Incidence of venous thromboembolism in patients with advanced stage ovarian cancer undergoing neoadjuvant chemotherapy: Is it time for thromboprophylaxis?

OBJECTIVES: Our objectives were to determine the incidence, timing, and risk factors for venous thromboembolisms (VTEs) in patients with advanced stage epithelial ovarian cancer (EOC) who received neoadjuvant chemotherapy (NACT). We explored the utilization of direct-acting oral anticoagulants (DOACs) for VTE treatment. METHODS: This retrospective cohort study included patients with advanced stage EOC receiving NACT followed by interval cytoreductive surgery (ICS) at a single institution. Risk factors were compared between patients with versus without VTE between EOC diagnosis and 180 days after ICS. Bleeding complications were compared between patient who received a DOAC versus non-DOAC. RESULTS: VTE cases occurred amongst 33 of the 154 (21.4%) patients with 4 (2.6%) concurrent with EOC diagnosis, 9 (5.8%) between EOC diagnosis and NACT start, 13 (8.4%) between NACT start and ICS, and 7 (4.5%) within 180 days after ICS. There were no statistically significant differences in risk factors assessed (age, body mass index, functional status, histology, Khorana score, and smoking history) between patients with versus without VTE. Eleven patients (33.3%) received a DOAC for VTE treatment. There were no significant differences in number of intraoperative blood transfusions (p = 0.38), blood loss (p = 0.95), or bleeding complications (p = 0.53) between patients treated with a DOAC versus a non-DOAC. CONCLUSION: There is a high incidence of VTE events (21.4%) in patients with advanced stage EOC undergoing NACT. Two-thirds of the VTEs may have been prevented with thromboprophylaxis as they occurred between EOC diagnosis and ICS. These data support consideration of thromboprophylaxis in all patients with advanced stage EOC undergoing NACT.

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.

Mohs surgery for female genital Paget's disease: a prospective observational trial.

BACKGROUND: Extramammary Paget's disease recurs often after traditional surgical excision. Margin-controlled surgery improves the recurrence rate for male genital disease but is less studied for female anatomy. OBJECTIVE: This study aimed to compare surgical and oncologic outcomes of margin-controlled surgery vs traditional surgical excision for female genital Paget's disease. STUDY DESIGN: We conducted a prospective observational trial of patients with vulvar or perianal Paget's disease treated with surgical excision guided by Mohs micrographic surgery between 2018 and 2022. The multidisciplinary protocol consisted of office-based scouting biopsies and modified Mohs surgery followed by surgical excision with wound closure under general anesthesia. Modified Mohs surgery cleared peripheral disease margins using a moat technique with cytokeratin 7 staining. Medial disease margins (the clitoris, urethra, vagina, and anus) were assessed using a hybrid of Mohs surgery and intraoperative frozen sections. Surgical and oncologic outcomes were compared with the outcomes of a retrospective cohort of patients who underwent traditional surgical excision. The primary outcome was 3-year recurrence-free survival. RESULTS: Three-year recurrence-free survival was 93.3% for Mohs-guided excision (n=24; 95% confidence interval, 81.5%-100.0%) compared to 65.9% for traditional excision (n=63; 95% confidence interval, 54.2%-80.0%) (P=.04). The maximum diameter of the excisional specimen was similar between groups (median, 11.3 vs 9.5 cm; P=.17), but complex reconstructive procedures were more common with the Mohs-guided approach (66.7% vs 30.2%; P<.01). Peripheral margin clearance was universally achieved with modified Mohs surgery, but positive medial margins were noted in 9 patients. Reasons included intentional organ sparing and poor performance of intraoperative hematoxylin and eosin frozen sections without cytokeratin 7. Grade 3 or higher postoperative complications were rare (0.0% for Mohs-guided excision vs 2.4% for traditional excision; P=.99). CONCLUSION: Margin control with modified Mohs surgery significantly improved short-term recurrence-free survival after surgical excision for female genital Paget's disease. Use on medial anatomic structures (the clitoris, urethra, vagina, and anus) is challenging, and further optimization is needed for margin control in these areas. Mohs-guided surgical excision requires specialized, collaborative care and may be best accomplished at designated referral centers.

Caprini assessment utilization and impact on patient safety in gynecologic surgery.

