History of infertility and risk of colorectal cancer.

BACKGROUND: There has been limited prior research on the association between infertility and risk of colorectal cancer. METHODS: Data from postmenopausal women in Women's Health Initiative (WHI) were used to estimate the association between self-reported infertility (twelve months of trying to get pregnant without achieving a pregnancy) with risk of colorectal cancer using Cox proportional hazard models. RESULTS: No association was observed between infertility and risk of postmenopausal colorectal cancer (RR: 0.97, 95% CI: 0.87-1.08), invasive colorectal cancer (RR:0.99, 95% CI: 0.88-1.10), or colorectal cancer mortality (RR: 0.89, 95% CI: 0.71-1.12). CONCLUSIONS: Infertility was not found to be associated with colorectal cancer risk among postmenopausal women. Risk did not vary by specific infertility diagnoses. IMPACT: Infertility may not be associated with colorectal cancer risk.

Infertility and risk of postmenopausal breast cancer in the women's health initiative.

PURPOSE: Although infertility (i.e., failure to conceive after ≥ 12 months of trying) is strongly correlated with established breast cancer risk factors (e.g., nulliparity, number of pregnancies, and age at first pregnancy), its association with breast cancer incidence is not fully understood. Previous studies were primarily small clinic-based or registry studies with short follow-up and predominantly focused on premenopausal breast cancer. The objective of this study was to assess the relationship between infertility and postmenopausal breast cancer risk among participants in the Women's Health Initiative (analytic sample = 131,784; > 25 years of follow-up). METHODS: At study entry, participants were asked about their pregnancy history, infertility history, and diagnosed reasons for infertility. Incident breast cancers were self-reported with adjudication by trained physicians reviewing medical records. Cox proportional hazards models were used to estimate risk of incident postmenopausal breast cancer for women with infertility (overall and specific infertility diagnoses) compared to parous women with no history of infertility. We examined mediation of these associations by parity, age at first term pregnancy, postmenopausal hormone therapy use at baseline, age at menopause, breastfeeding, and oophorectomy. RESULTS: We observed a modest association between infertility (n = 23,406) and risk of postmenopausal breast cancer (HR = 1.07; 95% CI 1.02-1.13). The association was largely mediated by age at first term pregnancy (natural indirect effect: 46.4% mediated, CI 12.2-84.3%). CONCLUSION: These findings suggest that infertility may be modestly associated with future risk of postmenopausal breast cancer due to age at first pregnancy and highlight the importance of incorporating reproductive history across the life course into breast cancer analyses.

Oncogenic Oral Human Papillomavirus Clearance Patterns over 10 Years.

BACKGROUND: Effective screening for oropharyngeal cancer is lacking. Four oncogenic HPV clearance definitions were explored to understand long-term natural history for persistent oncogenic oral HPV (oncHPV), the precursor of oropharyngeal cancer. METHODS: Prospective multicenter cohort of participants living with/at-risk for HIV, with oral rinse and gargle samples collected every 6 to 12 months for up to 10 years and tested for oncHPV. HPV clearance definitions included 1 (clear1), 2 (clear2), 3 (clear3) consecutive negatives, or being negative at last two visits (clearlast). RESULTS: Median time to clearance of oncHPV exceeded 2 years for conservative definitions (clear3: 2.38, clearlast: 2.43), but not lenient (clear1: 0.68, clear2: 1.15). By clear3, most incident infections cleared at 2, 5, 8 years (55.1%, 75.6%, 79.1%), contrary to prevalent infections (37.1%, 52.5%, 59.5%, respectively). In adjusted analysis, prevalent oncHPV, older age, male sex, and living with HIV were associated with reduced clearance. Of 1,833 subjects screened, 13.8% had prevalent oncHPV and 47.5% of those infections persisted ≥5 years, representing 6.5% of persons screened. Two men with prevalent oral HPV16 developed incident oropharyngeal cancer [IR = 1.62 per 100 person-years; 95% confidence interval (CI), 0.41-6.4]. Many with oral HPV16 persisted ≥5 years (and/or developed HPV-oropharyngeal cancer) among those with 2 (72.2%), ≥2 of first 3 (65.7%), or 3 (80.0%) consecutive positive oHPV16 tests, but not after 1 (39.4%). CONCLUSIONS: In our 10-year study, most incident infections cleared quickly. However, half of prevalent oncHPV persisted ≥5 years, suggesting increased risk with persistent oncHPV at >2 visits. IMPACT: We identified groups with persistent oncHPV at increased risk of oropharyngeal cancer and contextualized risk levels for those with oral HPV16 infection.

New-Onset Diabetes after an Obesity-Related Cancer Diagnosis and Survival Outcomes in the Women's Health Initiative.

