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Objective The evaluation of women with perimenopausal abnormal uterine bleeding (AUB) and postmenopausal bleeding (PMB) to detect endometrial cancer (EC) and its precursors is not standardized and can vary widely. Consequently, costs associated with the workup and management undoubtedly vary. This study aimed to quantify costs of AUB/PMB evaluation to understand the healthcare burden associated with securing a pathologic diagnosis. Methods Women ≥45 years of age presenting to a single institution gynecology clinic with AUB/PMB for diagnostic workup were prospectively enrolled February 2013–October 2017 for a lower genital tract biospecimen research study. Clinical workup of AUB/PMB was determined by individual provider discretion. Costs of care were collected from administrative billing systems from enrollment to 90 days post enrollment. Costs were standardized and inflation-adjusted to 2017 US Dollars (USD). Results In total, there were 1017 women enrolled with 5.6% diagnosed with atypical hyperplasia or endometrial cancer (EC). Within the full cohort, 90-day median cost for AUB/PMB workup and management was $2279 (IQR $512–4828). Among patients with a diagnostic biopsy, median 90-day costs ranged from $2203 (IQR $499–3604) for benign or disordered proliferative endometrium (DPE) diagnosis to $21,039 (IQR $19,084-24,536) for a diagnosis of EC. Conclusions The costs for diagnostic evaluation of perimenopausal AUB and PMB vary greatly according to ultimate tissue-based diagnosis. Even reassuring benign findings that do not require further intervention—the most common in this study's cohort—yield substantial costs. The development of sensitive, specific, and more cost-effective diagnostic strategies is warranted.

BACKGROUND: Women with uterine fibroids often seek uterine-preserving treatments, rather than hysterectomy. Imaging-defined endpoints following nonsurgical treatments for fibroids are limited. MATERIALS AND METHODS: Fibroid Interventions: Reducing Symptoms Today and Tomorrow (FIRSTT), a randomized controlled trial of uterine artery embolization (UAE) versus magnetic resonance imaging-guided focused ultrasound surgery (MRgFUS), enrolled premenopausal women with symptomatic uterine fibroids. In this subanalysis, we report imaging results up to 36 months after UAE or MRgFUS. Magnetic resonance imaging (MRI) was performed at baseline for all women and during the 36 months after treatment if they did not meet other study endpoints. The main outcome of this subanalysis was fibroid volume reduction (defined both in terms of total fibroid load and volume of the largest fibroid), uterine volume reduction, and nonperfused volume. RESULTS: During 2010–2014, 25 of the 37 women who were randomized and treated at Mayo Clinic had a 24-month follow-up MRI (11 UAE; 14 MRgFUS); among these women, 15 (7 UAE and 8 MRgFUS) had a 36-month follow-up MRI. Average age for the cohort was 44.1 (standard deviation, SD = 4.4) years. Nine patients had a second fibroid procedure by 36 months (seven in the MRgFUS arm and two in UAE arm). Median total fibroid load reduction was ∼50% in both treatment arms at both 24- and 36-month follow-up. Volume of the largest fibroid decreased more in the MRgFUS arm, whereas uterine volume decreased more in the UAE arm (neither reached statistical significance). At 24 months, median nonperfused volume was higher in the UAE arm (92%) than the MRgFUS arm (10%). CONCLUSIONS: Similar fibroid volume reduction was seen for the MRgFUS and UAE treatments in this comparative effectiveness study. Nonperfused volume 24 months after the procedure was higher in the UAE arm than in the MRgFUS arm. Clinical Trial Registration Number: NCT00995878, clinicaltrials.gov

Introduction There are no reliable blood biomarkers for monitoring endometrial cancer patients in the current clinical practice. Circulating tumor DNA (ctDNA) is emerging as a promising non-invasive method to measure tumor burden, define prognosis and monitor disease status in many solid cancers. In this pilot study, we investigated if unique tumor-specific DNA junctions can be used to detect ctDNA levels in patients with endometrial cancer. Methods Chromosomal rearrangements in primary tumors of eleven patients with high-grade or advanced stage endometrial cancer were determined by whole-genome Mate-Pair sequencing. Identified unique tumor-specific junctions were evaluated in pre- and six-week post-surgery patient plasma using individualized quantitative polymerase chain reaction (qPCR) assays. The relationship between clinicopathological features and detection of ctDNA was investigated. Results CtDNA was detected in 60% (6/10) of cases pre-surgery and in 27% (3/11) post-surgery. The detection of ctDNA pre-surgery was consistent with clinical indicators of aggressive disease such as advanced stage (80% - 4/5), lymphatic spread of disease (100% - 3/3), serous histology (80% - 4/5), deep myometrial invasion (100% - 3/3), lympho-vascular space invasion (75% - 3/4). All patients in which ctDNA was detected post-surgically had type II endometrial cancer. Discussion This pilot study demonstrates the feasibility of using personalized tumor-specific junction panels for detecting ctDNA in the plasma of endometrial cancer patients. Larger studies and longer follow-up are needed to validate the potential association between pre-surgical ctDNA detection and the presence of cancers with aggressive pathologic tumor characteristics or advanced stage observed in this study.

