Optimizing timing of adolescent vaccines: Impact of initiating HPV vaccination before Tdap or meningococcal vaccination on timely completion of the HPV vaccine series.

To explore the impact on timely series completion of initiating the HPV vaccine series prior to other vaccines in the adolescent platform (Tdap or meningococcal vacccines), we created a cohort of children aged 9 in 2015 who were continuously enrolled through the age of 13 (2019) from a national administrative database of employee-sponsored insurance in the United States (MarketScan). Logistic regressions were used to predict the odds of HPV vaccine series completion among those who started the series prior to, concurrent with, or after receiving Tdap or meningococcal vaccination. The cohort included 100,857 eligible children. Compared with adolescents who received their HPV and Tdap or HPV and meningococcal vaccinations concurrently, those who received HPV prior to other vaccines had higher completion (aOR = 1.38 for Tdap, aOR 1.62 for meningococcal), while those who received their HPV vaccination after other vaccines had lower odds of HPV vaccine series completion (aOR = 0.68 for Tdap, aOR = 0.62 for meningococcal). Other factors associated with series completion included female sex, residing in an urban (vs. rural) area, residing in the Northeast, and receiving primary care from a pediatrician (vs. family medicine physician). These data indicate that beginning the HPV vaccine series prior to the adolescent platform may improve on-time series completion.

Underscreening, overscreening, and guideline-adherent cervical cancer screening in a national cohort.

OBJECTIVE: To explore rates of under- and overscreening for cervical cancer among a national cohort. METHODS: The MarketScan database, a national administrative database of employee-sponsored insurance, was queried for elements relevant to cervical cancer screening among women aged 21-65 with 6 years of continuous enrollment (2015-2019). Average-risk women were defined as those without high-risk medical conditions or abnormal screening histories, and without evidence of hysterectomy with removal of the cervix for benign indications. Average-risk women were considered adequately screened if they had Pap tests alone at 2.5-3.5 year intervals, or HPV tests or co-tests at 4.5-5.5 year intervals. Logistic regressions were used to predict the odds of receiving guideline-adherent screening, underscreening, and overscreening. RESULTS: Among 1,872,809 eligible patients, 1,471,063 (78.5%) qualified for routine screening. Of these, only 18.1% received guideline-adherent screening, and 25.4% were unscreened during the 6-year period. Younger women (aged 21-39) were more likely to be overscreened [OR 1.46]. Older women (aged 50-64) were more likely to be underscreened or unscreened during the study period [OR 2.54]. Guideline-adherent screening was highest with HPV testing alone (80%) followed by co-testing (44%), and lowest with cytology alone (15%). A total of 329,062 women in this general population sample (18%) met high-risk criteria that required increased frequency of screening. CONCLUSIONS: High rates of both underscreening and overscreening indicate a need for additional strategies to improve guideline-adherent care. CLINICAL TRIAL REGISTRATION: N/A.

A Translational Model to Improve Early Detection of Epithelial Ovarian Cancers.

Neural network analyses of circulating miRNAs have shown potential as non-invasive screening tests for ovarian cancer. A clinically useful test would detect occult disease when complete cytoreduction is most feasible. Here we used murine xenografts to sensitize a neural network model to detect low volume disease and applied the model to sera from 75 early-stage ovarian cancer cases age-matched to 200 benign adnexal masses or healthy controls. The 14-miRNA model efficiently discriminated tumor bearing animals from controls with 100% sensitivity down to tumor inoculums of 50,000 cells. Among early-stage patient samples, the model performed well with 73% sensitivity at 91% specificity. Applied to a population with 1% disease prevalence, we hypothesize the model would detect most early-stage ovarian cancers while maintaining a negative predictive value of 99.97% (95% CI 99.95%-99.98%). Overall, this supports the concept that miRNAs may be useful as screening markers for early-stage disease.

Racial disparities in non-recommendation of adjuvant chemotherapy in stage II-III ovarian cancer.