BACKGROUND: Individuals diagnosed with an obesity-related cancer (ORC survivors) are at an elevated risk of incident diabetes compared with cancer-free individuals, but whether this confers survival disadvantage is unknown. METHODS: We assessed the rate of incident diabetes in ORC survivors and evaluated the association of incident diabetes with all-cause and cancer-specific mortality among females with ORC in the Women's Health Initiative cohort (N = 14,651). Cox proportional hazards regression models stratified by exposure-risk periods (0-1, >1-3, >3-5, >5-7, and >7-10 years) from ORC diagnosis and time-varying exposure (diabetes) analyses were performed. RESULTS: Among the ORC survivors, a total of 1.3% developed diabetes within ≤1 year of follow-up and 2.5%, 2.3%, 2.3%, and 3.6% at 1-3, 3-5, 5-7, and 7-10 years of follow-up, respectively, after an ORC diagnosis. The median survival for those diagnosed with diabetes within 1-year of cancer diagnosis and those with no diabetes diagnosis in that time frame was 8.8 [95% confidence interval (CI), 7.0-14.5) years and 16.6 (95% CI, 16.1-17.0) years, respectively. New-onset compared with no diabetes as a time-varying exposure was associated with higher risk of all-cause (HR, 1.27; 95% CI, 1.16-1.40) and cancer-specific (HR, 1.17; 95% CI, 0.99-1.38) mortality. When stratified by exposure-risk periods, incident diabetes in ≤1 year of follow-up was associated with higher all-cause (HR, 1.76; 95% CI, 1.40-2.20) and cancer-specific (HR0-1, 1.82; 95% CI, 1.28-2.57) mortality, compared with no diabetes diagnosis. CONCLUSIONS: Incident diabetes was associated with worse cancer-specific and all-cause survival, particularly in the year after cancer diagnosis. IMPACT: These findings draw attention to the importance of diabetes prevention efforts among cancer survivors to improve survival outcomes.

A novel human papillomavirus and host DNA methylation score and detection of cervical adenocarcinoma.

BACKGROUND: The widespread introduction of Pap testing in the 1960s was followed by substantial reductions in the incidence of cervical squamous cell cancer (SCC). However, the incidence of cervical adenocarcinoma (ADC) did not decrease, likely because of low Pap test sensitivity for ADC and adenocarcinoma in situ (AIS). This study assessed a novel human papillomavirus (HPV) and host DNA Methylation Score for AIS and ADC screening. METHODS: We measured methylation levels at CpG sites in the L2/L1 open reading frames of HPV16, HPV18, and HPV45-as well as 2 human loci, DCC and HS3ST2. Specifically, we tested exfoliated cervicovaginal cells from women in the HPV Persistence and Progression (PaP) cohort who were positive for 1 of HPV16, 18, or 45, including: 1) 176 with AIS/ADC, 2) 353 with cervical intraepithelial neoplasia-3 (CIN3) or SCC, and 3) controls who either cleared (HPV-Clearers; n = 579) or had persistent HPV16, 18, or 45 infection (HPV-Persisters; n = 292). CpG site-specific methylation percentages were measured using our reported next-generation methods. The Methylation Score was the average methylation percentage across all 35 CpG sites tested. RESULTS: Each individual CpG site had higher methylation percentages in exfoliated cervicovaginal cells collected from patients with AIS/ADC, and as well as those with CIN3/SCC, relative to either control group (weakest P = .004). The Methylation Score for AIS/ADC had a sensitivity of 74% and specificity of 89%. The multivariate odds ratio (OR) between the Methylation Score (4th vs 1st quartile) for AIS/ADC was ORq4-q1 = 49.01 (PBenjamini-Hochberg = 4.64E-12), using HPV-Clearers as controls. CIN3/SCC had similar, albeit weaker, associations with the Methylation Score. CONCLUSIONS: HPV16/18/45-infected women with Methylation Scores in the highest quartile had very high odds of AIS/ADC, suggesting they may warrant careful histologic evaluation of the cervical transition zone (eg, conization or loop electrosurgical excision procedure [LEEP]).

Diagnostic accuracy of cervical cancer screening strategies for high-grade cervical intraepithelial neoplasia (CIN2+/CIN3+) among women living with HIV: A systematic review and meta-analysis.

