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Introduction: Human papillomavirus (HPV) is an epidemic currently affecting 80 million people in the United States. The HPV virus can be passed from one person to another via sexual intercourse, oral sex, open mouth kissing and skin-to-skin contact. In some cases, the infection is not eliminated by the immune system and can cause cancer of the head and neck, cervix, anus, and genitals. There has been a rise in oropharyngeal cancer (OPC) associated with HPV, which can be missed on conventional dental screening examinations. Dentists should engage in promoting HPV vaccination as a primary measure for OPC prevention. The goal of this HPV pilot program was to educate and offer same day HPV vaccination to dental patients by using a multidisciplinary approach in a hospital setting., Methods: Patients 18 through 26 years of age who presented to the Erie County Medical Center's dental clinic were approached and educated on HPV. Eligible patients received a direct recommendation for the HPV vaccine. Those interested in same day vaccination were referred to the division of infectious diseases' YOU Center for Wellness. A retrospective chart review was completed for patients who were HPV educated from March 5, 2020, through December 15, 2021. Charts were evaluated for age, sex, race, ethnicity, reason for visit, HPV vaccine referral, and HPV vaccine administration., Results: 326 patients were included in the chart review. The prominent sex, race, and ethnicity were male, Black or African American, and non-Hispanic origin. The median age was 23. Most patients presented to the dental clinic for an emergency visit and were not previously vaccinated against HPV. 110 patients were unvaccinated, and 44 patients were referred to the division of infectious disease for same day vaccination. Of these 44, 24 patients initiated the vaccination process. Five patients received all three doses, three patients received two doses, and 16 patients received one dose., Conclusion: This pilot program successfully vaccinated 24 patients with at least a single dose of the HPV vaccine. This multidisciplinary model can be implemented in other health care settings., (© 2024 Special Care Dentistry Association and Wiley Periodicals LLC.)

The risks of secondary cancers associated with human papillomavirus (HPV) infection are as much as three times higher for survivors of pediatric, adolescent, and young adult cancer (PYAC) compared to the general population. Despite this, HPV vaccination rates among PYAC survivors remain low. Whereas pediatric oncology providers endorse HPV vaccination of PYAC survivors, many lack the resources or opportunities to intervene. The responsibility of HPV vaccination, therefore, falls to primary care providers and practices. This article provides an overview of the challenges with HPV vaccination that are distinct to PYAC survivors and discusses potential strategies to increase HPV vaccine coverage in this population.

Although pediatric, adolescent, and young adult (PAYA) cancer survivors are at increased risks for secondary cancers, their HPV vaccine uptake rates are poor. Therefore, we conducted a mixed-methods study to identify the barriers and opportunities for HPV vaccine delivery among PAYA cancer care providers. We distributed a semistructured questionnaire to a professional organization comprised of PAYA oncology and hematology healthcare providers between April and July 2022. Questionnaire measures included demographic and practice characteristics, HPV vaccine knowledge, willingness, barriers, opportunities, and roles for HPV vaccine delivery. Descriptive characteristics were generated for quantitative data, and content analysis was used to identify themes. A total of 49 providers responded to our survey. A majority were female (68%) and non-Hispanic white (74%). Approximately 76% were oncology or hematology physicians, and most worked in a cancer center or children's hospital (86%). Over half (63%) had been practicing for >15 years, and a majority saw patients ages 11 to 17. Although less than half reported discussing HPV vaccination with their patients, 69% were willing to become involved in HPV vaccine delivery. The most frequently reported barriers identified in our content analysis were related to system-level factors. Furthermore, providers identified opportunities within cancer prevention education, transitions in care, and at the system-level. Although barriers to HPV vaccination persist in cancer care, most providers perceived there to be opportunities to become involved in HPV vaccine delivery. Identifying strategies for PAYA oncology and hematology healthcare providers to adopt a stronger role in HPV vaccination remains a significant opportunity for future implementation research., Prevention Relevance: This mixed-methods study is the first to investigate and assess barriers and opportunities for HPV vaccine delivery among PAYA cancer healthcare providers. Our findings can serve as an important framework for future implementation research targeted towards HPV vaccine delivery in cancer clinical settings. See related Spotlight, p. 545., (©2023 American Association for Cancer Research.)

Objectives: This study aimed to determine whether condom use varied between adolescents and young women using long-acting reversible contraception (LARC) vs non-LARC hormonal methods and assess if the initiation of LARC was associated with lower condom use., Study Design: This study used data from a large longitudinal study of sexually active females aged 13-25 years. Questionnaires assessed contraception, condom use, sexual history, and partner characteristics at the baseline visit and every 6 months. Log-binomial regression analyses examined associations between hormonal contraceptive methods and condom use, and the moderating effects of age and number of sexual partners. Exploratory analyses compared condom use based on partner characteristics., Results: Of 1512 participants, 1116 reported LARC or non-LARC hormonal method use during any study visit. Among baseline and new LARC users, 75.7% and 84.7% reported intrauterine device (IUD) use, respectively. Condom use at baseline among hormonal non-LARC users (37.5%) was significantly higher (p < 0.01) than LARC users (23.5%). Condom use among LARC vs non-LARC users was moderated by age in that LARC was associated with lower condom use among participants aged 13-18 years, but not those aged 19-25 years. Number of sexual partners was not a significant moderator. Among participants with increased sexually transmitted infection (STI) risk based on partner characteristics, LARC users had lower condom use compared to non-LARC users., Conclusions: Condom discontinuation was common following initiation of LARC and hormonal non-LARC methods. However, condom use was lower in LARC users at baseline, among younger adolescents, and if partners had risk factors for STIs., Implications: Condom discontinuation following initiation of highly effective contraception increases the risk of STI. Young women using LARC may be at greater risk than non-LARC users given lower condom use despite having partners with risk factors for STIs. Condom use counseling for STI protection is critical for adolescents., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Trichomoniasis, caused by Trichomonas vaginalis (TV), is the most common non-viral sexually transmitted infection (STI) worldwide, affecting over 174 million people annually and is frequently associated with reproductive co-morbidities. However, its detection can be time-consuming, subjective, and expensive for large cohort studies. This case-control study, conducted at the Mount Sinai Adolescent Health Center in New York City, involved 36 women with prevalent TV infections and 36 controls. The objective was to examine Internal Transcribed Spacer region-1 (ITS1) amplicon-derived communities for the detection of prevalent TV infections with the same precision as clinical microscopy and the independent amplification of the TV-specific TVK3/7 gene. DNA was isolated from clinician-collected cervicovaginal samples and amplified using ITS1 primers in a research laboratory. Results were compared to microscopic wet-mount TV detection of concurrently collected cervicovaginal samples and confirmed against TV-specific TVK3/7 gene PCR. The area under the receiver operating characteristics curve (AUC) for diagnosing TV using ITS1 communities was 0.92. ITS1 amplicons displayed an intra-class correlation coefficient (ICC) of 0.96 (95% CI: 0.93-0.98) compared to TVK3/7 PCR fragment testing. TV cases showed an increased risk of bacterial vaginosis (BV) compared to the TV-negative controls (OR = 8.67, 95% CI: 2.24-48.54, p -value = 0.0011), with no significant differences regarding genital yeast or chlamydia infections. This study presents a bioinformatics approach to ITS1 amplicon next-generation sequencing that is capable of detecting prevalent TV infections. This approach enables high-throughput testing for TV in stored DNA from large-scale epidemiological studies.

Purpose: Seropositivity for the HPV16-E6 oncoprotein is a promising marker for early detection of oropharyngeal cancer (OPC), but the absolute risk of OPC after a positive or negative test is unknown., Methods: We constructed an OPC risk prediction model that integrates (1) relative odds of OPC for HPV16-E6 serostatus and cigarette smoking from the human papillomavirus (HPV) Cancer Cohort Consortium (HPVC3), (2) US population risk factor data from the National Health Interview Survey, and (3) US sex-specific population rates of OPC and mortality., Results: The nine HPVC3 cohorts included 365 participants with OPC with up to 10 years between blood draw and diagnosis and 5,794 controls. The estimated 10-year OPC risk for HPV16-E6 seropositive males at age 50 years was 17.4% (95% CI, 12.4 to 28.6) and at age 60 years was 27.1% (95% CI, 19.2 to 45.4). Corresponding 5-year risk estimates were 7.3% and 14.4%, respectively. For HPV16-E6 seropositive females, 10-year risk estimates were 3.6% (95% CI, 2.5 to 5.9) at age 50 years and 5.5% (95% CI, 3.8 to 9.2) at age 60 years and 5-year risk estimates were 1.5% and 2.7%, respectively. Over 30 years, after a seropositive result at age 50 years, an estimated 49.9% of males and 13.3% of females would develop OPC. By contrast, 10-year risks among HPV16-E6 seronegative people were very low, ranging from 0.01% to 0.25% depending on age, sex, and smoking status., Conclusion: We estimate that a substantial proportion of HPV16-E6 seropositive individuals will develop OPC, with 10-year risks of 17%-27% for males and 4%-6% for females age 50-60 years in the United States. This high level of risk may warrant periodic, minimally invasive surveillance after a positive HPV16-E6 serology test, particularly for males in high-incidence regions. However, an appropriate clinical protocol for surveillance remains to be established.

