Genetic and non-genetic factors contribute to breast cancer development. An epigenome-based signature capturing these components in easily accessible samples could identify women at risk. Here, we analyse the DNA methylome in 2,818 cervical, 357 and 227 matched buccal and blood samples respectively, and 42 breast tissue samples from women with and without breast cancer. Utilising cervical liquid-based cytology samples, we develop the DNA methylation-based Women’s risk IDentification for Breast Cancer index (WID-BC-index) that identifies women with breast cancer with an AUROC (Area Under the Receiver Operator Characteristic) of 0.84 (95% CI: 0.80–0.88) and 0.81 (95% CI: 0.76–0.86) in internal and external validation sets, respectively. CpGs at progesterone receptor binding sites hypomethylated in normal breast tissue of women with breast cancer or in BRCA mutation carriers are also hypomethylated in cervical samples of women with poor prognostic breast cancer. Our data indicate that a systemic epigenetic programming defect is highly prevalent in women who develop breast cancer. Further studies validating the WID-BC-index may enable clinical implementation for monitoring breast cancer risk.

Advanced maternal age (AMA) is a growing trend world-wide and is traditionally defined as childbearing in women over 35 years of age. The purpose of our study was to determine the maternal age group within the Korean population, in which the risk of early neonatal mortality is increased. Korean birth and mortality data from 2011 to 2015 were used to estimate the influence of maternal age on the risk of early neonatal mortality. A Poisson regression was used for the analysis of multiple clinical variables such as year of delivery, maternal age, gestational age, infant gender, birth weight, multiple birth, parity, and socioeconomic variables. Furthermore, a generalized additive model was used to determine the maternal age at which the risk for neonatal mortality increases. We included 2,161,908 participants and found that 49.4% of mothers were 30–34 years of age at delivery. The proportion of mothers aged 35 and above increased over the 5-year analysis period. A maternal age lower than 29 years or higher than 40 years was associated with a relatively higher risk of early neonatal mortality. The trend and magnitude of the age-related risk on early neonatal mortality were independent of maternal socioeconomic factors such as living in an obstetrically underserved area, education level, and employment status. Furthermore, we showed that the risk for early neonatal mortality was higher until the maternal age of 28. However, there were no significant changes in the risk between the age of 35 and 40 years. According to recent national-wide data, age-related risk for early neonatal mortality is only apparent for mothers ≥ 40 years old whereas, age between 35 and 39 are not at increased risk for early neonatal mortality, despite being classified as AMA.

Acute necrotizing encephalopathy (ANE) may be suspected when a young child presents with abrupt onset of altered mental status, seizures, or both. Definitive clinical diagnosis is based on magnetic resonance imaging (MRI) results. ANE is associated with influenza virus infections. Preliminary data suggests that up to 25% of ANE patients die, and up to 25% of ANE survivors develop substantial neurologic sequelae. Here, we describe a case of a comatose 22-month-old girl who was admitted to our hospital because of febrile illness and seizures. On day 13 of her illness, she died from ANE associated with infection from parainfluenza virus. Brain MRI results indicated diffuse bilateral symmetric signal changes in both basal ganglia, thalami, periventricular white matter, pons, and cerebral white matter, as well as generalized swelling of the brain.

IntroductionFluorescence image-guided sentinel lymph node (SLN) biopsy using a two-step mapping technique incorporates sequential injection of indocyanine green into the bilateral uterine cornus, followed by cervical injection. Outcomes were compared with the conventional cervical (one-step) method .MethodsPatients with FIGO stage I-III endometrial cancer who underwent laparoscopic or robotic staging, including SLN biopsy, from May 2014 to December 2018, were retrospectively reviewed. Patient characteristics, pre-operative imaging, SLN detection pattern, pathologic result, adjuvant, and recurrence locations were analyzed.ResultsA total of 199 patients received one-step (n=123) and two-step (n=76) SLN biopsy. Para-aortic SLN were more frequently identified in the two-step group. Lower and upper para-aortic SLN were identified in 67.1% and 38.2%, respectively, in the two-step group and in 18.7% and 5.7% in the one-step group (p<0.001). The number of para-aortic SLN harvested was superior in the two-step group (p<0.001). Metastatic para-aortic SLN were found in 7.9% of the two-step group and 2.4% of the one-step group (p=0.070). In detecting nodal metastasis, the sensitivities of the one- and two-step methods were 91.7% and 100.0%, negative predictive values were 99.0% and 100.0%, false-negative rates were 8.3% and 0%, and accuracy rates were 99.1% and 100.0%, respectively. The one-step method identified only three out of eight para-aortic lymph node metastases and missed five para-aortic lymph node metastases. There was no missed para-aortic lymph node metastasis in the two-step group. Recurrence was observed in two patients (2.6%; vaginal vault and adrenal gland) in the two-step group and seven patients (5.7%) including three nodal recurrences in the one-step group (p=0.307).DiscussionTwo-step SLN mapping improved the para-aortic SLN detection rate, a known pitfall of conventional cervical injection. Proper evaluation of aortic nodal status will assist in the tailoring of adjuvant and prevent undertreatment of patients with isolated para-aortic metastasis.