Background: We systematically reviewed the diagnostic accuracy of cervical cancer screening and triage strategies in women living with HIV (WLHIV). Methods: Cochrane Library, Embase, Global Health and Medline were searched for randomised controlled trials, prospective or cross-sectional studies published from database inception to 15 July 2022 reporting diagnostic accuracy of tests in cervical cancer screening and triage of screen-positive WLHIV. Studies were included if they reported the diagnostic accuracy of any cervical cancer screening or triage strategies for the detection of histologically-confirmed high-grade cervical intraepithelial neoplasia (CIN2+/CIN3+) among WLHIV. Summary data were extracted from published reports. Authors were contacted for missing data where applicable. Sensitivity and specificity estimates for CIN2/3+ were pooled using models for meta-analysis of diagnostic accuracy data. Study quality was assessed using the QUADAS-2 tool for the quality assessment of diagnostic accuracy studies. PROSPERO registration:CRD42020189031. Findings: In 38 studies among 18,737 WLHIV, the majority (n=19) were conducted in sub-Saharan Africa. The pooled prevalence was 12.0% (95%CI:9.8-14.1) for CIN2+ and 6.7% (95%CI:5.0-8.4) for CIN3+. The proportion of screen-positive ranged from 3-31% (visual inspection using acetic acid[VIA]); 2-46% (high-grade squamous intraepithelial lesions, and greater [HSIL+] cytology); 20-64% (high-risk[HR]-HPV DNA). In 14 studies, sensitivity and specificity of VIA were variable limiting the reliability of pooled estimates. In 5 studies where majority had histology-confirmed CIN2+, pooled sensitivity was 56.0% (95%CI:45.4-66.1; I2=65%) for CIN2+ and 65.0% (95%CI:52.9-75.4; I2 =42%) for CIN3+; specificity for

Healthy lifestyle index and the risk of ductal carcinoma in situ of the breast in the Women's Health Initiative.

A relatively high healthy lifestyle index (HLI) score, representing a healthy diet, participation in moderate to vigorous physical exercise, no smoking, low to no alcohol intake and a normal body mass index, has been associated with a reduced risk of invasive breast cancer. However, no study has shown an association between the HLI and the risk of ductal carcinoma in situ of the breast (DCIS), which is considered to be a nonobligate precursor of invasive breast cancer. We evaluated this association in a prospective cohort of 132 230 postmenopausal women, aged 50 to 79 years, recruited between 1993 and 1998 across the United States and enrolled in the Women's Health Initiative study. The HLI score was created and categorized into quartiles. During an average follow-up of 15.4 years, 2035 DCIS cases were ascertained. Multivariable-adjusted Cox regression was used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the association of HLI with the risk of DCIS. Women in the highest HLI quartile had a lower DCIS risk than those in the lowest quartile (HR4thQT  = 0.80, 95% CI, 0.70-0.92) and this association was stronger in women with a family history of breast cancer (HR4thQT  = 0.70, 95% CI, 0.52-0.93), and for ER+/PR+ DCIS (HR4thQT  = 0.66, 95% CI, 0.52-0.83). These findings suggest that there is an inverse association between HLI and risk of DCIS, and suggest that the adoption of a healthy lifestyle might lower the risk of DCIS.

Adiposity and breast, endometrial, and colorectal cancer risk in postmenopausal women: Quantification of the mediating effects of leptin, C-reactive protein, fasting insulin, and estradiol.

BACKGROUND: Mechanisms underlying the adiposity-cancer relationship are incompletely understood. We quantified the mediating roles of C-reactive protein (CRP), leptin, fasting insulin, and estradiol in the effect of adiposity on estrogen receptor (ER)-positive breast, endometrial, and colorectal cancer risk in postmenopausal women. METHODS: We used a case-cohort study within the Women's Health Initiative Observational Study, analyzed as a cumulative sampling case-control study. The study included 188 breast cancer cases, 98 endometrial cancer cases, 193 colorectal cancer cases, and 285 controls. Interventional indirect and direct effects on the risk ratio (RR) scale were estimated using causal mediation analysis. RESULTS: For breast cancer, the total effect RR for BMI ≥30 versus ≥18.5-<25 kg/m2 was 1.87 (95%CI,1.11-3.13). The indirect effect RRs were 1.38 (0.79-2.33) through leptin and CRP, 1.58 (1.17-2.43) through insulin, and 1.11 (0.98-1.30) through estradiol. The direct effect RR was 0.82 (0.39-1.68). For endometrial cancer, the total effect RR was 2.12 (1.12-4.00). The indirect effect RRs were 1.72 (0.85-3.98) through leptin and CRP, 1.42 (0.96-2.26) through insulin, and 1.24 (1.03-1.65) through estradiol. The direct effect RR was 0.70 (0.23-2.04). For colorectal cancer, the total effect RR was 1.70 (1.03-2.79). The indirect effect RRs were 1.04 (0.61-1.72) through leptin and CRP, 1.36 (1.00-1.88) through insulin, and 1.02 (0.88-1.17) through estradiol. The direct effect RR was 1.16 (0.58-2.43). CONCLUSION: Leptin, CRP, fasting insulin, and estradiol appear to mediate the effect of high BMI on cancer risk to different extents, with likely varying degrees of importance between cancers. These insights might be important in developing interventions to modify obesity-associated cancer risk in postmenopausal women.

molBV reveals immune landscape of bacterial vaginosis and predicts human papillomavirus infection natural history.

