Circulating tumor DNA monitoring for early recurrence detection in epithelial ovarian cancer.

OBJECTIVE: Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy. We examined the utility of circulating tumor DNA (ctDNA) as a prognostic biomarker for EOC by assessing its relationship with patient outcome and CA-125, pre-surgically and during post-treatment surveillance. METHODS: Plasma samples were collected from patients with stage I-IV EOC. Cohort A included patients with pre-surgical samples (N = 44, median follow-up: 2.7 years), cohort B and C included: patients with serially collected post-surgically (N = 12) and, during surveillance (N = 13), respectively (median follow-up: 2 years). Plasma samples were analyzed using a tumor-informed, personalized multiplex-PCR NGS assay; ctDNA status and CA-125 levels were correlated with clinical features and outcomes. RESULTS: Genomic profiling was performed on the entire cohort and was consistent with that seen in TCGA. In cohort A, ctDNA-positivity was observed in 73% (32/44) of presurgical samples and was higher in high nuclear grade disease. In cohort B and C, ctDNA was only detected in patients who relapsed (100% sensitivity and specificity) and preceded radiological findings by an average of 10 months. The presence of ctDNA at a single timepoint after completion of surgery +/- adjuvant chemotherapy and serially during surveillance was a strong predictor of relapse (HR:17.6, p = 0.001 and p < 0.0001, respectively), while CA-125 positivity was not (p = 0.113 and p = 0.056). CONCLUSIONS: The presence of ctDNA post-surgically is highly prognostic of reduced recurrence-free survival. CtDNA outperformed CA-125 in identifying patients at highest risk of recurrence. These results suggest that monitoring ctDNA could be beneficial in clinical decision-making for EOC patients.

Gaps and Opportunities to Improve Prevention of Human Papillomavirus-Related Cancers.

Human papillomavirus (HPV) infections cause more than 35,900 cancers annually in the United States. Although cervical cancer is the most prevalent HPV-related malignancy in women, the virus is also responsible for a significant percentage of anal, vaginal, and vulvar cancers. A comprehensive approach to mitigating cervical cancer includes HPV vaccination (primary prevention), screening and treatment of precancerous lesions (secondary prevention), and diagnosis and treatment of invasive cancer (tertiary prevention). Although a successful strategy, there are opportunities to innovate and increase access that can also be adapted to address the unique clinical care gaps that exist with the other anogenital cancers. The Society for Women's Health Research held a series of interdisciplinary meetings and events, during which expert researchers, clinicians, patient advocates, and health care policy leaders evaluated the current landscape of HPV-related cancers and their effects on women's health. This report summarizes the discussions of this working group and areas it identified in which to address gaps in primary and secondary prevention approaches to improve access and health outcomes for women with HPV-related anogenital cancers.

Prioritizing cervical cancer screening services during the COVID-19 pandemic: Response of an academic medical center and a public safety net hospital in California.

The expeditious diagnosis and treatment of high-grade cervical precancers are fundamental to cervical cancer prevention. However, during the COVID-19 pandemic healthcare systems have at times restricted in-person visits to those deemed urgent. Professional societies provided some guidance to clinicians regarding ways in which traditional cervical cancer screening might be modified, but many gaps remained. To address these gaps, leaders of screening programs at an academic medical center and an urban safety net hospital in California formed a rapid-action committee to provide guidance to its practitioners. Patients were divided into 6 categories corresponding to various stages in the screening process and ranked by risk of underlying high-grade cervical precancer and cancer. Tiers corresponding to the intensity of the local pandemic were constructed, and clinical delays were lengthened for the lowest-risk patients as tiers escalated. The final product was a management grid designed to escalate and de-escalate with changes in the local epidemiology of the COVID-19 pandemic. While this effort resulted in substantial delays in clinical screening services as mandated by the healthcare systems, the population effects of delaying on both cervical cancer outcomes as well as the beneficial effects related to decreasing transmission of severe acute respiratory coronavirus 2 have yet to be elucidated.

Reproductive tract immune cells from pregnant women or those using depot medroxyprogesterone acetate show no excess susceptibility to HIV-1: Results of an ex vivo fusion assay.

