Prenatal diagnosis (or lack thereof) of arthrogryposis multiplex congenita and its impact on the perinatal experience of parents: A retrospective survey.

OBJECTIVE: To examine parental experiences during pregnancies affected by Arthrogryposis Multiplex Congenita (AMC) by identifying commonalities, risk factors, and areas for improvement in detection rates, care protocols, and patient experience. STUDY DESIGN: An online survey was distributed via AMC support groups on Facebook. Topics included demographics, risk factors, parental recall of sonographic findings, delivery characteristics and neonatal findings. Responses were divided into antenatally detected cases (ADCs) and postnatally detected cases (PDCs). Quantitative responses were analyzed with the Fisher exact test. Qualitative data were analyzed with thematic analysis. RESULTS: The antenatal detection rate of arthrogryposis was 37%. Decreased fetal movement was reported by 53% and early bleeding by 21%. Sonographic findings in ADCs included clubfoot (83%), clenched hand (51%), decreased fetal movement (50%), elbow contracture (51%), and knee contracture (46%). Among ADCs, 29% delivered vaginally and 71% delivered by cesarean versus PDCs (44% vaginal, 56% cesarean). Neonatal intensive care unit admission rate was 63%. Bone fracture occurred in 9%. Detection led to a planned change in delivery mode in 33% and location in 50%. Among ADCs, 17% felt their concerns were not adequately addressed versus 43% of PDCs. CONCLUSIONS: Antenatal detection of arthrogryposis was low. We propose enhanced screening criteria to aid prenatal diagnosis and promote utilization of more robust practice guidelines.

CDK4/6 inhibitors target SMARCA4-determined cyclin D1 deficiency in hypercalcemic small cell carcinoma of the ovary.

Inactivating mutations in SMARCA4 (BRG1), a key SWI/SNF chromatin remodelling gene, underlie small cell carcinoma of the ovary, hypercalcemic type (SCCOHT). To reveal its druggable vulnerabilities, we perform kinase-focused RNAi screens and uncover that SMARCA4-deficient SCCOHT cells are highly sensitive to the inhibition of cyclin-dependent kinase 4/6 (CDK4/6). SMARCA4 loss causes profound downregulation of cyclin D1, which limits CDK4/6 kinase activity in SCCOHT cells and leads to in vitro and in vivo susceptibility to CDK4/6 inhibitors. SCCOHT patient tumors are deficient in cyclin D1 yet retain the retinoblastoma-proficient/p16INK4a-deficient profile associated with positive responses to CDK4/6 inhibitors. Thus, our findings indicate that CDK4/6 inhibitors, approved for a breast cancer subtype addicted to CDK4/6 activation, could be repurposed to treat SCCOHT. Moreover, our study suggests a novel paradigm whereby critically low oncogene levels, caused by loss of a driver tumor suppressor, may also be exploited therapeutically.

Small cell cancers of the female genital tract: Molecular and clinical aspects.

OBJECTIVE: Extra-pulmonary small cell carcinomas of the gynecologic tract (EPSCC-GTs) are a rare group of aggressive malignancies associated with poor prognoses and limited treatment options. Here, we review the clinical and molecular aspects of EPSCC-GTs and discuss how understanding their molecular features can assist in their diagnosis and the identification of novel effective treatments. METHODS: We searched PubMed and Scopus for articles using the following keywords: "small cell carcinoma" in combination with "neuroendocrine", "ovary", "vagina", "fallopian tube", "vulva", "endometrium", "uterus", "cervix", or "gynecologic". Articles were limited to those published in English from January 1984 to October 2017. RESULTS: EPSCC-GTs account for 2% of all gynecologic malignancies. The molecular features of EPSCC-GTs are largely understudied and unknown, with the exception of small cell carcinoma (SCC) of the ovary, hypercalcemic type (SCCOHT) and SCC of the cervix (SCCC). In nearly all cases, SCCOHT displays mutation in a single gene, SMARCA4, a member of the SWI/SNF chromatin remodeling complex. The loss of expression of the SWI/SNF protein SMARCA2 is another feature of SCCOHT. Dual negative staining for SMARCA2 and SMARCA4 is specific for SCCOHT and is generally used by gynecologic pathologists for the accurate diagnosis of this malignancy. Mutational analysis of SCCC has shown alterations in PIK3CA, KRAS and TP53, of which the last is the most common, although other actionable mutations have been identified. The molecular features of other EPSCC-GTs are largely unknown. CONCLUSIONS: Due to their rarity, the majority of EPSCC-GTs are understudied and poorly understood. As demonstrated in the case of SCCOHT, unraveling the mutational profiles of these tumors can lead to improved diagnosis and the identification of novel therapeutic targets.

Evaluation of extended antibiotic prophylaxis in patients undergoing indicated non-cosmetic panniculectomy at the time of gynecologic surgery.

BACKGROUND: Panniculectomy at time of gynecologic surgery is used to improve visualization and prevent major complications in morbidly obese patients. We examine the role of extended antibiotic prophylaxis in prevention of surgical site infections (SSI), specifically based on patient risk factors (hypertension, diabetes, smoking). METHODS: A prospective cohort study of all women who underwent panniculectomy at the time of gynecologic surgery from September 2014 to March 2016 at a university-affiliated hospital. The EAP cohort received standard antibiotics (cefazolin, 2 g) and continued oral antibiotic (doxycycline) for 10 days afterwards. Patients in this cohort were compared to historical controls from the same institution from 1990 to 2014. Specific attention was paid to the reduction of SSIs in patients with hypertension, diabetes, and a history of smoking. RESULTS: The mean age was 56.0 ± 12.6 years, and mean body mass index 44.5 ± 9.3 kg/m2 (range 31-63.4 kg/m2 ). The EAP cohort experienced fewer surgical-site infections overall, however these results were not significantly decreased from the historical controls, (13/56 [23.2%] vs 94/300 [31.3%]; P = 0.469). CONCLUSION: Though initially promising, extended antibiotic prophylaxis did not reduce surgical site infections in the obese women after indicated non-cosmetic panniculectomy at the time of gynecologic surgery.

Evaluation of indicated non-cosmetic panniculectomy at time of gynecologic surgery.

OBJECTIVE: To report postoperative outcomes among patients undergoing indicated non-cosmetic panniculectomy at the time of gynecologic surgery. METHODS: Medical charts were retrospectively reviewed for patients who underwent panniculectomy coupled with gynecologic surgery at a university-affiliated hospital in the USA in 1990-2014. The data reviewed included age, body mass index (BMI, calculated as weight in kilograms divided by the square of height in meters), surgical procedure, estimated blood loss, pathology, wound complication, diabetes, hypertension, smoking, and readmission rate. One-way analysis of variance and logistic regression were used to evaluate the data. RESULTS: In total, 300 patients underwent panniculectomy; the mean age was 51 years and the mean BMI was 46. Overall, there were 94 (31.3%) complications, including 85 (28.3%) cases of superficial cellulitis and 9 (3.0%) cases of surgical-site infection. In logistic regression, diabetes, hypertension, and smoking were significant predictors of wound complications, identifying 78% of women who subsequently developed wound complications. CONCLUSION: Panniculectomy combined with gynecologic surgery was found to be safe and effective for obese patients, with an acceptable incidence of wound infection. History of diabetes, hypertension, and smoking increased the risk of postoperative wound complications. These factors will help to predict patients at risk of wound complication.