Bacterial vaginosis (BV) is a highly prevalent condition that is associated with adverse health outcomes. It has been proposed that BV's role as a pathogenic condition is mediated via bacteria-induced inflammation. However, the complex interplay between vaginal microbes and host immune factors has yet to be clearly elucidated. Here, we develop molBV, a 16 S rRNA gene amplicon-based classification pipeline that generates a molecular score and diagnoses BV with the same accuracy as the current gold standard method (i.e., Nugent score). Using 3 confirmatory cohorts we show that molBV is independent of the 16 S rRNA region and generalizable across populations. We use the score in a cohort without clinical BV states, but with measures of HPV infection history and immune markers, to reveal that BV-associated increases in the IL-1ß/IP-10 cytokine ratio directly predicts clearance of incident high-risk HPV infection (HR = 1.86, 95% CI: 1.19-2.9). Furthermore, we identify an alternate inflammatory BV signature characterized by elevated TNF-α/MIP-1ß ratio that is prospectively associated with progression of incident infections to CIN2 + (OR = 2.81, 95% CI: 1.62-5.42). Thus, BV is a heterogeneous condition that activates different arms of the immune response, which in turn are independent risk factors for HR-HPV clearance and progression. Clinical Trial registration number: The CVT trial has been registered under: NCT00128661.

Molecular profiling of breast and lung cancer in women with HIV reveals high tumor mutational burden.

OBJECTIVE: This study compared the mutation profile and tumor mutational burden (TMB) in women with HIV (WWH) diagnosed with lung adenocarcinoma (n = 8) or breast ductal neoplasm (n = 13) who were enrolled into the Women's Interagency HIV Study (WIHS). DESIGN: Previous studies tended to focus on single institutions based on sample availability. This study is based on a representative, multicenter cohort that represents the racial and ethnic composition of women with HIV in the United States. METHODS: The study sequenced the complete human exome of n = 26 cancer samples from HIV-positive women, using Ion torrent next-generation sequencing. The study cohort was compared with a HIV-negative cohort obtained from the Genomic Data Commons Data Portal of the NCI. RESULTS: There were no differences in known cancer mutations between breast cancer and lung cancer that developed in WWH and those that developed in HIV-negative (HIV-) women; however, WWH presented a significantly higher TMB in comparison to HIV- patients. Seventy-five percent of lung cancers and 61% of breast cancers were defined as TMB-high (more than 10 mutation/mb of DNA). CONCLUSION: This study affirms the recommendation that WWH be included in clinical trials of novel treatments for these cancers. Although these data are preliminary, the high TMB in WLHV suggests, paradoxically, that this immune challenged population may benefit greatly from immune checkpoint inhibitor therapies.

Prospective associations of hemoglobin A1c and c-peptide with risk of diabetes-related cancers in the Cancer Prevention Study-II Nutrition Cohort.

Self-reported type 2 diabetes mellitus (T2DM) is a risk factor for many cancers, suggesting its pathology relates to carcinogenesis. We conducted a case-cohort study to examine associations of hemoglobin A1c (HbA1c) and c-peptide with cancers associated with self-reported T2DM. This study was drawn from a prospective cohort of 32,383 women and men who provided blood specimens at baseline: c-peptide and HbA1c were assessed in 3,000 randomly selected participants who were cancer-free-at-baseline and an additional 2,281 participants who were cancer-free-at-baseline and subsequently diagnosed with incident colorectal, liver, pancreatic, female breast, endometrial, ovarian, bladder, or kidney cancers. Weighted-Cox regression models estimated hazards ratios (HRs) and 95% confidence intervals (CI), adjusted for covariates. C-peptide was associated with higher risk of liver cancer (per standard deviation (SD) HR: 1.80; 95%CI: 1.32-2.46). HbA1c was associated with higher risk of pancreatic cancer (per SD HR: 1.21 95%CI 1.05-1.40) and with some suggestion of higher risks for all-cancers-of-interest (per SD HR: 1.05; 95%CI: 0.99-1.11) and colorectal (per SD HR: 1.09; 95%CI: 0.98-1.20), ovarian (per SD HR: 1.18; 95%CI 0.96-1.45) and bladder (per SD HR: 1.08; 95%CI 0.96-1.21) cancers. Compared to no self-reported T2DM and HbA1c <6.5% (reference group), self-reported T2DM and HbA1c <6.5% (i.e., T2DM in good glycemic control) was not associated with risk of colorectal cancer, whereas it was associated with higher risks of all-cancers-of-interest combined (HR: 1.28; 95%CI: 1.01-1.62), especially for breast and endometrial cancers. Additional large, prospective studies are needed to further explore the roles of hyperglycemia, hyperinsulinemia, and related metabolic traits with T2DM-associated cancers to better understand the mechanisms underlying the self-reported T2DM-cancer association and to identify persons at higher cancer risk.