Introduction: The risk of human papillomavirus (HPV)-associated cancers is significantly higher among survivors of a childhood cancer compared to the general population. Despite this, their HPV vaccine uptake rates are lower. We examined factors related to HPV vaccine uptake among childhood cancer survivors from Western New York over 13 years following the introduction of HPV vaccines., Methods: Retrospective review of patients diagnosed with invasive or noninvasive cancerous conditions at age 9 or younger treated at Roswell Park Oishei Children's Cancer and Blood Disorder Program. We matched vaccine date information for patients aged 9-26 years between 2006 and 2020 from the New York State Immunization Information System. Demographic and cancer-related information was abstracted from electronic medical records. Cumulative vaccine uptake was assessed by Kaplan-Meier and Cox proportional hazards regression models., Results: A total of 284 patients were included in the analyses. Most were non-Hispanic/White (80.3%) and resided in a metropolitan area (81.7%). Approximately half had leukemia or lymphoma (54.9%), and most received chemotherapy. Females were more likely to initiate the HPV vaccine and did so sooner (median = 5.5 years) than males (median = 5.7 years; log-rank p = .301). Patients who were older at vaccine eligibility and males who received blood product transfusions were significantly less likely to initiate the HPV vaccine., Conclusion: While rates of HPV vaccine initiation have been increasing with time among childhood cancer survivors, they remain low overall, with differences seen by treatment and diagnosis. Our findings support the need for further research to optimize HPV vaccine delivery in cancer care., (© 2022 Wiley Periodicals LLC.)

Background: Three genera of human papillomavirus (HPV) infect the oral cavity and oropharynx- alpha (α), beta (β) and gamma (γ). While α-HPV infection is an established risk factor for head and neck cancers (HNC), the role of other genera remains unclear. We aimed to estimate the effect of α-, β-, γ-HPV on HNC using a hospital-based case-control study., Methods: We recruited incident HNC cases (396) and controls (439), frequency-matched by age and sex from four main referral hospitals in Montreal, Canada. We collected information on sociodemographic and behavior characteristics using in-person interviews, and tested rinse, brush and tumor specimens for HPV genotypes. We estimated adjusted odds ratios (aOR) and 95% confidence intervals (CI) for the effect of HPV on HNC using logistic regression, adjusting for confounding. We conducted probabilistic bias analysis to account for potential exposure misclassification, selection bias, and residual confounding., Results: α-HPV genus had a strong effect on HNC, particularly HPV16 (aOR=22.6; 95% CI: 10.8, 47.2). β-HPV was more common among controls (aOR=0.80; 95% 0.57, 1.11). After adjustment for HPV16, we found weaker evidence for γ-HPV (aOR= 1.29; 95% CI: 0.80, 2.08). Combined bias analyses for HPV16 increased the strength of the point estimate, but added imprecision (aOR=54.2, 95% CI: 10.7, 385.9)., Conclusions: α-HPV, especially HPV16, appears to increase the risk for HNC, while there is little evidence for an effect of β- or γ-HPV. β-HPV may have a preventive effect, while γ-HPV may increase the risk of HNC, although to a lesser extent than that of α-HPV. Results for cutaneous HPV were imprecise and less conclusive. Due to possible epidemiologic biases, the true relation between HPV and HNC could be underestimated in the literature. Further improvement in current methods and more studies of the biologic mechanisms of the three genera in HNC development are warranted., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: HIV has been shown to increase the likelihood of oral HPV infection. In this study, we evaluated the risk of oral HPV in HIV infected patients compared with HIV-negative controls., Methods: 101 healthy adult volunteers (HIV-) and 245 adults living with HIV infection (HIV+) were recruited from 5 academic medical centers. Questionnaires and saliva samples were obtained every 3-8 months over a period of 2 years (2015-2017). DNA was isolated from the saliva samples and tested for 18 high- and low-risk genotypes., Results: Oral HPV was detected in 23% of HIV + vs. 10% of HIV- participants (p < 0.0001). Men had a higher oral HPV prevalence than women (27% vs. 15% HIV+, p = 0.03, 16% vs. 5% HIV-, p = 0.01). Risk factors among HIV + participants included more lifetime deep kissing and oral sex partners, and history of AIDS. Persistent oral HPV was detected in 23% of HIV + vs. 5% of HIV- participants (p < 0.001). Among 8 HIV + participants with CD4 counts <200 cell/μL none had cleared their HPV infection during the study., Conclusions: Risk of oral HPV infection and persistence was significantly higher in HIV + adults with a history of poorly controlled HIV, which may put them at increased risk of HPV-associated cancer., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Purpose: New York City (NYC) was the global epicenter of the COVID-19 pandemic in spring 2020. A "shelter in place" mandate was issued in March 2020. The effect on vulnerable populations of adolescent and young adult females has not been well documented., Methods: We administered a monthly online survey between May and November 2020 to adolescent and young adult females participating in a longitudinal study at Mount Sinai Adolescent Health Center. Surveys asked about death of loved ones, financial impacts, social interactions, exposure to dangerous situations, and mental health impacts. Differences in responses by age, race/ethnicity, and living situation were assessed, and compared to data obtained on the same cohort prior to the pandemic., Results: Four hundred seventeen females aged 15-28 years completed at least one survey, 94% of whom were youth of color. A third of responders (33%) had lost relatives or other people they were close to (loved ones). Most (68%) reported one or more financial losses, and 21% reported food insecurity, with those not living with parents or a guardian experiencing significantly higher rates. One in 10 reported experiencing sexual abuse or interpersonal partner violence during the "shelter in place" period. Over a third (37%) reported symptoms of clinical depression, which represented a significant increase compared to before the pandemic (p = .01). The negative financial impacts and higher proportion of patients with depressive symptomatology remained elevated for adolescents without support at home., Conclusions: The COVID-19 pandemic had unprecedented negative short-term financial and psychosocial health impacts on inner-city female youth with potential long-term negative impacts., (Copyright © 2021 Society for Adolescent Health and Medicine. Published by Elsevier Inc. All rights reserved.)

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-1β/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-1β 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., (© 2022. The Author(s).)

Purpose: The purpose of this study is to identify distinct neighborhood profiles patterned by key structural, physical, and social characteristics and test whether living in different profiles are associated with body mass index trajectories during adolescence in racial/ethnic minority female youth., Methods: Participants were 1,328 sexually active female adolescents and young adults aged 14-23 years, predominately Hispanic and black, enrolled in an human papillomavirus type 4 vaccine (Gardasil) surveillance study at a large adolescent health clinic in New York City between 2007 and 2018. Body mass index was calculated from weight and height every 6 months. A comprehensive set of neighborhood structural, social, and physical characteristics from multiple national and state datasets was linked to each participant based on home address., Results: Latent profile analysis revealed five distinct neighborhood profiles in New York City: High Structural/High Social Advantage, Moderate Advantage/Low Crime, Low SES (Socioeconomic Status)/High Activity, Low SES/High Social Advantage, and High Disadvantage. Results from multilevel growth curve analysis revealed that living in Low SES/High Activity neighborhoods was associated with a lower BMI at age 22 (b = -1.32, 95% confidence interval -2.49, -.16), as well as a slower increase in BMI from age 14 to 22 years (b = -.22, 95% confidence interval -.46, .02), compared to the High Disadvantage profile., Conclusions: Our findings suggest that improving neighborhood structural, social, and physical environments may help promote healthy weight and reduce health disparities during adolescence and young adulthood., (Copyright © 2021 Society for Adolescent Health and Medicine. Published by Elsevier Inc. All rights reserved.)

