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2.  Alternative dosage schedules with HPV VLP vaccines 
Expert review of vaccines  2014;13(8):1027-1038.
Summary
Human papillomavirus (HPV) vaccines can prevent multiple cancers in women and men. Difficulties in the cost and completion of the three-dose vaccine series have led to considerations of alternative dose schedules. In clinical trials, three doses given within a 12-month period versus the standard six-month period yielded comparable results, and immunogenicity appears comparable with two doses in adolescent females compared to the three-dose series in adult females. While the data are generally supportive of moving to a two-dose vaccine schedule among young female adolescents, the adoption of a two-dose vaccine schedule still poses a potential risk to the strength and longevity of the immune response. Public health authorities implementing a two-dose vaccine schedule should devise risk management strategies to minimize the potential impact on cancer prevention.
doi:10.1586/14760584.2014.935767
PMCID: PMC4147727  PMID: 25001893
HPV vaccination; dosing; virus-like particle; dose schedules; immunogenicity
3.  A prospective analysis of smoking and human papillomavirus (HPV) infection among men in The HPV in Men (HIM) Study 
At present it is unknown whether the higher prevalence of human papillomavirus (HPV) infection among smokers in men is attributed to a higher probability of acquiring an infection or because of longer infection persistence. Thus, we investigated the role of smoking on the (acquisition) and clearance (persistence) of genital HPV infections among 4,026 men in The HPV in Men (HIM) Study, a multinational prospective study of the natural history of genital HPV infection in men. Genital HPV infections were grouped any-, oncogenic-, and non-oncogenic HPV infections and smoking status was categorized as current-, former, and never smokers. The incidence of any-, oncogenic-, and non-oncogenic HPV infections was significantly higher among current smokers compared to former- and never smokers (P < 0.01). In multivariable analyses adjusting for sexual behavior and potential confounders, when compared to never smokers, current smokers exhibited significantly higher probability of acquiring any- (Hazard Ratio [HR] = 1.23; 95% confidence interval [CI] 1.02 – 1.50) and non-oncogenic (HR = 1.21; 95% CI 1.00 – 1.45) infections and a borderline significant probability for oncogenic infections (HR = 1.18; 95% CI 0.98 – 1.41). Although the median duration of HPV infection was generally longer among current smokers, we found no statistically significant associations in the multivariable analyses. Overall, these results demonstrated that current smoking exhibited the highest incidence and highest probability of acquiring genital HPV infections.
doi:10.1002/ijc.28567
PMCID: PMC3949156  PMID: 24222514
HPV; epidemiology; incidence; smoking
4.  Epidemiology of Human Papillomavirus Infection in Men, in Cancers other than Cervical and in Benign Conditions 
Vaccine  2008;26(0 10):K17-K28.
Human Papillomavirus (HPV) infection is commonly found in the genital tract of men and women with or without any clinical lesion. The association of HPV DNA with several different ano-genital cancers other than cervical has been reported for the vulva, vagina, anus and penis. HPV DNA has also been identified in head and neck cancers in the oral cavity, the oropharynx and the larynx in both sexes. In men, 80–85% of anal cancers and close to 50% of penile cancers are associated with HPV infection. In women, HPV DNA is prevalent in 36–40 % vulvar cancer cases and close to 90 % of vaginal cancers. There is limited data available on the natural history and HPV-related diseases in the genital tract in men, although studies are ongoing. Efficacy of HPV vaccines in the prevention of HPV infection and disease among men also remains unknown. Among HPV DNA positive ano-genital cancer cases, HPV-16 is the most frequently found followed distantly by HPV-18. In benign HPV-related diseases such as genital warts or recurrent respiratory papillomatosis HPV-6 and 11, the two most frequent non-oncogenic types, are the predominant types detected. Oncogenic types are rarely detected. In this article we summarize and review studies describing the natural history of HPV infections among men and its impact on HPV related disease in women. We summarize the evidence linking HPV in the epidemiology and etiology of cancers of the vulva, vagina, anus and oropharynx and present recent estimates of the burden of and HPV type distribution in genital warts and in cases of HPV infection of the airways.
doi:10.1016/j.vaccine.2008.06.021
PMCID: PMC4366004  PMID: 18847554
cancer; HPV; men; women; infection; genital warts; respiratory papillomatosis; anogenital cancer
5.  Epidemiology and pathology of HPV disease in males 
Gynecologic oncology  2010;117(2 0):S15-S19.