OBJECTIVES: To identify patient factors associated with not receiving a recommendation for adjuvant chemotherapy after primary surgery for ovarian cancer. METHODS: This retrospective cohort study used the National Cancer Database (NCDB) data from 2004 to 2015 to identify patients with stage II-III ovarian cancer who underwent primary surgery. Multivariate logistic regression analyses evaluated factors associated with notation in the NCDB that "chemotherapy was not recommended/administered because it was contraindicated due to patient risk factors (i.e., comorbid conditions, advanced age)." Survival data were assessed via Kaplan-Meier analyses. RESULTS: Of the 48,245 patients who met the inclusion criteria, 522 (1.08%) did not receive adjuvant chemotherapy because it was determined to be contraindicated. In multivariate analyses, independent predictors for not receiving a recommendation for adjuvant chemotherapy were age ≥ 70 years old (adjusted odds ratio, aOR = 2.43, p < 0.0001), non-zero Charlson-Deyo comorbidity scores (score 1, aOR = 1.41, p = 0.002; score ≥ 2, aOR = 2.57, p < 0.0001), and Black race (aOR = 2.12, p < 0.0001). For Black patients, recommendation against adjuvant chemotherapy occurred at a younger median age (64.5 years vs. 72 years) and was associated with lower 5-year survival (25.9% vs. 40.3%, p < 0.0001). CONCLUSIONS: Patients with ovarian cancer who underwent surgery but did not receive chemotherapy "because it was contraindicated due to patient risk factors" were older and had higher comorbidity scores. Even after controlling for these differences, Black patients were disproportionately not recommended for chemotherapy, which was associated with worse survival. Determining eligibility for adjuvant chemotherapy requires an individualized approach, and the possible influence of racial bias on risk estimation should be further investigated.

Voltage-Gated Sodium Channels as Potential Biomarkers and Therapeutic Targets for Epithelial Ovarian Cancer.

Abnormal ion channel expression distinguishes several types of carcinoma. Here, we explore the relationship between voltage-gated sodium channels (VGSC) and epithelial ovarian cancer (EOC). We find that EOC cell lines express most VGSC, but at lower levels than fallopian tube secretory epithelial cells (the cells of origin for most EOC) or control fibroblasts. Among patient tumor samples, lower SCN8A expression was associated with improved overall survival (OS) (median 111 vs. 52 months; HR 2.04 95% CI: 1.21-3.44; p = 0.007), while lower SCN1B expression was associated with poorer OS (median 45 vs. 56 months; HR 0.69 95% CI 0.54-0.87; p = 0.002). VGSC blockade using either anti-epileptic drugs or local anesthetics (LA) decreased the proliferation of cancer cells. LA increased cell line sensitivity to platinum and taxane chemotherapies. While lidocaine had similar additive effects with chemotherapy among EOC cells and fibroblasts, bupivacaine showed a more pronounced impact on EOC than fibroblasts when combined with either carboplatin (ΔAUC -37% vs. -16%, p = 0.003) or paclitaxel (ΔAUC -37% vs. -22%, p = 0.02). Together, these data suggest VGSC are prognostic biomarkers in EOC and may inform new targets for therapy.

Clinical characteristics and outcomes after bowel surgery and ostomy formation at the time of debulking surgery for advanced-stage epithelial ovarian carcinoma.