Background: The United States has experienced an increasing divergence in cannabis, tobacco, and alcohol use among adolescents and young adults (AYA). We assessed the changes in cannabis, tobacco and alcohol use in an inner-city population of predominantly minority AYA females attending a large adolescent-specific health center in New York City., Methods: This was a longitudinal study of AYA women recruited and followed over a twelve-year period between 2007 and 2019. Lifetime and past 30-day use were assessed by self-administered questionnaire every six months. In addition, we assessed associations with race, ethnicity, sexual behaviors, receipt of social services, living situation at home (e.g., with or without parents), and use of other drugs., Results: Participants included 1549 AYA females aged 13-21 at baseline, 95% of whom were youth of color. Use of cannabis increased significantly over the twelve-year period, with frequent cannabis use (≥20 times in 30-days) increasing almost 18% per year (OR = 1.18; 95%CI:1.13-1.23). In contrast, past 30-day tobacco use declined over the same period (OR = 0.86; 95%CI:0.83-0.89). Past 30-day cannabis use was more likely among African Americans (OR = 1.33; 95%CI:1.08-1.63), women who had sex with both men and women compared to with men only (OR = 1.44; 95%CI:1.18-1.75), recent users of tobacco (OR = 2.20; 95%CI:1.92-2.52) and alcohol (OR = 2.84; 95%CI:2.52-3.20), and ever users of other drugs (OR = 1.69; 95%CI:1.44-1.99), independent of age, time and living situation., Conclusions: Increasing rates of cannabis use and the association with concurrent tobacco and alcohol use in AYA females underscore the need to screen for unhealthy cannabis use, in addition to tobacco and alcohol, especially among inner-city AYA., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Nonadherence to NCCN Guidelines during time from surgery to postoperative radiotherapy (S-PORT) can alter survival outcomes in head and neck squamous cell carcinomna (HNSCC). There is a need to validate this impact in an underserved urban population and to understand risk factors and reasons for delay. We sought to investigate the impact of delayed PORT with outcomes of overall survival (OS) in HNSCC, to analyze predictive factors of delayed PORT, and to identify reasons for delay., Methods: We conducted a retrospective cohort study in an urban, community-based academic center. A total of 184 patients with primary HNSCC were identified through the Montefiore Medical Center cancer registry who had been treated between March 1, 2005, and March 8, 2017, and met the inclusion and exclusion criteria. The primary exposure was S-PORT. OS, recurrence, and risk factors and reasons for treatment delay were the main outcomes and measures., Results: Among 184 patients with HNSCC treated with PORT, the median S-PORT was 48.5 days (interquartile range, 41-67 days). The S-PORT threshold that optimally differentiated worse OS outcomes was >50 days (46.7% of our cohort; n=86). Independent of other relevant factors, patients with HNSCC and S-PORT >50 days had worse OS (hazard ratio, 2.30; 95% CI, 1.34-3.95) and greater recurrence (odds ratio, 3.51; 95% CI, 1.31-9.39). Predictors of delayed S-PORT included being underweight or obese, prolonged postoperative length of stay, and age >70 years. The most frequent reasons for PORT delay were complications related to surgery (22.09%), unrelated medical comorbidities (18.60%), and nonadherence/missed appointments (6.98%)., Conclusions: Delayed PORT beyond 50 days after surgery was associated with decreased OS and greater recurrence. Identification of predictive factors and reasons for treatment delay helps to target at-risk patients and facilitates interventions in underserved populations.

Objective: To identify differences in survival among women diagnosed with cancer of the anal canal from varying racial and ethnic backgrounds., Methods: Data from the Surveillance, Epidemiology and End Results (SEER) registry between the years of 1975 and 2016 were analyzed, which included 19,048 women with cancer of the anal canal. Multivariable Cox proportional hazard regression (HRs) was performed to examine the relative risk of dying among women with anal cancer. Multivariable odds ratios (ORs) with 95% confidence intervals (CIs) were used to examine odds of highly fatal disease (death within 12 months from diagnosis)., Results: Non-Hispanic Black women (n = 1694) had greater risk of dying when compared with non-Hispanic White women (n = 15,821) with anal cancer (HR = 1.26, CI: 1.17-1.35), independent of other prognostic indicators. Stratifying by age at diagnosis, risk of death was highest for non-Hispanic Black women diagnosed younger than age 50 years compared with non-Hispanic White women of similar age (HR = 1.60, CI: 1.34-1.89), and lowest for Hispanic women (n = 1533) older than 74 years at diagnosis (HR = 0.80, CI: 0.69-0.92). Stratifying by stage at diagnosis, disparities were not observed. When comparing across years of diagnoses, non-Hispanic Black women consistently had poorer survival compared with non-Hispanic White women diagnosed in the same year intervals. Finally, non-Hispanic Black women had greater odds of highly fatal disease (OR = 1.23, CI: 1.08-1.40) compared with non-Hispanic White women., Conclusion: Non-Hispanic Black women with anal cancer continue to experience poorer survival compared with non-Hispanic White women, whereas disparities were not identified for Hispanic women., (© 2020. Springer Science+Business Media, LLC, part of Springer Nature.)

The goal of this study was to investigate the serological titers of circulating antibodies against human papillomavirus (HPV) type 16 (anti-HPV16) prior to the detection of an incident HPV16 or HPV31 infection amongst vaccinated participants. Patients were selected from a prospective post-HPV vaccine longitudinal cohort at Mount Sinai Adolescent Health Center in Manhattan, NY. We performed a nested case-control study of 43 cases with incident detection of cervical HPV16 ( n = 26) or HPV31 ( n = 17) DNA who had completed the full set of immunizations of the quadrivalent HPV vaccine (4vHPV). Two control individuals whom had received three doses of the vaccine (HPV16/31-negative) were selected per case, matched on age at the first dose of vaccination and follow-up time in the study: a random control, and a high-risk control that was in the upper quartile of a sexual risk behavior score. We conducted an enzyme-linked immunosorbent assay (ELISA) for the detection of immunoglobulin G (IgG) antibodies specific to anti-HPV16 virus-like particles (VLPs). The results suggest that the average log antibody titers were higher among high-risk controls than the HPV16/31 incident cases and the randomly selected controls. We show a prospective association between anti-HPV16 VLP titers and the acquisition of an HPV16/31 incident infection post-receiving three doses of 4vHPV 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.

This study examines associations between childhood maltreatment and developmental trajectories of sexual risk behaviors (SRBs) in a sample of 882 sexually active adolescent girls, predominantly Hispanic or Black, assessed every 6 months between 13 and 23 years. Latent profile analyses revealed four distinct maltreatment profiles: Low Maltreatment (76%), Moderate Emotional Neglect Only (15%), Severe Physical/Emotional Abuse (3%), and Severe Sexual Abuse (6%). Multilevel growth analyses showed the Moderate Emotional Neglect Only and Severe Sexual Abuse profiles exhibited more SRBs starting in late adolescence, and the Severe Sexual Abuse profile also exhibited a faster increase than the Low Maltreatment profile. Understanding heterogeneity within maltreated populations may have important implications for healthy sexual development., (© 2021 Society for Research in Child Development.)

Background: To address a critical gap for application of cancer chronotherapy of when would be the best time(s) for treating an individual cancer patient, we conducted a pilot study to characterize diurnal variations of gene expression in oral mucosal tissue, which is vulnerable to damage from cancer therapies., Methods: We conducted RNA-seq assay on individual oral mucosal samples collected from 11 healthy volunteers every 4 hours (6 time points). Using a cosine-based method, we estimated the individual and average values of peak-time and amplitude for each gene. Correlations between gene expression peak-times and age was examined, adjusting for individual's sleep timing., Results: Among candidate gene pathways that are relevant to treatment response, 7 of 16 genes ( PER3, CIART, TEF, PER1, PER2, CRY2, ARNTL ) involved in circadian regulation and 1 of 118 genes ( WEE1 ) involved in cell cycle regulation achieved p-value ≤ 0.1 and relative amplitude>0.1. The average peak times were approximately 10:15 for PER3, CIART and TEF, 10:45 for PER1, 13:00 for WEE1, PER2 and CRY2, and 19:30 for ARNTL. Ranges in peak times across individuals differed by gene (e.g., 8 hours for PER1; 16.7 hours for WEE1). Older people had later peak times for PER1 (r = 0.77, p = 0.03) and PER3 (r = 0.69, p-value = 0.06)., Conclusion: In oral mucosa, expression of some genes relevant to treatment response displayed diurnal variation. These genes may be candidates for development of biomarkers for optimizing individual timing of cancer therapy using non-invasively collected oral mucosa., Competing Interests: The authors have no competing interests to declare., (Copyright: © 2021 The Author(s).)

