Single-molecule epiallelic profiling of DNA derived from routinely collected Pap specimens for noninvasive detection of ovarian cancer.

Recent advances in molecular analyses of ovarian cancer have revealed a wealth of promising tumour-specific biomarkers, including protein, DNA mutations and methylation; however, reliably detecting such alterations at satisfactorily high sensitivity and specificity through low-cost methods remains challenging, especially in early-stage diseases. Here we present PapDREAM, a new approach that enables detection of rare, ovarian-cancer-specific aberrations of DNA methylation from routinely-collected cervical Pap specimens. The PapDREAM approach employs a microfluidic platform that performs highly parallelized digital high-resolution melt to analyze locus-specific DNA methylation patterns on a molecule-by-molecule basis at or near single CpG-site resolution at a fraction (< 1/10th) of the cost of next-generation sequencing techniques. We demonstrate the feasibility of the platform by assessing intermolecular heterogeneity of DNA methylation in a panel of methylation biomarker loci using DNA derived from Pap specimens obtained from a cohort of 43 women, including 18 cases with ovarian cancer and 25 cancer-free controls. PapDREAM leverages systematic multidimensional bioinformatic analyses of locus-specific methylation heterogeneity to improve upon Pap-specimen-based detection of ovarian cancer, demonstrating a clinical sensitivity of 50% at 99% specificity in detecting ovarian cancer cases with an area under the receiver operator curve of 0.90. We then establish a logistic regression model that could be used to identify high-risk patients for subsequent clinical follow-up and monitoring. The results of this study support the utility of PapDREAM as a simple, low-cost screening method with the potential to integrate with existing clinical workflows for early detection of ovarian cancer. KEY POINTS: We present a microfluidic platform for detection and analysis of rare, heterogeneously methylated DNA within Pap specimens towards detection of ovarian cancer. The platform achieves high sensitivity (fractions <0.00005%) at a suitably low cost (∼$25) for routine screening applications. Furthermore, it provides molecule-by-molecule quantitative analysis to facilitate further study on the effect of heterogeneous methylation on cancer development.

Lunchbox trial: A randomized phase III trial of cisplatin and irradiation followed by carboplatin and paclitaxel versus sandwich therapy of carboplatin and paclitaxel followed by irradiation then carboplatin and paclitaxel for advanced endometrial carcinoma.

BACKGROUND: The objective was to compare sequencing strategies for treatment of advanced endometrial carcinoma. METHODS: Patients were eligible if they had FIGO 2009 Stage III or IVA endometrial carcinoma or Stage I or II serous or clear cell endometrial carcinoma and positive cytology. Patients were randomized to: Cisplatin 50 mg/m2 IV Days 1 and 29 plus radiation followed by Carboplatin AUC 5 or 6 plus Paclitaxel 175 mg/m2 q 21 days for 4 cycles (chemoRT then chemo) vs. Carboplatin AUC 6 plus Paclitaxel 175 mg/m2 q 21 days for 3 cycles followed by radiation followed by Carboplatin AUC 5 or 6 plus Paclitaxel 175 mg/m2 q 21 days for 3 cycles (sandwich therapy). Futility analysis was planned. The primary objective was to determine if chemoRT then chemo improves recurrence-free survival (RFS) compared to sandwich therapy. RESULTS: Of the 48 patients enrolled at 8 sites, 42 patients were eligible for futility analysis, and the trial was closed early. The median follow-up was 30.9 months. The 3-year RFS was 85.7% (95% confidence interval [CI], 62 to 95) in the chemoRT then chemo arm and 73.4% (95% CI, 43 to 89) in the sandwich therapy group (p = 0.58). The 3-year overall survival (OS) was 88.4% (95% CI, 61 to 97) in the chemoRT then chemo arm and 80.9% (95% CI, 51 to 93) in the sandwich therapy group (p = 0.55). CONCLUSION: There was no observed significant difference between chemoRT then chemo compared to sandwich therapy in terms of RFS, OS, or adverse events, although the trial was underpowered and closed early due to low accrual.

Immune responses, therapeutic anti-tumor effects, and tolerability upon therapeutic HPV16/18 E6/E7 DNA vaccination via needle-free biojector.