INTRODUCTION: Ex vivo fusion assays offer an efficient method for studying HIV-1 entry associated with contraceptive use and pregnancy outside of cohort studies of HIV-1 incidence. METHODS: We measured ex vivo HIV-1 fusion to cervical or endometrial immune cells from three groups of women: pregnant, non-pregnant not using hormonal or intrauterine contraception, and using depot medroxyprogesterone acetate (DMPA). RESULTS AND CONCLUSIONS: There was no excess susceptibility to HIV-1 fusion of cells from pregnant women or DMPA users compared to controls. Although the number of target cells in endometrium was higher in DMPA users compared to controls, HIV-1 fusion was lower. IMPLICATIONS: In ex vivo assays, HIV-1 showed no enhanced fusion to cervical immune cells from pregnant women or DMPA users compared to controls, and lower fusion to endometrial immune cells from DMPA users. This assay is useful for studying hormonal and contraceptive effects on HIV-1 entry into reproductive tract immune cells.

Discussing Cervical Cancer Screening Options: Outcomes to Guide Conversations Between Patients and Providers.

Purpose. In 2018, the US Preventive Services Task Force (USPSTF) endorsed three strategies for cervical cancer screening in women ages 30 to 65: cytology every 3 years, testing for high-risk types of human papillomavirus (hrHPV) every 5 years, and cytology plus hrHPV testing (co-testing) every 5 years. It further recommended that women discuss with health care providers which testing strategy is best for them. To inform such discussions, we used decision analysis to estimate outcomes of screening strategies recommended for women at age 30. Methods. We constructed a Markov decision model using estimates of the natural history of HPV and cervical neoplasia. We evaluated the three USPSTF-endorsed strategies, hrHPV testing every 3 years and no screening. Outcomes included colposcopies with biopsy, false-positive testing (a colposcopy in which no cervical intraepithelial neoplasia grade 2 or worse was found), treatments, cancers, and cancer mortality expressed per 10,000 women over a shorter-than-lifetime horizon (15-year). Results. All strategies resulted in substantially lower cancer and cancer death rates compared with no screening. Strategies with the lowest likelihood of cancer and cancer death generally had higher likelihood of colposcopy and false-positive testing. Conclusions. The screening strategies we evaluated involved tradeoffs in terms of benefits and harms. Because individual women may place different weights on these projected outcomes, the optimal choice for each woman may best be discerned through shared decision making.

Effectiveness of 'catch-up' human papillomavirus vaccination to prevent cervical neoplasia in immunosuppressed and non-immunosuppressed women.

It is unknown whether the HPV vaccine is effective in immunocompromised women during catch-up ages. We performed a case-control study of 4,357 women with incident CIN2+ (cases) and 5:1 age-matched, incidence-density selected controls (N = 21,773) enrolled in an integrated health care system from 2006 to 2014. Vaccine effectiveness was estimated from multivariable conditional logistic regression models, with results stratified by immunosuppression history, defined as prior HIV infection, solid organ transplant history, or recently prescribed immunosuppressive medications. HPV vaccination resulted in a 19% reduction in CIN2+ rates for women without an immunosuppression history but a nonsignificant 4% reduction for women with an immunosuppression history. Further research is needed to evaluate whether catch-up HPV vaccine effectiveness varies by immunosuppression status, especially given the recent approval of the HPV vaccine for adults up to 45 years of age.

Differential Effects of the Hormonal and Copper Intrauterine Device on the Endometrial Transcriptome.

The contraceptive effectiveness of intrauterine devices (IUDs) has been attributed in part to a foreign body reaction in the endometrium. We performed this study to better understand mechanisms of action of contraceptives of by studying their effects on endometrial and cervical transcriptomes. We collected endometrial and cervical biopsies from women using the levonorgestrel-releasing intrauterine system (LNG-IUS, n = 11), copper intrauterine device (cu-IUD, n = 13) or levonorgestrel-containing combined oral contraceptives (COC, n = 12), and from women not using contraceptives (control group, n = 11). Transcriptional profiling was performed with Affymetrix arrays, Principal Component Analysis and the bioconductor package limma. In endometrial samples from cu-IUD users, there were no genes with statistically significant differential expression compared to controls. In LNG-IUS users, 2509 genes were differentially expressed and mapped predominantly onto immune and inflammatory pathways. The cervical samples showed no statistically significant differential gene expression compared to controls. Hormonal and copper IUDs have significantly different effects on the endometrial transcriptome, with the LNG-IUS transcriptome showing pronounced inflammation and immune activation compared to controls whereas the cu-IUD transcriptome was indistinguishable from luteal phase endometrium. These findings argue against a foreign body reaction as a common mechanism of action of IUDs.