We demonstrate that inhibition of cyclin-dependent kinases 4/6 (CDK4/6) leads to senescence in human papillomavirus (HPV)-negative (-) head and neck squamous cell carcinoma (HNSCC), but not in HPV-positive (+) HNSCC. The BCL-2 family inhibitor, navitoclax, has been shown to eliminate senescent cells effectively. We evaluated the efficacy of combining palbociclib and navitoclax in HPV - HNSCC. Three HPV - HNSCC cell lines (CAL27, HN31, and PCI15B) and three HPV + HNSCC cell lines (UPCI-SCC-090, UPCI-SCC-154, and UM-SCC-47) were treated with palbociclib. Treatment drove reduced expression of phosphorylated Rb (p-Rb) and phenotypic evidence of senescence in all HPV - cell lines, whereas HPV + cell lines did not display a consistent response by Rb or p-Rb and did not exhibit morphologic changes of senescence in response to palbociclib. In addition, treatment of HPV - cells with palbociclib increased both β-galactosidase protein expression and BCL-xL protein expression compared with untreated controls in HPV - cells. Co-expression of β-galactosidase and BCL-xL occurred consistently, indicating elevated BCL-xL expression in senescent cells. Combining palbociclib with navitoclax led to decreased HPV - HNSCC cell survival and led to increased apoptosis levels in HPV - cell lines compared with each agent given alone. IMPLICATIONS: This work exploits a key genomic hallmark of HPV - HNSCC ( CDKN2A disruption) using palbociclib to induce BCL-xL-dependent senescence, which subsequently causes the cancer cells to be vulnerable to the senolytic agent, navitoclax., (©2021 American Association for Cancer Research.)

Peer navigators (PNs), including trained cancer survivor volunteers, can be an important resource to the cancer care team in reducing barriers to screening, treatment, and psychosocial care among underserved communities through their roles in outreach, education, advocacy, and peer support. As cancer centers face growing patient demand and evidence for integrating complementary therapies into conventional care, opportunities to envision new roles for PN arise. Based on psychosocial assessments conducted at an academic cancer center serving the low-income population of Bronx, NY, we found strong interest in both providing (44 %) and receiving (76 %) peer support, as well as in (76 %) mind-body practices (e.g., meditation). In research, these mind-body modalities and peer support have both been found to improve many aspects of physical and emotional outcomes in cancer patients, but none has looked at PNs as a potential resource for delivering such mind-body interventions. Towards this end, we conducted two pilot studies to train PN from an onsite peer navigation program called the BOLD Buddy Program, to deliver a well-defined, easy to learn, and culturally-aligned mind-body practice, i.e., Loving Kindness (LK) Meditation, to each other and to patients. Incorporating comparison to professional meditation instructors, our pilot work demonstrated that peer-lead LKM was associated with benefits to emotional well-being, relaxation, satisfaction, and perceived usability and that PNs were equally well-received in delivering LK as their professional counterparts. Evaluating 8 domains of feasibility using standardized measures, we were able to demonstrate that peer-lead LK was: in demand, acceptable, implementable, practical, adaptable, adoptable, expandable, and promising in efficacy., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objectives: To evaluate BCL-2 family signaling molecules in head and neck squamous cell carcinoma (HNSCC) and examine the ability of therapeutic agents with variable mechanisms of action to induce apoptosis in HNSCC cells., Methods: messenger ribonculeic acid (mRNA) expression of BAK, BAX, B-cell lymphoma (Bcl-2), BCL2 Like 1 (BCL2L1), and MCL1 were measured in The Cancer Genome Atlas (TCGA) head and neck cancer dataset, as well as in a dataset from a cohort at Montefiore Medical Center (MMC). Protein expression was similarly evaluated in a panel of HNSCC cell lines (HN30, HN31, HN5, MDA686LN, UMSCC47). Cell viability and Annexin V assays were used to assess the efficacy and apoptotic potential of a variety of agents (ABT-263 [navitoclax], A-1210477, and bortezomib., Results: Expression of BAK, BAX, BCL2L1, and MCL1 were each significantly higher than expression of BCL2 in the TCGA and MMC datasets. Protein expression demonstrated the same pattern of expression when examined in HNSCC cell lines. Treatment with combined ABT-263 (navitoclax)/A-1210477 or with bortezomib demonstrated apoptosis responses that approached or exceeded treatment with staurospaurine control., Conclusion: HNSCC cells rely on inhibition of apoptosis via BCL-xL and MCL-1 overexpression, and induction of apoptosis remains a potential therapeutic option as long as strategies overcome redundant anti-apoptotic signals., Level of Evidence: NA Laryngoscope, 130:2643-2649, 2020., (© 2020 The American Laryngological, Rhinological and Otological Society, Inc.)

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., Competing Interests: Declaration of competing interest The authors have no conflicts of interest relevant to this article to disclose., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: People living with HIV (PLWH) are more likely to smoke and harbor oral human papillomavirus (HPV) infections, putting them at higher risk for head and neck cancer. We investigated effects of HIV and smoking on oral HPV risk., Methods: Consecutive PLWH (n = 169) and at-risk HIV-negative individuals (n = 126) were recruited from 2 US health centers. Smoking history was collected using questionnaires. Participants provided oral rinse samples for HPV genotyping. We used multivariable logistic regression models with interaction terms for HIV to test for smoking effect on oral HPV., Results: PLWH were more likely to harbor oral HPV than HIV-negative individuals, including α (39% vs 28%), β (73% vs 63%), and γ-types (33% vs 20%). HIV infection positively modified the association between smoking and high-risk oral HPV: odds ratios for smoking 3.46 (95% confidence interval [CI], 1.01-11.94) and 1.59 (95% CI, .32-8.73) among PLWH and HIV-negative individuals, respectively, and relative excess risk due to interaction (RERI) 3.34 (95% CI, -1.51 to 8.18). RERI for HPV 16 was 1.79 (95% CI, -2.57 to 6.16) and 2.78 for β1-HPV (95% CI, -.08 to 5.65)., Conclusion: Results show tobacco smoking as a risk factor for oral HPV among PLWH., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Human papillomavirus (HPV) infection and tobacco smoking are well-known risk factors for head and neck cancers (HNC). Although an effect modification between oral HPV infection and tobacco smoking may exist, evidence is lacking on how they interact temporally. We investigated the latency and life course effects of tobacco smoking on risk of HNC among HPV-positive (HPV +ve ) and negative (HPV -ve ) individuals. We used data from 631 ever-smoker participants of a hospital-based case-control study conducted in four major hospitals in Montréal, Canada. Cases (n = 320), incident, histologically confirmed, primary squamous cell carcinomas, were frequency-matched to controls (n = 311) by age and sex. Sociodemographic and behavioral factors (e.g., tobacco and alcohol use and sexual history) were collected using a structured interview applying a life grid technique. Oral exfoliated cells were used for HPV DNA detection and genotyping. Latency effects were estimated flexibly using a Bayesian relevant exposure model and further extended with a life course approach. Retrospective smoking trajectories for HPV +ve cases and controls had similar shapes. Exposure to tobacco smoking even 40 years before diagnosis was associated with an increased HNC risk among both HPV +ve and HPV -ve participants. The effect of smoking before the start of sexual activity compared to afterwards was higher among HPV +ve individuals. This pattern of association was less profound among HPV -ve participants. Temporal interactions may exists between oral HPV infection and life course smoking trajectories in relation to HNC risk., (© 2019 UICC.)

Background: Limited treatment options are available for oral mucositis, a common, debilitating complication of cancer therapy. We examined the association between daily delivery time of radiotherapy and the severity of oral mucositis in patients with head and neck cancer., Methods: We used electronic medical records of 190 patients with head and neck squamous cell carcinoma who completed radiotherapy, with or without concurrent chemotherapy, at Roswell Park Comprehensive Cancer Center (Buffalo, NY) between 2015 and 2017. Throughout a 7-week treatment course, patient mouth and throat soreness (MTS) was self-reported weekly using a validated oral mucositis questionnaire, with responses 0 (no) to 4 (extreme). Average treatment times from day 1 until the day before each mucositis survey were categorized into seven groups. Multivariable-adjusted marginal average scores (LSmeans) were estimated for the repeated- and maximum-MTS, using a linear-mixed model and generalized-linear model, respectively., Results: Radiation treatment time was significantly associated with oral mucositis severity using both repeated-MTS ( n = 1,156; P = 0.02) and maximum-MTS ( n = 190; P = 0.04), with consistent patterns. The severity was lowest for patients treated during 8:30 to <9:30 am (LSmeans for maximum-MTS = 2.24; SE = 0.15), increased at later treatment times and peaked at early afternoon (11:30 am to <3:00 pm, LSmeans = 2.66-2.71; SEs = 0.16/0.17), and then decreased substantially after 3 pm., Conclusions: We report a significant association between radiation treatment time and oral mucositis severity in patients with head and neck cancer., Impact: Although additional studies are needed, these data suggest a potential simple treatment time solution to limit severity of oral mucositis during radiotherapy without increasing cost., (©2020 American Association for Cancer Research.)

