Impact of pharmacogenomic profiles on post-surgical pain following laparotomy for gynecologic pathology.

OBJECTIVES: The aim of this prospective study was to compare perioperative opioid use in women by status of CYP2D6, a highly polymorphic pharmacogene relevant to opioid metabolism. METHODS: Patients undergoing laparotomy were prospectively recruited and provided a preoperative saliva swab for a pharmacogenomic (PGx) gene panel. Postoperative opioid usage and pain scores were evaluated via chart review and a phone survey. Pharmacogenes known to be relevant to opioid metabolism were genotyped, and opioid metabolizing activity predicted by CYP2D6 genotyping. Patient and procedural factors were compared using Fisher's exact and Kruskal-Wallis tests. RESULTS: The 96 enrolled patients were classified as ultra-rapid (N = 3, 3%), normal (58, 60%), intermediate (27, 28%), and poor (8, 8%) opioid metabolizers. There was no difference in surgical complexity across CYP2D6 categories (p = 0.61). Morphine Milligram Equivalents (MME) consumed during the first 24 h after peri-operative suite exit were significantly different between groups: ultrarapid metabolizers had the highest median MME (75, IQR 45-88) compared to the other three groups (normal metabolizers 23 [8-45], intermediate metabolizers 48 [20-63], poor metabolizers 31 [12-53], p = 0.03). Opioid requirements were clinically greater in ultrarapid metabolizers during the second 24 h and last 24 h but were statistically similar (p = 0.07). There was no difference in MME prescribed at discharge (p = 0.22) or patient satisfaction with pain control (p = 0.64) between groups. CONCLUSIONS: A positive association existed between increased CYP2D6 activity and in-hospital opioid requirements, especially in the first 24 h after surgery. This provides important information to further individualize opioid prescriptions for patients undergoing laparotomy for gynecologic pathology.

Detection of endometrial cancer using tampon-based collection and methylated DNA markers.

OBJECTIVE: Alterations in DNA methylation are early events in endometrial cancer (EC) development and may have utility in EC detection via tampon-collected vaginal fluid. METHODS: For discovery, DNA from frozen EC, benign endometrium (BE), and benign cervicovaginal (BCV) tissues underwent reduced representation bisulfite sequencing (RRBS) to identify differentially methylated regions (DMRs). Candidate DMRs were selected based on receiver operating characteristic (ROC) discrimination, methylation level fold-change between cancers and controls, and absence of background CpG methylation. Methylated DNA marker (MDM) validation was performed using qMSP on DNA from independent EC and BE FFPE tissue sets. Women ≥45 years of age with abnormal uterine bleeding (AUB) or postmenopausal bleeding (PMB) or any age with biopsy-proven EC self-collected vaginal fluid using a tampon prior to clinically indicated endometrial sampling or hysterectomy. Vaginal fluid DNA was assayed by qMSP for EC-associated MDMs. Random forest modeling analysis was performed to generate predictive probability of underlying disease; results were 500-fold in-silico cross-validated. RESULTS: Thirty-three candidate MDMs met performance criteria in tissue. For the tampon pilot, 100 EC cases were frequency matched by menopausal status and tampon collection date to 92 BE controls. A 28-MDM panel highly discriminated between EC and BE (96% (95%CI 89-99%) specificity; 76% (66-84%) sensitivity (AUC 0.88). In PBS/EDTA tampon buffer, the panel yielded 96% (95% CI 87-99%) specificity and 82% (70-91%) sensitivity (AUC 0.91). CONCLUSION: Next generation methylome sequencing, stringent filtering criteria, and independent validation yielded excellent candidate MDMs for EC. EC-associated MDMs performed with promisingly high sensitivity and specificity in tampon-collected vaginal fluid; PBS-based tampon buffer with added EDTA improved sensitivity. Larger tampon-based EC MDM testing studies are warranted.

Fetal surgery is not associated with increased inflammatory placental pathology.