Parallel studies of mucosal immunity in the reproductive and gastrointestinal mucosa of HIV-infected women.

PROBLEM: The effects of HIV on the gastrointestinal tract (GIT), including CD4 depletion, epithelial disruption, and collagen deposition, are well documented and only partially reversed by combination antiretroviral therapy (cART). However, the effects of HIV on the female reproductive tract (FRT) are poorly understood, and most studies have focused on ectocervix and vagina without assessing the upper tract. Here, we investigated CD4+ T-cell frequency, phenotype, and HIV-specific T-cell responses in the endocervix and endometrium of HIV-infected women, comparing these tissues to the GIT. METHOD OF STUDY: Mucosal samples and blood were obtained from 18 women: four who were HIV-positive and not on cART for at least 3 years prior to sampling, including two natural controllers (viral load [VL] undetectable and CD4 >350); nine women on cART with low to undetectable VL; and five HIV-uninfected women. Mucosal samples included terminal ileum, sigmoid colon, endocervical cytobrush, endocervical curettage, and endometrial biopsy. T-cell frequency, phenotypes, and HIV-specific T-cell responses were analyzed by multiparameter flow cytometry. RESULTS: T-cell activation, measured by CD38/HLA-DR co-expression, remained significantly elevated in endometrium following cART, but was lower in gastrointestinal tissues. HIV-specific CD8+ T-cell responses were detected in ileum, colon, and endometrial tissues of women both on and off cART, and were of higher magnitude on those not on cART. CONCLUSION: Our findings reveal differences in CD4+ T-cell frequencies, immune activation, and HIV-specific T-cell responses between the gastrointestinal and reproductive tracts, and highlight differences between HIV controllers and women on cART.

Progestins Related to Progesterone and Testosterone Elicit Divergent Human Endometrial Transcriptomes and Biofunctions.

Progestins are widely used for the treatment of gynecologic disorders and alone, or combined with an estrogen, are used as contraceptives. While their potencies, efficacies and side effects vary due to differences in structures, doses and routes of administration, little is known about their effects on the endometrial transcriptome in the presence or absence of estrogen. Herein, we assessed the transcriptome and pathways induced by progesterone (P4) and the three most commonly used synthetic progestins, medroxyprogesterone acetate (MPA), levonorgestrel (LNG), and norethindrone acetate (NETA), on human endometrial stromal fibroblasts (eSF), key players in endometrial physiology and reproductive success. While there were similar transcriptional responses, each progestin induced unique genes and biofunctions, consistent with their structural similarities to progesterone (P4 and MPA) or testosterone (LNG and NETA), involving cellular proliferation, migration and invasion. Addition of estradiol (E2) to each progestin influenced the number of differentially expressed genes and biofunctions in P4 and MPA, while LNG and NETA signatures were more independent of E2. Together, these data suggest different mechanisms of action for different progestins, with progestin-specific altered signatures when combined with E2. Further investigation is warranted for a personalized approach in different gynecologic disorders, for contraception, and minimizing side effects associated with their use.

Effects of the levonorgestrel-containing intrauterine device, copper intrauterine device, and levonorgestrel-containing oral contraceptive on susceptibility of immune cells from cervix, endometrium and blood to HIV-1 fusion measured ex vivo.