Relationship of Vitamin D Deficiency and Fatty Liver in Children as Defined by Multiple Imaging and Histologic Endpoints.

OBJECTIVES: The relationship between vitamin D deficiency (VDD) and pediatric nonalcoholic fatty liver disease (NAFLD) remains uncertain due to conflicting results and few studies with histologic endpoints. We therefore used multiple imaging and histologic NAFLD endpoints to more comprehensively assess the association between VDD and NAFLD in a large pediatric population. METHODS: Data were obtained from an ongoing pediatric NAFLD study in Bronx, NY. Briefly, overweight and obese children aged 2-18 years with alanine aminotransferase (ALT) levels ≥ 35 U/L were serially enrolled. Liver biopsy was obtained in accordance with clinical guidelines. All participants had liver imaging, namely, controlled attenuation parameter (CAP; Echosens, France) to assess steatosis and, to assess fibrosis, vibration controlled transient elastography (VCTE; FibroScan™, Echosens, France) and acoustic radiation force impulse (ARFI; Philips, Netherlands) imaging. Levels of 25-hydroxyvitamin D were measured serologically. RESULTS: N=276 (88%) of 315 participants had 25-OH vitamin D results, of whom 241 (87%) were Hispanic, 199 (72%) were male, and 92 (33%) underwent liver biopsy. VDD was univariately associated with high waist circumference (p=0.004), high-density lipoprotein level (p=0.01), season (p=0.009), and CAP score (p=0.01). In multivariate analysis, only waist circumference (p=0.0002) and biopsy inflammation grade (p=0.03) were associated with VDD, though the latter had not approximated statistical significance in univariate analysis (p=0.56). There was no association between VDD and hepatic steatosis, ballooning, NAFLD Activity Score, ARFI or VCTE elasticity scores. CONCLUSIONS: VDD was not associated with NAFLD defined by imaging and histologic endpoints, except for a possible relation with histologic inflammation grade.

Incidence and Types of Human Papillomavirus Infections in Adolescent Girls and Young Women Immunized With the Human Papillomavirus Vaccine.

Importance: Rates of human papillomavirus (HPV) infection have decreased since the introduction of HPV vaccines in populations with high vaccine uptake. Data are limited for adolescent and young adult populations in US metropolitan centers. Objective: To determine HPV infection rates in adolescent girls and young women aged 13 to 21 years in New York City following HPV vaccination. Design, Setting, and Participants: This cohort study of type-specific cervical HPV detection was conducted at a large adolescent-specific integrated health center in New York City between October 2007 and September 2019. Participants included an open cohort of adolescent girls and young adult women who received the HPV vaccine (Gardasil; Merck & Co) over a 12-year period following HPV vaccination introduction. Data analysis was concluded September 2019. Exposures: Calendar date and time since receipt of first vaccine dose. Main Outcomes and Measures: Temporal associations in age-adjusted postvaccine HPV rates. Results: A total of 1453 participants, with a mean (SD) age at baseline of 18.2 (1.4) years, were included in the cohort (African American with no Hispanic ethnicity, 515 [35.4%] participants; African American with Hispanic ethnicity, 218 [15.0%] participants; Hispanic with no reported race, 637 [43.8%] participants). Approximately half (694 [47.8%] participants) were vaccinated prior to coitarche. Age-adjusted detection rates for quadrivalent vaccine types (HPV-6, HPV-11, HPV-16, and HPV-18) and related types (HPV-31, and HPV-45) decreased year over year, with the largest effect sizes observed among individuals who had been vaccinated before coitarche (adjusted odds ratio [aOR], 0.81; 95% CI, 0.67-0.98). By contrast, detection was higher year over year for nonvaccine high-risk cervical HPV types (aOR, 1.08; 95% CI, 1.04-1.13) and anal HPV types (aOR, 1.11; 95% CI, 1.05-1.17). The largest effect sizes were observed with nonvaccine types HPV-56 and HPV-68. Conclusions and Relevance: Whereas lower detection rates of vaccine-related HPV types were observed since introduction of vaccines in female youth in New York City, rates of some nonvaccine high-risk HPV types were higher. Continued monitoring of high-risk HPV prevalence is warranted.

Frequency of high-grade squamous cervical lesions among women over age 65 years living with HIV.