OBJECTIVE: Emerging technologies may enable detection of endometrial cancer with methods that are less invasive than standard biopsy methods. This study compares patient pain scores among 3 office gynecologic tract sampling methods and explores their potential determinants. METHODS: A prospective study including 3 sampling methods (tampon, Tao brush (TB), endometrial biopsy (EB)) was conducted between December 2015 and August 2017 and included women ≥45 years of age presenting with abnormal uterine bleeding, postmenopausal bleeding, or thickened endometrial stripe. Patients rated pain after each sampling procedure using a 100-point visual analog scale (VAS). RESULTS: Of 428 enrolled, 190 (44.39%) patients underwent all 3 sampling methods and reported a VAS score for each. Nearly half were postmenopausal (n=93, 48.9%); the majority were parous (172, 90.5%) of which 87.8% had at least one vaginal delivery. Among the 190 patients, the median (IQR) pain score was significantly lower for sampling via tampon (0 [0, 2]) compared to TB (28 [12, 52]) or EB (32 [15, 60]) (both p

Objectives: Up-regulation of ERBB pathways represent targetable alterations in many high grade endometrial cancers (EC); ERBB3 amplifications in particular may contribute to ineffective pathway targeting due to persistent co-activation of other ERBB binding partners, leading to tumor growth and survival. The efficacy of downstream dual-inhibition of MEK+AKT or MEK+PI3K in an ERBB3 amplified EC primary tumor was studied using a microcancer 3D ex-vivo tumor cell viability assay. Methods: Tumor was prospectively collected from a patient with stage II, FIGO grade 3, serous EC and genomic characterization was performed using multiple sequencing methods: whole exome, RNA, and MatePair analysis. Somatic mutations, structural variance, with transcriptomic profiling was used to identify potential driver pathways for subsequent pharmacologic inhibition. Primary tumor cells were grown in a three-dimensional environment and the formed microcancers were subjected to drug treatment. Cell viability was determined by the CellTiter-Glow Luminescent Assay. Data transformation and dose-response curves were generated using GraphPad PRISM using four parameter logistic regression. CompuSyn software with the Chou-Talalay method was used to analyze drug interactions and synergy. The Fractional response-Combination index (Fa-CI) plot was generated with Microsoft Excel. Capivasertib, GDC-0084, and cobimetinib were used to inhibit AKT, PI3K/mTOR, and MEK, respectively. Inhibitory effect was defined as percent reduction in ATP at clinically-defined predicted plasma maximum concentration (Cmax) values. Results: Genomic sequencing revealed overexpression of a mutated ERBB3 (c.889G>T; p.Asp297Tyr) transcript within a 6N focal amplification. Additional pertinent alterations included a MYC mid-level gain, and TP53 double hit (loss and exonic splicing silencer (ESS)). Inhibition of cell viability was moderate by single agents: capivasertib, cobimetanib, or GDC-0084, as shown by inhibitory effect values of 33.9%, 35.9% and 49.9%, respectively. Two combinations with cobimetinib demonstrated increasing inhibitory effect values of 76.2% for cobimetanib/capivasertib at the Cmax of capivasertib and 79.7% for cobimetanib/GDC-0084 at the Cmax of cobimetanib. Synergy was evidenced by a combination index 0.8 (Figure 1). Download : Download high-res image (185KB) Download : Download full-size image Conclusions: Combined inhibition of MEK and PI3K-AKT-mTOR pathways synergistically suppress viability in a patient-derived high-grade serous EC harboring a ERBB3 amplification. Further ex-vivo testing should be performed in endometrial tumors with other ERBB3 aberrations to allow generalization of results.

Objectives: Most splenectomies performed in ovarian cancer (OC) debulking are for disease resection; the impact of splenectomy on 30-day complication and oncologic outcomes is unclear. We aimed to determine the association of splenectomy with postoperative complications, overall survival (OS), and progression-free survival (PFS) in the setting of primary debulking surgery (PDS) for OC. Methods: We retrospectively evaluated women who underwent PDS or surgical staging for OC from 1/2003-07/2016. Perioperative variables and 30-day complications defined by ACS-NSQIP were abstracted. Among those with advanced stage (IIIC/IV) disease, complications were graded using the modified Accordion grading scale; severe was defined as grade 3 or 4. A propensity score (PS) matched cohort was evaluated to limit the effect of bias due to confounding variables between patients who did and did not have a splenectomy. The severe complication rate was compared between matched pairs using McNemar's test and time-to-event outcomes were compared using stratified Cox proportional hazards models. Results: Among 1311 patients in the cohort, 153 (11.7%) underwent splenectomy. Patients with splenectomy were more likely to have advanced stage disease (96.1 vs 60.6%), serous histology (89.5 vs 68.8%), ascites (83.0 vs 45.3%), higher median preoperative CA-125 (737 vs 388 U/mL), and residual disease (52.9 vs 31.3%), compared to patients without splenectomy (all p Download : Download high-res image (74KB) Download : Download full-size image Conclusions: We observed that splenectomy during PDS was associated with increased risk of progression and death compared to those not undergoing splenectomy but this risk was no longer observed with a PS-matched cohort. Splenectomy appears to be a marker for disease extent but does not increase the risk of progression or decreased survival in and of itself. Splenectomy was associated with a higher risk of severe postoperative complications including a 9% risk of pancreatic leak. These findings underscore the importance of preoperative surgical risk/benefit assessment and expertise in management of complications.

Objective In tampon samples from women with and without EC, we tested methylated DNA markers (MDMs) for EC originally identified through discovery and validation in tissue. Methods From 2/2013–8/2019, women ≥45 yrs with abnormal or postmenopausal bleeding or biopsy-proven EC were prospectively enrolled for vaginal fluid collection via tampon before endometrial sampling or hysterectomy, respectively. ECs were frequency matched by menopausal status and tampon collection date to benign endometrium (BE) controls. Tampons were placed in preservative buffer; extracted DNA from cell pellet was bisulfite-converted and underwent methylated specific PCR for 29 top performing EC and other solid tumor MDMs (MAX.chr12.52652301, CDH4, EMX2OS, c17orf64, NBPF8, SFMBT2, JSRP1, DIDO1, MAX.chr10.22624479, MPZ, ZNF506, VILL, GATA2, MAX.chr14.103021656, CYTH2, LRRC8D, LYPLAL1, MAX.chr8.145103829, SQSTM1, ZNF323, OBSCN, MAX.chr9.36739811, ZNF90, LRRC41.8188, LRRC34, GDF7, MDFI, EEF1A2, SEPT9). Random forest modeling analysis performed to generate predictive probability of underlying EC. Results 100 EC and 92 BE were enrolled. The 29-MDM panel highly discriminated between EC and BE (96% (95%CI 89–99%) specificity; 76% (66–84%) sensitivity (AUC 0.88). In 2/2017, the PBS-based tampon buffer was modified to include 50 mmol EDTA. The 29-MDM panel demonstrated greater sensitivity in tampon samples (57 EC; 52 BE) collected into PBS/EDTA buffer (96% (95% CI 87–99%) specificity; 81% (68–90%) sensitivity (AUC 0.90). Among endometrioid and serous histologies, the panel correctly identified 85% and 78%, respectively, and the majority of other subtypes (table 1). Conclusion Top EC plus other solid tumor MDMs performed with promisingly high sensitivity and specificity in tampon-collected vaginal fluid. PBS/EDTA buffer improves sensitivity.