Globally, HIV/AIDS is a leading cause of morbidity worldwide among reproductive-aged cisgender women, highlighting the importance of understanding effects of contraceptives on HIV-1 risk. Some observational studies suggest there may be an increased risk of HIV-1 acquisition among women using the long-acting injectable progestin contraceptive, depo-medroxyprogesterone acetate. The potential mechanism of this susceptibility is unclear. There are few data on the role of the upper female reproductive tract in HIV-1 transmission, and the mechanisms of HIV-1 infection are likely to differ in the upper compared to the lower reproductive tract due to differences in tissue composition and variable effects of sex steroids on mucosal immune cell distribution and activity. In this study, we measured the susceptibility of mucosal immune cells from the upper female reproductive tract to HIV-1 entry using the virion-based HIV-1 fusion assay in samples from healthy female volunteers. We studied 37 infectious molecular clones for their ability to fuse to cells from endometrial biopsies in three participants and found that subtype (B or C) and origin of the virus (transmitted founder or chronic control) had little influence on HIV-1 fusion susceptibility. We studied the effect of contraceptives on HIV-1 susceptibility of immune cells from the cervix, endometrium and peripheral blood by comparing fusion susceptibility in four groups: users of the copper intrauterine device (IUD), levonorgestrel-containing oral contraceptive, levonorgestrel-containing IUD and unexposed controls (n = 58 participants). None of the contraceptives was associated with higher rates of HIV-1 entry into female reproductive tract cells compared to control samples from the mid-luteal phase.

Menstrual cycle-dependent alterations in glycosylation: a roadmap for defining biomarkers of favorable and unfavorable mucus.

OBJECTIVE: To understand glycosylation of endocervical proteins at different times throughout the menstrual cycle in naturally cycling women and in women using hormonal or non-hormonal contraceptive methods, in order to characterize biochemical fingerprints of favorable and unfavorable cervical mucus. DESIGN: Lectin/antibody-probed protein blot analysis of endocervical mucus samples collected onto ophthalmologic sponges (wicks) from two groups: a longitudinal cohort of naturally cycling women at three time points in their menstrual cycles (discovery cohort), and a cross-sectional cohort of women on hormonal or non-hormonal contraceptive methods (validation cohort). SETTING: Participants were recruited from the San Francisco Bay Area from 2010 to 2016. PATIENT(S): Women with regular cycles not using hormonal or intrauterine device (IUD) contraceptives were recruited for the longitudinal cohort (n = 8). Samples from women using levonorgestrel-containing combined oral contraceptives (n = 16), levonorgestrel containing IUDs (n = 14), copper IUDs (n = 17), depo-medroxyprogesterone acetate (DMPA) (n = 15), and controls (n = 13) were used for validation. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Detection of specific glycosylation patterns on lectin/antibody probed protein blots. RESULT(S): Two lectins (Lens culinaris agglutinin and Lycopersicon esculentum [tomato lectin]), and the antibody MECA-79 demonstrated consistent cycle-dependent changes in protein binding. The glycan-binding patterns of the levonorgestrel-containing contraceptives were generally similar to each other and to those from women in the luteal phase. The DMPA samples showed slightly different binding patterns. CONCLUSION(S): We identified molecular signatures of unfavorable mucus from women in the luteal phase and on hormonal contraceptives. Further characterization of these biomarkers may be useful in contraceptive development and in evaluation of infertility.

Estimated Quality of Life and Economic Outcomes Associated With 12 Cervical Cancer Screening Strategies: A Cost-effectiveness Analysis.