It is currently recognized that besides the significant impact of human papillomavirus (HPV) infection in females, HPV causes substantial disease in men as well. Genital warts are a common manifestation of male infection with HPV. Genital warts are highly infectious and approximately 65% of people who have sex with an infected partner will develop warts themselves. More than 90% of genital warts are caused by non-oncogenic HPV types 6 and 11. In addition, recurrent respiratory papillomatosis is a rare disease most often associated with HPV types 6 and 11. Several cancers of the anogenital tract and upper aero-digestive tract, and their precursor lesions in men are now understood to be caused by infection with sexually transmitted HPV. For example, there is increasing incidence of anal cancer in western countries; however, there are limited data on its primary cause, anal canal HPV infection. Genital HPV infection is very common in men with an ongoing international study estimating a prevalence of 65.2% in asymptomatic males aged 18–70 years. Lifetime number of sexual partners was the most significant risk factor for the acquisition of HPV infection (P<0.05), and circumcision has been associated with reduced detection of HPV infection in men. HPV infections may be less likely to persist in men than in women. In men, the median time to clearance of any HPV infection was 5.9 months, with 75% of infections clearing within 12 months. More data are needed to better understand the natural history of HPV infection. Although the quadrivalent HPV vaccine has been shown to be effective and safe in men, low awareness of HPV in males may be a barrier to its use for the prevention of HPV infection.
doi:10.1016/j.ygyno.2010.01.026
PMCID: PMC4254924  PMID: 20138345
Male; HPV infection; Genital warts; Recurrent respiratory papillomatosis; Head and neck cancer; Penile cancer; Anal cancer; Transmission dynamics; Natural history
6.  Cutaneous human papillomavirus types detected on the surface of male external genital lesions: A case series within the HPV Infection in Men Study 
Background
Cutaneous human papillomaviruses (HPVs) may be associated with cutaneous epithelial lesions and non-melanoma skin cancers. No study has systematically evaluated the presence of genus beta [β]-HPV in male genital skin or external genital lesions (EGLs).
Objectives
To examine cutaneous β-HPV types detected on the surface of EGLs in men and describe their presence prior to EGL development.
Study design
A retrospective case series was conducted among 69 men with pathologically confirmed EGLs (n=72) who participated in the HPV Infection in Men Study. Archived exfoliated cells collected from the surface of each EGL and normal genital skin specimens 6–12 months preceding EGL development were tested for β-HPV DNA using a type-specific multiplex genotyping assay.
Results
β-HPV DNA was detected on 61.1% of all EGLs, with types 38 (16.7%), 5 (15.3%), and 12 (12.5%) most commonly identified. HPV prevalence differed across pathological diagnoses, with the largest number of β-HPV types detected on condylomas. Most β-HPV types were detected on normal genital skin prior to EGL development, though the prevalence was lower on EGLs compared to preceding normal genital skin.
Conclusions
EGLs and the normal genital skin of men harbor a large number of β-HPV types; however, it appears that β-HPVs are unrelated to EGL development in men. Despite evidence to support a causal role in skin carcinogenesis at UVR-exposed sites, cutaneous HPV appears unlikely to cause disease at the UVR-unexposed genitals.
doi:10.1016/j.jcv.2013.10.011
PMCID: PMC3866698  PMID: 24210970
7.  MAPK genes interact with diet and lifestyle factors to alter risk of breast cancer: The Breast Cancer Health Disparities Study 
Nutrition and cancer  2015;67(2):292-304.
