The detection of germline and somatic BRCA1/2 genetic variants through parallel testing of patients with high-grade serous ovarian cancer: a national retrospective audit.

OBJECTIVE: To determine the frequency of germline and somatic pathogenic BRCA1 and BRCA2 variants in patients with high-grade serous ovarian cancer tested by next-generation sequencing (NGS), with the aim of defining the best strategy to be implemented in future routine testing. DESIGN: National retrospective audit. SETTING: The All Wales Medical Genomics Service (AWMGS). POPULATION: Patients with high-grade serous ovarian/fallopian tube/peritoneal cancer referred by oncologists to the AWMGS between February 2015 and February 2021 for germline and/or tumour testing of the BRCA1 and BRCA2 genes by NGS. METHODS: Analysis of NGS data from germline and/or tumour testing. MAIN OUTCOME MEASURES: Frequency of BRCA1 and BRCA2 pathogenic variants. RESULTS: The overall observed germline/somatic pathogenic variant detection rate was 11.6% in the 844 patients included in this study, with a 9.2% (73/791) germline pathogenic variant detection rate. Parallel tumour and germline testing was carried out for 169 patients and the overall pathogenic variant detection rate for this cohort was 14.8%, with 6.5% (11/169) shown to have a somatic pathogenic variant. Two BRCA1 dosage variants were found during germline screens, representing 2.0% (2/98) of patients with a pathogenic variant that would have been missed through tumour testing alone. CONCLUSIONS: Parallel germline and tumour BRCA1 and BRCA2 testing maximises the detection of pathogenic variants in patients with high-grade serous ovarian cancer. TWEETABLE ABSTRACT: Parallel germline and tumour testing maximises BRCA pathogenic variant detection in ovarian cancer.

Ultrasound features prior to 11 weeks' gestation and first-trimester maternal factors in prediction of hypertensive disorders of pregnancy.

OBJECTIVES: Maternal hypertensive disorders (MHD), including pregnancy-induced hypertension and pre-eclampsia, are estimated to occur in 7-10% of pregnancies worldwide and have significant short- and long-term implications for both mother and fetus. This study aimed to determine the association of conventional and novel early first-trimester ultrasound measures with MHD and whether these ultrasound measures, combined with maternal characteristics and biochemistry, improve the prediction of MHD. METHODS: This was a prospective cohort study of consecutive women with a singleton pregnancy, attending for an early (5 + 1 to 11 + 0 weeks' gestation) ultrasound examination at a private obstetric ultrasound practice between February 2016 and August 2018. Recorded ultrasound measurements included mean sac diameter, yolk sac diameter, crown-rump length, fetal heart rate (FHR), trophoblast thickness, trophoblast volume (TV) and mean uterine artery pulsatility index. Maternal biochemistry was assessed at 10-14 weeks and included beta-human chorionic gonadotropin, pregnancy-associated plasma protein-A (PAPP-A), placental growth factor (PlGF) and maternal serum alpha-fetoprotein. Regression models were fitted for each ultrasound parameter and multiples of the median (MoM) were calculated. All measures were compared between women who had a normotensive outcome and those who subsequently developed MHD. Logistic regression analysis was used to create a prediction model for MHD based on maternal characteristics, ultrasound measurements at 5 + 1 to 11 + 0 weeks' gestation and maternal biochemistry at 10-14 weeks. RESULTS: In total, 1141 women were included in the analysis, of whom 1086 (95.2%) were normotensive at delivery and 55 (4.8%) developed MHD. Women who developed MHD weighed significantly more than did normotensive women (P < 0.0001). Mean MoM values for TV (P = 0.006), PAPP-A (P = 0.031) and PlGF (P = 0.044) were decreased significantly in pregnancies that subsequently developed MHD. The proposed logistic regression model includes maternal weight and height and MoM values for TV, FHR and PlGF, resulting in an area under the receiver-operating-characteristics curve of 0.80 (95% CI, 0.75-0.86). CONCLUSION: The combination of maternal weight and height, TV and FHR, measured prior to 11 weeks' gestation, and first-trimester PlGF appears to have good predictive value for development of MHD later in pregnancy. Copyright © 2020 ISUOG. Published by John Wiley & Sons Ltd.

Maternal abdominal subcutaneous fat thickness as a predictor for adverse pregnancy outcome: a longitudinal cohort study.