OBJECTIVE: There are limited data on clinical outcomes of patients with advanced-stage epithelial ovarian cancer who require ostomy formation at the time of either primary cytoreductive surgery or interval cytoreductive surgery. The objective of this study was to evaluate patients undergoing bowel surgery and ostomy formation after primary or interval surgery. METHODS: Patients with International Federation of Gynecology and Obstetrics (FIGO) stage IIIC-IV epithelial ovarian cancer who underwent cytoreductive surgery between January 2010 and December 2014 were identified retrospectively. Patients with non-epithelial histology, low-grade serous histology or incomplete medical records were excluded. Demographic and clinical data were collected and analyzed. Age, stage, co-morbidity index, pre-operative CA125, pre-operative albumin, and Aletti surgical complexity score were included in a multivariable logistic regression model to assess independent associations with ostomy formation. RESULTS: A total of 554 patients were included in the study. Of these, 261 (47%) underwent primary cytoreduction and 293 (53%) underwent interval cytoreduction. Patients undergoing primary surgery were more likely to undergo bowel resection, compared with interval surgery patients (37.2% vs 14%, p<0.001). Of the 139 (25.1%) patients who underwent bowel surgery, 25 (18%) underwent ostomy formation (11 ileostomies and 14 colostomies). Rates of ostomy formation were similar between the groups (6.1% primary vs 3.1% interval, p=0.10). Patients undergoing ostomy formation were more likely to have longer mean operative time (335 vs 229 min, p<0.001) and undergo small and large bowel resections at the time of cytoreductive surgery (44% vs 14%, p<0.001). Multivariate analysis revealed that a high surgical complexity score was associated with ostomy formation. Of the patients who underwent ostomy formation, 13 (43.3%) underwent stoma reversal including 11 ileostomies and two colostomies. Median time to ostomy reversal was 7 months. CONCLUSION: Bowel surgery is more common among patients undergoing primary surgery as compared with interval surgery, but this does not result in an increased risk of ostomy formation.

Liquid biopsy of HPV DNA in cervical cancer.

BACKGROUND: A blood test to serve as a tumor marker for cervical cancer would be useful to clinicians to guide treatment and provide an early signal for recurrence. The development of droplet digital PCR has enabled the detection of HPV DNA in patient serum, providing a potential marker for cervical cancer. OBJECTIVES: To report on a blood-based test for HPV-specific E7 and L1 genes, which may serve as a tumor marker to guide treatment and detect early recurrence in cervical cancer. STUDY DESIGN: Pre-treatment plasma samples were investigated from 138 Hong Kong Chinese women with primary invasive squamous cell carcinoma and adenocarcinoma of the cervix with tumor samples expressing HPV16 or HPV18. Two genes specific to the human papillomavirus, E7 and L1, were measured in cell free DNA (cfDNA) extracted from plasma using droplet digital PCR. Analysis of detectable E7 and L1 levels was performed to investigate the potential of liquid biopsy of E7 and L1 as a clinically useful molecular biomarker. RESULTS: The majority of patients had HPV16 (71.7%), squamous cell carcinoma (78.3%) and stage IB-II disease (82.6%). HPV E7 and L1 sequences were detected in plasma cfDNA from 61.6% (85/138) of patients. Patients with high viral load (defined as ≥20 E7 or L1 copies per 20 µL reaction volume) had increased risk of recurrence and death at 5 years on univariate analysis but not multivariate analysis. CONCLUSIONS: HPV DNA can be quantitatively detected with the use of cfDNA. This has the potential to provide a clinically useful tumor marker for patients with cervical cancer that can aid in post-treatment surveillance and estimating the risk of disease relapse.

Gender and the Balance of Parenting and Professional Life among Gynecology Subspecialists.

STUDY OBJECTIVE: To compare the parenting and career patterns of female and male gynecology subspecialists. DESIGN: Cross-sectional survey study (Canadian Task Force classification II-3). SETTING: Survey administered electronically in February 2015 to physician members of the Society of Gynecologic Oncology, the American Society for Reproductive Medicine, and the American Urogynecologic Society. PARTICIPANTS: All physician members of the 3 national gynecology subspecialty organizations listed above. MEASUREMENTS AND MAIN RESULTS: There were 75 questions in 4 domains: demographics, mentoring issues, work-life balance, and caregiving responsibilities. Data were analyzed for survey sampling weights. Six hundred seventy-seven physicians completed the survey, 62% of whom were women (n = 420; 20.2% response rate). Sixty-four percent were aged 36 to 55 years. Eighty-two percent of respondents had at least 1 child, and men had more children than women (42% of men had 3 or more children compared with 20% of women, p <.0001). Thirty-seven percent of women reported that career plans affected the decision to become a parent somewhat or very much compared with 23% of men (p = .0006). Eighty-three percent of women believed career affected the timing of becoming a parent somewhat or very much compared with 48% of men (p <.0001). In addition, 76% of female physicians perceived that having children decreased their academic productivity compared with 54% of male physicians (p <.0001). Most men and women believed having children had no effect or increased their clinical performance (76% and 65%, respectively), but this was significantly lower in women (p = .01). CONCLUSION: Female gynecology subspecialists perceive that their career impacted decisions on parenting more frequently than their male counterparts. They were also more likely than men to report that having children had a negative impact on academic and, to a lesser extent, clinical performance. Increased support for combining childbirth and parenting with training and academic careers is needed.

