Molecular testing for endometrial cancer: An SGO clinical practice statement.

The Cancer Genome Atlas publication first described the genomic landscape of endometrial cancer and characterized these cancers into four molecular subtypes with different prognoses. The Proactive Molecular Classifier for Endometrial Cancer was developed to more easily and inexpensively classify endometrial cancers into four similar molecular subtypes which are termed POLE, mismatch repair deficient, p53 abnormal and no specific molecular profile. Beyond these four subtypes, other molecular biomarkers may influence clinical behavior and response to targeted therapies and include beta-catenin, Her2 amplification, PI3K/mTOR/AKT alterations, L1CAM, hormone receptor expression, tumor mutational burden, and ARID1A. There are numerous clinical trials exploring treatment escalation and de-escalation within the four molecular subtypes as well as matching targeted therapies to specific mutational or biomarker profiles. All endometrial cancers should undergo basic molecular classification that includes assessment of mismatch repair status. POLE and p53 status are prognostic and may become actionable in the future. Clinicians who treat patients with endometrial cancer should understand the role of molecular classification in guiding treatment. The goal of this practice statement is to guide appropriate testing, interpretation, and application of molecular information in endometrial cancer.

Ongoing strategies and updates on pain management in gynecologic oncology patients.

The opioid crisis in the United States has been declared a public health emergency. Various governmental agencies, cancer care organizations and the Centers for Disease Control and Prevention have issued guidelines in hopes of managing this crisis. Curbing over-prescription of opioids by medical professionals has been a central theme in many of these guidelines. Gynecologic oncologists encounter patients with a variety of pain sources, including acute pain secondary to the underlying malignancy or surgical procedures as well as chronic pain related to the malignancy and the sequelae of treatments rendered. In this review, we discuss the various etiologies of pain experienced by gynecologic oncology patients and discuss modalities frequently used to treat this pain. We highlight strategies to reduce the number of opioids prescribed and focus on incorporating non-opioid pain relief management principles in this review. We also discuss the mechanisms and etiology of various types of pain, with a focus on multimodal treatment strategies including preoperative counseling, strategies to identify individuals at risk of developing opioid dependence, and the role of symptom management and palliative care teams. Finally, we provide a blueprint for gynecologic oncology practices to develop their practice-specific pain management contracts to engage patients in a meaningful conversation around the addictive potential of opioids.

Principles of Treatment for Borderline, Micropapillary Serous, and Low-Grade Ovarian Cancer.

Borderline ovarian tumors (BOTs) are less common than epithelial ovarian cancers (EOCs). Low-grade EOCs (LG-EOCs) occur even less frequently than BOTs. After primary therapy, recurrence rates of BOTs and LG-EOCs are significantly lower and the stage-adjusted survival is higher than for high-grade EOCs. Thus, determining the best management in terms of traditional ovarian cancer staging and debulking procedures is more challenging and has been recently brought to question. This article reviews the particulars of BOTs and LG-EOCs, their similarities and differences, and how they are best managed and treated, and emphasizes the major role of surgery and the controversial role of chemotherapy. Because these tumors disproportionately affect younger women, this review addresses ovarian preservation in circumstances when fertility or hormonal preservation is desired.

The DEK Oncoprotein Functions in Ovarian Cancer Growth and Survival.

DNA damage repair alterations play a critical role in ovarian cancer tumorigenesis. Mechanistic drivers of the DNA damage response consequently present opportunities for therapeutic targeting. The chromatin-binding DEK oncoprotein functions in DNA double-strand break repair. We therefore sought to determine the role of DEK in epithelial ovarian cancer. DEK is overexpressed in both primary epithelial ovarian cancers and ovarian cancer cell lines. To assess the impact of DEK expression levels on cell growth, small interfering RNA and short hairpin RNA approaches were utilized. Decreasing DEK expression in ovarian cancer cell lines slows cell growth and induces apoptosis and DNA damage. The biologic effects of DEK depletion are enhanced with concurrent chemotherapy treatment. The in vitro effects of DEK knockdown are reproduced in vivo, as DEK depletion in a mouse xenograft model results in slower tumor growth and smaller tumors compared to tumors expressing DEK. These findings provide a compelling rationale to target the DEK oncoprotein and its pathways as a therapeutic strategy for treating epithelial ovarian cancer.

Ninety-Day Mortality as a Reporting Parameter for High-Grade Serous Ovarian Cancer Cytoreduction Surgery.

