Delayed publication of clinical trials in gynecologic oncology.

OBJECTIVES: Delays in clinical trial publication can hinder timely implementation of evidence-based practices. We sought to determine publication rates and time to publication for clinical trials addressing gynecologic malignancies. METHODS: All clinical trials addressing gynecologic cancers in the ClinicalTrials.gov registry with a primary completion date between 1/1/2018 and 1/1/2020 were identified. The primary outcome was publication rate. All included studies had been completed for at least 3 years. Secondary outcomes were time to publication and associations between publication rate and sponsor, cancer type, and the number and location of primary study sites. RESULTS: Of the 290 trials included, 161 (55.5%) had a peer-reviewed publication for the primary outcome within at least 3 years after completion. Of these, 123 had positive results (76.4%) and 38 were negative (23.6%). The average duration from primary completion to manuscript publication was 23.6 months (SD 13.9; median 21.4, IQR 15.1-32.4). Only 73 had results posted on the ClinicalTrials.gov registry (25.2%). Studies with positive findings had a significantly faster time to publication than those with negative results (22.0 mo vs 29.0 mo, p = 0.009). There was no significant difference between publication rate and funding source, cancer type, or location and number of primary sites. CONCLUSIONS: Timely publication of clinical trials addressing gynecologic cancers remains an issue. Studies with positive findings were published faster than those with negative results, but the average publication time was still almost 2 years from trial completion. Further efforts should be made to identify and address barriers to clinical trial publication.

Optimizing Surgical Wound Care in Obstetrics and Gynecology.

Importance: Obstetrics and gynecology (OB/GYN) accounts for at least half of all open abdominal surgeries performed. Rates of surgical wound complications after open procedures in OB/GYN range from 5% to 35%. Therefore, optimizing management of surgical wound complications has the potential to significantly reduce cost and morbidity. However, guidelines addressing best practices for wound care in OB/GYN are limited. Objective: The objectives of this review are to describe the fundamentals of wound healing and to evaluate available evidence addressing surgical wound care. Based on these data, we provide recommendations for management of extrafascial surgical wound dehiscence after OB/GYN procedures. Evidence Acquisition: Literature search was performed in PubMed, Medline, OVID, and the Cochrane database. Relevant guidelines, systematic reviews, and original research articles investigating mechanisms of wound healing, types of wound closure, and management of surgical wound complications were reviewed. Results: Surgical wound complications in OB/GYN are associated with significant cost and morbidity. One of the most common complications is extrafascial dehiscence, which may occur in the setting of hematomas, seromas, or infection. Management includes early debridement and treatment of any underlying infection until healthy granulation tissue is present. For wounds healing by secondary intention, advanced moisture retentive dressings reduce time to healing and are cost-effective when compared with conventional wet-to-dry gauze dressings. Negative pressure wound therapy can be applied to deeper wounds healing by secondary intention. Review of published evidence also supports the use of delayed reclosure to expedite wound healing for select patients. Conclusions: Optimizing surgical wound care has the potential to reduce the cost and morbidity associated with surgical wound complications in OB/GYN. Advanced moisture retentive dressings should be considered for wounds healing by secondary intention. Data support delayed reclosure for select patients, although further studies are needed.

Validation of a sonographic checklist for the detection of histologic placenta accreta spectrum.

