed 33 pregnancies with placenta previa at Keio University Hospital. The PAI was assessed in the early third trimester, and PAS was diagnosed histologically or clinically defined as retained placenta after manual removal attempts. The PAI and incidence of PAS were analyzed. Ten women (30%) were diagnosed with PAS and had higher volumes of perioperative bleeding (p = 0.016), higher rate of requiring uterine artery embolization (p = 0.005), and peripartum hysterectomy (p = 0.0002) than women without PAS. A PAI > 2 was the most useful cut-off point for predicting PAS and was more sensitive than prediction values using traditional evaluation (history of cesarean section and placental location). Post-hoc analysis revealed a higher rate of previous history of cesarean delivery (30% vs. 4.4%, p = 0.038), severe placental lacunae (≥grade2) (70% vs. 8.7%, p = 0.0003), thin myometrial thickness (90% vs. 22%, p = 0.0003), anterior placenta (100% vs. 30%, p = 0.0002), and presence of bridging vessels (30% vs. 0%, p = 0.0059) in PAS women. PAI could help predict the outcomes of women with placenta previa with and without a history of cesarean delivery to reduce PAS-induced perinatal complications.

Obstetric outcomes after medroxyprogesterone acetate treatment for early stage endometrial cancer or atypical endometrial hyperplasia: a single hospital-based study.

BACKGROUND: To investigate perinatal outcomes in pregnancy after high-dose medroxyprogesterone acetate (MPA) therapy for early stage endometrial cancer (EC) and atypical endometrial hyperplasia (AEH) and to determine whether pregnancy after MPA therapy is at a higher risk of placenta accreta. METHODS: Data of 51 pregnancies in 46 women who received MPA therapy for EC or AEH and delivered after 22 weeks of gestation at Keio University Hospital were reviewed. A retrospective matched case-control study was performed to determine the risk of placenta accreta in pregnancy after MPA therapy compared with singleton pregnancies without any history of maternal malignancy treatments. RESULTS: The incidence of placenta accreta was higher in the MPA group than in the control group (15.7 vs. 0%, p = 0.0058). However, no differences in other perinatal outcomes were observed between groups. While gestational weeks at delivery in the MPA group were later than those in the control group (p = 0.0058), no difference in the incidence of preterm delivery was recorded between groups. In the MPA therapy group, the number of patients who underwent ≥ 6 dilation and curettage (D&C) was higher in the placenta accreta group than in the non-placenta accreta group (50.0 vs. 14.0%, p = 0.018). Patients with ≥ 6 D&Cs demonstrated a 6.0-fold increased risk of placenta accreta (p = 0.043, 95% CI 1.05-34.1) than those receiving ≤ 3 D&Cs. CONCLUSION: Pregnancy after MPA therapy is associated with a high risk of placenta accreta. In cases in which the frequency of D&C is high, placenta accreta should be considered.

The Associated Factors of Low Birthweight Among Term Singletons in Japan: A Pregnancy Birth Registry Analysis.

BACKGROUND: Progress in reducing the global low birthweight (LBW) has been insufficient. Although the focus has been on preventing preterm birth, evidence regarding LBW in term births is limited. Despite its low preterm birth prevalence, Japan has a higher LBW proportion than other developed countries. This study aimed to examine the prevalence of LBW in term singleton births and its associated factors using a national database. METHODS: We retrospectively analyzed the data of neonates registered in the Japan Society of Obstetrics and Gynecology Successive Pregnancy Birth Registry System who were born 2013-2017. Exclusion criteria included stillbirths, delivery after 42 gestational weeks, and missing data. Logistic regression analyses were performed to investigate the maternal and perinatal factors associated with LBW in term singletons using the data of 715,414 singleton neonates. RESULTS: The overall prevalence of LBW was 18.3%, and 35.7% of LBWs originated from singleton term pregnancies. Multiple logistic regression analyses indicated that both modifiable and non-modifiable factors were independently associated with LBW in term neonates. The modifiable maternal factors included pre-pregnancy underweight, inadequate gestational weight gain, and smoking during pregnancy, while the non-modifiable factors included younger maternal age, nulliparity, hypertensive disorders of pregnancy, cesarean section delivery, female offspring, and congenital anomalies. CONCLUSION: Using the Japanese pregnancy birth registry data, more than one-third of LBWs were found to originate from singleton term pregnancies. Both modifiable and non-modifiable factors were independently associated with LBW in term neonates. Prevention strategies on modifiable risk factor control will be effective in reducing LBW worldwide.