IMPORTANCE: Respectively, HPV16 and HPV18 cause 50% and 20% of cervical cancer cases globally. Viral proteins E6 and E7 are obligate drivers of oncogenic transformation. We recently developed a candidate therapeutic DNA vaccine, pBI-11, that targets HPV16 and HPV18 E6 and E7. Single-site intramuscular delivery of pBI-11 via a needle elicited therapeutic anti-tumor effects in mice and is now being tested in high-risk human papillomavirus+ head and neck cancer patients (NCT05799144). Needle-free biojectors such as the Tropis device show promise due to ease of administration, high patient acceptability, and the possibility of improved delivery. For example, vaccination of patients with the ZyCoV-D DNA vaccine using the Tropis device is effective against COVID19, well tolerated, and licensed. Here we show that split-dose, multi-site administration and intradermal delivery via the Tropis biojector increase the delivery of pBI-11 DNA vaccine, enhance HPV antigen-specific CD8+ T-cell responses, and improve anti-tumor therapeutic effects, suggesting its translational potential to treat HPV16/18 infection and disease.

Postmenopausal mixed gestational trophoblastic neoplasia with complete response to immunotherapy - A case report.

•Mixed GTN.•GTN in a post-menopausal woman.•Treatment of GTN with immunotherapy.

Disparities in Diagnosis and Treatment of Cervical Adenocarcinoma Compared With Squamous Cell Carcinoma: An Analysis of the National Cancer Database, 2004-2017.

OBJECTIVES: The aim of the study are to compare trends in diagnosis and treatment of adenocarcinoma of the cervix (AC) to squamous cell carcinoma of the cervix (SCC) and to examine associations between stage at diagnosis and guideline-concordant treatment with race, age, and insurance type for AC and SCC. MATERIALS AND METHODS: We performed a retrospective cohort study of cervical AC ( n = 18,811) and SCC ( n = 68,421) from the 2004-2017 National Cancer Database. We used generalized linear models to evaluate trends in frequency of histologies and to evaluate associations between race, age, and insurance status with stage of diagnosis and receipt of National Comprehensive Cancer Network guideline-concordant treatment for AC and SCC. RESULTS: The proportion of AC relative to SCC increased from 19.4% (95% CI = 18.4-20.5) to 23.2% (95% CI = 22.2-24.2) from 2004 to 2017 ( p < .001). Compared with SCC, women with AC were younger, more likely to be White, and privately insured ( p < .001). Older women with AC were 44% less likely to be diagnosed with early-stage disease than younger women (adjusted relative risk = 0.56, 95% CI = 0.52-0.60); there was no significant difference for SCC. Black women with AC were 16% less likely to be diagnosed with early-stage disease (adjusted relative risk [aRR] = 0.84, 95% CI = 0.79-0.89) than White women. Women with public insurance were less likely to be diagnosed at an early stage for both AC (aRR = 0.81, 95% CI = 0.78-0.84) and SCC (aRR = 0.79, 95% CI = 0.77-0.81). Rates of guideline-concordant treatment were similar for AC and SCC, with minimal differences by age, race, and insurance. CONCLUSIONS: As the proportion of AC to SCC rises, important race and age-related disparities must be addressed to reduce unnecessary morbidity and death.

Gynecologic oncology HPV vaccination practice patterns: Investigating practice barriers, knowledge gaps and opportunities for maximizing cervical cancer prevention.

Objective: HPV vaccination is an important form of cancer prevention. Gynecologic oncologists have an opportunity to improve adult vaccination rates. We aimed to describe current HPV vaccination practices and barriers to vaccination reported by gynecologic oncologists. Methods: An online survey was developed, pilot tested and sent to U.S. members of the Society of Gynecologic Oncology. Results: Of the 226 respondents, most were female (73%), < 45 years old (64%) and practiced in urban (60%) and academic settings (69%). Ninety percent had recommended the HPV vaccine in the past year. Nearly half (47%) had facilitated vaccination by: administering the HPV vaccine in clinic (40%), stocking the vaccine (35%), or prescribing the vaccine (30%). Recommending the vaccine was associated with higher outpatient volume, practicing in the South vs. Northeast, and having higher levels of vaccine knowledge.Of the 90% who recommended the vaccine, 60% did not prescribe or know if they could prescribe the vaccine in their state. Prioritization of cancer treatment was the most commonly reported barrier to HPV vaccination (88%). Approximately half of providers reported other systems-level hinderances such as high cost of stocking the vaccine, clinic flow disruption, or uncertainty surrounding insurance coverage. Almost all recommenders offered the vaccine at HPV-related dysplasia (92%) or cancer (80%) visits, while only 24-50% offered it at non-HPV-related visits. Conclusions: These survey results identify patient, provider, and systems-level barriers that could be targeted to help increase adult HPV vaccination in gynecologic oncology clinics.