BACKGROUND: Current US cervical cancer screening guidelines recommend screening cessation at the age of 65 years provided women have adequate previous screening and no history of precancer. Women living with HIV are at higher risk of cervical cancer than women living without HIV. Furthermore, limited data exists to quantify the risk of cervical cancer among women who otherwise would qualify for screening cessation. OBJECTIVE: This study aimed to determine whether guidelines recommending women to discontinue cervical cancer screening at the age of 65 years are appropriate for women living with HIV. STUDY DESIGN: Semiannual Papanicolaou testing was performed as part of surveillance visits in the Women's Interagency HIV Study. Launched in October 1994, the Women's Interagency HIV Study is a federally funded US multisite cohort study that has enrolled 3678 women living with HIV and 1304 women living without HIV; we included data throughout September 2019 onward. Conventional Papanicolaou tests were collected at scheduled 6-month visits and read centrally according to the 1991 Bethesda System criteria. Results were analyzed among women at least 65 years of age. The primary endpoint was high-grade cytology, including high-grade squamous intraepithelial lesions; atypical glandular cells; atypical squamous cells, cannot exclude high-grade lesions; and malignant cytology. Wilcoxon rank-sum tests were used to compare the continuous variables, and Chi-square tests or the Fisher exact tests were used to compare the categorical variables. The Kaplan-Meier method was used to calculate the cumulative incidence. Poisson regression was used to compare 2 incidence rates. RESULTS: Of 169 eligible women (121 women living with HIV and 48 women living without HIV) who contributed 678.4 person-years of observation after reaching the age of 65 years, 2.2% had high-grade cytologic abnormalities. However, no cancer was found. Furthermore, 20 women had previous precancer results, and 74 women had abnormal Papanicolaou test results in the previous decade. Among 50 women (38 women living with HIV and 12 women living without HIV) with a previous hysterectomy and no history of cervical precancer, the cumulative incidence rates of high-grade squamous intraepithelial lesions were 0.6 (95% confidence interval, 0.0-3.2) per 100 person-years for women living with HIV and 0.0 (95% confidence interval, 0.0-8.1) per 100 person-years for women living without HIV (P=.61). Only 48 women (27 women living with HIV and 21 women living without HIV) had cervices and met the current guidelines to discontinue screening; their risk of experiencing high-grade squamous intraepithelial lesions was 2.2 (95% confidence interval, 0.6-5.5) per 100 person-years overall and did not vary by HIV status (2.3 [95% confidence interval, 0.5-6.8] per 100 person-years for women living with HIV and 1.8 [95% confidence interval, 0.0-9.8] per 100 person-years for women living without HIV; P=.81). CONCLUSION: Most women living with HIV do not meet the criteria for cervical cancer screening cessation and will need to continue screening over the age of 65 years; however, women who meet the criteria for screening cessation have risks of high-grade squamous lesions similar to women living without HIV and may choose to discontinue.

Sex Hormones, Insulin, and Insulin-like Growth Factors in Recurrence of High-Stage Endometrial Cancer.

BACKGROUND: The influence of sex hormone and insulin/insulin-like growth factor (IGF) axis signaling on endometrial cancer recurrence is unknown. We evaluated these pathways in a prospective cohort of Gynecologic Oncology Group (GOG)0210 trial endometrial adenocarcinoma patients. METHODS: Stage II-IV patients (N = 816) were included in this study. Pretreatment specimens were tested for tumor mRNA and protein expression of IGF1, IGF2, IGF-binding proteins (IGFBP)-1 and -3, insulin (IR) and IGF-I receptors (IGF1R), phosphorylated IR/IGF1R (pIGF1R/pIR), and estrogen (ER) and progesterone receptors (PR) using qPCR and IHC. Serum concentrations of insulin, IGF-I, IGFBP-3, estradiol, estrone, and sex hormone binding globulin were measured. HRs and 95% confidence intervals (CI) for progression-free survival were calculated from Cox models adjusting for age, stage, and grade. RESULTS: Recurrence occurred in 280 (34%) cases during a median of 4.6 years of follow-up. ER positivity (HR, 0.67; 95% CI, 0.47-0.95), IR positivity (HR, 0.53; 95% CI, 0.29-0.98), and circulating IGF-I (highest vs. lowest quartile: HR, 0.66; 95% CI, 0.47-0.92) were inversely associated with recurrence risk. Circulating estradiol (highest vs. lowest tertile: HR, 1.55; 95% CI, 1.02-2.36) and pIGF1R/pIR positivity (HR, 1.40; 95% CI, 1.02-1.92) were associated with increased recurrence risk. CONCLUSIONS: Circulating estradiol and tumor tissue phosphorylated (activated) IGR1R/IR were independently associated with higher risk of recurrence in patients with endometrial cancer. IMPACT: This study may inform future clinical trials of endocrine-targeted adjuvant therapies in patients with endometrial cancer that could include baseline assessment of serum and tissue biomarkers of estradiol and insulin signaling pathways.