PURPOSE: Postoperative venous thromboembolism (VTE) can potentially be associated with significant morbidity, mortality, and healthcare costs. The aim of this study was to determine the utilization of Caprini guideline indicated VTE in elective gynecologic surgery patients and its impact on postoperative VTE and bleeding complications. METHODS: This was a retrospective cohort study of elective gynecologic surgical procedures performed between January 1, 2016, and May 31, 2021. Two study cohorts were generated: (1) those who received and (2) those who did not receive VTE prophylaxis based on Caprini score risk stratification. Outcome measures were then compared between the study cohorts and included the development of a VTE up to 90-days postoperatively. Secondary outcome measures included postoperative bleeding events. RESULTS: A total of 5471 patients met inclusion criteria and the incidence of VTE up to 90 days postoperatively was 1.04%. Overall, 29.6% of gynecologic surgery patients received Caprini score-based guideline VTE prophylaxis. 39.2% of patients that met high-risk VTE criteria (Caprini > 5) received appropriate Caprini score-based prophylaxis. In multivariate regression analysis, the American Society of Anesthesiologists (ASA) score (OR 2.37, CI 1.27-4.45, p < 0.0001) and Caprini score (OR 1.13, CI 1.03-1.24, p = 0.008) predicted postoperatively VTE occurrence. Increasing Charlson comorbidity score (OR 1.39, CI 1.31-1.47, P < 0.001) ASA score (OR 1.36, CI 1.19-1.55, P < 0.001) and Caprini score (OR 1.10, CI 1.08-1.13, P < 0.001) were associated with increased odds of receiving appropriate inpatient VTE prophylaxis. CONCLUSION: While the overall incidence of VTE was low in this cohort, enhanced adherence to risk-based practice guidelines may provide more patient benefit than harm to postoperative gynecologic patients.

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.

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.

NCCN Guidelines® Insights: Ovarian Cancer, Version 3.2022.

Epithelial ovarian cancer is the leading cause of death from gynecologic cancer in the United States, with less than half of patients living >5 years following diagnosis. The NCCN Guidelines for Ovarian Cancer provide recommendations for the diagnosis, evaluation, treatment, and follow-up for patients with ovarian, fallopian tube, and primary peritoneal cancers. These NCCN Guidelines Insights summarize the panel discussion behind recent important updates to the guidelines, including revised guidance on alternative chemotherapy regimens for patients with advanced age and/or comorbidities, a new algorithm for recurrent low-grade serous carcinoma based on developing research and novel therapeutic agents, and updated language regarding tumor molecular analysis applications in ovarian cancer.

PP2A and E3 ubiquitin ligase deficiencies: Seminal biological drivers in endometrial cancer.

OBJECTIVE: PI3K-AKT pathway mutations initiate a kinase cascade that characterizes endometrial cancer (EC). As kinases seldom cause oncogenic transformation without dysregulation of antagonistic phosphatases, pivotal interactions governing this pathway were explored and correlated with clinical outcomes. METHODS: After exclusion of patients with POLE mutations from The Cancer Genome Atlas EC cohort with endometrioid or serous EC, the study population was 209 patients with DNA sequencing, quantitative gene-specific RNA expression, copy number variation (CNV), and surveillance data available. Extracted data were annotated and integrated. RESULTS: A PIK3CA, PTEN, or PIK3R1 mutant (-mu) was present in 83% of patients; 57% harbored more than 1 mutation without adversely impacting progression-free survival (PFS) (P = .10). PIK3CA CNV of at least 1.1 (CNV high [-H]) was detected in 26% and linked to TP53-mu and CIP2A expression (P < .001) but was not associated with PFS (P = .24). PIK3CA expression was significantly different between those with CIP2A-H and CIP2A low (-L) expression (the endogenous inhibitor of protein phosphatase 2A [PP2A]), when stratified by PIK3CA mutational status or by PIK3CA CNV-H and CNV-L (all P < .01). CIP2A-H or PPP2R1A-mu mitigates PP2A kinase dephosphorylation, and FBXW7-mu nullifies E3 ubiquitin ligase (E3UL) oncoprotein degradation. CIP2A-H and PPP2R1A-mu (PP2A impairment) and FBXW7-mu (E3UL impairment) were associated with compromised PFS (P < .001) and were prognostically discriminatory for PIK3CA-mu and PIK3CA CNV-H tumors (P < .001). Among documented recurrences, 84% were associated with impaired PP2A (75%) and/or E3UL (20%). CONCLUSION: PP2A and E3UL deficiencies are seminal biological drivers in EC independent of PIK3CA-mu, PTEN-mu, and PIK3R1-mu and PIK3CA CNV.