Background: Over six million children each year are referred to child protective services for child abuse (sexual, physical and emotional) and neglect (physical and emotional)., Objective: While the relationship between child sexual abuse and sexually transmitted infections has been documented, there has been little research regarding the effects of other forms of maltreatment., Participants and Setting: 882 inner-city females aged 12-20 years of age seen at a large adolescent and young adult (AYA) health center in New York City between 2012-2017., Methods: History of maltreatment was assessed using the Childhood Trauma Questionnaire. Associations with depressive symptoms, antisocial behavior, peer deviancy, drug/alcohol use, and risky sexual behaviors were assessed., Results: History of maltreatment was common in our cohort of inner-city AYA females, with 59.6 % reporting any type of maltreatment, including sexual abuse (17.5 %), physical abuse (19.5 %) or neglect (26.2 %), and emotional abuse (30.7 %) or neglect (40.4 %). We observed significant associations between all forms of maltreatment and risk of depression, drug/alcohol use, antisocial behaviors, peer deviancy, and risky sexual risk behaviors (including having a higher number of sexual partners, having a sexual partner 5+ years older, and anal sex). Physical and emotional abuse were associated with having unprotected sex while under the influence of drugs/alcohol., Conclusions and Relevance: Reporting a history of maltreatment was associated with an increased likelihood of engaging in risky sexual and antisocial behaviors, as well as depression in inner-city female youth. These data highlight the broad, lingering repercussions of all types of child maltreatment., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest relevant to this article to disclose., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Importance: Delay in time to treatment initiation (TTI) can alter survival and oncologic outcomes. There is a need to characterize these consequences and identify risk factors and reasons for treatment delay, particularly in underserved urban populations., Objectives: To investigate the association of delayed treatment initiation with outcomes of overall survival and recurrence among patients with head and neck squamous cell carcinoma (HNSCC), to analyze factors that are predictive of delayed treatment initiation, and to identify specific reasons for delayed treatment initiation., Design, Setting, and Participants: Retrospective cohort study at an urban community-based academic center. Participants were 956 patients with primary HNSCC treated between February 8, 2005, and July 17, 2017, identified through the Montefiore Medical Center Cancer Registry., Exposures: The primary exposure was TTI, defined as the duration between histopathological diagnosis and initial treatment. The threshold for delayed treatment initiation was determined by recursive partitioning analysis., Main Outcomes and Measures: Overall survival, recurrence, and reasons for treatment delay., Results: Among 956 patients with HNSCC (mean [SD] age, 60.8 [18.2] years; 72.6% male), the median TTI was 40 days (interquartile range, 28-56 days). The optimal TTI threshold to differentiate overall survival was greater than 60 days (20.8% [199 of 956] of patients in our cohort). Independent of other relevant factors, patients with HNSCC with TTI exceeding 60 days had poorer survival (hazard ratio, 1.69; 95% CI, 1.32-2.18). Similarly, TTI exceeding 60 days was associated with greater risk of recurrence (odds ratio, 1.77; 95% CI, 1.07-2.93). Predictors of delayed TTI included African American race/ethnicity, Medicaid insurance, body mass index less than 18.5, and initial diagnosis at a different institution. Commonly identified individual reasons for treatment delay were missed appointments (21.2% [14 of 66]), extensive pretreatment evaluation (21.2% [14 of 66]), and treatment refusal (13.6% [9 of 66])., Conclusions and Relevance: Delaying TTI beyond 60 days was associated with decreased overall survival and increased HNSCC recurrence. Identification of predictive factors and reasons for treatment delay will help target at-risk patients and facilitate intervention in hospitals with underserved urban populations.

Importance: Human papillomavirus (HPV) is the most common sexually transmitted infection in the United States, and oral HPV infection is associated with increased risk of oropharyngeal cancer., Objective: To describe the risk factors for oral HPV in sexually active female adolescents receiving the quadrivalent vaccine., Design, Setting, and Participants: Longitudinal cohort study involving repeated collection of oral rinse specimens from sexually active female adolescents conducted between October 19, 2007, and March 9, 2017, at a large adolescent health center in New York, New York, that provides free health care, including HPV vaccination., Exposures: Human papillomavirus vaccination and self-reported history of sexual behavior., Main Outcomes and Measures: Prevalence of HPV in the oral cavity., Results: Among the 1259 participants who were included in this study, median age at entry into the study was 18 (range, 13-21) years; 638 (50.7%) were of African American descent, 569 (45.2%) were of Hispanic descent, 43 (3.4%) reported another race/ethnicity, and race/ethnicity was unspecified for 9 (0.7%). The median (mode) age at first sexual activity was 14.8 (14) years, and 1161 (92.2%) reported having had oral sex. Human papillomavirus DNA was detected in baseline oral rinse samples of 78 of the 1259 participants (6.2%; 95% CI, 4.9%-7.6%). There was a significant decrease in oral HPV detection with time (in years) since first engaging in sexual activities, independent of age and concurrent detection of cervical HPV; comparing 4 or more years with 1 year or less, the odds ratio was 0.45 (95% CI, 0.21-0.96). Detection of vaccine types (HPV-6, HPV-11, HPV-16, and HPV-18) was significantly lower among participants who had received at least 1 dose of the quadrivalent HPV vaccine at the time of enrollment compared with those who were unvaccinated (odds ratio, 0.20; 95% CI, 0.04-0.998)., Conclusions and Relevance: This study's findings suggest that detection of HPV in the oral cavity is not uncommon in sexually active female adolescents. In addition, HPV vaccination is associated with a significant decrease in detection of HPV vaccine types in the oral cavity.

The evidence for genetic polymorphisms in genes encoding cytochrome P450 (CYP) and glutathione S-transferase (GST) enzymes as risk factors for squamous cell carcinomas of the head and neck (SCCHN) in Caucasians is conflicting. Furthermore, the interactive effects with smoking have not been documented. We estimated the effects of five single nucleotide polymorphisms and two copy number variants associated with CYP and GST genes, as well as their interactive effects with smoking, on SCCHN risk among Caucasians from a case-control study conducted in Montreal, Canada. The study involved 389 incident SCCHN cases and 429 controls, frequency-matched by age and sex, recruited from four main hospitals between 2005 and 2013. Life-course-based interviews collected information on tobacco smoking history and other risk behaviors. DNA was isolated from oral exfoliated cells and genotyped for genetic variants. Unconditional logistic regression models estimated odds ratios (OR) and 95% confidence intervals (CI) for main, joint effect, stratum-specific and interaction estimates among non-, moderate and heavy smokers. Carriers of GSTP1 105Val (versus non-carriers) had a lower risk of SCCHN (OR = 0.71, 95% CI: 0.53, 0.95), which was observed for heavy smokers (OR = 0.59, 95% CI: 0.36, 0.95) and non-smokers alike (OR = 0.49, 95% CI: 0.24, 0.98). The decreased risk associations were also conserved among human papillomavirus negative individuals. There was no evidence for statistical interaction with smoking on additive or multiplicative scales for any of the variants analyzed. Of CYP and GST polymorphisms detected in Canadian Caucasians, only GSTP1 105Val was associated with a decreased risk for SCCHN., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: This study aimed to estimate the extent to which oral sex behavior is associated with an increased risk of oropharyngeal cancers (OPCs), and how much of the association is mediated by oral human papillomavirus (HPV) infection., Methods: We used data from a hospital-based case-control study conducted in Montreal, Canada. Information on oral sex behaviors was collected. Oral rinse and oral brush specimens were analyzed for HPV positivity and genotyping. Logistic regression estimated the odds ratios (OR) and 95% confidence intervals (CI) for the association between oral sex behaviors and OPC., Results: Onset of oral sex practice at age 16 years or younger had an increased risk of OPCs relative to those with onset after age 30 years (OR = 2.98; 95% CI 1.37-6.47). This association decreased (OR = 1.09; 95% CI 0.25-4.71) when restricted to those positive for HPV., Conclusions: Our results suggest that the association between oral sex and OPC seems mediated by oral HPV infection., (© 2019 Wiley Periodicals, Inc.)

Background: Body mass index (BMI), sarcopenia, and obesity-related comorbidities have been associated with head and neck squamous cell carcinoma (HNSCC) progression., Methods: We conducted a retrospective analysis of 441 normal-weight, overweight, and obese HNSCC patients treated at Montefiore Medical Center (New York). Patients were grouped by BMI prior to treatment and assessed for differences in survival adjusting for comorbid conditions (cardiovascular disease and diabetes). Evidence of sarcopenia was also assessed using pretreatment abdominal CT scans in a subset of 113 patients., Results: Prior to treatment, 55% of HNSCC patients were overweight or obese. Overweight/obese patients had significantly better overall survival (hazard ratio [HR] = 0.4, 95% CI: 0.3-0.6) compared to normal-weight patients, independent of comorbid conditions. Patients with sarcopenia had significantly poorer survival (HR = 2.1, 95% CI: 1.1-3.9) compared to non-sarcopenic patients, with the strongest association seen among overweight/obese patients., Conclusion: Our data support the importance of sarcopenia assessment, in addition to BMI, among patients with HNSCC., (© 2018 Wiley Periodicals, Inc.)

