ARID1A suppresses R-loop-mediated STING-type I interferon pathway activation of anti-tumor immunity.

Clinical trials have identified ARID1A mutations as enriched among patients who respond favorably to immune checkpoint blockade (ICB) in several solid tumor types independent of microsatellite instability. We show that ARID1A loss in murine models is sufficient to induce anti-tumor immune phenotypes observed in ARID1A mutant human cancers, including increased CD8+ T cell infiltration and cytolytic activity. ARID1A-deficient cancers upregulated an interferon (IFN) gene expression signature, the ARID1A-IFN signature, associated with increased R-loops and cytosolic single-stranded DNA (ssDNA). Overexpression of the R-loop resolving enzyme, RNASEH2B, or cytosolic DNase, TREX1, in ARID1A-deficient cells prevented cytosolic ssDNA accumulation and ARID1A-IFN gene upregulation. Further, the ARID1A-IFN signature and anti-tumor immunity were driven by STING-dependent type I IFN signaling, which was required for improved responsiveness of ARID1A mutant tumors to ICB treatment. These findings define a molecular mechanism underlying anti-tumor immunity in ARID1A mutant cancers.

Overnight pain and opioid use after osmotic cervical dilator placement for second trimester dilation and evacuation.

OBJECTIVE: The aim of the study was to evaluate pain following overnight osmotic cervical dilator placement for second trimester dilation and evacuation (D&E). METHODS: A retrospective cohort study surveyed pain and quantified prescription opioid use among 100 women who underwent overnight osmotic cervical dilator placement for D&E. Participants were given opioid and non-steroidal anti-inflammatory (NSAID) prescriptions and were asked to rate their level of pain on a Likert scale (1-10). Demographic and medical information was abstracted from electronic medical records. Bivariate analyses of demographic and clinical characteristics by pain score and opioid use were conducted. Multivariate linear regression analyses were performed for pain score. A multivariate logistic regression model was fitted for factors associated with opioid use. RESULTS: Gestational age ranged from 14 to 23 weeks (average 19 ± 3 weeks). The mean score of worst pain experienced was 5.3 out of 10. Participants reported 3.4 h of moderate pain (4-6 out of 10) and 1.0 h of severe pain (7-10 out of 10); 54% of women took at least one opioid (mean 2.8 ± 1.5). Multivariate analysis showed that higher pain was associated with younger age (p = .0363) and no prior vaginal delivery (p = .0296). The number of osmotic cervical dilators was associated with pain in the bivariate analysis (r = 0.216, p = .0311) but was not significant in the multivariate analysis (p = .0634). An increasing number of cervical dilators (p = .0323) and a higher pain score (p = .004) were associated with opioid use. CONCLUSION: Most participants with overnight cervical dilators for D&E experienced at least moderate pain and used opioid pain medication in addition to NSAIDs when available. A shared decision-making model may be appropriate for determining which patients may benefit from opioids.

Practice patterns and survival in FIGO 2009 stage 3B endometrial cancer.

OBJECTIVE: To describe the practice patterns and outcomes of patients with stage 3B endometrial cancer. METHODS: We queried the National Cancer Database for all surgically staged, stage 3 patients between 2012 and 2016. Patients who received any pre-operative therapy were excluded. Demographics, tumor factors, and adjuvant therapy for the stage 3 substages were compared. Logistic regression was used to identify factors associated with adjuvant therapy. Kaplan Meier curves were generated and compared using the log-rank test. Multivariable Cox Proportional Hazards Model was used to adjust for prognostic factors. Findings with p < 0.05 were considered significant. RESULTS: Of 7363 patients with stage 3 disease, 478 (6%) had stage 3B; 1732 (23%) had stage 3A, 3457 (48%) had stage 3C1, and 1696 (23%) had stage 3C2 disease. Post-surgical treatment consisted of: combined chemotherapy (CT) and radiation (RT) (49%), CT alone (28%), RT alone (9%), 14% received no postoperative therapy. Among all stage 3 substages, patients with stage 3B disease were the least likely to receive any CT, and the most likely to receive RT alone. After adjusting for known prognostic factors, patients with stage 3A (Hazard ratio (HR) of death = 0.64) and 3C1 (HR of death = 0.79) disease had significantly worse overall survival compared to stage 3B; survival was not demonstrably different from patients with stage 3C2 disease. Patients with stage 3B disease who received CT + RT had the best overall survival. CONCLUSION: Survival of patients with stage 3B disease is similar to that of patients with para-aortic node metastases and is inferior to all others with stage 3 endometrial cancer. Less frequent CT and a higher rate of post-operative RT alone, describes a distinct practice from that seen in other stage 3 patients.

Periviable delivery of a pregnancy in a rudimentary uterine horn: A case report.