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.

Ovarian Cancer, Version 2.2020, NCCN Clinical Practice Guidelines in Oncology.

Epithelial ovarian cancer is the leading cause of death from gynecologic cancer in the United States and is the country's fifth most common cause of cancer mortality in women. A major challenge in treating ovarian cancer is that most patients have advanced disease at initial diagnosis. These NCCN Guidelines discuss cancers originating in the ovary, fallopian tube, or peritoneum, as these are all managed in a similar manner. Most of the recommendations are based on data from patients with the most common subtypes─high-grade serous and grade 2/3 endometrioid. The NCCN Guidelines also include recommendations specifically for patients with less common ovarian cancers, which in the guidelines include the following: carcinosarcoma, clear cell carcinoma, mucinous carcinoma, low-grade serous, grade 1 endometrioid, borderline epithelial, malignant sex cord-stromal, and malignant germ cell tumors. This manuscript focuses on certain aspects of primary treatment, including primary surgery, adjuvant therapy, and maintenance therapy options (including PARP inhibitors) after completion of first-line chemotherapy.

Ultrasound detection of endometrial cancer in women with postmenopausal bleeding: Systematic review and meta-analysis.

OBJECTIVE: To assess the performance of endometrial thickness (ET) cut-offs for detecting endometrial cancer (EC) in women with postmenopausal bleeding (PMB) and evaluate the clinical utility of additional ultrasound measures such as endometrial volume (EV), vascular flow index (VFI), vascularization index (VI), and uterine artery flow index (FI). METHODS: Clinicaltrials.gov and MEDLINE database via PubMed were queried for studies published between 1/1990 and 3/2016 using specific MeSH terms. Original, peer-reviewed cohort studies reporting EC outcomes and specific ultrasound findings by PMB status were included. RESULTS: Study design, country, clinical setting inclusion/exclusion criteria, aggregate study-level demographic and clinical data were extracted from 44 studies including 17,339 women with PMB and 1341 cases of EC (7.7%). In women with PMB and EC (n = 417), pooled mean ET was 16.4 mm (95% CI, 14.8-18.1 mm). In women with PMB without EC, pooled mean ET was 4.1 mm. 31 studies reported outcomes using different ET cut-off values ranging from 3 to 20 mm. Compared to ≥3 or 4 mm, a cutoff of ≥5 mm had similar sensitivity (96.2, 95%CI 92.3, 98.1) with improved specificity for EC (51.5, 95%CI 42.3-60.7), allowing to reduce the rate of invasive workup for PMB by 17%. EV, VI, VFI, and FI were significantly correlated with EC, but performance of specific cut-offs was not analyzed due to limited data. CONCLUSION: Among women with PMB mean ET is substantially higher in women with EC compared to those without EC. An ET cutoff of ≥5 mm shows an acceptable tradeoff between sensitivity and specificity for diagnosis of EC.

Invasive vulvar extramammary Paget's disease in the United States.

OBJECTIVE: To assess the incidence, treatment, and outcomes in patients with invasive vulvar extramammary Paget's disease (EMPD) in a national cohort of patients. METHODS: Patients from the Surveillance, Epidemiology and End Results (SEER) database with diagnoses of vulvar EMPD from 1992 to 2016 were included. Demographic, treatment, and outcome data were analyzed. RESULTS: A total of 1268 cases of invasive EMPD were identified. Of those, 69.6% had localized disease, 12.0% regional disease, 1.3% distant disease, and 17.1% were unstaged. The annual incidence of invasive vulvar EMPD was 0.36 per 100,000 person years: rates have increased >2-fold since 1992 (1992: 0.19 per 100,000 person years to 0.50 per 100,000 person years in 2016). Most patients underwent primary surgery (n = 1034; 81.5%). Five-year cancer specific survival (CSS) was 95.5% and was associated with stage. Compared to patients with localized disease, patients with distant metastases had dramatically worse CSS (HR: 85.8 (31.8-248) p < 0.0001). Synchronous cancers (diagnosed within one calendar year of EMPD diagnosis year) were observed in 35 cases (2.8%), and 195 patients (15.4%) developed a secondary malignancy (diagnosed >one year from year of EMPD diagnosis year). The most common synchronous breast, gastrointestinal tract, melanoma and the most common secondary cancers were breast, gastrointestinal tract and genitourinary tract. CONCLUSIONS: The incidence of invasive vulvar EMPD has increased over time. CSS is excellent for localized disease, but those with metastatic disease are in need of novel therapies. Approximately 15% will develop a secondary malignancy, indicating that patients with invasive vulvar EMPD should undergo site specific preventative health screens during recurrence surveillance.