Understanding cervical cancer after the age of routine screening: Characteristics of cases, treatment, and survival in the United States.

OBJECTIVE: Given that cervical cancer incidence rates do not decline in women >65, there is generally limited screening, and these women have a poor prognosis, it is imperative to better understand this population. We aim to describe the characteristics, treatment, and survival of women >65 diagnosed with cervical cancer. METHODS: SEER-Medicare 2004-2013 data was used to describe 2274 patients >65 diagnosed with cervical cancer. Five-year cancer-specific survival was estimated using the Kaplan-Meier method. Multivariable Poisson and Cox regression analyses identified characteristics associated with treatment and mortality. RESULTS: The median age was 76.1 years, with nearly one-third of cases occurring in women >80 years. Most patients were non-Hispanic White (64.8%), had comorbidity scores ≥ 1 (53.9%) and squamous histology (66.3%). Most women were diagnosed at stage II or higher (62.7%), including nearly one-quarter at Stage IV (23.1%). Nearly 15% of patients were not treated (14.6%). Lack of treatment was associated with oldest age (>80), comorbidity scores ≥3, and stage IV disease. Five-year cancer-specific survival was 50%. Increasing age and stage at diagnosis were significantly associated with lower cancer-specific survival whereas treatment was strongly associated with increased survival. CONCLUSION: Most women >65 with cervical cancer are diagnosed with locally advanced or metastatic disease and many do not receive treatment. Survival is improved with early-stage diagnosis and treatment. These findings, coupled with the fact that women >65 constitute an increasing proportion of the population, highlight the need to re-evaluate screening and treatment practices in this population to detect cervical cancer at earlier stages and increase survival. NOVELTY AND IMPACT STATEMENT: In SEER-Medicare linked data from 2004 to 2013, most women >65 with cervical cancer were diagnosed with locally advanced or metastatic disease. Both receipt of treatment and survival decreased with increasing age. These findings, coupled with the fact that women aged >65 constitute an increasing proportion of the population, highlight the need to re-evaluate screening and treatment practices in older women to detect cervical cancer at earlier stages and increase survival.

Epidemiology of Cervical Adenocarcinoma and Squamous Cell Carcinoma Among Women Living With Human Immunodeficiency Virus Compared With the General Population in the United States.

BACKGROUND: Although cervical cancer risk overall is elevated among women living with human immunodeficiency virus (HIV; WLH), it is unclear whether risks are similarly elevated across histologic subtypes. METHODS: Data from the HIV/AIDS Cancer Match Study, a linkage of 12 US HIV and cancer registries during 1996 -2016, were used. Cervical cancers were categorized as adenocarcinoma (AC), squamous cell carcinoma (SCC), or other histologic subtype. Standardized incidence ratios compared rates of AC and SCC in WLH to those in general population. For WLH, risk factors for AC and SCC were evaluated using Poisson regression. Five-year survival was estimated by HIV status and histology. RESULTS: Overall, 62 615 cervical cancers were identified, including 609 in WLH. Compared with the general population, incidence of AC was 1.47 times higher (95% confidence interval [CI]: 1.03-2.05) and SCC was 3.62 times higher among WLH (95% CI: 3.31-3.94). Among WLH, there was no difference in AC rates by race/ethnicity or HIV transmission group, although SCC rates were lower among White women (vs Black) and higher among women who inject drugs (vs heterosexual transmission). Among WLH, 5-year overall survival was similar for AC (46.2%) and SCC (43.8%) but notably lower than for women not living with HIV. CONCLUSIONS: Among WLH, AC rates were modestly elevated, whereas SCC rates were greatly elevated compared with the general population. These findings suggest there may be differences in the impact of immunosuppression and HIV in the development of AC versus SCC, given their common etiology in human papillomavirus infection.

Treatment of vulvar and vaginal dysplasia: plasma energy ablation versus carbon dioxide laser ablation.