BACKGROUND: Most endometrial cancer cases are preceded by abnormal uterine bleeding, offering a potential opportunity for early detection and cure of endometrial cancer. While clinical guidelines exist for diagnostic workup of abnormal uterine bleeding, consensus is lacking regarding optimal management for women with abnormal bleeding to diagnose endometrial cancer. OBJECTIVE: We report the baseline data from a prospective clinical cohort study of women referred for endometrial evaluation at the Mayo Clinic, designed to evaluate risk stratification in women at increased risk for endometrial cancer. Here, we introduce a risk-based approach to evaluate diagnostic tests and clinical management algorithms in a population of women with abnormal bleeding undergoing endometrial evaluation at the Mayo Clinic. STUDY DESIGN: A total of 1,163 women aged ≥45 years were enrolled from February 2013-May 2019. We evaluated baseline absolute risks and 95% confidence intervals of endometrial cancer and endometrial intraepithelial neoplasia according to clinical algorithms for diagnostic workup of women with postmenopausal bleeding (assessment of initial vs. recurrent bleeding episode and endometrial thickness measured via transvaginal ultrasound). We also evaluated risks among women with postmenopausal bleeding according to baseline age (4mm. We assessed the clinical efficiency of each strategy by estimating the percent of women who would be referred for endometrial biopsy, the percent of cases detected and missed, and the ratio of biopsies per case detected. RESULTS: Among the 593 women with postmenopausal bleeding, 18 (3.0%) had endometrial intraepithelial neoplasia and 47 (7.9%) had endometrial cancer and among the 570 premenopausal women with abnormal bleeding, 8 (1.4%) had endometrial intraepithelial neoplasia and 7 (1.2%) had EC. Risks were highest in women aged 60+ years 17.7% (13.0–22.3%), followed by those with recurrent bleeding (14.7%, 11.0–18.3%). Among women with an initial bleeding episode in whom transvaginal ultrasound is recommended, endometrial thickness did not provide meaningful risk stratification: risks of endometrial cancer/endometrial intraepithelial neoplasia were nearly identical in women with an endometrial thickness of >4mm (5.8%; 1.3–10.3%) and ≤4mm (3.6%; 0.9–8.6%). In contrast, among those aged 4mm, the risk of endometrial cancer/endometrial intraepithelial neoplasia was 8.4% (4.3–12.5%) and in those with an endometrial thickness of ≤4mm, the risk was 0% (0.0–3.0%; p=0.010). The most efficient strategy was to perform biopsy in all women aged 60+ years and among those aged 4mm, with the lowest percentage referred to biopsy while still detecting all cases. CONCLUSIONS: Current clinical recommendations for endometrial cancer detection in women with abnormal bleeding are not consistent with underlying risk. Endometrial cancer risk factors such as age can provide important risk stratification compared to the assessment of recurrent bleeding. Future research will include a formal assessment of clinical and epidemiologic risk prediction models in our study population as well as validation of our findings in other populations.

Objective To introduce the prenatal regenerative medicine service at Mayo Clinic for fetal endoscopic tracheal occlusion (FETO) care for severe congenital diaphragmatic hernia (CDH). Patients and Methods Two cases of prenatal management of severe CDH with FETO between January and August 2017 are reported. Per protocol, FETO was offered for life-threatening severe CDH at between 26 and 29 weeks' gestation. Regenerative outcome end point was fetal lung growth. Gestational age at procedure and maternal and perinatal outcomes were additional monitored parameters. Results Diagnosis by ultrasonography of severe CDH was based on extremely reduced lung size (observed-to-expected lung area to head circumference ratio [o/e-LHR], eg, o/e-LHR of 20.3% for fetus 1 and 23.0% for fetus 2) along with greater than one-third of the liver herniated into the chest in both fetuses. Both patients underwent successful FETO at 28 weeks. At the time of intervention, no maternal or fetal complications were observed. Postintervention, fetal lung growth was observed in both fetuses, reaching an o/e-LHR of 62.7% at 36 weeks in fetus 1 and 52.4% at 32 weeks in fetus 2. The balloons were removed successfully at 35 weeks and 4 days by ultrasound-guided puncture in the first patient and at 32 weeks and 3 days by ex utero intrapartum therapy-to-airway procedure in the second patient. Postnatal management followed standard of care with patch CDH therapy. At discharge, one patient was breathing normally, whereas the other required minimal nasal cannula oxygen support. Conclusion The successful launch of the first fetoscopic therapy for CDH at Mayo Clinic reveals its feasibility and safety, with early signs of benefit documented by fetal lung growth and reversal of severe pulmonary hypoplasia. Trial Registration clinicaltrials.gov Identifier: G170062.