BACKGROUND: To standardize research terminology and to reduce unanticipated placenta accreta spectrum, the European Working Group for Abnormally Invasive Placenta developed a consensus checklist for reporting suspected placenta accreta spectrum observed during an antenatal ultrasound. The diagnostic accuracy of the European Working Group for Abnormally Invasive Placenta checklist has not been assessed. OBJECTIVE: This study aimed to test the performance of the European Working Group for Abnormally Invasive Placenta sonographic checklist in predicting histologic placenta accreta spectrum. STUDY DESIGN: This was a multisite, blinded, retrospective review of transabdominal ultrasound studies performed between 26 to 32 weeks' gestation for subjects with histologic placenta accreta spectrum between 2016 and 2020. We matched a control cohort of subjects without histologic placenta accreta spectrum in a 1:1 ratio. To reduce reader bias, we matched the control cohort for known risk factors including previa, number of previous cesarean deliveries, previous dilation and curettage, in vitro fertilization, and clinical factors affecting image quality including multiple gestation, body mass index, and gestational age at the ultrasound. Nine sonologists from 5 referral centers, blinded to the histologic outcomes, interpreted the randomized ultrasound studies using the European Working Group for Abnormally Invasive Placenta checklist. The primary outcome was the sensitivity and specificity of the checklist to predict placenta accreta spectrum. Two separate sensitivity analyses were performed. First, we excluded subjects with mild disease (ie, only assessed subjects with histologic increta and percreta). Second, we excluded interpretations from the 2 most junior sonologists. RESULTS: A total of 78 subjects were included (39 placenta accreta spectrum, 39 matched control). Clinical risk factors and image quality markers were statistically similar between the cohorts. The checklist sensitivity (95% confidence interval) was 76.6% (63.4-90.6) and the specificity (95% confidence interval) was 92.0% (63.4-99.9) with a positive and negative likelihood ratio of 9.6 and 0.3, respectively. When we excluded subjects with mild placenta accreta spectrum disease, the sensitivity (95% confidence interval) increased to 84.7% (73.6-96.4) and the specificity was unchanged at 92.0% (83.2-99.9). Sensitivity and specificity were unchanged when the interpretations from the 2 most junior sonologists were excluded. CONCLUSION: The 2016 European Working Group for Abnormally Invasive Placenta checklist for interpreting placenta accreta spectrum has a reasonable performance in detecting histologic placenta accreta spectrum and excluding cases without placenta accreta spectum.

Implementing guidelines for risk-stratified thromboprophylaxis among gynecologic oncology patients: A quality improvement initiative.

OBJECTIVE(S): Risk-stratified thromboprophylaxis is recommended for oncology patients with a Khorana risk score (KS) ≥ 2 receiving cancer-directed therapy. We describe a quality improvement (QI) initiative designed to increase adherence to thromboprophylaxis guidelines for patients with gynecologic malignancies initiating outpatient treatment. METHODS: Provider awareness and documentation of venous thromboembolism (VTE) risk assessment and thromboprophylaxis eligibility were identified as key QI drivers. Starting May 2021, a KS calculator and thromboprophylaxis algorithm were incorporated into outpatient documentation templates. Patients with gynecologic malignancies initiating outpatient therapy from January - December 2021 were eligible. The primary process measure was the percentage of patients with KS eligibility documented each month during the baseline (Jan - Apr) versus implementation (May - Dec) periods. Rate of appropriate thromboprophylaxis initiation and incidence of VTE served as outcome measures. Incidence of adverse bleeding events served as the balancing measure. RESULTS: 337 patients accounted for the initiation of 383 treatment regimens, including 128 in the baseline period and 255 in the implementation period. KS documentation increased significantly between the baseline and implementation periods (7% vs 62.4%, p < 0.001). 73 of the 177 eligible patients (46.2%; 166 unique patients) had appropriate documentation; of these, 57 initiated thromboprophylaxis. There was no difference in VTE rates or adverse bleeding events between eligible patients who initiated thromboprophylaxis compared with those who did not (12.3% vs 15.6%; p = 0.65 and 7.0% vs 8.2%; p = 1.0, respectively). CONCLUSION(S): This QI initiative resulted in greater adherence to risk-stratified thromboprophylaxis guidelines. No bleeding signals were identified. Studies addressing cost, medication adherence, and long-term outcomes are necessary.

Placental uterine artery embolization followed by delayed hysterectomy for placenta percreta: A case series.

We describe outcomes of patients with suspected placenta percreta treated with placental uterine artery embolization (P-UAE) followed by delayed hysterectomy. This is a prospective case series of subjects from 2005 to 2018 with suspected placenta percreta who underwent P-UAE at the time of cesarean delivery followed by delayed hysterectomy. Both scheduled and unscheduled surgical cases were included. Maternal characteristics, surgical approaches, intra- and postoperative outcomes were abstracted from medical records. In total, twenty-two subjects were included. Median (interquartile range, IQR) delivery gestational age was 34.6 (31.9, 35.7) weeks, occurring as scheduled in 17 (77.3%) subjects and unscheduled in 5 (22.7%). Delayed hysterectomy was performed as scheduled in 17 (77.3%) subjects at a median (IQR) 40.5 (38.0, 44.0) days after delivery, and 5 (22.7%) subjects had a hysterectomy prior to scheduled date, median (IQR) 27.0 (17.0, 35.0) days after delivery. Indications for the 5 unscheduled hysterectomies included bleeding (n = 3) and suspected endometritis (n = 2). Three subjects (13.6%) received a blood transfusion (1, 3, 3 units) during delivery, and 7 (31.8%) were transfused during delayed hysterectomy (median [IQR] 2 [1,3] units). Three (13.6%) subjects had bladder resection at the time of hysterectomy; 1 (4.5%) had an unintentional cystotomy and 1 (4.5%) had a ureteral injury. P-UAE followed by delayed hysterectomy appears to be a safe and feasible, although appropriate patient selection and close surveillance are imperative, as 22.7% of patients underwent unscheduled hysterectomy.

