Sarah N. Cross

Does prenatal stress alter the developing connectome

Human neurodevelopment requires the organization of neural elements into complex structural and functional networks called the connectome. Emerging data suggest that prenatal exposure to maternal stress plays a role in the wiring, or miswiring, of the developing connectome. Stress-related symptoms are common in women during pregnancy and are risk factors for neurobehavioral disorders ranging from autism spectrum disorder, attention deficit hyperactivity disorder, and addiction, to major depression and schizophrenia. This review focuses on structural and functional connectivity imaging to assess the impact of changes in women’s stress-based physiology on the dynamic development of the human connectome in the fetal brain.

EGFR/HER-targeted therapeutics in ovarian cancer

Despite decades of research and evolving treatment modalities, survival among patients with epithelial ovarian cancer has improved only incrementally. During this same period, the development of biologically targeted therapeutics has improved survival for patients with diverse malignancies. Many of these new drugs target the human epidermal growth factor receptor (EGFR/HER/ErbB) family of tyrosine kinases, which play a major role in the etiology and progression of many carcinomas, including epithelial ovarian cancer. While several HER-targeted therapeutics are US FDA approved for the treatment of various malignancies, none have gained approval for the treatment of ovarian cancer. Here, we review the published literature on HER-targeted therapeutics for the treatment of ovarian cancer, including novel HER-targeted therapeutics in various stages of clinical development, as well as the challenges that have limited the use of these inhibitors in clinical settings.

Differential sensitivity to platinum-based chemotherapy in primary uterine serous papillary carcinoma cell lines with high vs low HER-2/neu expression in vitro

OBJECTIVE We sought to identify effective chemotherapy regimens against uterine serous papillary adenocarcinoma (USPC). STUDY DESIGN Six USPC, half of which overexpress HER-2/neu at 3+ level, were evaluated for growth rate and in vitro sensitivity to 14 single-agent chemotherapies and 5 combinations by ChemoFx (Precision Therapeutics Inc, Pittsburgh, PA). RESULTS Cell lines overexpressing HER-2/neu showed higher proliferation when compared to low HER-2/neu-expressing cell lines and a lower half maximum inhibitory concentration (IC(50)) when exposed to the majority of single-agent chemotherapies. High HER-2/neu expressors were more sensitive to platinum compounds, manifesting a 5.22-fold decrease in carboplatin-IC(50) (P = .005) and a 5.37-fold decrease in cisplatin-IC(50) (P = .02). When all cell lines were analyzed as a group, chemotherapy agents tested demonstrated lower IC(50) when used in combination than as individual agents. CONCLUSION USPC overexpressing HER-2/neu display greater in vitro sensitivity to platinum compounds when compared to low HER-2/neu expressors. Higher proliferative capability rather than increased drug resistance may be responsible for the adverse prognosis associated with HER-2/neu overexpression in USPC.

Antenatal Corticosteroids Impact the Inflammatory Rather Than the Antiangiogenic Profile of Women With Preeclampsia

Circulating antiangiogenic factors and proinflammatory cytokines are implicated in the pathogenesis of preeclampsia. This study was performed to test the hypothesis that steroids modify the balance of inflammatory and proangiogenic and antiangiogenic factors that potentially contribute to the patient’s evolving clinical state. Seventy singleton women, admitted for antenatal corticosteroid treatment, were enrolled prospectively. The study group consisted of 45 hypertensive women: chronic hypertension (n=6), severe preeclampsia (n=32), and superimposed preeclampsia (n=7). Normotensive women with shortened cervix (<2.5 cm) served as controls (n=25). Maternal blood samples of preeclampsia cases were obtained before steroids and then serially up until delivery. A clinical severity score was designed to clinically monitor disease progression. Serum levels of angiogenic factors (soluble fms-like tyrosine kinase-1 [sFlt-1], placental growth factor [PlGF], soluble endoglin [sEng]), endothelin-1 (ET-1), and proinflammatory markers (IL-6, C-reactive protein [CRP]) were assessed before and after steroids. Soluble IL-2 receptor (sIL-2R) and total immunoglobulins (IgG) were measured as markers of T- and B-cell activation, respectively. Steroid treatment coincided with a transient improvement in clinical manifestations of preeclampsia. A significant decrease in IL-6 and CRP was observed although levels of sIL-2R and IgG remained unchanged. Antenatal corticosteroids did not influence the levels of angiogenic factors but ET-1 levels registered a short-lived increase poststeroids. Although a reduction in specific inflammatory mediators in response to antenatal steroids may account for the transient improvement in clinical signs of preeclampsia, inflammation is unlikely to be the major contributor to severe preeclampsia or useful for therapeutic targeting.

Viral Infection Sensitizes Human Fetal Membranes to Bacterial Lipopolysaccharide by MERTK Inhibition and Inflammasome Activation.

Chorioamnionitis, premature rupture of fetal membranes (FMs), and subsequent preterm birth are associated with local infection and inflammation, particularly IL-1β production. Although bacterial infections are commonly identified, other microorganisms may play a role in the pathogenesis. Because viral pandemics, such as influenza, Ebola, and Zika, are becoming more common, and pregnant women are at increased risk for associated complications, this study evaluated the impact that viral infection had on human FM innate immune responses. This study shows that a herpes viral infection of FMs sensitizes the tissue to low levels of bacterial LPS, giving rise to an exaggerated IL-1β response. Using an ex vivo human FM explant system and an in vivo mouse model of pregnancy, we report that the mechanism by which this aggravated inflammation arises is through the inhibition of the TAM receptor, MERTK, and activation of the inflammasome. The TAM receptor ligand, growth arrest specific 6, re-establishes the normal FM response to LPS by restoring and augmenting TAM receptor and ligand expression, as well as by preventing the exacerbated IL-1β processing and secretion. These findings indicate a novel mechanism by which viruses alter normal FM immune responses to bacteria, potentially giving rise to adverse pregnancy outcomes.