Association of liver enzymes with incident diabetes in US Hispanic/Latino adults.

INTRODUCTION: Non-alcoholic fatty liver disease (NAFLD) has been associated with increased risk of incident diabetes. But such evidence is lacking in the Hispanic/Latino population, which has high prevalence of obesity and NAFLD. METHODS: We conducted a prospective cohort study of 6,928 adults of Hispanic/Latino background who had no diabetes, did not report excessive alcohol use, and no hepatitis B and C infection at baseline (2008-2011). We estimated risk ratios (RR) for incident diabetes, identified from visit 2 examination by glucose measurements or antidiabetic medication use, with baseline liver enzymes (alanine aminotransferase (ALT), aspartate aminotransferase (AST) and gamma-glutamyl transpeptidase (GGT)). RESULTS: A total of 738 adults developed diabetes during 6 years of follow-up. After adjusting for participant characteristics at baseline, versus the lowest quartile, highest quartiles of ALT and GGT were associated with risks for incident diabetes (RR for ALT: 1.51 [95% CI 1.03-2.22], p-trend = 0.006; RR for GGT: 2.39 [1.60-3.55], p-trend = 0.001). Higher GGT levels predicted increased risk of incident diabetes even among those with ALT or AST below the median levels. The associations of ALT and GGT with incident diabetes were similar among most Hispanic background but were not seen among Dominicans (p for interaction <0.05). The association of AST with incident diabetes was found only among light-to-moderate alcohol drinkers (RR = 1.50 [1.20-1.86]) but not abstainers (RR = 0.91 [0.69-1.20], p for interaction = 0.006). CONCLUSION: Higher ALT and GGT levels are associated with increased risk of developing diabetes among Latinos. Liver enzyme tests might aid in diabetes prevention by identifying high-risk individuals.

The relationship of human papillomavirus and cytology co-testing results with endometrial and ovarian cancer diagnoses.

BACKGROUND: To investigate whether routine cervical screening using human papillomavirus (HPV) and cytology co-testing effectively identifies women with endometrial (EC) or ovarian (OvC) cancer. METHODS: In 2003, Kaiser Permanente Northern California implemented triennial co-testing in women aged ≥30 years. Index screening results (n = 2,385,729) were linked to subsequent EC (n = 3434) and OvC (n = 1113) diagnoses from January 1, 2003 to December 31, 2017. EC were categorized as type 1 or 2, and, selectively, EC and OvC diagnoses were stratified on whether symptoms were present at the time of the co-test. Fractions and absolute risks of EC or OvC of each co-testing result were calculated. RESULTS: Most EC (82.18%) and OvC (88.68%) were preceded by a negative HPV and negative cytology co-test. More EC were preceded by atypical squamous cells of undetermined significance (ASC-US) or more severe (ASC-US+) cytology and negative HPV test (n = 290) (8.44% of EC) compared to a negative cytology and a positive HPV test (n = 31) (0.89% of EC) (p < 0.001). The absolute risk of any EC diagnosis following ASC-US+ and negative HPV test was 0.48%. Atypical glandular cells (AGC) cytology and a negative HPV result preceded 6.92% of any EC diagnosis, with an absolute risk of 4.02%, but preceded only 1.13% of type 2 EC cases, with an absolute risk of 0.24%, in asymptomatic women. AGC cytology and a negative HPV result preceded 1.44% of OvC, with an absolute risk of 0.28%. CONCLUSIONS: Abnormal cervical screening tests, even AGC cytology, rarely precedes and poorly predict women with EC or OvC.

Primary HPV and Molecular Cervical Cancer Screening in US Women Living With Human Immunodeficiency Virus.