Objectives: The evaluation of perimenopausal AUB and PMB for underlying neoplasia is not standardized and can vary widely among patients. Similarly, costs for workup and management of underlying cause may vary. This study aimed to quantify costs of perimenopausal AUB/PMB evaluation and treatment according to ultimate tissue-based diagnosis. Methods: Women ≥45 years of age presenting to a single institution gynecology clinic with abnormal uterine bleeding (AUB) or postmenopausal bleeding (PMB) for an office endometrial biopsy were prospectively enrolled from February 2013 to October 2018 for a lower genital tract biospecimen research study. Clinical workup of their AUB or PMB was per provider discretion. CPT and ICD-10 codes were abstracted retrospectively at a minimum of 90 days post enrollment. Medicare reimbursement rates were assigned to all professional billed services to estimate standardized costs with inflation adjustment to 2017 dollars. The study cohort was stratified based on final diagnosis as endometrial cancer (EC), atypical hyperplasia (AH), hyperplasia without atypia, polyp, benign or disordered proliferative endometrium (DPE), no biopsy preformed, and inadequate biopsy. Only disease related costs were considered in the analysis. Descriptive statistics of cost at 7 day, 30 day, and 90 day follow up timeframes were completed for each diagnosis. Results: In total, there were 1017 women included with 5.6% diagnosed with AH or EC. The patient demographics included mean age 55.2 years (standard deviation (SD) 7.9), mean body mass index (BMI) 30.3 (SD 8.0), 431 (42.4%) BMI greater than or equal to 30, 541 (53.2%) postmenopausal, 161 (15.8%) nulliparous, 253 (24.9%) with hypertensive disease, 73 (7.2%) with diabetes mellitus, and 212 (20.9%) with history of hormone replacement therapy or tamoxifen use. Within the full cohort, costs for perimenopausal AUB/PMB workup and management were as follows: 7 day median $628 (interquartile range (IQR) $333-2,298), 30 day median $1,959 (IQR $431-3,653), and 90 day median $2,279 (IQR $512-4,828). Among patients with a diagnostic biopsy, median 90 day costs ranged from $2,203 (IQR $499-3604) for benign/DPE diagnosis to $21,039 (IQR $19,084-24,536) for a diagnosis of EC. Among women with a non-diagnostic office-based endometrial biopsy, the median 90 day cost was $2205 (IQR $424-2972). Table 1 details 7-day, 30-day, and 90-day costs per office-based tissue diagnosis. Conclusions: The costs for diagnostic evaluation and management of perimenopausal AUB and PMB vary greatly according to ultimate tissue diagnosis. Even reassuring benign findings that do not require further intervention-the most common in this study's cohort-yield substantial costs. The development of sensitive, specific, and more cost effective diagnostic strategies is warranted. Download : Download high-res image (102KB) Download : Download full-size image

Objective To evaluate endometrial cancer (EC) risk assessment and early detection strategies in high-risk populations, we designed a large, prospective cohort study of women undergoing endometrial evaluation to assess risk factors and collect novel biospecimens for future testing of emerging EC biomarkers. Here we report on the baseline findings of this study. Methods Women aged ≥45 years were enrolled at the Mayo Clinic from February 2013–June 2018. Risk factors included age, body mass index (BMI), smoking, oral contraceptive and hormone therapy use, and parity. We collected vaginal tampons, endometrial biopsies, and Tao brush samples. We estimated mutually-adjusted odds ratios (OR) and 95% confidence intervals (CI) using multinomial logistic regression; outcomes included EC, atypical hyperplasia, hyperplasia without atypia, disordered proliferative endometrium, and polyps, versus normal endometrium. Results Subjects included 1205 women with a mean age of 55 years; 55% were postmenopausal, and 90% had abnormal uterine bleeding. The prevalence of EC was 4.1% (n = 49), predominantly diagnosed in postmenopausal women (85.7%). Tampons and Tao brushings were obtained from 99% and 68% of women, respectively. Age (OR 1.14, 95% CI 1.1–1.2) and BMI (OR 1.39, 95% CI 1.1–1.7) were positively associated with EC; atypical hyperplasia (OR 1.07, 95% CI 1.0–1.1; OR 2.00, 95% CI 1.5–2.6, respectively), and polyps (OR 1.06, 95% CI 1.0–1.1; OR 1.17, 95% CI 1.0–1.3, respectively); hormone therapy use and smoking were inversely associated with EC (OR 0.42, 95%, 0.2–0.9; OR 0.43, 95% CI, 0.2–0.9, respectively). Parity and past oral contraception use were not associated with EC. Conclusions Well-established EC risk factors may have less discriminatory accuracy in high-risk populations. Future analyses will integrate risk factor assessment with biomarker testing for EC detection.

5526 Background: HR-HPV DNA testing, with or without cervical cytology, provides excellent sensitivity for detection of cervical cancer (CC) and its precursors; negative test results indicate that risk of disease is extremely low and enable women to undergo reduced screening with safety. However, management of women who screen positive remains challenging as many will prove to have self-limited HR-HPV infections. DNA methylation is an early event in carcinogenesis that could enhance CC screening specificity. Methods: For discovery, DNA from 70 FFPE CC (36 squamous, 34 adenocarcinoma) tissues that were reviewed microscopically, 18 fresh frozen benign cervicovaginal (BCV) tissues collected at the time of benign hysterectomy, and 18 buffy coats from cancer-free women underwent reduced representation bisulfite sequencing (RRBS) to identify MDMs associated with CC. Candidate MDM selection was based on area under the receiver operating characteristic curve (AUC) discrimination, methylation fold change, and low background methylation among benign controls. Candidate MDMs were re-tested using methylation-specific PCR (MSP) to confirm performance. Blinded biological validation was performed using MSP on DNA extracted from independent FFPE CC (38 squamous, 43 adenocarcinoma) and BCV (40) tissues. The performance of CC MDMs was also tested in DNA extracted from cervical dysplasia (36 adenocarcinoma in situ (AIS), 32 cervical intraepithelial neoplasia (CIN) 2/3, 11 CIN 1) FFPE tissues. Results: From RRBS discovery and technical validation via MSP, 30 candidate MDMs showed marked methylation fold changes (10 to >1000) across both CC histologies compared to BCV tissue from cancer-free women. Each of the 30 MDMs highly discriminated CC from BCV tissue with 9 MDMs having an AUC >0.90 (Table). CC MDMs also highly discriminated AIS from BCV but did not perform well in CIN 2/3 and CIN 1 (Table). Conclusions: Whole methylome sequencing, stringent filtering criteria, and biological validation have yielded outstanding candidate MDMs for CC that highly discriminate CC from BCV, notably with high specificity. Performance in cervical dysplasias varied with higher positivity rates in AIS than in CIN 2/3 and CIN 1. Translation to testing these novel MDMs in lower genital tract biospecimens and the addition of HR-HPV to the CC panel are warranted.[Table: see text]

