5-Hydroxymethylcytosine signals in serum are a predictor of chemoresistance in high-grade serous ovarian cancer.

OBJECTIVE: The genome-wide profiling of 5-hydroxymethylcytosines (5hmC) on circulating cell-free DNA (cfDNA) has revealed promising biomarkers for various diseases. The purpose of this study was to investigate 5hmC signals in serum cfDNA and identify novel predictive biomarkers for the development of chemoresistance in high-grade serous ovarian cancer (HGSOC). We hypothesized that 5hmC profiles in cfDNA reflect the development of chemoresistance and elucidate pathways that may drive chemoresistance in HGSOC. Moreover, we sought to identify predictors that would better stratify outcomes for women with intermediate-sensitive HGSOC. METHODS: Women diagnosed with HGSOC and known platinum sensitivity status were selected for this study. Nano-hmC-Seal was performed on cfDNA isolated from archived serum samples, and differential 5hmC features were identified using DESeq2 to establish a model predictive of chemoresistance. RESULTS: A multivariate model consisting of three features (preoperative CA-125, largest residual implant after surgery, 5hmC level of OSGEPL), stratified samples from intermediate sensitive, chemo-naive women diagnosed with HGSOC into chemotherapy-resistant- and sensitive-like strata with a significant difference in overall survival (OS). Independent analysis of The Cancer Genome Atlas data further confirmed that high OSGEPL1 expression is a favorable prognostic factor for HGSOC. CONCLUSIONS: We have developed a novel multivariate model based on clinico-pathologic data and a cfDNA-derived 5hmC modified gene, OSGEPL1, that predicted response to platinum-based chemotherapy in intermediate-sensitive HGSOC. Our multivariate model applies to chemo-naïve samples regardless if the patint was treated with adjuvant or neoadjuvant chemotherapy. These results merit further investigation of the predictive capability of our model in larger cohorts.

The interval between births and the risk of recurrent preeclampsia among predominantly high risk women in urban tertiary care center.

INTRODUCTION: Women with a history of preeclampsia have a higher risk of recurrent preeclampsia. This study sought to ascertain the relationship between the interbirth interval and the risk of recurrent preeclampsia and difference in angiogenic markers between the two groups. METHODS: Data was collected from an ongoing cohort study of women with hypertensive disorders of pregnancy (HDP) enrolled at the admission to the labor and delivery floor. From this dataset, multigravida women with a prior diagnosis of preeclampsia were identified and compared to women with no prior history of preeclampsia. RESULTS: Of the 375 women with HDP who were predominantly African American, 245 were multigravida and 44 (18.0%) had a prior history of preeclampsia. Women with prior preeclampsia had an earlier gestational age of delivery, higher rates of preterm delivery and a higher incidence of preeclampsia with severe features (56.8% vs 29.8%) in the index pregnancy (p-values ≤ 0.001) than those without. The median number of years between history of preeclampsia in previous pregnancy and current pregnancy was 6 years (IQR 3, 8). Among patients with a prior history of preeclampsia, the interbirth interval was not associated with severe preeclampsia (p = 0.60) and there was no difference in angiogenic factors between patients with a prior history of preeclampsia compared to those without. CONCLUSIONS: In this study, the duration of the interbirth interval was not identified as a risk factor of developing severe preeclampsia in a subsequent pregnancy and angiogenic factors are not a reflection of maternal predisposition to recurrent preeclampsia.

The Ratio of Toxic-to-Nontoxic miRNAs Predicts Platinum Sensitivity in Ovarian Cancer.

Ovarian cancer remains one of the deadliest gynecologic malignancies affecting women, and development of resistance to platinum remains a major barrier to achieving a cure. Multiple mechanisms have been identified to confer platinum resistance. Numerous miRNAs have been linked to platinum sensitivity and resistance in ovarian cancer. miRNA activity occurs mainly when the guide strand of the miRNA, with its seed sequence at position 2-7/8, is loaded into the RNA-induced silencing complex (RISC) and targets complementary short seed matches in the 3' untranslated region of mRNAs. Toxic 6mer seeds, which target genes critical for cancer cell survival, have been found in tumor-suppressive miRNAs. Many siRNAs and short hairpin RNAs (shRNA) can also kill cancer cells via toxic seeds, the most toxic of which carry G-rich 6mer seed sequences. We showed here that treatment of ovarian cancer cells with platinum led to increased RISC-bound miRNAs carrying toxic 6mer seeds and decreased miRNAs with nontoxic seeds. Platinum-tolerant cells did not exhibit this toxicity shift but retained sensitivity to cell death mediated by siRNAs carrying toxic 6mer seeds. Analysis of RISC-bound miRNAs in tumors from patients with ovarian cancer revealed that the ratio between miRNAs with toxic versus nontoxic seeds was predictive of treatment outcome. Application of the 6mer seed toxicity concept to cancer relevant miRNAs provides a new framework for understanding and predicting cancer therapy responses. SIGNIFICANCE: These findings demonstrate that the balance of miRNAs that carry toxic and nontoxic 6mer seeds contributes to platinum resistance in ovarian cancer.