OBJECTIVE: Plasma energy ablation vaporizes tissues similar to carbon dioxide laser ablation, but is not hindered by the unique hazards and regulation of laser technology. We aimed to evaluate the complication rate and effectiveness of plasma versus laser ablation in the treatment of vulvovaginal high-grade squamous intra-epithelial lesions (HSIL). METHODS: We performed a retrospective cohort study of women treated with plasma or carbon dioxide laser ablation for histologically proven HSIL of the vulva or vagina from January 2014 to October 2019 at a single institution. Demographic factors, surgical characteristics, and complications were compared by ablation type using Fisher's exact tests. Recurrence-free survival was evaluated by ablation type using Kaplan-Meier curves, weighted log-rank tests, and Cox proportional hazards ratio estimates. RESULTS: Forty-two women were included; 50% underwent plasma and 50% underwent carbon dioxide laser ablation. Demographic factors were similar between the groups. 50% (n=21) were immunosuppressed, 45.2% (n=19) had prior vulvovaginal HSIL treatment, and 35.7% (n=15) were current smokers. Most women (n=25, 59.5%) were treated for vulvar HSIL, 38.1% (n=16) for vaginal HSIL. Complication rates did not differ by treatment: 9.5% (n=2) for laser ablation versus 4.8% (n=1) for plasma ablation (p=1.0). Over a median follow-up time of 29.3 months (IQR 11.0-45.0 months), recurrence rates were similar: 28.6% in the laser ablation group versus 33.3% in the plasma ablation group (weighted log rank p=0.43; 24-month HR 0.54, 95% CI 0.15 to 2.01). CONCLUSION: Plasma energy ablation of vulvovaginal HSIL has similar complication rates and recurrence risk to carbon dioxide laser ablation. This technique could be considered as an alternative treatment modality for vulvovaginal HSIL and warrants further investigation.

Beyond Sedlis-A novel histology-specific nomogram for predicting cervical cancer recurrence risk: An NRG/GOG ancillary analysis.

PURPOSE: The Sedlis criteria define risk factors for recurrence warranting post-hysterectomy radiation for early-stage cervical cancer; however, these factors were defined for squamous cell carcinoma (SCC) at an estimated recurrence risk of ≥30%. Our study evaluates and compares risk factors for recurrence for cervical SCC compared with adenocarcinoma (AC) and develops histology-specific nomograms to estimate risk of recurrence and guide adjuvant treatment. METHODS: We performed an ancillary analysis of GOG 49, 92, and 141, and included stage I patients who were surgically managed and received no neoadjuvant/adjuvant therapy. Multivariable Cox proportional hazards models were used to evaluate independent risk factors for recurrence by histology and to generate prognostic histology-specific nomograms for 3-year recurrence risk. RESULTS: We identified 715 patients with SCC and 105 with AC; 20% with SCC and 17% with AC recurred. For SCC, lymphvascular space invasion (LVSI: HR 1.58, CI 1.12-2.22), tumor size (TS ≥4 cm: HR 2.67, CI 1.67-4.29), and depth of invasion (DOI; middle 1/3, HR 4.31, CI 1.81-10.26; deep 1/3, HR 7.05, CI 2.99-16.64) were associated with recurrence. For AC, only TS ≥4 cm, was associated with recurrence (HR 4.69, CI 1.25-17.63). For both histologies, there was an interaction effect between TS and LVSI. For those with SCC, DOI was most associated with recurrence (16% risk); for AC, TS conferred a 15% risk with negative LVSI versus a 25% risk with positive LVSI. CONCLUSIONS: Current treatment standards are based on the Sedlis criteria, specifically derived from data on SCC. However, risk factors for recurrence differ for squamous cell and adenocarcinoma of the cervix. Histology-specific nomograms accurately and linearly represent risk of recurrence for both SCC and AC tumors and may provide a more contemporary and tailored tool for clinicians to base adjuvant treatment recommendations to their patients with cervical cancer.

Survey of trends in authorship assignment in gynecologic oncology: Keeping score and playing fair.