OBJECTIVE To compare efficacy and safety of retropubic Burch urethropexy and a midurethral sling in women with stress urinary incontinence (SUI) undergoing concomitant pelvic floor repair with sacrocolpopexy. METHODS Women were randomly assigned to Burch retropubic urethropexy (n=56) or retropubic midurethral sling (n=57) through dynamic allocation balancing age, body mass index, history of prior incontinence surgery, intrinsic sphincter deficiency, preoperative incontinence diagnosis, and prolapse stage. Overall and stress-specific continence primary outcomes were ascertained with validated questionnaires and a blinded cough stress test. RESULTS Enrollment was June 1, 2009, through August 31, 2013. At 6 months, no difference was found in overall (29 midurethral sling [51%] compared with 23 Burch [41%]; P=.30) (odds ratio [OR] 1.49, 95% confidence interval [CI] 0.71-3.13) or stress-specific continence rates (42 midurethral sling [74%] compared with 32 Burch [57%]; P=.06) (OR 2.10, 95% CI 0.95-4.64) between groups. However, the midurethral sling group reported greater satisfaction (78% compared with 57%; P=.04) and were more likely to report successful surgery for SUI (71% compared with 50%; P=.04) and to resolve pre-existing urgency incontinence (72% compared with 41%; P=.03). No difference was found in patient global impression of severity or symptom improvement, complication rates, or mesh exposures. CONCLUSION There was no difference in overall or stress-specific continence rates between midurethral sling and Burch urethropexy groups at 6 months. However, the midurethral sling group reported better patient-centered secondary outcomes.

6072 Background: Effective screening tests for ovarian cancer (OC) are lacking; most cases present at advanced stage and portend poor prognosis. DNA methylation is an early event in carcinogenesis and can be detected in blood plasma samples from cancer patients. In DNA extracted from tissues, we first discovered, then validated discriminant methylated DNA marker (MDM) candidates for OC and subsequently tested independent plasma from women with and without OC. Methods: For discovery, DNA from 67 frozen tissues (18 high grade serous (HGS), 18 endometrioid, 15 clear cell (CC), 6 mucinous OCs; 10 benign fallopian tube epithelium (FT); and 19 buffy coats from cancer-free women underwent reduced representation bisulfite sequencing (RRBS) to identify MDMs associated with OC. Candidate MDM selection was based on receiver operating characteristic (ROC) discrimination, methylation fold change, and low background methylation among controls. Blinded biological validation was performed using methylated specific PCR on DNA extracted from independent FFPE tissues from OCs (36 HGS, 22 endometrioid, 21 CC, and 14 mucinous) and 29 FT. Top performing MDMs in tissue were tested using long-probe quantitative amplified signal assays in independent pre-treatment plasma samples from women newly-diagnosed with OC and population-sampled healthy women. A random forest modeling analysis was performed to generate predictive probability of disease; results were 500-fold in silico cross-validated. Results: After RRBS discovery and biological validation, 33 MDMs showed marked methylation fold changes (10 to > 1000) across all OC histologies vs FT. The top 11 MDMs ( GPRIN1, CDO1, SRC, SIM2, AGRN, FAIM2, CELF2, DSCR6, GYPC, CAPN2, BCAT1) were tested on plasma from 91 women with OC (76 (84%) HGS) and 91 without OC; the cross-validated 11-MDM panel highly discriminated OC from controls (96% (95%CI 89-99%) specificity; 79% (69-87%) sensitivity, and AUC 0.91 (0.86 - 0.96)). Among HGS, the panel correctly identified 83%, including 5/6 stage I/II, and the majority of other subtypes (Table). Conclusions: Whole methylome sequencing, stringent filtering criteria, and biological validation yielded outstanding candidate MDMs for OC that performed with promisingly high sensitivity and specificity in plasma. Larger plasma-based OC MDM testing studies, with larger numbers of non-HGS histologies are warranted. [Table: see text]

Background Uterine leiomyomas (fibroid tumors) cause considerable symptoms in 30–50% of women and are the leading cause of hysterectomy in the United States. Women with uterine fibroid tumors often seek uterine-preserving treatments, but comparative effectiveness trials are lacking. Objective The purpose of this study was to report treatment effectiveness and ovarian function after uterine artery embolization vs magnetic resonance imaging–guided focused ultrasound surgery from the Fibroid Interventions: Reducing Symptoms Today and Tomorrow study. Study Design The Fibroid Interventions: Reducing Symptoms Today and Tomorrow study, which is a randomized controlled trial of uterine artery embolization vs magnetic resonance imaging–guided focused ultrasound surgery, enrolled premenopausal women with symptomatic uterine fibroid tumors; women who declined randomization were enrolled in a parallel observational cohort. A comprehensive cohort design was used for outcomes analysis. Our target enrollment was 220 women, of which we achieved 41% (n=91) in the randomized and parallel arms of the trial. Primary outcome was reintervention for uterine fibroid tumors within 36 months. Secondary outcomes were change in serum anti-Mullerian hormone levels and standardized measures of fibroid symptoms, quality of life, pain, and sexual function. Results From 2010–2014, 83 women (mean age, 44.4 years) were treated in the comprehensive cohort design (43 for magnetic resonance imaging–guided focused ultrasound surgery [27 randomized]; 40 for uterine artery embolization [22 randomized]); baseline clinical and uterine characteristics were similar between treatment arms, except for higher fibroid load in the uterine artery embolization arm. The risk of reintervention was higher with magnetic resonance imaging–guided focused ultrasound surgery than uterine artery embolization (hazard ratio, 2.81; 95% confidence interval, 1.01–7.79). Uterine artery embolization showed a significantly greater absolute decrease in anti-Mullerian hormone levels at 24 months compared with magnetic resonance imaging–guided focused ultrasound surgery. Quality of life and pain scores improved in both arms but to a greater extent in the uterine artery embolization arm. Higher pretreatment anti-Mullerian hormone level and younger age at treatment increased the overall risk of reintervention. Conclusion Our study demonstrates a lower reintervention rate and greater improvement in symptoms after uterine artery embolization, although some of the effectiveness may come through impairment of ovarian reserve. Both pretreatment anti-Mullerian hormone level and age are associated with risk of reintervention. Clinical Trial Registration Number: NCT00995878 , clinicaltrials.gov