Mechanisms of treatment resistance in head and neck squamous cell carcinoma (HNSCC) are not well characterized. In this study, HNSCC tumors from a cohort of prospectively enrolled subjects on an ongoing tissue banking study were divided into those that persisted or recurred locoregionally (n=23) and those that responded without recurrence (n=35). Gene expression was evaluated using llumina HumanHT-12-v3 Expression BeadChip microarrays. Sparse Partial Least Squares - Discriminant Analysis (sPLS-DA) identified 135 genes discriminating treatment-resistant from treatment-sensitive tumors. BCL-xL was identified among 23% of canonical pathways derived from this set of genes using Ingenuity Pathway analysis. The BCL-xL protein was expressed in 8 HNSCC cell lines examined. Cells were treated with the BCL-xL inhibitor, ABT-263 (navitoclax): the average half maximal inhibitory concentration (IC50) was 8.9μM (range 6.6μM - 13.9μM). Combining ABT-263 did not significantly increase responses to 2 Gy radiation or cisplatin in the majority of cell lines. MCL-1, a potential mediator of resistance to ABT-263, was expressed in all cell lines and HNSCC patient tumors, in addition to BCL-xL. Treatment with the MCL-1 inhibitor, A-1210477, in HNSCC cell lines showed an average IC50 of 10.7μM (range, 8.8μM to 12.7μM). Adding A-1210477 to ABT-263 (navitoclax) treatment resulted in an average 7-fold reduction in the required lethal dose of ABT-263 (navitoclax) when measured across all 8 cell lines. Synergistic activity was confirmed in PCI15B, Detroit 562, MDA686LN, and HN30 based on Bliss Independence analysis. This study demonstrates that targeting both BCL-xL and MCL-1 is required to optimally inhibit BCL-family pro-survival molecules in HNSCC, and co-inhibition is synergistic in HNSCC cancer cells., Competing Interests: CONFLICTS OF INTEREST The authors declare no potential conflicts of interest.

Objectives: The incidence of oral cancer has been rapidly increasing in India, calling for evidence contributing to a deeper understanding of its determinants. Although disadvantageous life-course socioeconomic position (SEP) is independently associated with the risk of these cancers, the explanatory mechanisms remain unclear. Possible pathways may be better understood by testing which life-course model most influences oral cancer risk. We estimated the association between life-course SEP and oral cancer risk under three life-course models: critical period, accumulation and social mobility., Methods: We recruited incident oral cancer cases (N = 350) and controls (N = 371) frequency-matched by age and sex from two main referral hospitals in Kozhikode, Kerala, India, between 2008 and 2012. We collected information on childhood (0-16 years), early adulthood (17-30 years) and late adulthood (above 30 years) SEP and behavioural factors along the life span using interviews and a life-grid technique. Odds ratios (OR) and 95% confidence intervals (CI) were estimated for the association between life-course SEP and oral cancer risk using inverse probability weighted marginal structural models., Results: Relative to an advantageous SEP in childhood and early adulthood, a disadvantageous SEP was associated with oral cancer risk [(OR = 2.76, 95% CI: 1.99, 3.81) and (OR = 1.84, 95% CI: 1.21, 2.79), respectively]. In addition, participants who were in a disadvantageous (vs advantageous) SEP during all three periods of life had an increased oral cancer risk (OR = 4.86, 95% CI: 2.61, 9.06). The childhood to early adulthood social mobility model and overall life-course trajectories indicated strong influence of exposure to disadvantageous SEP in childhood on the risk for oral cancer., Conclusions: Using novel approaches to existing methods, our study provides empirical evidence that disadvantageous childhood SEP is critical for oral cancer risk in this population from Kerala, India., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

To assess the relationship of E2 gene disruption with viral gene expression and clinical outcome in human papillomavirus (HPV) positive head and neck squamous cell carcinoma, we evaluated 31 oropharyngeal and 17 non-oropharyngeal HPV16 positive carcinomas using two PCR-based methods to test for disruption of E2, followed by Sanger sequencing. Expression of HPV16 E6, E7 and E2 transcripts, along with cellular ARF and INK4A, were also assessed by RT-qPCR. Associations between E2 disruption, E2/E6/E7 expression, and clinical outcome were evaluated by Kaplan-Meier analysis for loco-regional recurrence and disease-specific survival. The majority (n = 21, 68%) of HPV16 positive oropharyngeal carcinomas had an intact E2 gene, whereas the majority of HPV16 positive non-oropharyngeal carcinomas (n = 10, 59%) had a disrupted E2 gene. Three of the oropharyngeal tumors and two of the non-oropharyngeal tumors had deletions within E2. Detection of an intact E2 gene was associated with a higher DNA viral load and increased E2/E6/E7, ARF and INK4A expression in oropharyngeal tumors. Oropharyngeal carcinomas with an intact E2 had a lower risk of loco-regional recurrence (log-rank p = 0.04) and improved disease-specific survival (p = 0.03) compared to tumors with disrupted E2. In addition, high E7 expression was associated with lower risk of loco-regional recurrence (p = 0.004) as was high E6 expression (p = 0.006). In summary, an intact E2 gene is more common in HPV16 positive oropharyngeal than non-oropharyngeal carcinomas; the presence of an intact E2 gene is associated with higher HPV viral load, higher viral oncogene expression, and improved clinical outcome compared to patients with a disrupted E2 gene in oropharyngeal cancer.

Objective Our objective was to compare the accuracy of preoperative positron emission tomography (PET)/computed tomography (CT) and contrast-enhanced CT (CECT) in detecting cervical nodal metastases in patients treated with neck dissection and to scrutinize the ability of each modality to determine nodal stage. Study Design Case series with chart review. Setting Montefiore Medical Center, Bronx, New York. Subjects and Methods Patients who underwent neck dissection at our institution for primary treatment of head and neck squamous cell carcinoma (HNSCC) and had received preoperative PET/CT and CECT were included in this study. Imaging studies were reinterpreted by 3 specialists within the field and compared for interreader agreement. Concordance between radiology and histopathology was measured using neck levels and sides, along with patient nodal stage. Sensitivity, specificity, accuracy, positive predictive value, negative predictive value, and agreement coefficients were calculated. Results Seventy-three patients were included in the study. Sensitivity was 0.69 and 0.94 (level and side) for PET/CT vs 0.53 and 0.66 for CECT ( P = .056, P = .001). Specificity was 0.86 and 0.56 for PET/CT vs 0.91 and 0.76 for CECT ( P = .014, P = .024). No significant difference was found in overall accuracy ( P = .33, P = .88). The overall agreement percentages between N stage called by imaging modality and pathology were 52% and 55% for PET/CT and CECT, respectively. Conclusion No significant difference in sensitivity was found between PET/CT and CECT. CECT was found to have superior specificity compared with PET/CT. The information gleaned from each modality in the pretreatment evaluation of HNSCC appears to be complementary.

Objective: Human papillomaviruses (HPV) are changing dramatically the epidemiologic landscape of head and neck cancers (HNCs). Their role in the aetiology of these cancers varies widely among HNCs subsites, sex and geographical regions worldwide. We describe HPV prevalence and its association with HNCs risk overall and by anatomical subsite in a sample of Canadians., Materials and Methods: The HeNCe Life study recruited 460 incident HNCs cases and 458 controls frequency-matched by age and sex from four Montreal hospitals in 2005-2013. We tested oral rinse and oral brush specimens for mucosal HPV genotypes. HPV positivity was categorized hierarchically as either negative, exclusively non-α-9 species types, α-9 types other than HPV16, and HPV16. We estimated odds ratios (OR) and 95% confidence intervals (CI) for the associations between HPV and HNCs using unconditional logistic regression, controlling for confounders., Results: The prevalence of HPV infection among controls and cases was 14.5% and 41.2% in oral rinse and 3.1% and 24.4% in oral brush samples, respectively. HPV16 was the predominant genotype with an oral rinse and oral brush prevalence of 26.3% and 16.2% among cases and 2.4% and 0.2% among controls, respectively. HPV infection was associated with an increased risk of HNCs overall (OR=4.18; 95% CI, 2.94-5.95) and oropharyngeal cancer only (OR=10.3; 95% CI, 6.8-15.7). HNCs and oropharyngeal cancer were strongly associated with HPV16 (OR=18.1; 95% CI, 9.1-35.8, and OR=47.2; 95% CI, 23.1-96.6, respectively)., Conclusion: HPV infection, particularly HPV16, was associated with an increased HNCs risk, most strongly for oropharyngeal cancers., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