Authorship confers credit to those responsible for a publication. In 1985, the International Committee of Medical Journal Editors criteria were founded to standardize authorship assignment. We sought to investigate practices and values in authorship assignment in Society of Gynecologic Oncology (SGO) members. An anonymous online survey was distributed to SGO members from 09/2018-10/2018. Three multivariable logistic regression models were fit to predict ICJME authorship acceptance, assignment and denial. Of 1111 members surveyed, 266 responses were received (23.9%); 30.6% reported prior authorship assignment that did not meet ICMJE criteria, and 18.8% (n = 50) reported a history of accepting authorship not meeting ICJME criteria. Reasons for non-adherence included: inclusion of the author's patients in the study (59.3%), resumé building (45.7%), and networking for career advancement (22.2%). The majority responded that ICJME criteria were generalizable (91.3%), helpful (83.8%), and considered non-adherence as scientific misconduct (66.0%). On multivariable analysis, practice duration of 5-20 years (HR 0.40, 95% CI 0.16, 0.99, p < 0.05) or > 20 years (HR 0.22, 95% CI 0.08, 0.59, p < 0.05) were significant predictors for adherence with ICMJE authorship assignment compared to fellows and those in practice < 5 years. Similarly, practice duration of 5-20 years (HR 10.0, 95% CI 2.0, 49.2, p < 0.05) or > 20 years (HR 25.9, 95% CI 1.06, 3.9, p < 0.05) were significant predictors for denial of authorship assignment compared to fellows and those in practice < 5 years. While the majority of respondents report that ICJME criteria are helpful, adherence to these criteria is a concern, especially in fellows and early-career faculty.

Phase II study of intraperitoneal submicron particle paclitaxel (SPP) plus IV carboplatin and paclitaxel in patients with epithelial ovarian cancersurgery.

Submicron particles (~800 nm) of paclitaxel (SPP) contain 1-2 billion molecules of pure drug that release tumoricidal levels of paclitaxel over many weeks. This study compared two dose-levels of SPP instilled into the peritoneal cavity (IP) in 200 ml of saline post-cytoreductive surgery. Eligible patients with primary (n = 6) or recurrent (n = 4) epithelial ovarian cancer who underwent complete cytoreductive surgery were enrolled to receive a single instillation of IP SPP followed by standard IV carboplatin and paclitaxel. Endpoints were PFS and evaluation of treatment emergent adverse events. Clinical response was determined by symptoms, physical exams, CT scans, and serum CA-125 measurements. Of the 24 subjects screened, 10 were enrolled and received treatment: seven patients received 100 mg/m2 and three received 200 mg/m2. Seven subjects completed the 12-month follow-up period. Six patients were evaluable due to one subject who had unevaluable scans throughout the follow-up period and was thus excluded from PFS determination. Upon completion of planned chemotherapy post-SPP instillation, the PFS at 6 months was 66% (4/6) and at 12-months 66% (4/6) using RECIST 1.1. One subject had a complete response at the end of IV treatment but died (unrelated to study treatment) before PFS evaluation. There was one case of incision dehiscence and one case of vaginal cuff leakage after surgery. This pilot study supports further evaluation of IP SPP to treat peritoneal carcinomas.

Basic social resource needs screening in the gynecologic oncology clinic: a quality improvement initiative.

BACKGROUND: Social determinants of health are known to contribute to disparities in health outcomes. Routine screening for basic social needs is not a part of standard care; however, the association of those needs with increased healthcare utilization and poor compliance with guideline-directed care is well established. OBJECTIVE: In this study, we aimed to assess the prevalence of basic social resource needs identified through a quality improvement initiative in a gynecologic oncology outpatient clinic. In addition, we aimed to identify clinical and demographic factors associated with having basic social resource needs. STUDY DESIGN: We performed a prospective cohort study of women presenting to a gynecologic oncology clinic at an urban academic institution who were screened for basic social resource needs as part of a quality improvement initiative from July 2017 to May 2018. The following 8 domains of resource needs were assessed: food insecurity, housing insecurity, utility needs, financial strain, transportation, childcare, household items, and difficulty reading hospital materials. Women with needs were referred to resources to address those needs. Demographic and clinical information were collected for each patient. The prevalence of needs and successful follow-up interventions were calculated. Patient factors independently associated with having at least 1 basic social resource need were identified using multivariable Poisson regression. RESULTS: A total of 752 women were screened in the study period, of whom 274 (36%) reported 1 or more basic social resource need, with a median of 1 (range, 1-7) need. Financial strain was the most commonly reported need (171 of 752, 23%), followed by transportation (119 of 752, 16%), difficulty reading hospital materials (54 of 752, 7%), housing insecurity (31 of 752, 4%), food insecurity (28 of 752, 4%), household items (22 of 752, 3%), childcare (15 of 752, 2%), and utility needs (13 of 752, 2%). On multivariable analysis, independent factors associated with having at least 1 basic social resource need were being single, divorced or widowed, nonwhite race, current smoker, nonprivate insurance, and a history of anxiety or depression. A total of 36 of 274 (13%) women who screened positive requested assistance and were referred to resources to address those needs. Of the 36 women, 25 (69%) successfully accessed a resource or felt equipped to address their needs, 9 (25%) could not be reached despite repeated attempts, and 2 (6%) declined assistance. CONCLUSION: Basic social resource needs are prevalent in women presenting to an urban academic gynecologic oncology clinic and can be identified and addressed through routine screening. To help mitigate ongoing disparities in this population, screening for and addressing basic social resource needs should be incorporated into routine comprehensive care in gynecologic oncology clinics.