Background Radiofrequency endometrial ablation (REA) is currently a second line treatment in women with heavy menstrual bleeding (MHB) if medical therapy (MTP) is contraindicated or unsatisfactory. Our objective is to compare the effectiveness and cost burden of MTP and REA in the initial treatment of HMB. Methods We performed a randomized trial at Mayo Clinic Rochester, Minnesota. The planned sample size was 60 patients per arm. A total of 67 women with HMB were randomly allocated to receive oral contraceptive pills (Nordette ®) or Naproxen (Naprosyn®) (n = 33) or REA (n = 34). Primary 12-month outcome measures included menstrual blood loss using pictorial blood loss assessment chart (PBLAC), patients’ satisfaction, and Menorrhagia Multi-Attribute Scale (MMAS). Secondary outcomes were total costs including direct medical and indirect costs associated with healthcare use, patient out-of-pocket costs, and lost work days and activity limitations over 12 months. Results Compared to MTP arm, women who received REA had a significantly lower PBLAC score (median [Interquartile range, IQR]: 0 [0–4] vs. 15 [0–131], p = 0.003), higher satisfaction rates (96.8%vs.63.2%, p = 0.003) and higher MMAS (median [IQR]: 100 [100–100] vs. 100 [87–100], p = 0.12) at 12 months. Direct medical costs were higher for REA ($5,331vs.$2,901, 95% confidence interval (CI) of mean difference:$727,$4,852), however, when indirect costs are included, the difference did not reach statistical significance ($5,469 vs. $3,869, 95% CI of mean difference:-$339, $4,089). Conclusion For women with heavy menstrual bleeding, initial radiofrequency endometrial ablation compared to medical therapy offered superior reduction in menstrual blood loss and improvement in quality of life without significant differences in total costs of care. Clinical trial registration NCT01165307.

ObjectivePerioperative packed red blood cell transfusion (PRBCT) has been implicated as a negative prognostic marker in surgical oncology. There is a paucity of evidence on the impact of PRBCT on outcomes in epithelial ovarian cancer (EOC). We assessed whether PRBCT is an independent risk factor of recurrence and death from EOC.MethodsPerioperative patient characteristics and process-of-care variables (defined by the National Surgical Quality Improvement Program) were retrospectively abstracted from 587 women who underwent primary EOC staging between January 2, 2003, and December 29, 2008. Associations with receipt of PRBCT were evaluated using univariate logistic regression models. The associations between receipt of PRBCT and disease-free survival and overall survival were evaluated using multivariable Cox proportional hazards models and using propensity score matching and stratification, respectively.ResultsThe rate of PRBCT was 77.0%. The mean ± SD units transfused was 4.1 ± 3.1 U. In the univariate analysis, receipt of PRBCT was significantly associated with older age, advanced stage (≥IIIA), undergoing splenectomy, higher surgical complexity, serous histologic diagnosis, greater estimated blood loss, longer operating time, the presence of residual disease, and lower preoperative albumin and hemoglobin. Perioperative packed red blood cell transfusion was not associated with an increased risk for recurrence or death, in an analysis adjusting for other risk factors in a multivariable model or in an analysis using propensity score matching or stratification to control for differences between the patients with and without PRBCT.ConclusionsPerioperative packed red blood cell transfusion does not seem to be directly associated with recurrence and death in EOC. However, lower preoperative hemoglobin was associated with a higher risk for recurrence. The need for PRBCT seems to be a stronger prognostic indicator than the receipt of PRBCT.

ObjectiveThe aim of this study was to determine the incidence and the risk factors of venous thromboembolism (VTE) within 30 days after primary surgery for epithelial ovarian cancer (EOC).MethodsIn a historical cohort study, we estimated the postoperative 30-day cumulative incidence of VTE among consecutive Mayo Clinic patients undergoing primary cytoreduction for EOC between January 2, 2003, and December 29, 2008. We tested perioperative patient characteristics and process-of-care variables (defined by the National Surgical Quality Improvement Program, >130 variables) as potential predictors of postoperative VTE using the Cox proportional hazards modeling.ResultsAmong 569 cases of primary EOC cytoreduction and/or staging and no recent VTE, 35 developed symptomatic VTE within 30 days after surgery (cumulative incidence = 6.5%; 95% confidence interval, 4.4%–8.6%). Within the cohort, 95 (16.7%) received graduated compression stockings (GCSs), 367 (64.5%) had sequential compression devices + GCSs, and 69 (12.1%) had sequential compression devices + GCSs + postoperative heparin, with VTE rates of 1.1%, 7.4%, and 5.8%, respectively (P= 0.07, χ2test). The remaining 38 (6.7%) received various other chemical and mechanical prophylaxis regimens. In the multivariate analysis, current or past tobacco smoking, longer hospital stay, and a remote history of VTE significantly increased the risk for postoperative VTE.ConclusionsVenous thromboembolism is a substantial postoperative complication among women with EOC, and the high cumulative rate of VTE within 30 days after primary surgery suggests that a more aggressive strategy is needed for VTE prevention. In addition, because longer hospital stay is independently associated with a higher risk for VTE, methods to decrease length of stay and minimize factors that contribute to prolonged hospitalization are warranted.