OBJECTIVE: Fetal surgery has improved neonatal outcomes; however, it is unknown if the intervention contributes to the developmental of inflammatory pathologies in the placenta. Here, an association between fetal surgery and placental pathology was examined. METHOD: This case-control study compared pregnancies with fetal surgery (n = 22), pregnancies with an indication for fetal surgery but without an intervention being done (n = 13), and gestational-age and fetus-number matched controls (n = 36). Data on maternal, infant, and placental outcomes were abstracted. Additionally, immunohistochemistry identified expression of lymphoid and myeloid cells in the placenta on a subset of cases. Comparisons were performed using Kruskal-Wallis or Pearson's chi-squared tests. RESULTS: Maternal characteristics were comparable between groups. Most fetal interventions were for diaphragmatic hernia, spina bifida, or twin-to-twin transfusion syndrome. Fetuses who were operated on before birth were more likely to be born preterm (p = 0.02). There was no increase in the rate of observed placental pathologies or immune cell infiltration in fetal surgery cases compared to controls. CONCLUSION: The data suggest that fetal surgery is not associated with increased inflammatory or morphologic pathology in the placenta. This observation supports the growing field of fetal surgery.

Methylated DNA markers for plasma detection of ovarian cancer: Discovery, validation, and clinical feasibility.

OBJECTIVE: Aberrant DNA methylation is an early event in carcinogenesis which could be leveraged to detect ovarian cancer (OC) in plasma. METHODS: DNA from frozen OC tissues, benign fallopian tube epithelium (FTE), and buffy coats from cancer-free women underwent reduced representation bisulfite sequencing (RRBS) to identify OC MDMs. 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 OC and FTE FFPE tissues. MDMs were tested using Target Enrichment Long-probe Quantitative Amplified Signal (TELQAS) assays in pre-treatment plasma 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: Thirty-three MDMs showed marked methylation fold changes (10 to >1000) across all OC subtypes vs FTE. Eleven MDMs (GPRIN1, CDO1, SRC, SIM2, AGRN, FAIM2, CELF2, RIPPLY3, GYPC, CAPN2, BCAT1) were tested on plasma from 91 women with OC (73 (80%) high-grade serous (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 the 5 stage I/II HGS OCs included, all were correctly identified. CONCLUSIONS: Whole methylome sequencing, stringent filtering criteria, and biological validation yielded candidate MDMs for OC that performed with high sensitivity and specificity in plasma. Larger plasma-based OC MDM studies, including testing of pre-diagnostic specimens, are warranted.

Uterine and Fibroid Imaging Analysis from the FIRSTT Study.

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.

The cost of diagnosing endometrial cancer: Quantifying the healthcare cost of an abnormal uterine bleeding workup.

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.

Personalized tumor-specific DNA junctions to detect circulating tumor in patients with endometrial cancer.

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.

Quantifying procedural pain associated with office gynecologic tract sampling methods.

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 < 0.001, Wilcoxon signed rank test). Among women who underwent tampon sampling, age and pain scores showed a weak positive correlation (Spearman rank correlation, r = 0.14; p = 0.006); EB sampling was associated with a weak inverse correlation between parity and pain scores (r = -0.14; p = 0.016). CONCLUSION: Gynecologic tract sampling using a tampon had significantly lower pain than both EB and TB. Pain with tampon sampling was positively correlated with age and pain with EB sampling was inversely correlated with parity. Pain scores for TB and EB were not significantly related to age, menopausal status, or BMI.

Risk assessment of endometrial cancer and endometrial intraepithelial neoplasia in women with abnormal bleeding and implications for clinical management algorithms.

BACKGROUND: Most endometrial cancer cases are preceded by abnormal uterine bleeding, offering a potential opportunity for early detection and cure of endometrial cancer. Although 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 1163 women aged ≥45 years were enrolled from February 2013 to 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 through transvaginal ultrasound). We also evaluated risks among women with postmenopausal bleeding according to baseline age (<60 vs 60+ years) as an alternative example. For this approach, biopsy would be conducted for all women aged 60+ years and those aged <60 years with an endometrial thickness of >4 mm. We assessed the clinical efficiency of each strategy by estimating the percentage of women who would be referred for endometrial biopsy, the percentage 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 endometrial cancer. Maximum risk was noted 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 for whom transvaginal ultrasound was recommended, endometrial thickness did not provide meaningful risk stratification: risks of endometrial cancer and endometrial intraepithelial neoplasia were nearly identical in women with an endometrial thickness of >4 mm (5.8%; 1.3%-10.3%) and ≤4 mm (3.6%; 0.9%-8.6%). In contrast, among those aged <60 years with an endometrial thickness of >4 mm, the risk of endometrial cancer and endometrial intraepithelial neoplasia was 8.4% (4.3%-12.5%), and in those with an endometrial thickness of ≤4 mm, the risk was 0% (0.0%-3.0%; P=.01). The most efficient strategy was to perform biopsy in all women aged 60+ years and among those aged <60 years with an endometrial thickness of >4 mm, with the lowest percentage referred to biopsy while still detecting all cases. CONCLUSION: Existing clinical recommendations for endometrial cancer detection in women with abnormal bleeding are not consistent with the underlying risk. Endometrial cancer risk factors such as age can provide important risk stratification compared with 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.