Adjuvant Human Papillomavirus Vaccine to Reduce Recurrent Cervical Dysplasia in Unvaccinated Women: A Systematic Review and Meta-analysis.

OBJECTIVE: To perform a systematic review and meta-analysis evaluating the efficacy of adjuvant human papillomavirus (HPV) vaccination in preventing recurrent cervical intraepithelial neoplasia (CIN) 2 or greater after surgical excision. DATA SOURCES: Electronic databases (Cochrane, PubMed, EMBASE, MEDLINE, Scopus, and ClinicalTrials.gov) were searched for studies comparing surgical excision alone to surgical excision with adjuvant HPV vaccination for CIN 2 or greater. Studies published from January 1990 to January 2019 were included. METHODS: A total of 5,901 studies were reviewed. The primary outcomes evaluated included: recurrence of CIN 2 or greater, CIN 1 or greater, and HPV 16,18 associated CIN within 6-48 months. We used Covidence software to assist with screening, and meta-analysis was performed using Review Manager. TABULATION, INTEGRATION, AND RESULTS: Six studies met inclusion criteria and were included in the final analysis. In total 2,984 women were included; 1,360 (45.6%) received adjuvant HPV vaccination after surgical excision, and 1,624 (54.4%) received either placebo or surgical management alone for CIN 2 or greater. Recurrence of CIN 2 or greater occurred within 6-48 months in 115 women (3.9%) overall; however, recurrence was significantly lower for vaccinated women: 26 of 1,360 women (1.9%) vs 89 of 1,624 unvaccinated women (5.9%) (relative risk [RR] 0.36 95% CI 0.23-0.55). The risk of CIN 1 or greater was also significantly lower with adjuvant HPV vaccination, occurring in 86 of 1,360 vaccinated women (6.3%) vs 157 of 1,624 unvaccinated women (9.7%) (RR 0.67 95% CI 0.52-0.85). Thirty-five women developed recurrent CIN 2 or greater lesions specific to HPV 16,18; nine received adjuvant vaccination (0.9%) vs 26 who were unvaccinated (2.0%) (RR 0.41 95% CI 0.20-0.85). CONCLUSION: Adjuvant HPV vaccination in the setting of surgical excision for CIN 2 or greater is associated with a reduced risk of recurrent cervical dysplasia overall and a reduction in the risk of recurrent lesions caused by the most oncogenic strains (HPV 16,18). Human papillomavirus vaccination should therefore be considered for adjuvant treatment in patients undergoing surgical excision for CIN 2 or greater. SYSTEMATIC REVIEW REGISTRATION: PROSPERO, CRD42019123786.

A first-in-human proof-of-concept trial of intravaginal artesunate to treat cervical intraepithelial neoplasia 2/3 (CIN2/3).