Preoperative thrombocytosis has been implicated as a negative prognostic marker for epithelial ovarian cancer (EOC). We assessed whether thrombocytosis is an independent risk factor for EOC recurrence and death.Perioperative patient characteristics and process-of-care variables (National Surgical Quality Improvement Program (NSQIP)-defined) were retrospectively abstracted from 587 women who underwent EOC staging between 1/2/03-12/29/08. Thrombocytosis was defined as platelet count450 × 10(9)/L. Disease-free survival (DFS) and overall survival (OS) were determined using Kaplan-Meier methods. Associations were evaluated with Cox proportional hazards regression and hazard ratios (HR).The incidence of preoperative thrombocytosis was 22.3%. DFS was 70.8% and 36.0% at 1 and 3 years. OS was 83.3% and 54.3% at 1 and 3 years. Ascites, lower hemoglobin, advanced disease, and receipt of perioperative packed red blood cell transfusion were independently associated with thrombocytosis. Older age and the presence of coronary artery disease were associated with lower likelihood of thrombocytosis. Overall, thrombocytosis was an independent predictor of increased risk of recurrence. Among early stage (I/II) cases, there was a 5-fold increase in the risk of death and nearly 8-fold risk of disease recurrence independently associated with thrombocytosis.Preoperative thrombocytosis portends worse DFS in EOC. In early stage disease, thrombocytosis is a potent predictor of worse DFS and OS and further assessment of the impact of circulating platelet-derived factors on EOC survival is warranted. Thrombocytosis is also associated with extensive initial disease burden, measurable residual disease, and postoperative sequelae. Preoperative platelet levels may have value in primary cytoreduction counseling.

Objective Thorough primary cytoreduction for epithelial ovarian carcinoma (EOC) improves survival. The incidence of postoperative ileus (POI) in these patients may be underreported because of varying POI definitions and the evolving, increasingly complex contemporary surgical approach to EOC. We sought to determine the current incidence of POI and its risk factors in women undergoing debulking and staging for EOC. Methods We retrospectively identified the records of women who underwent primary staging and cytoreduction for EOC between 2003 and 2008. POI was defined as a surgeon's diagnosis of POI, return to nothing-by-mouth status, or reinsertion of a nasogastric tube. Perioperative patient characteristics and process-of-care variables were analyzed. Univariate analyses were used to identify POI risk factors; variables with P ≤.20 were included in multivariate analysis. Results Among 587 women identified, the overall incidence of POI was 30.3% (25.9% without bowel resection, 38.5% with bowel resection; P =.002). Preoperative thrombocytosis, involvement of bowel mesentery with carcinoma, and perioperative red blood cell transfusion were independently associated with increased POI. Postoperative ibuprofen use was associated with decreased POI risk. Women with POI had a longer length of stay (median, 11 vs 6days) and increased time to recovery of the upper (7.5 vs 4days) and lower (4 vs 3days) gastrointestinal tract ( P Conclusions The rate of POI is substantial among women undergoing staging and cytoreduction for EOC and is associated with increased length of stay. Modifiable risk factors may include transfusion and postoperative ibuprofen use. Alternative interventions to decrease POI are needed.

Background: Endometrial cancer (EC) is the most common gynecologic malignancy in developed countries and the incidence and mortality of EC continue to rise in the US. When detected early, EC is highly curable, suggesting that early detection strategies could reduce EC mortality. Women who develop EC often have a prolonged history of abnormal bleeding, offering a window for identifying many at-risk women prior to the development of advanced cancer. To evaluate risk prediction, novel sampling and early detection strategies in women at increased risk of EC, we established a prospective cohort of women with abnormal bleeding that is followed for endometrial hyperplasia and cancer endpoints. Methods: We consecutively enrolled women ≥45 years old presenting to the Mayo Clinic for evaluation of abnormal uterine bleeding (AUB), postmenopausal bleeding (PMB), thickened endometrial stripe (ES) on imaging, or Lynch Syndrome (LS). From all women, an intravaginal tampon and an endometrial brushing via Tao brush were collected before endometrial biopsy. Epidemiological EC risk factor data, clinical data, and endometrial biopsy histology results were abstracted from medical records. Absolute risk of endometrial hyperplasia and EC were calculated overall and in strata based on clinical symptoms and risk factors. Results: Among the first 1,000 women enrolled into the study, 712 (71%) were overweight or obese, 534 (53%) were postmenopausal, and 214 (22%) were current hormone replacement therapy (HRT) users. Endometrial biopsy and, if indicated, subsequent hysterectomy, detected 39 ECs, 16 atypical hyperplasias, and 28 hyperplasias without atypia at baseline evaluation. Among 534 postmenopausal women, 453 (85%) reported any type of bleeding, with spotting (39%) and light bleeding (27%) being more common than heavy bleeding (14%). Among perimenopausal women with AUB (n=452), the absolute risk of EC at baseline was 0.9% and among women with PMB, the absolute risk of EC at baseline was 7.5%. Among women with PMB, EC risk was modified by HRT use (risk of 2.6% in women on HRT and 8.2% in women not on HRT, respectively), obesity (risk of 5.3%, 8.1% and 9.5% for women with normal, overweight, and obese BMI, respectively), and type of bleeding (risk of 9.7%, 4.9%, and 8.2% in women with spotting, light or heavy bleeding, respectively). Discussion: While risk of endometrial cancer in perimenopausal women with AUB is low, approximately 8% of women presenting for clinical work up of PMB have underlying EC. Clinical presentation and risk factors modify the absolute risk of EC and may inform clinical management. Additional recruitment and prospective follow-up is underway to improve estimates of short- and long-term EC risk in women with PMB. With its collection of tampon and Tao brush samples, the study will provide a unique resource to evaluate molecular markers of EC and EC risk in elevated-risk women. Citation Format: Nicolas A. Wentzensen, Megan Clarke, Viji Shridhar, Maureen Lemens, Matthew Hopkins, Lisa Ahlberg, Shannon Laughlin-Tommaso, Karl Podratz, Mark Sherman, Jamie Bakkum-Gamez. A prospective study of endometrial cancer detection in women presenting for evaluation of abnormal peri- and postmenopausal bleeding [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2203.