Importance: Many cervical cancer screening strategies are now recommended in the United States, but the benefits, harms, and costs of each option are unclear. Objective: To estimate the cost-effectiveness of 12 cervical cancer screening strategies. Design, Setting, and Participants: The cross-sectional portion of this study enrolled a convenience sample of 451 English-speaking or Spanish-speaking women aged 21 to 65 years from September 22, 2014, to June 16, 2016, identified at women's health clinics in San Francisco. In this group, utilities (preferences) were measured for 23 cervical cancer screening-associated health states and were applied to a decision model of type-specific high-risk human papillomavirus (hrHPV)-induced cervical carcinogenesis. Test accuracy estimates were abstracted from systematic reviews. The evaluated strategies were cytologic testing every 3 years for women aged 21 to 65 years with either repeat cytologic testing in 1 year or immediate hrHPV triage for atypical squamous cells of undetermined significance (ASC-US), cytologic testing every 3 years for women age 21 to 29 years followed by cytologic testing plus hrHPV testing (cotesting), or primary hrHPV testing alone for women aged 30 to 65 years. Screening frequency, abnormal test result management, and the age to switch from cytologic testing to hrHPV testing (25 or 30 years) were varied. Analyses were conducted from both the societal and health care sector perspectives. Main Outcomes and Measures: Utilities for 23 cervical cancer screening-associated health states (cross-sectional study) and quality-adjusted life-years (QALYs) and total costs for each strategy. Results: Utilities were measured in a sociodemographically diverse group of 451 women (mean [SD] age, 38.2 [10.7] years; 258 nonwhite [57.2%]). Cytologic testing every 3 years with repeat cytologic testing for ASC-US yielded the most lifetime QALYs and conferred more QALYs at higher costs ($2166 per QALY) than the lowest-cost strategy (cytologic testing every 3 years with hrHPV triage of ASC-US). All cytologic testing plus hrHPV testing (cotesting) and primary hrHPV testing strategies provided fewer QALYs at higher costs. Adding indirect costs did not change the conclusions. In sensitivity analyses, hrHPV testing every 5 years with genotyping triage beginning at age 30 years was the lowest-cost strategy when hrHPV test sensitivity was markedly higher than cytologic test sensitivity or when hrHPV test cost was equated to the lowest reported cytologic test cost ($14). Conclusions and Relevance: Cytologic testing every 3 years for women aged 21 to 29 years with either continued cytologic testing every 3 years or switching to a low-cost hrHPV test every 5 years confers a reasonable balance of benefits, harms, and costs. Comparative modeling is needed to confirm the association of these novel utilities with cost-effectiveness.

Effectiveness of catch-up human papillomavirus vaccination on incident cervical neoplasia in a US health-care setting: a population-based case-control study.

BACKGROUND: The population effectiveness of human papillomavirus (HPV) catch-up vaccination, defined in the USA as first vaccination at ages 13-26 years, has not been studied extensively. We aimed to assess the risk of cervical intraepithelial neoplasia (CIN) 2, CIN3, adenocarcinoma in situ, or cancer (CIN2+ and CIN3+) by prior HPV vaccination status, age at first dose, and number of doses in women participating in a screening programme within a large integrated health-care system. METHODS: We performed a nested case-control study of women enrolled in Kaiser Permanente Northern California (an integrated health-care delivery system in California, USA). Cases were women with CIN2+ or CIN3+ confirmed by histology between Jan 1, 1995, and June 30, 2014, and incidence density-selected controls were age-matched women without CIN2+ or CIN3+ at the time each case occurred. For each case, we randomly selected five controls. Cases and controls were aged 26 years or younger when the HPV quadrivalent vaccine became available in 2006. Rate ratios (RRs) from conditional logistic regression were estimated by age at time of first HPV quadrivalent vaccine dose (14-17 years, 18-20 years, and ≥21 years), and number of doses (one, two, and three or more doses) compared with no prior vaccination, with adjustment for smoking, hormonal contraceptive prescription, race or ethnicity, sexually transmitted infections, immunosuppression, parity, and number of outpatient visits. FINDINGS: 4357 incident CIN2+ cases and 21 773 matched controls were included in the study. Of these, 1849 were incident CIN3+ cases with 9242 matched controls. The youngest age at time of first vaccination was 14 years. One or more HPV vaccine doses conferred protection against CIN2+ (RR 0·82, 95% CI 0·73-0·93) and CIN3+ (0·77, 0·64-0·94). We found the strongest protection against CIN2+ in women who had received at least three vaccine doses and had received their first dose aged 14-17 years (0·52, 0·36-0·74) or aged 18-20 years (0·65, 0·49-0·88). No significant protection was found in women aged 21 years or older at time of first dose (0·94, 0·81-1·09). Inferences were similar for CIN3+, but with stronger effects for women who received at least three vaccine doses and had received their first dose aged 14-17 years (0·27, 0·13-0·56) or aged 18-20 years (0·59, 0·36-0·97). INTERPRETATION: Catch-up quadrivalent HPV vaccination with three doses was effective against CIN2+ and CIN3+ in girls and women aged 14-20 years at time of first vaccine dose but not for women aged 21 years and older at first dose. FUNDING: US National Cancer Institute.