OBJECTIVE: Most treatment options for cervical intraepithelial neoplasia 2/3 (CIN2/3) are either excisional or ablative, and require sequential visits to health care providers. Artesunate, a compound that is WHO-approved for treatment of acute malaria, also has cytotoxic effect on squamous cells transformed by HPV. We conducted a first-in-human Phase I dose-escalation study to assess the safety and efficacy of self-administered artesunate vaginal inserts in biopsy-confirmed CIN2/3. METHODS: Safety analyses were based on patients who received at least one dose, and were assessed by the severity, frequency, and duration of reported adverse events. Tolerability was assessed as the percentage of subjects able to complete their designated dosing regimen. Modified intention-to-treat analyses for efficacy and viral clearance were based on patients who received at least one dose for whom endpoint data were available. Efficacy was defined as histologic regression to CIN1 or less. Viral clearance was defined as absence of HPV genotoype (s) detected at baseline. RESULTS: A total of 28 patients received 1, 2, or 3 five-day treatment cycles at study weeks 0, 2, and 4, respectively, prior to a planned, standard-of-care resection at study week 15. Reported adverse events were mild, and self-limited. In the modified intention-to-treat analysis, histologic regression was observed in 19/28 (67.9%) subjects. Clearance of HPV genotypes detected at baseline occurred in 9 of the 19 (47.4%) subjects whose lesions underwent histologic regression. CONCLUSIONS: Self-administered vaginal artesunate inserts were safe and well-tolerated, at clinically effective doses to treat CIN2/3. These findings support proceeding with Phase II clinical studies.

The impact of an enhanced recovery after minimally invasive surgery program on opioid use in gynecologic oncology patients undergoing hysterectomy.

OBJECTIVES: To evaluate the effects of an enhanced recovery after minimally invasive surgery (MIS-ERAS) protocol on opioid requirements and post-operative pain in patients undergoing minimally invasive hysterectomy on a gynecologic oncology service. METHODS: For this retrospective study, opioid use (oral morphine equivalents (OME)) and post-operative pain scores were compared between patients undergoing minimally invasive hysterectomy pre and post MIS-ERAS protocol implementation. Patients with chronic opioid use or chronic pain were excluded. Opioid use and pain scores were compared between groups using Wilcoxon Rank Sum, Student's t-test, and multiple linear regression. Compliance and factors associated with opioid use and pain scores were assessed. RESULTS: The MIS-ERAS cohort (n = 127) was compared to the historical cohort (n = 99) with no differences in patient demographic, clinical or surgical characteristics observed between groups. Median intra-operative and inpatient post-operative opioid use were lower among the MIS-ERAS cohort (12.0 vs 32.0 OME, p < .0001 and 20.0 vs 35.0 OME, p = .02, respectively). Pain scores among MIS-ERAS patients were also lower (mean 3.6 vs 4.1, p = .03). After controlling for age, BMI, operative time, length of stay, cancer diagnosis, and surgical approach, the MIS-ERAS cohort used 10.43 fewer OME intra-operatively (p < .001), 10.97 fewer OME post-operatively (p = .019) and reported pain scores 0.56 points lower than historical controls (p = .013). Compliance was ≥81% for multimodal analgesia elements and ≥75% overall. CONCLUSIONS: Enhanced recovery after minimally invasive surgery protocol implementation is an effective means to reduce opioid use, both in the intra-operative and post-operative phases of care, among gynecologic oncology patients undergoing minimally invasive hysterectomy.

The addition of metformin to progestin therapy in the fertility-sparing treatment of women with atypical hyperplasia/endometrial intraepithelial neoplasia or endometrial cancer: Little impact on response and low live-birth rates.

OBJECTIVE: Our objectives were 1) to compare the efficacy of progestin therapy combined with metformin (Prog-Met) to Prog alone as primary fertility sparing treatment in women with atypical hyperplasia/endometrial intraepithelial neoplasia (AH/EIN) or early-stage endometrioid carcinoma (EC), and 2) to analyze the proportion of women achieving live birth following treatment. METHODS: A retrospective cohort study of all reproductive-aged women with AH/IN or EC treated with Prog ± Met from 1999-2018 was conducted. Complete response (CR) was assessed and Kaplan-Meier analysis used to calculate time to CR. Comparison of potential response predictors was performed with multivariable Cox regression models. RESULTS: Ninety-two women met criteria; 59% (n = 54) were treated for AH/EIN and 41% (n = 38) for EC. Their median age, body mass index, and follow up time was 35 years, 37.7 kg/m2, and 28.4 months, respectively. Fifty-eight women (63%) received Prog and 34 (37%) received Prog-Met. Overall, 79% (n = 73) of subjects responded to treatment with a CR of 69% (n = 63). There was no difference in CR (p = 0.90) or time to CR (p = 0.31) between the treatment cohorts. Overall, 22% experienced a disease recurrence. On multivariable analysis, EC histology was the only covariate associated with a decreased Prog response (HR 0.48; p = 0.007). Only 17% of the cohort achieved a live-birth pregnancy, the majority of which required assisted reproductive technologies (81%) and occurred in the Prog treatment group. CONCLUSIONS: Our study does not support the use of Prog-Met therapy for treatment of AH/EIN or EC. Additionally, fewer than 20% of women achieved a live-birth pregnancy during the study period, with most requiring ART.