While women await surgery for type I endometrial cancer, depot medroxyprogesterone acetate reduces tumor glandular cellularity.

BACKGROUND: Multiple population-level studies have demonstrated an adverse effect of long wait times to surgery on survival for women with endometrial cancer. Other retrospective and nonrandomized prospective studies have shown that preoperative administration of depot medroxyprogesterone acetate decreases tumor glandular cellularity, which may be a surrogate marker for clinically meaningful tumor response. OBJECTIVE: We sought to determine whether preoperative injection with depot medroxyprogesterone acetate decreases tumor glandular cellularity when compared to placebo injection in women awaiting hysterectomy for endometrial intraepithelial neoplasia or type I endometrial cancer, and to determine whether depot medroxyprogesterone acetate injection affects quality of life while waiting for surgery. STUDY DESIGN: This was a double-blind, randomized controlled trial of 400-mg depot medroxyprogesterone acetate injection or 0.9% saline injection at the preoperative visit. Patients with recent use of progesterone analogs were excluded. A sample size of 76 patients (38 per arm) was calculated to detect a 20% difference in decreased glandular cellularity between arms. Pathologic characteristics including the primary outcome, tumor glandular cellularity, from patients' diagnostic biopsies were reviewed by 2 dedicated gynecologic pathologists and compared to posttreatment hysterectomy specimens. On the night prior to surgery, patients completed the Functional Assessment of Cancer Therapy-Endometrial Survey (Version 4) to report quality of life while waiting for surgery. In comparing characteristics between the intervention and control groups, t tests were used for continuous variables, and χ2 or Fisher exact tests were used where appropriate for categorical data. RESULTS: From March 2015 through March 2016, 148 women were screened and 76 patients were enrolled. In all, 38 patients were randomized to and received depot medroxyprogesterone acetate injection and 38 were randomized to and received placebo injection. Demographics were similar between groups. Patients who received depot medroxyprogesterone acetate injection experienced a larger decrease in tumor glandular cellularity (mean change -64 [-31.8%] vs -14 [-5.5%] cells per quarter high-powered field in depot medroxyprogesterone acetate vs placebo groups, P = .002). This effect was most pronounced in women waiting ≥3 weeks for surgery. Several additional histologic and immunohistochemical markers of tumor differentiation and decreased cell proliferation were more pronounced in the depot medroxyprogesterone acetate group than in the placebo group. There were no significant differences in quality of life between groups on the Functional Assessment of Cancer Therapy-Endometrial Survey. Only 5.3% of patients who were approached declined to participate due to concerns regarding an intramuscular injection. CONCLUSION: Administration of depot medroxyprogesterone acetate prior to surgery for type I endometrial cancers caused greater tumor effect than placebo injection. Injection of depot medroxyprogesterone acetate was acceptable to and well tolerated by patients. Depot medroxyprogesterone acetate may represent a meaningful bridge to surgery in women who can expect long wait times.

Diagnostic potential for a serum miRNA neural network for detection of ovarian cancer.