A prospective clinical cohort study of women at increased risk for endometrial cancer.

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.

FIRSTT study: randomized controlled trial of uterine artery embolization vs focused ultrasound surgery.

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-Müllerian 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-Müllerian 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-Müllerian 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-Müllerian hormone level and age are associated with risk of reintervention. CLINICAL TRIAL REGISTRATION NUMBER: NCT00995878, clinicaltrials.gov.

Fetoscopic Therapy for Severe Pulmonary Hypoplasia in Congenital Diaphragmatic Hernia: A First in Prenatal Regenerative Medicine at Mayo Clinic.

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.

Medical therapy versus radiofrequency endometrial ablation in the initial treatment of heavy menstrual bleeding (iTOM Trial): A clinical and economic analysis.

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.

Burch Retropubic Urethropexy Compared With Midurethral Sling With Concurrent Sacrocolpopexy: A Randomized Controlled Trial.

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.

Fibroid interventions: reducing symptoms today and tomorrow: extending generalizability by using a comprehensive cohort design with a randomized controlled trial.

BACKGROUND: Uterine 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 care providers 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. OBJECTIVE: We 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 DESIGN: Premenopausal 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 (<700 and ≥700 cc(3)) to undergo embolization or focused ultrasound surgery. Women who met the same inclusion criteria but declined randomization were offered enrollment in a parallel cohort. Both cohorts were followed up for a maximum of 36 months after treatment. The measures addressed in this report were baseline demographics, symptoms, fibroid and uterine characteristics, and scores on validated quality-of-life measures. RESULTS: Of 723 women screened, 57 were randomized and 49 underwent treatment (27 with focused ultrasound and 22 with embolization). Seven of the 8 women randomized but not treated were assigned to embolization. Of 34 women in the parallel cohort, 16 elected focused ultrasound and 18 elected embolization. Compared with nonrandomized participants, randomized participants had higher mean body mass index (28.7 vs 25.3 kg/m(2); P = .01) and were more likely to be gravid (77% vs 47%; P = .003) and smokers (42% vs 12%; P = .003). Age, race, uterine volume, number of fibroids, and baseline validated measures of general and disease-specific quality of life, pain, depression, and sexual function did not differ between the groups. When we performed a comprehensive cohort analysis and analyzed by treatment arm, the only baseline difference observed was a higher median McGill Pain Score among women undergoing focused ultrasound (10.5 vs 6; P = .03); a similar but nonsignificant trend was seen in visual analog scale scores for pain (median, 39.0 vs 24.0; P = .06). CONCLUSION: Using a comprehensive cohort analysis of study data could result in additional power and greater generalizability if results are adjusted for baseline differences.

Surgical site infection after primary surgery for epithelial ovarian cancer: predictors and impact on survival.

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 5kg/m(2)), 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 ≤1cm 1.77 [0.96, 3.27]; suboptimal >1cm (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.

The impact of perioperative packed red blood cell transfusion on survival in epithelial ovarian cancer.

OBJECTIVE: Perioperative 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. METHODS: Perioperative 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. RESULTS: The 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. CONCLUSIONS: Perioperative 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.

Incidence and predictors of venous thromboembolism after debulking surgery for epithelial ovarian cancer.

OBJECTIVE: The 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). METHODS: In 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. RESULTS: Among 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, χ(2) test). 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. CONCLUSIONS: Venous 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.

Incidence of and risk factors for postoperative ileus in women undergoing primary staging and debulking for epithelial ovarian carcinoma.

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 6 days) and increased time to recovery of the upper (7.5 vs 4 days) and lower (4 vs 3 days) gastrointestinal tract (P<.001 for each). 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.