OBJECTIVE: To evaluate the utility of using 90-day as an adjunct to 30-day mortality rates after surgical cytoreduction for serous ovarian cancer and to compare them across hospitals of differing case volumes over time. METHODS: We performed a retrospective cohort study using the National Cancer Database of women undergoing cytoreductive surgery for high-grade serous carcinoma between 2004 and 2012. The primary outcome of the study was mortality rate by hospital volume. The secondary outcome was to evaluate the performance of hospital rankings based on 30- and 90-day mortality rates. Hospitals were categorized by cases per year as low volume (10 or fewer), intermediate (11-20), high (21-30), and ultra-high (31 or more). RESULTS: A total of 24,827 women from 602 hospitals were included. Overall 30-day mortality was 2.1% (95% CI 1.95-2.3) compared with 90-day mortality of 5.1% (95% CI 4.8-5.4%, P<.001). For each hospital volume category, the 90-day mortality was approximately double that of the 30-day mortality. Substituting 90-day in place of 30-day mortality for hospital ranking, 57 hospitals (9.5%) changed ranks (26 worsened and 31 improved). Based on the logistic regression model (after controlling for age, race-ethnicity, income, Charlson comorbidity index, insurance status, hospital volume, distance from place of residence to the hospital, receipt of neoadjuvant chemotherapy, and year of diagnosis), care at the ultra-high-volume centers was an independent predictor of lower odds of death at 90 days [adjusted odds ratios (OR) 0.60, 95% CI 0.38-0.96, P=.034] but not at 30 days (adjusted OR 0.64, 95% CI 0.35-1.18). CONCLUSION: Compared with low-volume centers, ultra-high-volume centers are associated with significantly lower 30- and 90-day risk-adjusted mortality. The 90-day mortality rate is double that of the 30-day rate and may be a better metric for assessing the initial quality of care for patients with ovarian cancer.

Development and characterization of a reverse genetic system for studying dengue virus serotype 3 strain variation and neutralization.

Dengue viruses (DENV) are enveloped single-stranded positive-sense RNA viruses transmitted by Aedes spp. mosquitoes. There are four genetically distinct serotypes designated DENV-1 through DENV-4, each further subdivided into distinct genotypes. The dengue scientific community has long contended that infection with one serotype confers lifelong protection against subsequent infection with the same serotype, irrespective of virus genotype. However this hypothesis is under increased scrutiny and the role of DENV genotypic variation in protection from repeated infection is less certain. As dengue vaccine trials move increasingly into field-testing, there is an urgent need to develop tools to better define the role of genotypic variation in DENV infection and immunity. To better understand genotypic variation in DENV-3 neutralization and protection, we designed and constructed a panel of isogenic, recombinant DENV-3 infectious clones, each expressing an envelope glycoprotein from a different DENV-3 genotype; Philippines 1982 (genotype I), Thailand 1995 (genotype II), Sri Lanka 1989 and Cuba 2002 (genotype III) and Puerto Rico 1977 (genotype IV). We used the panel to explore how natural envelope variation influences DENV-polyclonal serum interactions. When the recombinant viruses were tested in neutralization assays using immune sera from primary DENV infections, neutralization titers varied by as much as ∼19-fold, depending on the expressed envelope glycoprotein. The observed variability in neutralization titers suggests that relatively few residue changes in the E glycoprotein may have significant effects on DENV specific humoral immunity and influence antibody mediated protection or disease enhancement in the setting of both natural infection and vaccination. These genotypic differences are also likely to be important in temporal and spatial microevolution of DENV-3 in the background of heterotypic neutralization. The recombinant and synthetic tools described here are valuable for testing hypotheses on genetic determinants of DENV-3 immunopathogenesis.

The twin-arginine translocation pathway of Mycobacterium smegmatis is functional and required for the export of mycobacterial beta-lactamases.

The twin-arginine translocation (Tat) pathway exports folded proteins across the bacterial cytoplasmic membrane and is responsible for the proper extracytoplasmic localization of proteins involved in a variety of cellular functions, including pathogenesis. The Mycobacterium tuberculosis and Mycobacterium smegmatis genomes contain open reading frames with homology to components of the Tat export system (TatABC) as well as potential Tat-exported proteins possessing N-terminal signal sequences with the characteristic twin-arginine motif. Due to the importance of exported virulence factors in the pathogenesis of M. tuberculosis and the limited understanding of mycobacterial protein export systems, we sought to determine the functional nature of the Tat export pathway in mycobacteria. Here we describe phenotypic analyses of DeltatatA and DeltatatC deletion mutants of M. smegmatis, which demonstrated that tatA and tatC encode components of a functional Tat system capable of exporting characteristic Tat substrates. Both mutants displayed a growth defect on agar medium and hypersensitivity to sodium dodecyl sulfate. The mutants were also defective in the export of active beta-lactamases of M. smegmatis (BlaS) and M. tuberculosis (BlaC), both of which possess twin-arginine signal sequences. The Tat-dependent nature of BlaC was further revealed by mutation of the twin-arginine motif. Finally, we demonstrated that replacement of the native signal sequence of BlaC with the predicted Tat signal sequences of M. tuberculosis phospholipase C proteins (PlcA and PlcB) resulted in the Tat-dependent export of an enzymatically active 'BlaC. Thus, 'BlaC can be used as a genetic reporter for Tat-dependent export in mycobacteria.