Postpartum Outcomes With Systematic Treatment and Management of Postpartum Hypertension.

OBJECTIVE: To test the ability of a hospital-wide, bundled quality-improvement initiative to improve postpartum maternal blood pressure control and adherence to postpartum follow-up among patients with hypertensive disorders of pregnancy. METHODS: This quality-improvement initiative consisted of a bundle of clinical interventions including health care professional and patient education, a dedicated nurse educator, and protocols for postpartum hypertensive disorders of pregnancy care in the inpatient, outpatient and readmission setting. We implemented this initiative in patients with hypertensive disorders of pregnancy starting in January 2019 at the University of Chicago. The study period was divided into four periods, which correspond to preintervention, distinct bundle roll outs, and postintervention. Our primary outcome was postpartum hypertension visit adherence. Secondary outcomes included blood pressure values and antihypertensive medication use in the immediate postpartum and outpatient postpartum time periods. We then stratified our outcomes by race to assess whether the effect size differed. RESULTS: A total of 926 patients who delivered between September 2018 and November 2019 were included. Postpartum hypertension visit adherence improved from preintervention period compared with the full implementation period (33.5% vs 59.4%, P<.001). Blood pressure in the first 24 hours postpartum decreased from preintervention compared with full implementation (preintervention median [interquartile range] systolic blood pressure 149 mm Hg [138, 159] vs 137 [131, 146] in postimplementation; P<.001). After implementation, fewer patients experienced a blood pressure of 140/90 mm Hg or higher at the first postpartum blood pressure check, when compared with preintervention (39.1% vs 18.5%, P=.004). The effect size did not differ by race. CONCLUSION: A bundled quality-improvement initiative for patients with hypertensive disorders of pregnancy was associated with improved postpartum visit adherence and blood pressure control in the postpartum period.

Evaluation of angiogenic factors in the decision to admit women with suspected preeclampsia.

OBJECTIVE: To compare outcomes, specifically development of preeclampsia with severe features (sPE), between angiogenic biomarker-based admission and admission based on routine clinical care. STUDY DESIGN: This secondary analysis of a prospective study evaluated soluble fms-like tyrosine kinase-1 (sFlt1)/placental growth factor (PlGF) ratio in women presenting to triage for preeclampsia evaluation. Biomarkers levels were measured in samples collected from triage and analyzed retrospectively after outcomes were achieved. For this analysis patients would be hypothetically assigned to 'discharged' with a sFlt1/PlGF ratio ≤ 38 and 'admitted' with a sFlt1/PlGF ratio > 85. Development of sPE and other outcomes were then compared using the biomarker and clinical criteria for admission. RESULTS: 459 patients were included in this analysis. Using biomarker criteria, a larger proportion of patients were hypothetically discharged (67.8% vs 51.0%, p < 0.0001). A larger proportion of patients 'admitted' with a high biomarker level developed sPE (69.5% vs 40.9%, p < 0.0001). A sFlt1/PlGF ratio ≤ 38 had a negative predictive value of 96.8% for development of sPE within two weeks. CONCLUSION: Assessment of angiogenic biomarkes that 'discharges' patients with a low sFlt1/PlGF ratio and 'admits' patients with high ratio could result in reduced admissions and increased admission of patients at risk for developing sPE. Randomized trials are needed to determine the effectiveness of angiogenic biomarker use in decision making in a triage setting among women with suspected preeclampsia.

Antepartum Aspirin Administration Reduces Activin A and Cardiac Global Longitudinal Strain in Preeclamptic Women.

Background Approximately 60% of women have Stage B heart failure 1 year after a preeclamptic delivery. Emerging evidence suggests that the profibrotic growth factor activin A, which has been shown to induce cardiac fibrosis and hypertrophy, is elevated in preeclampsia and may be inhibited by aspirin therapy. We hypothesized that preeclamptic women receiving aspirin would have lower activin A levels and reduced global longitudinal strain (GLS), a sensitive measure of cardiac dysfunction, than women who do not receive aspirin. To test our hypothesis, we performed a cohort study of women with preeclampsia or superimposed preeclampsia and compared activin A levels and GLS in parturients who did or did not receive aspirin. Methods and Results Ninety-two parturients were enrolled, of whom 25 (27%) received aspirin (81 mg/day) therapy. GLS, plasma activin A, and follistatin, which inactivates activin A, were measured. Women receiving aspirin therapy had lower median (interquartile range) levels of activin A (8.17 [3.70, 10.36] versus 12.77 [8.37, 31.25] ng/mL; P=0.001) and lower activin/follistatin ratio (0.59 [0.31, 0.93] versus 1.01 [0.64, 2.60] P=0.002) than women who did not receive aspirin, which also remained significant after multivariable analysis. Furthermore, GLS was worse in patients who did not receive aspirin (-19.84±2.50 versus -17.77±2.60%; P=0.03) despite no differences in blood pressure between groups. Conclusions Our study suggests that antepartum aspirin therapy reduced serum activin A levels and improved GLS in preeclamptic patients, suggesting that aspirin may mitigate the postpartum cardiac dysfunction seen in women with preeclampsia.