OBJECTIVE: To assess maternal abdominal subcutaneous fat thickness (SFT) measured by ultrasound as an independent predictor of adverse pregnancy outcomes. DESIGN: A prospective longitudinal cohort study performed on pregnancies delivered between 2012 and 2014. SETTING: Sydney, Australia. POPULATION: About 1510 pregnant women attending routine obstetric ultrasounds. METHODS: Maternal SFT was measured on routine ultrasounds at 11-14 weeks' gestation (SFT1) and 18-22 weeks' gestation (SFT2). SFT measurements were assessed for estimating risks for obesity-related pregnancy outcomes using logistic regression modelling adjusted for maternal age, parity, smoking status and body mass index (BMI). MAIN OUTCOME MEASURES: Hypertensive disease, gestational diabetes, caesarean section, low birthweight, preterm delivery, neonatal respiratory distress, Apgar scores, and admission to a neonatal intensive care unit. RESULTS: SFT1 and SFT2 were measured on 1461 and 1363 women, respectively. Mean thickness (range) were 21.2 mm (6.9-73.9) for SFT1 and 20.3 mm (7.5-68.0) for SFT2. Complete outcome data were available for 1385 pregnancies. In all, 54% of the women were overweight/obese. The SFT measures decreased from early to mid-pregnancy in overweight/obese women. There was moderate correlation between BMI and SFT1 (R(2) = 0.56) and BMI and SFT2 (R(2) = 0.55). In a multivariate model, SFT1 and SFT2 were better predictors for adverse pregnancy outcomes than BMI. CONCLUSION: Maternal SFT is a significant independent predictor of adverse pregnancy outcomes. Incorporation of SFT into future models for adverse pregnancy outcome may prove valuable.

Smaller fetal thymuses in pre-eclampsia: a prospective cross-sectional study.

OBJECTIVE: To determine whether the thymus is smaller in fetuses of pre-eclamptic mothers than in those of normal controls. METHODS: This was a cross-sectional, prospective, comparative study of sonographically determined fetal thymus measurements in 39 pregnancies with pre-eclampsia and 70 healthy pregnancies. RESULTS: Both the diameter and the perimeter of the fetal thymus were smaller in pregnancies with pre-eclampsia than in healthy controls. The means of the thymus diameters were 28.6 ± 5.9 and 32.9 ± 4.5 mm and of thymus perimeters 80.9 ± 16.5 and 93.1 ± 16.6 mm for pre-eclamptic and healthy pregnancies, respectively (P < 0.001). General linear models showed that smaller fetal thymuses in pre-eclampsia were independent of gestational age, estimated fetal weight, small for gestational age status and antenatal steroid use. CONCLUSIONS: Pre-eclampsia is associated with smaller fetal thymuses.

The relationship between cigarette smoking, endothelial function and intrauterine growth restriction in human pregnancy.

This study examined the relationship of cigarette smoking and endothelial function in pregnant women by comparing smokers with nonsmokers. Endothelial function was assessed at 28-32 weeks of gestation by flow-mediated dilatation (FMD) using ultrasound of the brachial artery. The initial FMD was significantly different between the smoking group (n = 21) at 4.0 +/- 2.3, indicating endothelial dysfunction, and the nonsmoking group (n = 20) at 9.7 +/- 4.0 (P < 0.001). After smoking, this difference in the groups persisted. Babies who were growth restricted (<10th percentile) had mothers with a significantly lower FMD, that is endothelial dysfunction. This work demonstrates persistent endothelial dysfunction in smoking pregnant women.

Nab-paclitaxel in combination with gemcitabine for the treatment of metastatic pancreas cancer: the South Wales experience.

The prognosis of pancreatic cancer remains very poor, with a 5-year survival rate of around 3%. There has been little impact from various chemotherapy regimens on improving outcome for several decades. Gemcitabine has been the mainstay chemotherapy for around two decades with little improvement in overall survival (OS) for patients with advanced disease. However, more recently, there has been a paradigm shift in treatment options for these patients. Reported in 2011, combination therapy with FOLFIRINOX (oxaliplatin, irinotecan, leucovorin, and fluorouracil) showed a long awaited but modest improvement in survival, but is reserved only for a small proportion of very fit patients due to concerns over its toxicities. In 2013, the landmark phase III international study MPACT demonstrated an improvement in OS with the combination of nab-paclitaxel and gemcitabine (GEMBRAX) for the treatment of patients more akin to the real-world population. In the United Kingdom (UK), it was first made widely available on the National Health Service (NHS) in Wales in September 2014 and only recently received a final positive appraisal by NICE (National Institute of Clinical Excellence) for England in 2017. In this paper, we present our data on the use of this treatment for patients in South Wales and compare real-life practical experience with the MPACT data and reflecting the impact of this paradigm shift.

Congenital lobar emphysema--the disappearing chest mass: antenatal ultrasound appearance.

Prenatal diagnosis of congenital lobar emphysema is rarely reported in the literature. This case presents a fetus with an echogenic lung diagnosed at 18 weeks' gestation, that resolved completely during the pregnancy. This case is unique in that sonographic increased echogenicity was first noted at 18 weeks' gestation and had disappeared by 29 weeks' gestation. The diagnosis was made in the postnatal period as a result of follow up of the prenatal findings. This case reinforces the importance of continuing postnatal investigations of prenatal sonographic abnormalities even when they appear to have disappeared. A discussion of the causes of congenital lobar emphysema is presented.