DNA methylation analysis of cord blood samples in neonates born to gestational diabetes mothers diagnosed before 24 gestational weeks.

INTRODUCTION: Genome-wide methylation analyses of gestational diabetes mellitus (GDM) diagnosed after 24 gestational weeks (late GDM (L-GDM)) using cord blood have been reported. However, epigenetic changes in neonates born to mothers with GDM diagnosed before 24 gestational weeks (early GDM (E-GDM)) have not been reported. We investigated DNA methylation in neonates born to mothers with E-GDM using cord blood samples. RESEARCH DESIGN AND METHODS: Genome-wide DNA methylation analysis was performed using an Illumina EPIC array to compare methylation rates of 754 255 autosomal sites in cord blood samples from term neonates born to 162 mothers with GDM (E-GDM: n=84, L-GDM: n=78) and 60 normal glucose tolerance (normal OGTT) pregnancies. GDM was diagnosed based on Japan Society of Obstetrics and Gynecology criteria modified with International Association of Diabetes in Pregnancy Study Group criteria. In this study, all GDM mothers underwent dietary management, while self-monitoring of blood glucose and insulin administration was initiated when dietary modification did not achieve glycemic control. RESULTS: There were no significant differences in genome-wide DNA methylation of cord blood samples between the GDM (E-GDM and L-GDM) groups and normal OGTT group or between the E-GDM and normal OGTT groups, L-GDM and normal OGTT groups, and E-GDM and L-GDM groups. CONCLUSIONS: This is the first report to determine the DNA methylation patterns in neonates born to mothers with E-GDM. Neonates born to mothers with GDM, who were diagnosed based on Japan Society of Obstetrics and Gynecology criteria, may not differ in DNA methylation compared with those born to normal OGTT mothers.

Epigenetic Changes in Neonates Born to Mothers With Gestational Diabetes Mellitus May Be Associated With Neonatal Hypoglycaemia.

The detection of epigenetic changes associated with neonatal hypoglycaemia may reveal the pathophysiology and predict the onset of future diseases in offspring. We hypothesized that neonatal hypoglycaemia reflects the in utero environment associated with maternal gestational diabetes mellitus. The aim of this study was to identify epigenetic changes associated with neonatal hypoglycaemia. The association between DNA methylation using Infinium HumanMethylation EPIC BeadChip and neonatal plasma glucose (PG) level at 1 h after birth in 128 offspring born at term to mothers with well-controlled gestational diabetes mellitus was investigated by robust linear regression analysis. Cord blood DNA methylation at 12 CpG sites was significantly associated with PG at 1 h after birth after adding infant sex, delivery method, gestational day, and blood cell compositions as covariates to the regression model. DNA methylation at two CpG sites near an alternative transcription start site of ZNF696 was significantly associated with the PG level at 1 h following birth (false discovery rate-adjusted P < 0.05). Methylation levels at these sites increased as neonatal PG levels at 1 h after birth decreased. In conclusion, gestational diabetes mellitus is associated with DNA methylation changes at the alternative transcription start site of ZNF696 in cord blood cells. This is the first report of DNA methylation changes associated with neonatal PG at 1 h after birth.

Predictors of later insulin therapy for gestational diabetes diagnosed in early pregnancy.

Interventions for gestational diabetes mellitus (GDM), diagnosed in early pregnancy, have been a topic of controversy. This study aimed to elucidate factors that predict patients with GDM diagnosed before 24 gestational weeks (early GDM: E-GDM) who require insulin therapy later during pregnancy. Furthermore, we identified patients whose impaired glucose tolerance should be strictly controlled from early gestation onward. Women diagnosed with GDM were categorized based on the gestational age at diagnosis into E-GDM (n = 388) or late GDM (L-GDM, diagnosed after 24 weeks, n = 340) groups. Clinical features were compared between the groups, and the predictors for insulin therapy was evaluated in the E-GDM group. There were no significant between-group differences in terms of perinatal outcomes (e.g., gestational weeks at delivery, fetal growth, hypertensive disorder of pregnancy), with the exception of the Apgar score at 5 min. Moreover, there was no significant difference in the frequency of insulin therapy during pregnancy between the two groups. Using multiple logistic regression analysis, pre-pregnancy body mass index (BMI) ≥25 kg/m2, a family history of diabetes, and higher fasting plasma glucose (FPG), 1 h-plasma glucose (PG), and 2 h-PG values increased insulin therapy risk during pregnancy in the E-GDM group. Furthermore, since E-GDM patients with abnormal levels of FPG, as well as 1 h-PG or 2 h-PG, and those with pre-pregnancy BMI ≥25 kg/m2 and a family history of diabetes had a higher risk of later insulin therapy during pregnancy, they may require more careful follow-up in the perinatal period.