Is hormonal therapy after risk-reducing salpingo-oophorectomy associated with an increased risk of malignancy in pathogenic variant carriers?

OBJECTIVES: This study aimed to assess the association between hormone replacement therapy and the incidence of subsequent malignancies in patients who underwent risk-reducing salpingo-oophorectomy and had mutations predisposing them to Müllerian cancers. METHODS: This Institutional Review Board-approved retrospective study was performed at five academic institutions. Women were included if they were age 18-51 years, had one or more confirmed germline highly penetrant pathogenic variants, and underwent risk-reducing salpingo-oophorectomy. Patients with a prior malignancy were excluded. Clinicodemographic data were collected by chart review. Patients with no documented contact for one year prior to study termination were called to confirm duration of hormone use and occurrence of secondary outcomes. Hormone replacement therapy included any combination of estrogen or progesterone. RESULTS: Data were analyzed for 159 women, of which 82 received hormone replacement therapy and 77 did not. In both groups an average of 6 years since risk reduction had passed. The patients treated with hormone replacement therapy did not have a higher risk of subsequent malignancy than those not treated with hormone replacement therapy (6 out of 82 vs. 7 out of 77, P = .68). Patients who received hormone replacement therapy were younger than those who did not receive hormone replacement therapy (39.0 vs. 43.9 years, P < .01) and were more likely to have undergone other risk reductive procedures including mastectomy and/or hysterectomy, though this difference was not statistically significant (69.5% vs. 55.8%, P = .07). CONCLUSIONS: In this multi-institution retrospective study of data from patients with high-risk variant carriers who underwent risk-reducing salpingo-oophorectomy, there was no statistically significant difference in the incidence of malignancy between women who did and did not receive hormone replacement therapy.

Combining copy number, methylation markers, and mutations as a panel for endometrial cancer detection via intravaginal tampon collection.

OBJECTIVE: We aimed to assess whether endometrial cancer (EC) can be detected in shed DNA collected with vaginal tampon by analyzing copy number, methylation markers, and mutations. METHODS: Tampons were collected prior to hysterectomy from 38 EC patients and 28 women with benign indications. Extracted tampon DNA underwent the following: 1) low-coverage whole genome sequencing (LC-WGS) to assess copy number, 2) pyrosequencing to measure percent promotor methylation of HOXA9, RASSF1, and CDH13 and 3) next generation sequencing (NGS) to identify mutations in 19 genes associated with EC identified through The Cancer Genome Atlas. Sensitivity and specificity for each test and test combinations were calculated. RESULTS: Methylation analysis yielded the highest specificities but lowest sensitivities (37-40% sensitivity; 100% specificity for HOXA9, RASSF1 and HTR1B) while mutation analysis had improved sensitivity (50% sensitivity; 83% specificity). Only one "false positive" result for copy number variants was identified among women with benign surgical indications, which was based on detection of copy number changes, and associated with a leiomyosarcoma that was only recognized at hysterectomy. Considering any of the 3 biomarker classes as a positive, resulted in a sensitivity of 92% and specificity of 86%. Mutation analysis did not add sensitivity to the combination of analysis of copy number and methylation. CONCLUSIONS: This study demonstrates a proof-of-principle for non-invasive yet precise detection of endometrial cancer. We propose that with improved biomarker testing, it may be possible to develop a clinically useful test for detecting EC.

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.

When to Operate, Hesitate and Reintegrate: Society of Gynecologic Oncology Surgical Considerations during the COVID-19 Pandemic.