Objective Surgical site infection (SSI) following epithelial ovarian cancer (EOC) primary surgery (PS) occurs in 10–15% of women. Perioperative factors associated with SSI and impact of SSI on survival were determined. Methods EOC cases that underwent PS from 1/2/2003 to 12/30/2011 were retrospectively reviewed. SSIs were defined according to ACS NSQIP. Logistic regression models were fit to identify factors associated with SSI. Cox proportional hazards models were utilized to evaluate the association of patient and perioperative characteristics with overall survival (OS) and disease-free survival (DFS). Results Among 888 cases, 96 (10.8%) developed SSI: 32 superficial, 2 deep, and 62 organ/space. Factors independently associated with superficial SSI were increasing BMI (odds ratio 1.41 [95% confidence interval, 1.12, 1.76] per 5 kg/m2), increasing operative time (1.24 [1.02, 1.50] per hour), and advanced stage (III/IV) (10.22 [1.37, 76.20]). Factors independently associated with organ/space SSI were history of gastroesophageal reflux disease (2.13 [1.23, 3.71]), surgical complexity (intermediate 3.11 [1.02, 9.49]; high 8.07 [2.60, 25.09]; referent: low), and residual disease (RD) (measureable ≤ 1 cm 1.77 [0.96, 3.27]; suboptimal > 1 cm (3.36 [1.48, 7.61]; referent: microscopic). Occurrence of superficial (hazard ratio 1.69 [1.12, 2.57]) or organ/space (1.46 [1.07, 2.00]) SSI was independently associated with worse OS. SSI occurrence was not independently associated with DFS. Conclusions SSI after PS is associated with decreased OS. Most risk factors for SSI are not modifiable. Alternative measures to lower rates of SSIs are needed as this may improve OS. Preoperative identification of SSI risk factors may assist in risk-assessment and operative planning.

BackgroundUterine fibroids are an important source of morbidity for reproductive-aged women. Despite an increasing number of alternatives, hysterectomies account for about 75% of all fibroid interventional treatments. Evidence is lacking to help women and their health careproviders decide among alternatives to hysterectomy. Fibroid Interventions: Reducing Symptoms Today and Tomorrow (NCT00995878, clinicaltrials.gov) is a randomized controlled trial to compare the safety, efficacy, and economics of 2 minimally invasive alternatives to hysterectomy: uterine artery embolization and magnetic resonance imaging-guided focused ultrasound surgery. Although randomized trials provide the highest level of evidence, they have been difficult to conduct in the United States for interventional fibroid treatments. Thus, contemporaneously recruiting women declining randomization may have value as an alternative strategy for comparative effectiveness research.ObjectiveWe sought to compare baseline characteristics of randomized participants with nonrandomized participants meeting the same enrollment criteria and to determine whether combining the 2 cohorts in a comprehensive cohort design would be useful for analysis.Study designPremenopausal women with symptomatic uterine fibroids seeking interventional therapy at 3 US academic medical centers were randomized (1:1) in 2 strata based on calculated uterine volume (

5554 Background: Surgical site infection (SSI) following epithelial ovarian cancer (EOC) primary debulking surgery (PDS) occurs in 10-15% of patients. Perioperative factors associated with SSI as w...

5577 Background: Perioperative red blood cell transfusion (PRBCT) may be a negative prognostic marker in surgical oncology. We assessed PRBCT as an independent risk factor for recurrence and death from epithelial ovarian cancer (EOC) in the largest cohort to date. Methods: Patient characteristics and process-of-care variables (NSQIP-defined, >130 variables) were retrospectively abstracted from 587 women who underwent primary staging and cytoreduction for EOC (1/1/03-12/29/08). Evaluated using propensity scoring with univariate logistic regression and odds ratios (OR) and Cox proportional hazards regression and hazard ratios (HR). Factors with p1cm), and lower preop hemoglobin (Hb) (1.89[1.59, 2.27]per 1g/dL decrease). In univariable analysis, PRBCT was associated with a higher risk of recurrence (HR 1.96[95% CI 1.43, 2.68]) and death (1.71[1.28, 2.28]). However, in multivariable analysis, stage≥IIIa (4.03[2.05, 6.49]), splenectomy (1.41[1.02, 1.95]), residual disease (1.86[1.41, 2.46]≤1cm; 2.91[2.02, 4.18]>1cm), and lower preop Hb (1.09[1.01, 1.19]) were associated with higher risk of recurrence. Older age (1.24[1.12, 1.37]), stage≥IIIa (3.07[1.93, 4.90]), albumin ≤3 g/dL (2.06[1.28, 3.31]), residual disease (1.63[1.22, 2.19]≤1cm; 3.03[2.19, 4.18]>1cm), and low Hb (1.08[1.00, 1.19]) were associated with higher risk of death. Serous histology (0.70[0.52, 0.95]) associated with lower risk of death. Conclusions: PRBCT does not appear to be directly associated with disease-free and overall survival in EOC. Lower preoperative Hb was associated with a higher risk of both recurrence and death. The need for PRBCT appears to be a stronger prognostic indicator than the receipt of PRBCT.