Recent studies posit a role for non-coding RNAs in epithelial ovarian cancer (EOC). Combining small RNA sequencing from 179 human serum samples with a neural network analysis produced a miRNA algorithm for diagnosis of EOC (AUC 0.90; 95% CI: 0.81-0.99). The model significantly outperformed CA125 and functioned well regardless of patient age, histology, or stage. Among 454 patients with various diagnoses, the miRNA neural network had 100% specificity for ovarian cancer. After using 325 samples to adapt the neural network to qPCR measurements, the model was validated using 51 independent clinical samples, with a positive predictive value of 91.3% (95% CI: 73.3-97.6%) and negative predictive value of 78.6% (95% CI: 64.2-88.2%). Finally, biologic relevance was tested using in situ hybridization on 30 pre-metastatic lesions, showing intratumoral concentration of relevant miRNAs. These data suggest circulating miRNAs have potential to develop a non-invasive diagnostic test for ovarian cancer.

Topical 5-Fluorouracil for Women With High-Grade Vaginal Intraepithelial Neoplasia.

OBJECTIVE: To examine success rates of 5-fluorouracil, excision, and laser ablation as the initial and secondary management strategies for women with high-grade vaginal intraepithelial neoplasia. METHODS: We conducted a retrospective case series of women referred to a single center for management of biopsy-proven, high-grade vaginal intraepithelial neoplasia between April 1994 and May 2016. Data including demographic characteristics, human papillomavirus risk factors, antecedent Pap cytology, concurrent or prior cervical and vulvar dysplasia, and treatment outcome including follow-up Pap cytology were recorded. All women were counseled on options of excision, laser ablation, or 5-fluorouracil, which was administered intravaginally according to a standardized regimen. Recurrence was defined as a biopsy showing any vaginal intraepithelial neoplasia diagnosis after primary treatment. RESULTS: Forty-seven patients were treated initially with 5-fluorouracil, 35 were treated with excision, and 22 were treated with laser ablation. Demographics were similar between groups. No recurrence was noted in 35 women treated with 5-fluorouracil (74%; 95% CI 62-87%), 20 treated with excision (57%; 95% CI 41-74%), and nine treated with laser ablation (41%; 95% CI 20-61%). Among 13 patients treated with 5-fluorouracil for recurrence, eight (62%) did not experience a second recurrence. Nine of 58 (16%) patients ever treated with 5-fluorouracil reported a side effect, most commonly irritation and dyspareunia. CONCLUSION: 5-fluorouracil was associated with a 74% success rate as the initial treatment modality for high-grade vaginal dysplasia. There is also a role for 5-fluorouracil in the management of recurrent or persistent high-grade vaginal intraepithelial neoplasia.

Liquid biopsy of PIK3CA mutations in cervical cancer in Hong Kong Chinese women.

INTRODUCTION: Cervical cancer is the fourth most common female cancer worldwide. The prognosis for women with advanced-stage or recurrent cervical cancer remains poor and response to treatment is variable. Standardized management protocols leave little room for individualization. We report on a novel blood-based liquid biopsy for specific PIK3CA mutations as a clinically useful biomarker in patients with invasive cervical cancer. METHODS: One hundred seventeen Hong Kong Chinese women with primary invasive cervical cancer and their pre-treatment plasma samples were investigated. Two PIK3CA mutations, p.E542K and p.E545K were measured in cell free DNA (cfDNA) extracted from plasma using droplet digital PCR. This liquid biopsy of PIK3CA in cervical cancer was correlated to clinico-pathological features to verify the potential of PIK3CA as a clinically useful molecular biomarker for predicting disease prognosis and monitoring for progression. RESULTS: PIK3CA mutations, either p.E542K or p.E545K, were detected in plasma cfDNA from 22.2% of the patients. PIK3CA mutation status was significantly correlated to median tumor size (p<0.01). PIK3CA mutations detected in the plasma were significantly associated with decreased disease-free survival and overall survival (p<0.05). CONCLUSIONS: As a liquid molecular biopsy, analysis of circulating PIK3CA mutations shows promise as a way to refine risk stratification of individual patients with cervical cancer, and provides a platform for further research to offer individualized therapy with the purpose of improving outcomes.

Four Residents' Narratives on Abortion Training: A Residency Climate of Reflection, Support, and Mutual Respect.