Recent intrauterine device use and the risk of precancerous cervical lesions and cervical cancer.

OBJECTIVE: Understanding the effect of contraceptives on the development of precancerous lesions of the cervix and cervical cancer may provide information that is valuable to women in contraceptive decision-making. The purpose of this study was to evaluate the association between recent intrauterine device (IUD) use (by type) and cervical intraepithelial neoplasia 2, 3, adenocarcinoma in situ or cancer (CIN2+ or CIN3+). STUDY DESIGN: Case-control study of 17,559 women age 18-49 with incident CIN2+ cases and 5:1 age-matched, incidence-density selected controls (N=87,378) who were members of Kaiser Permanente Northern California Healthcare System from 1996 to 2014. Recent IUD use, within 18 months prior to index, was the exposure of interest. RESULTS: We identified 1,657 IUD users among the cases and 7,925 IUD users among controls. After adjusting for sexually transmitted infection testing, smoking, HPV vaccination, hormonal contraceptive use, parity, race and number of outpatient healthcare system visits, IUD use was associated with an increased rate of CIN2+ [rate ratio (RR) 1.12, 95% confidence interval (1.05-1.18), p<0.001] but not CIN3+ [RR 1.02 (0.93-1.11), p=0.71]. Levonorgestrel-IUD use was associated with an increased rate of CIN2+ [RR 1.18 (1.08-1.30), p<0.001] but not CIN3+ [RR 1.05 (0.91-1.21), p=0.48]. Copper-IUD use was not associated with CIN2+ [RR 0.88 (0.75-1.04), p=0.13] or CIN3+ [RR 0.81 (0.64-1.02), p=0.07]. CONCLUSION: Recent IUD use had variable weak associations with CIN2+ but was not associated with increased risk of CIN3+. IMPLICATIONS: Recent levonorgestrel-IUD use may be associated with CIN2, a lesion with a high rate of regression, but not CIN3, which is considered a true pre-cancerous lesion. The observed association between levonorgestrel-IUDs and CIN2+ was modest but warrants further investigation. It may have clinical importance for contraceptive counseling if this finding is shown to be consistent across other studies and other populations.

Human Immunodeficiency Virus (HIV)- and Non-HIV-Associated Immunosuppression and Risk of Cervical Neoplasia.

OBJECTIVE: To estimate the risk of cervical intraepithelial neoplasia grade 2, 2-3, 3, adenocarcinoma in situ, or cancer (CIN 2 or worse) among women with human immunodeficiency virus (HIV)- and non-HIV-associated immunosuppression. METHODS: We performed a case-control study of 20,146 women with incident CIN 2 or worse and 5:1 age-matched, incidence-density selected women in a control group (n=100,144) enrolled in an integrated health care system from 1996 to 2014. Adjusted rate ratios (RRs) from conditional logistic regression were obtained for HIV status (stratified by CD4 T-cells), solid organ transplant history, and immunosuppressive medication use. RESULTS: Risk of CIN 2 or worse was increased among women with HIV (n=36 women in the case group and 79 women in the control group; adjusted RR 2.0, 95% CI 1.3-3.0) compared with those without HIV and in solid organ transplant recipients (n=51 women in the case group and 68 women in the control group; RR 3.3, 95% CI 2.3-4.8) compared with women without a prior transplant. The highest risks were among women with HIV and less than 200 CD4 T-cells/microliter (n=9 women in the case group and eight women in the control group; RR 5.6, 95% CI 2.1-14.7) compared with those without HIV and in solid organ transplant recipients prescribed three or greater immunosuppressive medication classes (n=32 women in the case group and 33 women in the control group; RR 4.1, 95% CI 2.5-6.8) compared with women without a prior transplant and zero medication classes. No increased risks were observed for women with HIV and 500 or greater CD4 T-cells/microliter (n=9 women in the case group and 43 women in the control group; RR 0.8, 95% CI 0.4-1.7) compared with those without HIV or women without prior solid organ transplantation prescribed two or fewer immunosuppressive medication classes (n=1,262 women in the case group and 6,100 women in the control group; RR 0.95, 95% CI 0.89-1.01) compared with women without and a prior transplant and zero medication classes. CONCLUSION: Risk of CIN 2 or worse is increased in women with a prior solid organ transplant or who have HIV and CD4 cells/microliter less than 500 but not in women with HIV and higher CD4 levels or in women without a prior solid organ transplant but who are prescribed only one or two immunosuppressive medication classes.