We previously reported a novel association between CDKN2A nonpromoter methylation and transcription (ARF/INK4a) in human papillomavirus associated oropharyngeal tumors. In this study we assessed whether nonpromoter CDKN2A methylation in laryngeal squamous cell carcinomas (LXSCC) conferred a similar association with transcription that predicted patient outcome. We compared DNA methylation and ARF/INK4a RNA expression levels for the CDKN2A locus using the Illumina HumanMethylation27 beadchip and RT-PCR in 43 LXSCC tumor samples collected from a prospective study of head and neck cancer patients treated at Montefiore Medical Center (MMC). Validation was performed using RNAseq data on 111 LXSCC tumor samples from the Cancer Genome Atlas (TCGA). The clinical relevance of combined nonpromoter CDKN2A methylation and transcription was assessed by multivariate Cox regression for locoregional recurrence on a subset of 69 LXSCC patients with complete clinicopathologic data from the MMC and TCGA cohorts. We found evidence of CDKN2A nonpromoter hypermethylation in a third of LXSCC from our MMC cohort, which was significantly associated with increased ARF and INK4a RNA expression (Wilcoxon rank-sum, P = 0.007 and 0.003, respectively). A similar association was confirmed in TCGA samples (Wilcoxon rank-sum test P < 0.0001 for ARF and INK4a). Patients with CDKN2A hypermethylation or high ARF/INK4a expression were significantly less likely to develop a locoregional recurrence compared to those with neither of the features, independent of other clinicopatholgic risk factors (adjusted hazard ratio=0.21, 95% confidence interval:0.05-0.81). These results support the conclusion that CDKN2A nonpromoter methylation is associated with increased ARF and INK4a RNA expression, and improved locoregional control in LXSCC., (© 2016 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Objective Preterm birth is a leading cause of perinatal morbidity and mortality. Prevention strategies rarely focus on preconception care. We sought to create a preconception nomogram that identifies nonpregnant women at highest risk for preterm birth using the Pregnancy Risk Assessment Monitoring System (PRAMS) surveillance data. Methods We used PRAMS data from 2004 to 2009. The odds ratios (ORs) of preterm birth for each preconception variable was estimated and adjusted analyses were conducted. We created a validated nomogram predicting the probability of preterm birth using multivariate logistic regression coefficients. Results 192,208 cases met inclusion criteria. Demographic/maternal health characteristics and associations with preterm birth and ORs are reported. After validation, we identified the following significant predictors of preterm birth: prior history of preterm birth or low birth weight baby, prior spontaneous or elective abortion, maternal diabetes prior to conception, maternal race (e.g., non-Hispanic black), intention to get pregnant prior to conception (i.e., did not want or wanted it sooner), and smoking prior to conception (p < 0.05). Overall, our preconception preterm risk model correctly classified 76.1 % of preterm cases with a negative predictive value (NPV) of 76.7 %. A nomogram using a 0-100 scale illustrates our final preconception model for predicting preterm birth. Conclusion This preconception nomogram can be used by clinicians in multiple settings as a tool to help predict a woman's individual preterm birth risk and to triage high-risk non-pregnant women to preconception care. Future studies are needed to validate the nomogram in a clinical setting.

Background:  Uptake of human papillomavirus (HPV) vaccine in the United States is slow, and the effectiveness of the vaccine has not been assessed in high-risk adolescent populations., Methods:  We conducted a longitudinal study of 1139 sexually active, inner-city adolescent women receiving the 3-dose quadrivalent (4vHPV) vaccine. Cervical and anal specimens collected semiannually were tested using an L1-specific polymerase chain reaction assay. Postvaccination incidence of 4vHPV vaccine and nonvaccine HPV types, and risk of cervical cytological abnormalities, were assessed in relation to time to completion of all 3 vaccine doses., Results:  Compared to vaccine naive women at enrollment, vaccinated women had significantly lower incidence rate ratios of cervical infection with HPV6/11/16/18 (0.2; 95% confidence interval [CI], .1-.4) and the related types HPV31 and HPV45 (0.4 [95% CI, .2-1.0] and 0.3 [95% CI, .1-.6], respectively), as well as significantly lower incidence rate ratios of anal infection with HPV6/11/16/18 (0.4; 95% CI, .2-.7). Notably, we observed higher risks of cervical HPV6/11/16/18 infection (hazards ratio [HR], 2.9; 95% CI, 1.0-8.0) and associated cytological abnormalities (HR, 4.5; 95% CI, .7-26.0) among women immunized at ≥15 years of age who took ≥12 months (vs <12 months) to complete the 3-dose regimen., Conclusions:  Among adolescents immunized at ≥15 years of age, a longer time to complete the 3-dose schedule was associated with an increased risk of anogenital HPV6/11/16/18 infection and an increased incidence of associated cervical cytological abnormalities., (© The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.)

Some studies suggest that periodontal diseases increase the risk of oral cancer, but contradictory results also exist. Inadequate control of confounders, including life course exposures, may have influenced prior findings. We estimate the extent to which high levels of periodontal diseases, measured by gingival inflammation and recession, are associated with oral cancer risk using a comprehensive subset of potential confounders and applying a stringent adjustment approach. In a hospital-based case-control study, incident oral cancer cases (N = 350) were recruited from two major referral hospitals in Kerala, South India, from 2008 to 2012. Controls (N = 371), frequency-matched by age and sex, were recruited from clinics at the same hospitals. Structured interviews collected information on several domains of exposure via a detailed life course questionnaire. Periodontal diseases, as measured by gingival inflammation and gingival recession, were evaluated visually by qualified dentists following a detailed protocol. The relationship between periodontal diseases and oral cancer risk was assessed by unconditional logistic regression using a stringent empirical selection of potential confounders corresponding to a 1% change-in-estimates. Generalized gingival recession was significantly associated with oral cancer risk (Odds Ratio = 1.83, 95% Confidence Interval: 1.10-3.04). No significant association was observed between gingival inflammation and oral cancer. Our findings support the hypothesis that high levels of periodontal diseases increase the risk of oral cancer., (© 2016 UICC.)

Crumbs 3 (CRB3) is a component of epithelial junctions, which has been implicated in apical-basal polarity, apical identity, apical stability, cell adhesion, and cell growth. CRB3 undergoes alternative splicing to yield two variants: CRB3a and CRB3b. Here, we describe novel data demonstrating that, as with previous studies on CRB3a, CRB3b also promotes the formation of tight junctions (TJs). However, significantly we demonstrate that the 4.1-ezrin-radixin-moesin-binding motif of CRB3b is required for CRB3b functionality and that ezrin binds to the FBM of CRB3b. Furthermore, we show that ezrin contributes to CRB3b functionality and the correct distribution of TJ proteins. We demonstrate that both CRB3 isoforms are required for the production of functionally mature TJs and also the localization of ezrin to the plasma membrane. Finally, we demonstrate that reduced CRB3b expression in head and neck squamous cell carcinoma (HNSCC) correlates with cytoplasmic ezrin, a biomarker for aggressive disease, and shows evidence that while CRB3a expression has no effect, low CRB3b and high cytoplasmic ezrin expression combined may be prognostic for HNSCC., (© The Author (2016). Published by Oxford University Press on behalf of Journal of Molecular Cell Biology, IBCB, SIBS, CAS. All rights reserved.)

Human body sites represent ecological niches for microorganisms, each providing variations in microbial exposure, nutrient availability, microbial competition, and host immunological responses. In this study, we investigated the oral, anal, and cervical microbiomes from the same 20 sexually active adolescent females, using culture-independent, next-generation sequencing. DNA from each sample was amplified for the bacterial 16S rRNA gene and sequenced on an Illumina platform using paired-end reads. Across the three anatomical niches, we found significant differences in bacterial community composition and diversity. Overall anal samples were dominated with Prevotella and Bacteriodes , oral samples with Streptococcus and Prevotella , and cervical samples with Lactobacillus . The microbiomes of a few cervical samples clustered with anal samples in weighted principal coordinate analyses, due in part to a higher proportion of Prevotella in those samples. Additionally, cervical samples had the lowest alpha diversity. Our results demonstrate the occurrence of distinct microbial communities across body sites within the same individual.