Cost-Effectiveness of Venous Thromboembolism Prophylaxis During Neoadjuvant Chemotherapy for Ovarian Cancer.

PURPOSE: Two recent clinical trials have demonstrated that direct oral anticoagulants (DOACs) are effective as venous thromboembolism (VTE) prophylaxis in patients with moderate-to-high risk ambulatory cancer initiating chemotherapy. Patients with advanced ovarian cancer receiving neoadjuvant chemotherapy are at particularly increased risk of VTE. We performed a cost-effectiveness analysis from a health system perspective to determine if DOACs are a feasible prophylactic strategy in this population. METHODS: A simple decision tree was created from a health system perspective, comparing two strategies: prophylactic DOAC taken for 18 weeks during chemotherapy versus no VTE prophylaxis. Rates of VTE (7.3% DOAC v 13.6% no treatment), major bleeding (2.6% v 1.3%), and clinically relevant nonmajor bleeding (4.6% v 3.3%) were modeled. Cost estimates were obtained from wholesale drug costs, published studies, and Medicare reimbursement data. Probabilistic, one-way, and two-way sensitivity analyses were performed. RESULTS: In the base case model, DOAC prophylaxis is more costly and more effective than no therapy (incremental cost-effectiveness ratio = $256,218 in US dollars/quality-adjusted life year). In one-way sensitivity analyses, reducing the DOAC cost by 32% or raising the baseline VTE rate above 18% renders this strategy potentially cost-effective with an incremental cost-effectiveness ratio below $150,000 in US dollars/quality-adjusted life year. CONCLUSION: Further confirmation of the true baseline VTE rate among women initiating neoadjuvant chemotherapy for ovarian cancer will determine whether prophylactic dose DOAC is a value-based strategy. Less costly VTE prophylaxis options such as generic DOACs (once available) and aspirin also warrant investigation.

A prospective blinded comparison of second trimester fetal measurements by expert and novice readers using low-cost novice-acquired 3D volumetric ultrasound.

RATIONALE AND OBJECTIVES: Two-dimensional (2D) ultrasound (US) is operator dependent, requiring operator skill and experience to selectively identify and record planes of interest for subsequent interpretation. This limits the utility of US in settings in which expert sonographers are unavailable. Three-dimensional (3D) US acquisition of an anatomic target, which enables reconstruction of any plane through the acquired volume, might reduce operator dependence by providing any desired image plane for interpretation, without identification of target planes of interest at the time of acquisition. We applied a low-cost 3DUS technology because of the wider potential application compared with dedicated 3DUS systems. We chose second trimester fetal biometric parameters for study because of their importance in maternal-fetal health globally. We hypothesized that expert and novice interpretations of novice-acquired 3D volumes would not differ from each other nor from expert measurements of expert-acquired 2D images, the clinical reference standard. MATERIALS AND METHODS: This was a prospective, blinded, observational study. Expert sonographers blinded to 3DUS volumes acquired 2DUS images of second trimester fetuses from 32 subjects, and expert readers performed interpretation, during usual care. A novice sonographer blinded to other clinical data acquired oriented 3DUS image volumes of the same subjects on the same date. Expert readers blinded to other data assessed placental location (PL), fetal presentation (FP), and amniotic fluid volume (AFV) in novice-acquired 3D volumes. Novice and expert raters blinded to other data independently measured biparietal diameter (BPD), humerus length (HL), and femur length (FL) for each fetus from novice-acquired 3D volumes. Corresponding gestational age (GA) estimates were calculated. Inter-rater reliability of measurements and GAs (expert 3D versus expert 2D, novice 3D versus expert 2D, and expert 3D versus novice 3D) were assessed by intraclass correlation coefficient (ICC). Mean inter-rater measurement differences were analyzed using one-way ANOVA. RESULTS: 3D volume acquisition and reconstruction required mean 30.4 s (±5.7) and 70.0 s (±24.0), respectively. PL, FP, and AFV were evaluated from volumes for all subjects; mean time for evaluation was 16 s (±0.0). PL, FP, and AFV could be evaluated for all subjects. At least one biometric measurement was possible for 31 subjects (97%). Agreement between rater pairs for a composite of all measures was excellent (ICCs ≥ 0.95), and for individual measures was good to excellent (ICCs ≥ 0.75). Inter-rater differences were not significant (p > .05). CONCLUSIONS: Expert and novice interpretations of novice-acquired 3DUS volumes of second trimester fetuses provided reliable biometric measures compared with expert interpretation of expert-acquired 2DUS images. 3DUS volume acquisition with a low-cost system may reduce operator dependence of ultrasound.