The decision on the part of obstetrics and gynecology residents to opt in or out of abortion training is, for many, a complex one. Although the public debate surrounding abortion can be filled with polarizing rhetoric, residents often discover that the boundaries between pro-choice and pro-life beliefs are not so neatly divided. We present narratives from four residents, training at a 32-resident program in the Northeast, who have a range of views surrounding abortion. Their stories reveal how some struggle with the real-life experience of providing abortions, while others feel angst over lacking the skills to terminate a life-threatening pregnancy. These residents have found that close relationships with coworkers from all sides of this issue, along with a residency program that encourages open conversation, have fostered understanding. Their narratives demonstrate that reasonable providers can disagree fundamentally and still work effectively with one another and that the close relationships formed in residency can allow both sides to see beyond the black and white of the public abortion debate. Our objectives in this commentary are to encourage a more nuanced discussion of abortion among obstetrician-gynecologists, to describe the aspects of our residency program that facilitate open dialogue and respect across diverse viewpoints, and to demonstrate that the clear distinction between being pro-life and pro-choice often breaks down when one is immediately responsible for the care of pregnant women.

Predictive factors for the presence of malignant transformation of pelvic endometriosis.

OBJECTIVES: To determine predictive factors for the presence of malignant transformation in ovarian endometriotic cysts. STUDY DESIGN: This was an IRB approved, case control study analyzing patient data from 2004 to 2013. Pathology database records were searched to identify patients with benign endometrioma and ovarian carcinoma arising in the background of endometriosis. Inclusion criteria required each patient to have a preoperative diagnosis of adnexal mass and no other findings concerning for malignancy. Patient clinical records were queried for preoperative symptoms, serum CA125 levels and radiologic findings. Pathologic data were collected including histology, tumor grade and stage. RESULTS: A total of 138 patients met inclusion criteria; 42 women with ovarian cancer arising in the background of endometriosis and 96 women with benign endometrioma. Women diagnosed with ovarian cancer were significantly older than women with endometriosis (53.6 vs. 39.2 years). There was no difference in presence of symptoms between the two groups. Women with malignant tumors were found to have significantly larger cysts (14 cm vs. 7.5 cm; p<0.0001) that were more often multilocular (45.7% vs. 12.2%; p<0.0001), and contained solid components (77.1% vs. 14.5%; p<0.0001). Among patients that were observed prior to surgery there was a significant difference in the change in size of the mass over time with 4.2 cm increase for cases vs. 1.0 cm increase for controls (p=0.02). Multiple logistic regression analysis indicated that for every 5 years increase in age there was an adjusted OR of 2.17 (p=0.003). An age of 49 years or greater had an 80.6% sensitivity (95% CI: 62.5-92.5%) and an 82.9% specificity (95% CI: 67.9-92.8%) for malignancy, and solid component on imaging had an adjusted OR of 23.7 (p<0.0001). Serum CA125 levels tended to be higher in patients with malignant tumors but did not reach statistical significance with a mean of 204.9 vs. 66.9 (p=0.1). CONCLUSIONS: Significant predictors for malignant transformation of endometriosis include cyst characteristics and age. Women above the age of 49 with multilocular cysts and solid components are at high risk for malignant transformation of endometriosis. Serum CA125 level is not a significant predictor of malignant transformation.

Vulvar cancer and sentinel lymph nodes: a new standard of care?

The treatment of early-stage vulvar cancer has remained surgical over time. Fortunately, less invasive surgical options have emerged, decreasing the significant morbidity associated with treatment. In the past decade, sentinel lymph node (SLN) dissection alone in select patients with vulvar cancer has been shown to be safe, feasible and has decreased surgical morbidity. In addition, multiple recent studies have reported low groin recurrence rates in women that underwent SLN dissection alone, which are similar to groin recurrence rates seen among women that underwent complete inguinal lymph node dissection. We believe SLN dissection should be the standard of care in select patients at institutions with surgeons experienced in the SLN technique. We feel caution should be used when performing SLN dissections in large vulvar lesions and in midline lesions. Further information is needed regarding the appropriate treatment of positive sentinel lymph nodes and, in particular, on the management of micrometastases.