Mitogen-activated protein kinases (MAPK) are integration points for multiple biochemical signals. We evaluated 13 MAPK genes with breast cancer risk and determined if diet and lifestyle factors mediated risk. Data from three population-based case-control studies conducted in Southwestern United States, California, and Mexico included 4183 controls and 3592 cases. Percent Indigenous American (IA) ancestry was determined from 104 Ancestry Informative Markers. The adaptive rank truncated product (ARTP) was used to determine the significance of each gene and the pathway with breast cancer risk, by menopausal status, genetic ancestry level, and ER/PR strata.
MAP3K9 was associated with breast cancer overall (PARTP=0.02) with strongest association among women with the highest IA ancestry (PARTP=0.04). Several SNPs in MAP3K9 were associated with ER+/PR+ tumors and interacted with dietary oxidative balance score (DOBS), dietary folate, body mass index (BMI), alcohol consumption, cigarette smoking, and a history of diabetes. DUSP4 and MAPK8 interacted with calories to alter breast cancer risk; MAPK1 interacted with DOBS, dietary fiber, folate and BMI; MAP3K2 interacted with dietary fat; and MAPK14 interacted with dietary folate and BMI. The patterns of association across diet and lifestyle factors with similar biological properties for the same SNPs within genes provide support for associations.
doi:10.1080/01635581.2015.990568
PMCID: PMC4450722  PMID: 25629224
Breast Cancer; Indigenous Ancestry; MAPK; MAP3K9; diet; diabetes; body size; polymorphisms
8.  Overall and abdominal adiposity and premenopausal breast cancer risk among Hispanic women: The Breast Cancer Health Disparities Study 
Background
Few studies in Hispanic women have examined the relation between adult body size and risk of premenopausal breast cancer defined by hormone receptor status.
Methods
The Breast Cancer Health Disparities Study pooled interview and anthropometric data from two large U.S. population-based case-control studies. We examined associations of overall and abdominal adiposity with risk of estrogen receptor and progesterone receptor positive (ER+PR+) and negative (ER−PR−) breast cancer in Hispanic and non-Hispanic White (NHW) women, calculating odds ratios (OR) and 95% confidence intervals (CI).
Results
Among Hispanics, young-adult and current body mass index (BMI) were inversely associated with both ER+PR+ and ER−PR− breast cancer. For ER+PR+ disease, risk was substantially reduced among those with elevated BMI throughout adulthood (OR=0.35, 95% CI=0.19-0.62). Height and height-to-waist ratio were positively associated with ER−PR− breast cancer. After adjustment for current BMI, two-fold increased risks were seen for large waist and hip circumferences, regardless of tumor receptor status. Genetic ancestry appeared to modify some of the associations with overall and abdominal adiposity. Among NHWs, findings for overall adiposity were similar to those for Hispanics, but there was no evidence of associations with abdominal adiposity.
Conclusions
Our findings for Hispanic women were generally similar to those reported for NHW women in other studies, with inverse associations for overall adiposity and positive associations for abdominal adiposity.
Impact
Abdominal obesity in young adulthood is an important risk factor for premenopausal breast cancer among Hispanic women.
doi:10.1158/1055-9965.EPI-13-1007-T
PMCID: PMC4294975  PMID: 25352526
Breast cancer; BMI; body size; estrogen receptor status; genetic ancestry; Hispanics; Latinas; premenopausal; progesterone receptor status; weight gain
9.  Body size throughout adult life influences postmenopausal breast cancer risk among Hispanic women: The Breast Cancer Health Disparities Study 
Background
Few studies have assessed the association of body size with postmenopausal breast cancer (BC) risk in Hispanic women. Findings are inconsistent and appear to contradict those reported for non-Hispanic White (NHW) women.
Methods
We pooled interview and anthropometric data for 2,023 Hispanic and 2,384 NHW women from two U.S. population-based case-control studies. Using logistic regression analysis, we examined associations of overall and abdominal adiposity with risk of postmenopausal BC defined by estrogen receptor (ER) and progesterone receptor (PR) status.
