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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., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

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., (Copyright © 2023 Elsevier Inc. All rights reserved.)

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., (Copyright © 2022 Elsevier Inc. All rights reserved.)

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., Competing Interests: Declaration of Competing Interest Dr. Jamie Bakkum-Gamez was funded as noted above by The V Foundation for Cancer Research (T2016–001-03) and National Cancer Institute (grants P30 CA 15083 and Z01CP010124–21). She is also listed as an inventor on intellectual property owned by Mayo Clinic and licensed to Exact Sciences. Bijan Borah is a consultant for Exact Sciences. Dr. Mark Sherman participates in research on developing an early endometrial cancer detection test, which is partly funded by Exact Sciences., (Copyright © 2021 Elsevier Inc. All rights reserved.)

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., Competing Interests: Declaration of Competing Interest Dr. Bakkum-Gamez has an intellectual property disclosure filed on endometrial cancer methylated DNA markers with Mayo Clinic Ventures (Rochester, MN) and Exact Sciences (Madison, WI)., (Copyright © 2021 Elsevier Inc. All rights reserved.)

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., (Published by Elsevier Inc.)

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., (Copyright © 2014 Elsevier Inc. All rights reserved.)

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., (Copyright © 2012 Elsevier Inc. All rights reserved.)