BACKGROUND: Primary human papillomavirus (HPV) screening (PHS) utilizes oncogenic human papillomavirus (oncHPV) testing as the initial cervical cancer screening method and typically, if positive, additional reflex-triage (eg, HPV16/18-genotyping, Pap testing). While US guidelines support PHS usage in the general population, PHS has been little studied in women living with HIV (WLWH). METHODS: We enrolled n = 865 WLWH (323 from the Women's Interagency HIV Study [WIHS] and 542 from WIHS-affiliated colposcopy clinics). All participants underwent Pap and oncHPV testing, including HPV16/18-genotyping. WIHS WLWH who tested oncHPV[+] or had cytologic atypical squamous cells of undetermined significance or worse (ASC-US+) underwent colposcopy, as did a random 21% of WLWH who were oncHPV[-]/Pap[-] (controls). Most participants additionally underwent p16/Ki-67 immunocytochemistry. RESULTS: Mean age was 46 years, median CD4 was 592 cells/µL, 95% used antiretroviral therapy. Seventy WLWH had histologically-determined cervical intraepithelial neoplasia grade 2 or greater (CIN-2+), of which 33 were defined as precancer (ie, [i] CIN-3+ or [ii] CIN-2 if concurrent with cytologic high grade squamous intraepithelial lesions [HSILs]). PHS had 87% sensitivity (Se) for precancer, 9% positive predictive value (PPV), and a 35% colposcopy referral rate (Colpo). "PHS with reflex HPV16/18-genotyping and Pap testing" had 84% Se, 16% PPV, 30% Colpo. PHS with only HPV16/18-genotyping had 24% Colpo. "Concurrent oncHPV and Pap Testing" (Co-Testing) had 91% Se, 12% PPV, 40% Colpo. p16/Ki-67 immunochemistry had the highest PPV, 20%, but 13% specimen inadequacy. CONCLUSIONS: PHS with reflex HPV16/18-genotyping had fewer unnecessary colposcopies and (if confirmed) could be a potential alternative to Co-Testing in WLWH.

Long-term Persistence of Oral HPV Over 7 Years of Follow-up.

BACKGROUND: Human papillomavirus-related oropharyngeal cancer (HPV-OPC) incidence is increasing, but the natural history of the precursor-oral HPV-has not been well described. METHODS: This observational cohort study of people living with HIV and at-risk HIV uninfected people evaluated participants semiannually using 30-second oral rinse and gargle specimens over 7 years. Initially, 447 participants were followed for 4 years as part of the Persistent Oral Papillomavirus Study, and a subset of 128 who showed persistent infections at the last Persistent Oral Papillomavirus Study visit had an additional visit, as part of the Men and Women Understanding Throat HPV Study, on average 2.5 years later. Extracted DNA from oral rinse and gargle specimens was amplified using polymerase chain reaction and type specification of 13 oncogenic HPV types. Risk factors for oncogenic oral HPV clearance were evaluated using Cox models. RESULTS: The majority of oncogenic oral HPV infections cleared quickly, with a median time to clearance of 1.4 years (interquartile range = 0.5-3.9 years). After 7 years of follow-up, 97% of incident and 71% of prevalent infections had cleared. Lower HPV-16 viral load was statistically significantly associated with clearance (per 10-fold decrease in copy number: adjusted hazard ratio [aHR] = 2.51, 95% confidence interval [CI] = 1.20 to 5.26; P = .01). Adjusted analyses showed that oncogenic oral HPV clearance was lower among prevalent than incident-detected infections (aHR = 0.44, 95% CI = 0.35 to 0.55), among men than women (aHR = 0.74, 95% CI = 0.60 to 0.91), for older participants (aHR per 10 years increasing age = 0.81, 95% CI = 0.74 to 0.89), and among people living with HIV (aHR = 0.76, 95% CI = 0.60 to 0.95). One participant who had oral HPV-16 consistently detected at 10 study visits over 4.5 years was subsequently diagnosed with HPV-OPC. CONCLUSIONS: This prospective study of oncogenic oral HPV infection is the longest and largest quantification of oral HPV-16 infections to date.

The interaction between pubertal timing and childhood maltreatment on the risk of human papillomavirus infection among adolescent girls and young women.

PURPOSE: The goal of this study was to evaluate the effect of pubertal timing, and its interaction with prior childhood maltreatment, on the risk of cervical human papillomavirus (HPV) among sexually active adolescent minority female adolescents and young adults. METHODS: This cross-sectional study includes 842 adolescent girls and young women (aged 12 to 20 years; predominately Black and Hispanic) enrolled in an HPV vaccine surveillance study at a large adolescent health clinic in New York City between 2007 and 2016. Pubertal timing was assessed by self-reported age at menarche at baseline, with "early" and "late" defined as one standard deviation below (<11 years) or above (>13 years) the mean. Childhood exposure to abuse (sexual, physical and emotional) and neglect (physical and emotional) was assessed using the Childhood Trauma Questionnaire. Over 40 types of HPV infection were detected using the polymerase chain reaction in cervical Pap specimens. RESULTS: Results from multivariable logistic regression showed that early and late pubertal timing were marginally associated with a higher risk of HPV infection, adjusting for demographic and health covariates. Childhood maltreatment moderated the association between early pubertal timing and HPV infection: early pubertal timing was associated with a higher risk for HPV infection among maltreated girls (OR = 3.32, 95%CI:1.61-6.85), but not among non-maltreated girls (OR = 0.96, 95%CI:0.61-1.50; p-interaction<0.01). CONCLUSIONS: Variation in the timing of puberty and history of childhood maltreatment may have implications for adolescent sexual and reproductive health. Findings suggest that clinicians need to assess the biological and psychosocial risks in caring for youth.