Laparoscopic surgical access in morbidly obese women undergoing endometrial cancer surgery: Repurposing the left upper quadrant approach.

OBJECTIVE: The study purpose was to report the outcomes of patients undergoing endometrial cancer surgical staging with laparoscopic abdominal access entry using a left upper quadrant (LUQ) access technique. METHODS: This was a retrospective cohort study conducted from 1 January 2013 to 1 January 2018. The setting was an academic, single institution gynecologic oncology service with a high volume of minimally invasive surgery (MIS). The patient cohort included obese (defined as BMI > 30 kg/m2) or morbidly obese (BMI > 40 kg/m2) women undergoing MIS for endometrial cancer staging. All patients underwent laparoscopic abdominal access via a 5-mm or 10-mm optical trocar system using a LUQ technique. RESULTS: In total, 317 patients were included with a median age of 54 years (range, 24-79) and median BMI 42.5 kg/m2 (range, 32-70); 60 % morbidly obese. Successful LUQ access was achieved in 98.1 %. Of those with a failed LUQ approach, two had undergone previous LUQ surgery and 4 had ≥1 previous midline vertical incisions. There was one LUQ trocar-related visceral injury (0.3 %) and no vascular injuries during the study period. CONCLUSION: A LUQ abdominal technique is a safe and reliable method of laparoscopic access in morbidly obese women undergoing MIS for endometrial cancer staging. This may be the preferred method of laparoscopic access for women with a panniculus or central adiposity, given the caudal displacement of the umbilicus and poor correlation with intraperitoneal anatomic landmarks in this setting.

Lower Genital Tract Dysplasia in Female Solid Organ Transplant Recipients.

OBJECTIVE: To examine the incidence of lower genital tract dysplasia in women after solid organ transplantation, to evaluate risk factors associated with development of dysplasia, and to assess the timeline of disease development. METHODS: This was a retrospective study of female patients who underwent solid organ transplantation at a large-volume tertiary care center between 2000 and 2015. Demographic and clinicopathologic factors were extracted from electronic medical records. Cumulative incidence of lower genital tract dysplasia was calculated, and univariate and multivariable logistic regression were performed to identify risk factors for the development of dysplasia. RESULTS: Among 394 female solid organ transplant recipients, the median age was 41 years (interquartile range 29-53). Forty-seven (11.9%; 95% CI 8.8-15.9%) women developed lower genital tract dysplasia over a median follow-up of 7.8 years (interquartile range 4.6-12.9). Thirty-eight (9.6%) developed cervical intraepithelial neoplasia (CIN), with 14 (3.6%) diagnosed with CIN 2 or worse (one was cervical carcinoma). Nineteen (4.8%) developed noncervical lower genital tract dysplasia, including vulvar, vaginal, or anal dysplasia, with 13 (3.3%) diagnosed with high-grade dysplasia or worse (five were lower genital tract carcinoma [three anal, one vulvar, and one vaginal]). Ten (2.5%) developed both cervical and noncervical lower genital tract dysplasia. Black race was significantly associated with developing dysplasia (odds ratio [OR] 2.86; 95% CI 1.33-6.13) as was hydroxychloroquine use (OR 5.95; 95% CI 1.96-18.09). High-grade cervical dysplasia was diagnosed at a median interval of 3.18 years after transplant; noncervical high-grade lower genital tract dysplasia was diagnosed at a median interval of 3.94 years. CONCLUSIONS: One in eight transplant recipients developed lower genital tract dysplasia and approximately half were high-grade dysplasia or cancer. Black race and hydroxychloroquine use were associated with an increased risk of dysplasia. Yearly cervical screening and comprehensive lower genital examination beyond the cervix is indicated in this population.