Activity-dependent dendritic elaboration requires Pten.

Pten, a gene associated with autism spectrum disorder, is an upstream regulator of receptor tyrosine kinase intracellular signaling pathways that mediate extracellular cues to inform cellular development and activity-dependent plasticity. We therefore hypothesized that Pten loss would interfere with activity dependent dendritic growth. We investigated the effects of this interaction on the maturation of retrovirally labeled postnatally generated wild-type and Pten knockout granule neurons in male and female mouse dentate gyrus while using chemogenetics to manipulate the activity of the perforant path afferents. We find that enhancing network activity accelerates the dendritic outgrowth of wild-type, but not Pten knockout, neurons. This was specific to immature neurons during an early developmental window. We also examined synaptic connectivity and physiological measures of neuron maturation. The input resistance, membrane capacitance, dendritic spine morphology, and frequency of spontaneous synaptic events were not differentially altered by activity in wild-type versus Pten knockout neurons. Therefore, Pten and its downstream signaling pathways regulate the activity-dependent sculpting of the dendritic arbor during neuronal maturation.

Gender trends in gynecologic oncology authorship: Implications for the critical evaluation of gender distribution in academic rank and leadership positions.

OBJECTIVE: To investigate trends in the representation of women as first, last, or co-authors in Gynecologic Oncology (GO) publications over the past 15 years. To compare rates of female authorship in GO versus general Obstetrics and Gynecology (Ob/Gyn) and with the gender distribution of membership in the Society of Gynecologic Oncology (SGO). METHODS: Gender was determined for first and last authors of GO publications from three major journals for 2000, 2005, 2010, and 2015. The Z test was used to assess differences in proportions of female authors between 2000 and 2015 and first versus last female authors in each year. GO authorship trends were compared to those of general Ob/Gyn and new and total membership in SGO using the chi squared test. RESULTS: 1815 publications were included. Percentages of female first, last, and co-authors increased over time (p < 0.001), reaching 52%, 39%, and 23%, respectively, by 2015. Fewer women were listed as last than as first authors at each time point (p < 0.01). Proportions of female authors in general Ob/Gyn exceeded those of GO. Women comprised a growing proportion of both new and total SGO members over time (p < 0.01). New female SGO membership outpaced rates of female GO authorship, but GO female first authorship surpassed total female SGO membership (p < 0.001). CONCLUSIONS: Women comprise a growing proportion of GO providers and SGO members and have become increasingly productive in academic GO. Differences in publication authorship alone cannot account for gender disparities in the distribution of academic rank and leadership positions in the field.

Designing, Packaging, and Delivery of High Titer CRISPR Retro and Lentiviruses via Stereotaxic Injection.

Replication defective lentiviruses or retroviruses are capable of stably integrating transgenes into the genome of an infected host cell. This technique has been widely used to encode fluorescent proteins, opto- or chemo-genetic controllers of cell activity, or heterologous expression of human genes in model organisms. These viruses have also successfully been used to deliver recombinases to relevant target sites in transgenic animals, or even deliver small hairpin or micro RNAs in order to manipulate gene expression. While these techniques have been fruitful, they rely on transgenic animals (recombinases) or frequently lack high efficacy and specificity (shRNA/miRNA). In contrast, the CRISPR/Cas system uses an exogenous Cas nuclease which targets specific sites in an organism's genome via an exogenous guide RNA in order to induce double stranded breaks in DNA. These breaks are then repaired by non-homologous end joining (NHEJ), producing insertion and deletion (indel) mutations that can result in deleterious missense or nonsense mutations. This manuscript provides detailed methods for the design, production, injection, and validation of single lenti/retro virus particles that can stably transduce neurons to express a fluorescent reporter, Cas9, and sgRNAs to knockout genes in a model organism.