Clear cell carcinoma and endometrioid adenocarcinoma are histologic subtypes of ovarian and uterine cancer that demonstrate unique clinical behavior but share common underlying genomic aberrations and oncogenic pathways. ARID1A mutations are more frequently identified in these tumors, in comparison to other gynecologic histologies, and loss of ARID1A tumor suppressor function is thought to be an essential component of carcinogenic transformation. Several therapeutic targets in ARID1A mutated cancers are in development, including EZH2 inhibitors. EZH2 facilitates epigenetic methylation to modulate gene expression, and both uterine and ovarian cancers show evidence of EZH2 over expression. EZH2 inhibition in ARID1A mutated tumors acts in a synthetically lethal manner to suppress cell growth and promote apoptosis, revealing a unique new therapeutic opportunity. Several phase 1 and 2 clinical trials of EZH2 inhibitors are ongoing currently and there is considerable promise in translational trials for utilization of this new targeted therapy, both to capitalize on ARID1A loss of function and to increase sensitivity to platinum-based adjuvant chemotherapies. This review will synthesize the molecular carcinogenesis of these malignancies and their unique clinical behavior, as a foundation for an emerging frontier of targeted therapeutics – the synergistic inhibition of EZH2 in ARID1A mutated cancers.

Background. Treatment options for women with metastatic, persistent, or recurrent cervical cancer are limited and thus the disease portends a poor prognosis. It is critical to understand the pathophysiology of cervical cancer to better delineate therapeutic targets. The development of antiangiogenic therapies and their subsequent analysis in rigorous therapeutic trials have redefined current management strategies and is an exciting area of current exploration. Results. Translational trials have furthered the understanding of molecular determinants of angiogenesis. Phase II trials have shown promising trends with developing antiangiogenic

PurposeOvarian and uterine clear cell carcinomas (CCCs) are rare but associated with poor prognosis. This study explored RNA transcription patterns characteristic of these tumors.Experimental DesignRNA sequencing (RNA-seq) of 11 ovarian CCCs and five uterine CCCs was performed and compared to publicly available data from high grade serous ovarian cancers (HGSOCs). Ingenuity Pathway Analyses were performed. CIBERSORT analyses estimated relative fractions of 22 immune cell types in each RNA-seq sample. Sequencing data was correlated with PD-L1 immunohistochemical expression.ResultsRNA-seq revealed 1,613 downregulated and 1,212 upregulated genes (corrected p < 0.05, |FC |≥10) in ovarian CCC versus HGSOC. Two subgroups were identified in the ovarian CCC, characterized by ethnicity and expression differences in ARID1A. There were 3,252 differentially expressed genes between PD-L1+/− ovarian CCCs, revealing immune response, cell death, and DNA repair networks, negatively correlated with PD-L1 expression, whereas cellular proliferation networks positively correlated with expression. In clear cell ovarian versus clear cell uterine cancer, 1,607 genes were significantly upregulated, and 109 genes were significantly downregulated (corrected p < 0.05, |FC|≥10). Comparative pathway analysis of late and early stage ovarian CCCs revealed unique metabolic and PTEN pathways, whereas uterine CCCs had unique Wnt/Ca+, estrogen receptor, and CCR5 signaling. CIBERSORT analysis revealed that activated mast cells and regulatory T cell populations were relatively enriched in uterine CCCs. The PD-L1+ ovarian CCCs had enriched resting NK cells and memory B cell populations, while PD-L1− had enriched CD8 T-cells, monocytes, eosinophils, and activated dendritic cells.ConclusionsUnique transcriptional expression profiles distinguish clear cell uterine and ovarian cancers from each other and from other more common histologic subtypes. These insights may aid in devising novel therapeutics.

Introduction The perineum stretches naturally during obstetrical labor, but it is unknown if this stretch has a negative impact on pelvic floor outcomes after a vaginal birth (VB). We aimed to evaluate whether perineal stretch was associated with postpartum pelvic floor dysfunction. Materials and Methods This was a prospective cohort study of primiparous women who had a VB. Perineal body (PB) length was measured antepartum, during labor, and 6 months postpartum. We determined the maximum PB (PB Max) measurements during the second stage of labor and PB change (ΔPB) between time points. Women completed functional questionnaires and had a POP-Q exam 6 months postpartum. We analyzed the relationship of PB measurements to perineal lacerations and postpartum outcomes including urinary, anal, or fecal incontinence, sexual activity and function, and POP-Q measurements. Results 448 women with VB had a mean age of 24 ± 5.0 years and rare (5%) third or fourth degree lacerations. During the second stage of labor, 270/448 (60%) had perineal measurements. Mean antepartum PB length was 3.7 ± 0.8 cm with a maximum mean PB length (PB Max) during the second stage of 6.1 ± 1.5 cm, an increase of 65%. The change in PB length (ΔPB) from antepartum to 6 months postpartum was a net decrease (−0.39 ± 1.02 cm). PB at any time point and PB Max were not associated with perineal lacerations or outcomes postpartum (all p>0.05). Discussion PB stretch during labor is unrelated to perineal laceration or postpartum incontinence, sexual activity, or sexual function.

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