Human papillomavirus (HPV)-associated cervical carcinoma is preceded by stages of cervical intra-epithelial neoplasia (CIN) that can variably progress to malignancy. Understanding the different molecular processes involved in the progression of pre-malignant CIN is critical to the development of improved predictive and interventional capabilities. We tested the role of regulators of transcription in both the development and the progression of HPV-associated CIN, performing the most comprehensive genomic survey to date of DNA methylation in HPV-associated cervical neoplasia, testing ~2 million loci throughout the human genome in biopsies from 78 HPV+ women, identifying changes starting in early CIN and maintained through carcinogenesis. We identified loci at which DNA methylation is consistently altered, beginning early in the course of neoplastic disease and progressing with disease advancement. While the loss of DNA methylation occurs mostly at intergenic regions, acquisition of DNA methylation is at sites involved in transcriptional regulation, with strong enrichment for targets of polycomb repression. Using an independent cohort from The Cancer Genome Atlas, we validated the loci with increased DNA methylation and found that these regulatory changes were associated with locally decreased gene expression. Secondary validation using immunohistochemistry showed that the progression of neoplasia was associated with increasing polycomb protein expression specifically in the cervical epithelium. We find that perturbations of genomic regulatory processes occur early and persist in cervical carcinoma. The results indicate a polycomb-mediated epigenetic field defect in cervical neoplasia that may represent a target for early, topical interventions using polycomb inhibitors., Competing Interests: The authors declare no potential conflicts of interest.

Objective: To conduct a comprehensive mapping of the genomic DNA methylation in CDKN2A, which codes for the p16(INK4A) and p14(ARF) proteins, and 14 of the most promising DNA methylation marker candidates previously reported to be associated with progression of low-grade cervical intraepithelial neoplasia (CIN1) to cervical cancer., Methods: We analyzed DNA methylation in 68 HIV-seropositive and negative women with incident CIN1, CIN2, CIN3 and invasive cervical cancer, assaying 120 CpG dinucleotide sites spanning APC, CDH1, CDH13, CDKN2A, CDKN2B, DAPK1, FHIT, GSTP1, HIC1, MGMT, MLH1, RARB, RASSF1, TERT and TIMP3 using the Illumina Infinium array. Validation was performed using high resolution mapping of the target genes with HELP-tagging for 286 CpGs, followed by fine mapping of candidate genes with targeted bisulfite sequencing. We assessed for statistical differences in DNA methylation levels for each CpG loci assayed using univariate and multivariate methods correcting for multiple comparisons., Results: In our discovery sample set, we identified dose dependent differences in DNA methylation with grade of disease in CDKN2A, APC, MGMT, MLH1 and HIC1, whereas single CpG locus differences between CIN2/3 and cancer groups were seen for CDH13, DAPK1 and TERT. Only those CpGs in the gene body of CDKN2A showed a monotonic increase in methylation between persistent CIN1, CIN2, CIN3 and cancers., Conclusion: Our data suggests a novel link between early cervical disease progression and DNA methylation in a region downstream of the CDKN2A transcription start site that may lead to increased p16(INK4A)/p14(ARF) expression prior to development of malignant disease., Competing Interests: The other authors declare that there are no conflicts of interest., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Whether higher penile human papillomavirus (HPV) viral load is associated with a lower rate of HPV clearance remains unknown., Objectives: We examined the association between penile HPV16 and HPV18 viral load and subsequent HPV clearance in uncircumcised Kenyan men., Study Design: Participants were human immunodeficiency virus (HIV)-seronegative, sexually active, 18- to 24-year-old men randomized to the control arm of a male circumcision trial in Kisumu, Kenya. Men provided exfoliated penile cells from two anatomical sites (glans/coronal sulcus and shaft) every 6 months for 2 years. GP5+/6+ polymerase chain reaction was used to identify 44 HPV-DNA types. Human papillomavirus viral load testing was conducted using a LightCyler real-time polymerase chain reaction assay; viral load was classified as high (>250 copies/scrape) or low (≤250 copies/scrape), for nonquantifiable values. The Kaplan-Meier method and Cox regression modeling were used to examine the association between HPV viral load and HPV clearance., Results: A total of 1097 men, with 291 HPV16 and 131 HPV18 cumulative infections over 24 months were analyzed. Human papillomavirus clearance at 6 months after first HPV detection was lower for high versus low viral load HPV16 infections in the glans (adjusted hazard ratio [aHR], 0.65; 95% confidence interval [CI], 0.46-0.92)] and shaft (aHR, 0.44; 95% CI, 0.16-0.90), and HPV18 infections in the glans (aHR, 0.05; 95% CI, 0.01-0.17)., Discussion: High versus low HPV viral load was associated with a reduced HPV clearance for HPV16 infections in the glans and shaft, and for HPV18 infections in the glans, among young uncircumcised men. Reduced clearance of high viral load HPV16 and HPV18 infections in men may increase HPV transmission to their female partners as well as enhance the development of penile lesions in comparison to men with low viral load HPV infections.

Purpose: Betel quid chewing is a major oral cancer risk factor and the human papillomaviruses (HPV) may play an aetiological role in these cancers. However, little is known about the shape of the dose-response relationship between the betel quid chewing habit and oral cancer risk in populations without HPV. We estimate the shape of this dose-response relationship, and discuss implications for prevention., Methods: Cases with oral squamous cell carcinoma (350) and non-cancer controls (371) were recruited from two major teaching hospitals in South India. Information on socio-demographic and behavioral factors was collected using a questionnaire and the life grid technique. The effect of daily amount of use and duration of the habit were estimated jointly as risk associated with cumulative exposure (chew-years). The shape of the dose-response curve was estimated using restricted cubic spline transformation of chew-years in a conditional logistic regression model. Risk estimates for low dose combinations of daily amount and duration of the habit were computed from flexible regression., Results: Most (72%) oral cancer cases were betel quid chewers in contrast to only 18% of controls. A nonlinear dose-response relationship was observed; the risk increased steeply at low doses and plateaued at high exposures to betel quid (>425 chew-years). A threefold increase in risk (OR=3.92, 95%CI: 1.87-8.21) was observed for the lowest dose; equivalent to the use of one quid per day for one year., Conclusion: Our findings may be used to counsel people to refrain from even low betel quid chewing., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: The epidermal growth factor receptor (EGFR) signaling network is involved in lung carcinogenesis. This study examined whether ligands that activate or suppress the EGFR signaling network were associated with lung cancer risk in ever smokers., Methods: A nested case-control study within the Women's Health Initiative assessed baseline plasma levels of insulin, insulin-like growth factor (IGF)-1, insulin-like growth factor binding protein (IGFBP)-3, interleukin (IL)-6, hepatocyte growth factor (HGF), and nerve growth factor (NGF) in 1143 ever-smoking lung cancer cases and 1143 controls. Leptin was measured as an adiposity biomarker. Conditional logistic regression was used in data analyses., Results: Leptin was inversely associated with lung cancer risk (odds ratio [ORcontinuous] per Ln [pg/mL] = 0.85, 95% confidence interval [CI] = 0.74 to 0.98). After adjusting for adiposity and other risk factors, null associations were found for IL-6, HGF, and NGF. In current smokers, but not former smokers, high insulin levels were associated with increased lung cancer risk (OR for 4th quartile vs others [ORq4] = 2.06, 95% CI = 1.30 to 3.26) whereas IGFBP-3 had a linear inverse association (ORcontinuous per μg/mL = 0.64, 95% CI = 0.41 to 0.98). The insulin association was consistent across subgroups defined by body mass index and histological type, but the IGFBP-3 association was specific to small cell lung cancer. There was a modest positive association between IGF-1 and lung cancer risk in current smokers (ORq4 = 1.44, 95% CI = 0.90 to 2.29)., Conclusions: Independent of obesity, high insulin levels but reduced levels of IGFBP-3 were associated with increased lung cancer risk in current smokers., (© The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Objective: To examine the association of knowledge about human papillomavirus (HPV) on the time to completion of the 3-dose quadrivalent vaccine series in an inner-city population of adolescent female subjects at high risk for infection., Study Design: We prospectively followed 139 female subjects aged 14-20 years enrolled in a vaccine surveillance study in New York City during a period of at least 24 months. Participants were given a 30-item true or false survey on HPV at enrollment and ranked according to the number of correct responses. Multivariate Cox regression was used to examine the association between level of knowledge about HPV and time to completion (in days) of vaccine dose 1-3, dose 1-2, and dose 2-3., Results: Overall time to completion of the 3-dose vaccine ranged from 158 days to 1114 days. Participants in the high knowledge group (top quartile) were significantly more likely to complete the 3-dose series earlier (hazard ratio 1.69, 95% CI 1.03-2.77; P = .04), in particular doses 2-3 (hazard ratio 1.71, 95% CI 1.02-2.89; P = .04), than those with low-to-moderate knowledge (bottom 3 quartiles)., Conclusions: These findings suggest that knowledge of HPV is associated with shorter time to complete the 3-dose HPV vaccine series. Educational campaigns at time of vaccination may be important to improve vaccine adherence., (Copyright © 2016 Elsevier Inc. All rights reserved.)