The COVID-19 pandemic has challenged our ability to provide timely surgical care for our patients. In response, the U.S. Surgeon General, the American College of Srugeons, and other surgical professional societies recommended postponing elective surgical procedures and proceeding cautiously with cancer procedures that may require significant hospital resources and expose vulnerable patients to the virus. These challenges have particularly distressing for women with a gynecologic cancer diagnosis and their providers. Currently, circumstances vary greatly by region and by hospital, depending on COVID-19 prevalence, case mix, hospital type, and available resources. Therefore, COVID-19-related modifications to surgical practice guidelines must be individualized. Special consideration is necessary to evaluate the appropriateness of procedural interventions, recognizing the significant resources and personnel they require. Additionally, the pandemic may occur in waves, with patient demand for surgery ebbing and flowing accordingly. Hospitals, cancer centers and providers must prepare themselves to meet this demand. The purpose of this white paper is to highlight all phases of gynecologic cancer surgical care during the COVID-19 pandemic and to illustrate when it is best to operate, to hestitate, and reintegrate surgery. Triage and prioritization of surgical cases, preoperative COVID-19 testing, peri-operative safety principles, and preparations for the post-COVID-19 peak and surgical reintegration are reviewed.

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.

Preventing Ovarian Cancer in High-risk Women: One Surgery at a Time.

Eleven genes have been identified that increase the lifetime risk of developing ovarian cancer. The cumulative cancer risk of ovarian cancer varies with the mutation type and age. Ovarian cancer risk management options include surgical risk reduction with salpingo-oophorectomy and a newer step-wise approach with interval salpingectomy and delayed oophorectomy. Women should be counseled on the pros and cons of hysterectomy in the setting of reducing the risk of other cancers; eliminating the risk of endometrial cancer in Lynch Syndrome, potential risk of serous/serous-like endometrial cancer in BRCA1 carriers, and elimination of progestogen therapy that may increase breast cancer risk.

Quality improvement in gynecologic oncology: Current successes and future promise.

Quality improvement in healthcare has accelerated over the past two decades, including in gynecologic oncology. Improvements have been made on a practice, institution, system and national scale, and efforts have focused on improving safety, efficiency, and cost of care. Gynecologic oncology practitioners ought to engage in this work to improve patient outcomes, comply with federal regulation, and continue to meet required educational requirements of training programs. In gynecologic oncology there are already many examples of successful quality improvement initiatives that have resulted in improved patient care, including the implementation of enhanced recovery after surgery programs, reduction in blood transfusion, and increases in guideline adherent cancer care. Quality improvement methodology is born out of industrial engineering and includes Six Sigma and Lean; both are frameworks for implementing quality improvement as a process and can be adopted in healthcare settings to achieve the desired outcomes. Six Sigma is a system that aims to have a 99.9997% defect free process, and uses the DMAIC (Define-Measure-Analyze-Improve-Control) framework to guide stakeholders in their work. Lean is a concept aimed at reducing waste in process. Regardless of methodology used, the most important aspect of successful quality improvement is the use of change-management theory to achieve stakeholder buy-in and institutional participation. The physician champion is a key element to this. Finally, once a project has been completed, successfully or not, it is important to disseminate the experience. This will allow for adoption and replication in other institutions. It also can serve as a mechanism for academic recognition and advancement. Quality improvement is an important and growing field in medicine, and has an important role in the future of gynecologic oncology.

Beyond prophylaxis: Extended risk of venous thromboembolism following primary debulking surgery for ovarian cancer.

OBJECTIVE: To determine the incidence and risk factors for venous thromboembolism (VTE) within six months after primary debulking surgery (PDS) for epithelial ovarian cancer (EOC). METHODS: In a historical cohort, we estimated the cumulative incidence of clinically diagnosed VTE within 6 months among consecutive women who underwent PDS for EOC at a single institution from 1/1/2003 to 12/31/2011. We evaluated perioperative variables as potential risk factors of VTE within 6 months during the postoperative period using univariate and multivariable Cox proportional hazards models. RESULTS: Among 860 women without an immediate history (past 30 days) of a VTE, the cumulative incidence of VTE was 7.5% (95% CI, 5.7-9.3) by 30 days and 13.8% (95% CI, 11.4-16.2) by 6 months following surgery. Macroscopic residual disease (adjusted HR 1.99 [95% CI 1.35-2.94] vs microscopic), increasing estimated blood loss (1.25 [1.05-1.49] per doubling), longer hospital length of stay (3.00 [1.57-5.75]), and experiencing a cardiac event within 30 postoperative days (2.72 [1.55-4.80]) were independently associated with subsequent VTE within 6 months. In-hospital VTE prophylaxis included heterogeneous approaches; dual prophylaxis did not impact 30-day or 6-month VTE rates. CONCLUSIONS: VTE occurred in 1 in 7 women with EOC within 6 months of PDS-a substantial risk of VTE that extends into the adjuvant chemotherapy period. Novel prophylactic measures should be explored in these women at high risk for VTE.