Pregnancy in a rudimentary uterine horn is an extremely rare form of ectopic pregnancy, with an incidence of 1 in 76,000-140,000 pregnancies. Given its high-risk nature, the standard of care is to terminate such pregnancies at the time of diagnosis. This is a case of a nulliparous patient at 23 5/7 weeks of gestation with a new diagnosis of a rudimentary horn pregnancy. She elected to proceed with full intervention for her fetus and was delivered at 24 0/7 weeks after administration of antenatal corticosteroid therapy. While the infant did have some adverse effects related to prematurity, she met developmental milestones and was alive and well at the age of two. Although the standard of care is to manage these cases as ectopic pregnancies, when diagnosed at a periviable gestational age, optimization of fetal status prior to delivery may be an alternative approach to immediate delivery.

Prevalence and predictors of HIV screening in invasive cervical cancer: a 10 year cohort study.

BACKGROUND: Invasive cervical carcinoma is associated with a human immunodeficiency virus (HIV) prevalence of >0.1%, and screening is recommended and cost-effective for cancer populations exceeding this threshold. HIV status is also prognostic for cancer-specific survival, but compliance with HIV screening is poor in the USA and abroad. OBJECTIVES: This study aims to describe HIV screening practices in a US comprehensive cancer center. To guide quality improvement, we identify characteristics which may predict compliance with screening. STUDY DESIGN: Women treated for invasive cervical cancer from January 2007 to December 2017 were identified by local cancer registry and billing data. We assessed age, race, ethnicity, insurance status, histology, stage, pregnancy, drug use, and HIV testing status. Univariate logistical regression was performed to assess predictors of completed HIV screening. RESULTS: Of 492 eligible women, the cumulative screening rate was 7.6%. Race, ethnicity, histology, and funding source were not predictive of screening. Every 5 year increase in age was associated with a lower chance of screening (OR 0.86, p=0.015), as was earlier stage at diagnosis (OR 0.43, p=0.017). Pregnancy during, or antecedent to, invasive cervical cancer diagnosis was significantly more predictive of screening compliance (OR 10.57, p=0.0007). Only 8/492 (1.6%) women in the cohort were active or former drug users, but within this group HIV screening was performed more frequently (OR 22.7, p<0.0001). CONCLUSION: Despite US and international recommendations for HIV screening in AIDS-defining cancers, compliance remains low. In our centers, factors including earlier age, advanced stage, active pregnancy at diagnosis, and any drug use history were predictive of greater compliance with screening. These data will inform a tailored intervention to improve compliance with HIV screening in our population.

Fertility preserving treatment for gynecologic malignancies: a review of recent literature.

PURPOSE OF REVIEW: A significant number of women diagnosed with a gynecologic malignancy meet criteria for fertility-sparing treatment. Women are continuing to delay childbearing; the importance of fertility-sparing therapy is, therefore, increasing. It is imperative that physicians understand the options for, and limitations of, these treatments. RECENT FINDINGS: Recent research has demonstrated improved outcomes for endometrial cancer by adding targeted hysteroscopic resection to progestin therapy. Cervical cancer research has focused on oncologic and pregnancy outcomes following management with radical trachelectomy, confirming its safety. Given the high rates of preterm birth following trachelectomy, studies have evaluated the adequacy of fertility counseling prior to treatment, and have looked for predictive factors for preterm birth. Additionally, research has shown a rise in the percentage of women receiving conservative treatment for both endometrial and cervical cancer. SUMMARY: With an increasing number of women seeking conservative treatment, physicians must understand the safety and implications of such therapy. Retrospective studies have demonstrated the safety of fertility-sparing treatment for both endometrial and cervical cancer; prospective research is currently underway to provide better guidance for future directions of fertility-sparing treatment for gynecologic malignancies.

PPARγ agonists enhance ET-743-induced adipogenic differentiation in a transgenic mouse model of myxoid round cell liposarcoma.

Myxoid round cell liposarcoma (MRCLS) is a common liposarcoma subtype characterized by a translocation that results in the fusion protein TLS:CHOP as well as by mixed adipocytic histopathology. Both the etiology of MRCLS and the mechanism of action of TLS:CHOP remain poorly understood. It was previously shown that ET-743, an antitumor compound with an unclear mechanism of action, is highly effective in patients with MRCLS. To identify the cellular origin of MRCLS, we engineered a mouse model in which TLS:CHOP was expressed under the control of a mesodermally restricted promoter (Prx1) in a p53-depleted background. This model resembled MRCLS histologically as well as functionally in terms of its specific adipocytic differentiation-based response to ET-743. Specifically, endogenous mesenchymal stem cells (MSCs) expressing TLS:CHOP developed into MRCLS in vivo. Gene expression and microRNA analysis of these MSCs showed that they were committed to adipocytic differentiation, but unable to terminally differentiate. We also explored the method of action of ET-743. ET-743 downregulated TLS:CHOP expression, which correlated with CEBPα expression and adipocytic differentiation. Furthermore, PPARγ agonists enhanced the differentiation process initiated by ET-743. Our work highlights how clinical observations can lead to the generation of a mouse model that recapitulates human disease and may be used to develop rational treatment combinations, such as ET-743 plus PPARγ agonists, for the treatment of MRCLS.