Effect of professional society recommendations on women's desire for a routine pelvic examination.

BACKGROUND: The American College of Physicians strongly recommends against performing pelvic examinations in asymptomatic, nonpregnant women, citing evidence of harm (false-positive testing, unnecessary surgery) and no evidence of benefit. In contrast, the American Congress of Obstetricians and Gynecologists recommends pelvic examinations in asymptomatic women beginning at age 21 years, citing expert opinion. OBJECTIVE: We sought to evaluate if providing women with professional societies' conflicting statements about pelvic examinations (recommendations and rationales) would influence their desire for a routine examination. STUDY DESIGN: We recruited 452 women ages 21-65 years from 2 women's clinics to participate in a 50-minute face-to-face interview about cervical cancer screening that included a 2-phase study related to pelvic examinations. In the first phase, 262 women were asked about their desire for the examination without being provided information about professional societies' recommendations. In the second phase, 190 women were randomized to review summaries of the American College of Physicians or American Congress of Obstetricians and Gynecologists statement followed by an interview. RESULTS: First-phase participants served as the referent: 79% (208/262) indicated they would want a routine examination if given a choice. In the second phase, a similar percentage of women randomized to the American Congress of Obstetricians and Gynecologists summary had this desire (82%: 80/97; adjusted odds ratio, 1.37; 95% confidence interval, 0.69-2.70). Women randomized to the American College of Physicians summary, however, were less likely to indicate they would opt for an examination (39%: 36/93; adjusted odds ratio, 0.12; 95% confidence interval, 0.06-0.21). Overall, 94% (179/190) believed the potential benefits and harms should be discussed prior to the examination. CONCLUSION: Providing women with a professional society's recommendation advising against routine pelvic examinations substantially reduced their desire to have one. Educational materials are needed to ensure women's informed preferences and values are reflected in decisions about pelvic examinations.

The effect of intrauterine devices on acquisition and clearance of human papillomavirus.

BACKGROUND: Previous studies have shown a decrease in cervical cancer associated with intrauterine device use. It has been hypothesized that intrauterine device use may alter the natural history of human papillomavirus infections, preempting development of precancerous lesions of the cervix and cervical cancer, but the effect of intrauterine devices on the natural history of human papillomavirus infection and subsequent development of cervical cancer is poorly understood. OBJECTIVE: The purpose of this study was to evaluate the association between intrauterine device use and cervical high-risk human papillomavirus acquisition and clearance. STUDY DESIGN: This is a prospective cohort study conducted from October 2000 through June 2014 among 676 sexually active young women and girls enrolled from family planning clinics in San Francisco, CA. Data were analyzed using a Cox proportional hazards model, including time-varying indicators of intrauterine device use, and adjusting for fixed and time-dependent predictor variables. RESULTS: A total of 85 women used an intrauterine device at some time during follow-up. Among 14,513 study visits, women reported intrauterine device use at 505 visits. After adjusting for potential behavioral confounders, there was no association between intrauterine device use and human papillomavirus acquisition (hazard ratio, 0.50; 95% confidence interval, 0.20-1.23; P = .13) or clearance of human papillomavirus infection (hazard ratio, 1.44; 95% confidence interval, 0.76-2.72; P = .26). CONCLUSION: Current intrauterine device use is not associated with acquisition or persistence of human papillomavirus infection. Intrauterine device use is safe among women and girls with human papillomavirus infections and at risk for human papillomavirus acquisition. Intrauterine device use may play a role further downstream in the natural history of cervical cancer by inhibiting the development of precancerous lesions of the cervix in human papillomavirus-infected women, or enhancing clearance of established precancerous lesions.