Background A variety of epigenetic clocks utilizing DNA methylation changes have been developed; these clocks are either tissue-independent or designed to predict chronological age based on blood or saliva samples. Whether discordant tick rates between tissue-specific and general epigenetic clocks play a role in health and disease has not yet been explored. Results Here we analyze 1941 cervical cytology samples, which contain a mixture of hormone-sensitive cervical epithelial cells and immune cells, and develop the WID general clock (Women’s IDentification of risk), an epigenetic clock that is shared by epithelial and immune cells and optimized for cervical samples. We then develop the WID epithelial clock and WID immune clock, which define epithelial- and immune-specific clocks, respectively. We find that the WID-relative-epithelial-age (WID-REA), defined as the difference between the epithelial and general clocks, is significantly reduced in cervical samples from pre-menopausal women with breast cancer (OR 2.7, 95% CI 1.28-5.72). We find the same effect in normal breast tissue samples from pre-menopausal women at high risk of breast cancer and show that potential risk reducing anti-progesterone drugs can reverse this. In post-menopausal women, this directionality is reversed. Hormone replacement therapy consistently leads to a significantly lower WID-REA in cancer-free women, but not in post-menopausal women with breast or ovarian cancer. Conclusions Our findings imply that there are multiple epigenetic clocks, many of which are tissue-specific, and that the differential tick rate between these clocks may be an informative surrogate measure of disease risk.

The dynamic changes in the tumor immune microenvironment (TIME) triggered by neoadjuvant chemotherapy (NAC) have not been clearly defined in advanced-stage ovarian cancer. We analyzed the immunologic changes induced by NAC to correlate them with clinical outcomes. We compared the changes in the immune infiltration of high-grade serous carcinoma biopsies before and after NAC via immunohistochemistry (147 paired samples) and whole transcriptome sequencing (35 paired samples). Immunohistochemistry showed significantly increased PD-L1 levels and TIL levels after NAC. Whole transcriptome sequencing revealed that the stromal score, immune score, and cytolytic activity score significantly increased after NAC. An increased tumor-infiltrating lymphocyte (TIL) level in response to NAC was associated with shorter progression-free survival compared with decreased TIL level after NAC. In tumors with increased TIL levels after NAC, the relative fraction of CD8 T cells and regulatory T cells significantly increased with immunohistochemistry. Post-NAC tumors were enriched in gene sets associated with immune signaling pathways, such as regulatory T cell and JAK/STAT signaling pathways. NAC induced dynamic changes in the TIME that increased TIL levels, but their high abundance did not impart any survival benefit. Our data may provide therapeutic strategies to improve the survival benefit from immunotherapies in ovarian cancer.

PurposeCervical smear samples are easily obtainable and may effectively reflect the tumor microenvironment in gynecological cancers. Therefore, we investigated the feasibility of genomic profiling based on tumor DNA analysis from cervical smear samples from endometrial cancer patients.Materials and methodsPreoperative cervical smear samples were obtained via vaginal sampling in 50 patients, including 39 with endometrial cancer and 11 with benign uterine disease. Matched blood samples were obtained simultaneously. Genomic DNA (gDNA) from cervical smear and/or cell-free DNA from whole blood were extracted and sequenced using the Pan100 panel covering 100 endometrial cancer-related genes.ResultsCervical swab-based gDNA analysis detected cancer with 67% sensitivity and 100% specificity, showing a superior performance compared to that of the matched blood or Pap smear tests. Cervical swab-based gDNA effectively identified patients with loss of MSH2 or MSH6 and aberrant p53 expression based on immunohistochemistry. Genomic landscape analysis of cervical swab-based gDNA identified PTEN, PIK3CA, TP53, and ARID1A as the most frequently altered genes. Furthermore, 26 endometrial cancer patients could be classified according to the Proactive Molecular Risk Classifier for Endometrial Cancer.ConclusionCervical swab-based gDNA test showed an improved detection potential and allowed the classification of patients, which has both predictive and prognostic implications.

Aim: Predictive accuracy of cervical funneling for successful vaginal delivery prior to labor induction was compared to that of conventional methods such as Bishop score and cervical length. Methods: Prospective observational study was conducted on nulliparous women at 38 gestational weeks or more with intact membranes who delivered vaginally following labor induction. Transvaginal ultrasound was performed prior to labor induction to evaluate the cervix, to determine the cervical length and to check for the presence of funneling. Following pelvic examinations, the Bishop score was calculated. Predictive accuracy of the three different methods, namely cervical funneling, cervical length and Bishop, were compared. Results: A total of 235 nulliparous women with intact membranes were recruited. Of these, 194 women (82.6%) had successful vaginal deliveries following induction. Cervical funneling was observed in 105 women (44.7%). The rate of successful vaginal delivery was significantly higher in women with cervical funneling than in those without funneling (90.5% vs 76.2%, P < 0.004). Multivariable analysis showed that cervical funneling, similar to traditional measures such as the Bishop score and cervical length, was an independent predictor of successful vaginal delivery following labor induction (odds ratio = 2.95; 95% confidence interval: 1.38-6.47; P = 0.007). Conclusions: Similar to the conventional methods of cervical evaluation, such as the Bishop score and cervical length, cervical funneling may serve as a useful and valid predictor of successful vaginal deliveries prior to labor induction.