The Clinical Impact of Gynecologic MRI

OBJECTIVE. This study assessed the clinical impact of pelvic MRI performed after the diagnosis of an indeterminate pelvic mass on ultrasound or CT. MATERIALS AND METHODS. The radiologic records of 567 patients who underwent pelvic MRI at our hospital from 2004 to 2006 were reviewed. Of these patients, 214 patients underwent pelvic MRI for evaluation of a gynecologic mass detected on a preceding ultrasound or CT examination; this group of patients constituted the basis of our study. The imaging and clinical records from the database were used for our analysis. The medical records were reviewed for the impact of the radiologic findings on patient treatment, and the results were tabulated for the findings of the first modality, whether the first modality provided a diagnosis, what management plan would be made according to the first modality, and what management plan would be made as a result of the MRI. The adequacy of the imaging study was assessed on the basis of either obtaining an accurate exact diagnosis or ascertaining at the minimum whether the mass was benign or malignant. Further endpoints included specificity and sensitivity of the individual modalities in the diagnosis of a specific gynecologic mass and whether clinical management was altered. Exact binomial CIs were computed for individual proportions. RESULTS. The clinical management of the patient was altered as a result of MRI in 77% of the cases (CI = 0.70-0.82). Surgery was avoided in 36% (CI = 0.29-0.43), and surgery was changed to a more appropriate method (laparoscopy vs laparotomy, involvement or not of a gynecologic oncologist) in an additional 17% (CI = 0.12-0.23). CONCLUSION. Without having undergone MRI, many of the women and girls in this study would have undergone unnecessary surgery; a more costly type of surgery; or long-term follow-up with the associated financial costs, personal and physical costs, and mental costs from the resultant anxiety of an unresolved indeterminate mass.

Postnatal Sonographic Spectrum of Prenatally Detected Abdominal and Pelvic Cysts

OBJECTIVE The purpose of this article is to illustrate the sonographic findings of a spectrum of neonatal abdominal and pelvic cystic lesions. CONCLUSION Neonatal abdominal and pelvic cystic lesions can arise from many organs, and they have a broad differential diagnosis. Distinctive sonographic findings may be present and can help establish the correct cause and guide proper management.

Abdominal Pain after Gastric Bypass: Labor, Uterine Rupture, or Obstruction and Internal Hernia

Background. Although gastric bypass may reduce obesity-related complications of subsequent pregnancies, surgical complications requiring antenatal and postpartum interventions are not uncommon. Case. A 26-year-old G4P1112 status post-Roux-en-Y gastric bypass required multiple urgent antenatal evaluations due to frequent episodes of abdominal pain. At 35 + 4 weeks, she presented with severe abdominal pain; initial evaluation was negative for gastrointestinal pathology. The patient was found to be in preterm labor and underwent a repeat cesarean section. The postoperative course was complicated by bowel obstruction due to internal hernia resulting in an emergent laparotomy and a prolonged hospital course. Conclusion. As more reproductive-aged women opt for surgical treatment of obesity, it is essential that obstetricians recognize complications to be able to counsel and appropriately care for these patients.

Minimally invasive abdominal cerclage compared to laparotomy: a comparison of surgical and obstetric outcomes

The objective of this study is to report surgical and obstetric outcomes of patients following abdominal cerclage placement through either minimally invasive or open techniques. Subjects of this retrospective cohort study were patients at two referral centers specializing in high-risk pregnancy and minimally invasive gynecologic surgery. Electronic medical records of all patients who underwent abdominal cerclage placement between December 2011 and December 2015 at Yale New Haven Hospital and Bridgeport Hospital were reviewed. The patients included were women who underwent abdominal cerclage placement either during pregnancy or prior to conception. One cohort of women had their abdominal cerclage placed using traditional laparoscopy or robotic-assisted laparoscopy. The other cohort consisted of women whose abdominal cerclage was placed through laparotomy. Electronic medical charts were reviewed to collect baseline demographic and pre-procedure obstetric information, as well as surgical and subsequent obstetric outcomes. Eleven minimally invasive and nine open abdominal cerclages were performed during the study period. Seven of the minimally invasive and two open cerclages were done outside of pregnancy. Average operative time was longer in the minimally invasive cohort. Estimated blood loss was typically lower in the minimally invasive group. Length of hospital stay was shorter in the minimally invasive group. Obstetric outcomes were similar between the two cohorts, with a total of nine live births in the minimally invasive group and seven live births in the open group. Minimally invasive abdominal cerclage is a safe alternative when performed by a surgeon with appropriate training and technical skills, and obstetric outcomes are comparable to those after open abdominal cerclage.

Magnesium sulfate differentially modulates fetal membrane inflammation in a time-dependent manner

Chorioamnionitis and infection‐associated inflammation are major causes of preterm birth. Magnesium sulfate (MgSO4) is widely used in obstetrics as a tocolytic; however, its mechanism of action is unclear. This study sought to investigate how MgSO4 modulates infection‐associated inflammation in fetal membranes (FMs), and whether the response was time dependent.