Feasibility of clinical detection of cervical dysplasia using angle-resolved low coherence interferometry measurements of depth-resolved nuclear morphology.

This study sought to establish the feasibility of using in situ depth-resolved nuclear morphology measurements for detection of cervical dysplasia. Forty enrolled patients received routine cervical colposcopy with angle-resolved low coherence interferometry (a/LCI) measurements of nuclear morphology. a/LCI scans from 63 tissue sites were compared to histopathological analysis of co-registered biopsy specimens which were classified as benign, low-grade squamous intraepithelial lesion (LSIL), or high-grade squamous intraepithelial lesion (HSIL). Results were dichotomized as dysplastic (LSIL/HSIL) versus non-dysplastic and HSIL versus LSIL/benign to determine both accuracy and potential clinical utility of a/LCI nuclear morphology measurements. Analysis of a/LCI data was conducted using both traditional Mie theory based processing and a new hybrid algorithm that provides improved processing speed to ascertain the feasibility of real-time measurements. Analysis of depth-resolved nuclear morphology data revealed a/LCI was able to detect a significant increase in the nuclear diameter at the depth bin containing the basal layer of the epithelium for dysplastic versus non-dysplastic and HSIL versus LSIL/Benign biopsy sites (both p < 0.001). Both processing techniques resulted in high sensitivity and specificity (>0.80) in identifying dysplastic biopsies and HSIL. The hybrid algorithm demonstrated a threefold decrease in processing time at a slight cost in classification accuracy. The results demonstrate the feasibility of using a/LCI as an adjunctive clinical tool for detecting cervical dysplasia and guiding the identification of optimal biopsy sites. The faster speed from the hybrid algorithm offers a promising approach for real-time clinical analysis.

Performance of p16INK4a ELISA as a primary cervical cancer screening test among a large cohort of HIV-infected women in western Kenya: a 2-year cross-sectional study.

OBJECTIVE: A biomarker with increased specificity for cervical dysplasia compared with human papillomavirus (HPV) testing would be an attractive option for cervical cancer screening among HIV-infected women in resource-limited settings. p16(INK4a) has been explored as a biomarker for screening in general populations. DESIGN: A 2-year cross-sectional study. SETTING: 2 large HIV primary care clinics in western Kenya. PARTICIPANTS: 1054 HIV-infected women in western Kenya undergoing cervical cancer screening as part of routine HIV care from October 2010 to November 2012. INTERVENTIONS: Participants underwent p16(INK4a) specimen collection and colposcopy. Lesions with unsatisfactory colposcopy or suspicious for cervical intraepithelial neoplasia 2+ (CIN2+; including CIN2/3 or invasive cervical cancer) were biopsied. Following biopsy, disease status was determined by histopathological diagnosis. PRIMARY AND SECONDARY OUTCOME MEASURES: We measured the sensitivity, specificity and predictive values of p16(INK4a) ELISA for CIN2+ detection among HIV-infected women and compared them to the test characteristics of current screening methods used in general as well as HIV-infected populations. RESULTS: Average p16(INK4a) concentration in cervical samples was 37.4 U/mL. After colposcopically directed biopsy, 127 (12%) women were determined to have CIN2+. Receiver operating characteristic analysis showed an area under the curve of 0.664 for p16(INK4a) to detect biopsy-proven CIN2+. At a p16(INK4a) cut-off level of 9 U/mL, sensitivity, specificity, positive and negative predictive values were 89.0%, 22.9%, 13.6% and 93.8%, respectively. The overall p16(INK4a) positivity at a cut-off level of 9 U/mL was 828 (78.6%) women. There were 325 (30.8%) cases of correct p16(INK4a) prediction to detect or rule out CIN2+, and 729 (69.2%) cases of incorrect p16(INK4a) prediction. CONCLUSIONS: p16(INK4a) ELISA did not perform well as a screening test for CIN2+ detection among HIV-infected women due to low specificity. Our study contributes to the ongoing search for a more specific alternative to HPV testing for CIN2+ detection.