Expectant management for early pregnancy miscarriage after radical trachelectomy: A single hospital-based study.

INTRODUCTION: Women who have undergone radical trachelectomy as a fertility-sparing treatment for early-stage cervical cancer may be at higher risk for retained tissues after early-term miscarriage due to cervical cerclage or cervical necrosis. Dilatation and curettage or aspiration may present additional risks in these women. The aim of this study was to assess the efficacy of expectant management for early pregnancy miscarriage after radical trachelectomy. MATERIAL AND METHODS: Keio University Hospital records were reviewed for women who conceived after abdominal radical trachelectomy and received perinatal care between 1 April 2012 and 31 March 2020. A total of 62 women (76 pregnancies) were identified, and 13 of these women experienced miscarriage before 12 gestational weeks. The management and outcome of these cases were reviewed in detail. RESULTS: The median maternal age at miscarriage was 39 years (range 31-42 years) and the median duration from abdominal radical trachelectomy to conception was 2.60 years (range 0.49-7.30 years). Cervical necrosis before conception occurred in one case (8%). One patient requested treatment with aspiration and the remaining 12 cases were managed with observation for a median of 23 days (range 7-50 days). There were no cases of endometritis or cases requiring dilatation and curettage for residue tissue. Further, no cases developed laceration of the residual cervix and no loss of cerclage sutures after discharge was noted. CONCLUSIONS: Expectant management seems to be safe and appropriate for first trimester miscarriage after abdominal radical trachelectomy.

Ipsilateral EEG mu rhythm reflects the excitability of uncrossed pathways projecting to shoulder muscles.

BACKGROUND: Motor planning, imagery or execution is associated with event-related desynchronization (ERD) of mu rhythm oscillations (8-13 Hz) recordable over sensorimotor areas using electroencephalography (EEG). It was shown that motor imagery involving distal muscles, e.g. finger movements, results in contralateral ERD correlating with increased excitability of the contralateral corticospinal tract (c-CST). Following the rationale that purposefully increasing c-CST excitability might facilitate motor recovery after stroke, ERD recently became an attractive target for brain-computer interface (BCI)-based neurorehabilitation training. It was unclear, however, whether ERD would also reflect excitability of the ipsilateral corticospinal tract (i-CST) that mainly innervates proximal muscles involved in e.g. shoulder movements. Such knowledge would be important to optimize and extend ERD-based BCI neurorehabilitation protocols, e.g. to restore shoulder movements after stroke. Here we used single-pulse transcranial magnetic stimulation (TMS) targeting the ipsilateral primary motor cortex to elicit motor evoked potentials (MEPs) of the trapezius muscle. To assess whether ERD reflects excitability of the i-CST, a correlation analysis between between MEP amplitudes and ipsilateral ERD was performed. METHODS: Experiment 1 consisted of a motor execution task during which 10 healthy volunteers performed elevations of the shoulder girdle or finger pinching while a 128-channel EEG was recorded. Experiment 2 consisted of a motor imagery task during which 16 healthy volunteers imagined shoulder girdle elevations or finger pinching while an EEG was recorded; the participants simultaneously received randomly timed, single-pulse TMS to the ipsilateral primary motor cortex. The spatial pattern and amplitude of ERD and the amplitude of the agonist muscle's TMS-induced MEPs were analyzed. RESULTS: ERDs occurred bilaterally during both execution and imagery of shoulder girdle elevations, but were lateralized to the contralateral hemisphere during finger pinching. We found that trapezius MEPs increased during motor imagery of shoulder elevations and correlated with ipsilateral ERD amplitudes. CONCLUSIONS: Ipsilateral ERD during execution and imagery of shoulder girdle elevations appears to reflect the excitability of uncrossed pathways projecting to the shoulder muscles. As such, ipsilateral ERD could be used for neurofeedback training of shoulder movement, aiming at reanimation of the i-CST.