Results
Weight gain was associated with increased risk of ER+PR+ BC in Hispanics not currently using menopausal hormone therapy (HT), but only among those with a low young-adult body mass index (BMI). In the subset of Hispanics with data on genetic ancestry, the association with weight gain was limited to women with lower Indigenous American ancestry. Young-adult BMI was inversely associated with both ER+PR+ and ER-PR- BC for both ethnicities combined, with similar, although non-significant, inverse trends in Hispanics and NHWs. Among all Hispanics, regardless of HT use, height was associated with risk of ER-PR-BC and hip circumference with risk of BC overall.
Conclusions
Body size throughout adult life is associated with BC risk among postmenopausal Hispanic women, as has been reported for NHW women. Associations were specific for BC subtypes defined by hormone receptor status.
Impact
Avoiding weight gain and maintaining a healthy weight are important strategies to reduce the risk of postmenopausal ER+PR+ BC, the most common BC subtype.
doi:10.1158/1055-9965.EPI-14-0560
PMCID: PMC4295775  PMID: 25352523
Breast cancer; BMI; body size; estrogen receptor status; epidemiology; genetic ancestry; Hispanics; Latinas; postmenopausal; progesterone receptor status; weight gain
10.  Consistent Condom Use Reduces the Genital Human Papillomavirus Burden Among High-Risk Men: The HPV Infection in Men Study 
The Journal of Infectious Diseases  2013;208(3):373-384.
Background. Data supporting the efficacy of condoms against human papillomavirus (HPV) infection in males are limited. Therefore, we examined the effect of consistent condom use on genital HPV acquisition and duration of infection.
Methods. A prospective analysis was conducted within the HPV Infection in Men Study, a multinational HPV cohort study. Men who were recently sexually active (n = 3323) were stratified on the basis of sexual risk behaviors and partnerships. Using Cox proportional hazards regression, type-specific incidence of HPV infection and clearance were modeled for each risk group to assess independent associations with condom use.
Results. The risk of HPV acquisition was 2-fold lower among men with no steady sex partner who always used condoms, compared with those who never used condoms (hazard ratio, 0.54), after adjustment for country, age, race, education duration, smoking, alcohol, and number of recent sex partners. The probability of clearing an oncogenic HPV infection was 30% higher among nonmonogamous men who always used condoms with nonsteady sex partners, compared with men who never used condoms (hazard ratio, 1.29), after adjustment for country, age, race, education duration, marital status, smoking, alcohol, and number of recent sex partners. No protective effects of condom use were observed among monogamous men.
Conclusions. Condoms should be promoted in combination with HPV vaccination to prevent HPV infection in men.
doi:10.1093/infdis/jit191
PMCID: PMC3699010  PMID: 23644283
condoms; human papillomavirus; males; cohort study; HIM Study
11.  Association of Chlamydia trachomatis infection and herpes simplex virus type 2 serostatus with genital human papillomavirus infection in men: the HIM Study 
Sexually transmitted diseases  2013;40(6):508-515.
Background
Studies in women indicate that some sexually transmitted infections promote human papillomavirus (HPV) persistence and carcinogenesis. Little is known about this association in men, therefore we assessed whether Chlamydia trachomatis (CT) infection and herpes simplex virus type 2 (HSV-2) serostatus are associated with genital HPV prevalence, an early event in HPV related pathogenesis.
Methods
Genital exfoliated cells, first-void urine and blood from 3,971 men recruited in the USA, Mexico, and Brazil, were tested for HPV, CT, and HSV-2 antibodies, respectively. Multivariable logistic regression was used to assess the association of CT infection and HSV-2 serostatus with four HPV outcomes (any, oncogenic, non-oncogenic only, and multiple infections).
Results
A total of 64 (1.6%) men were CT positive and 811 (20.4%) men were HSV-2 seropositive. After adjustment for potential confounders, CT was associated with any HPV (aOR 2.19, 95%CI: 1.13–4.24), oncogenic HPV (aOR 3.10, 95%CI: 1.53–6.28), and multiple HPV (aOR 3.43, 95%CI: 1.69-6.95) prevalence. HSV-2 serostatus was associated with any HPV (aOR 1.25, 95%CI: 1.02-1.52), non-oncogenic HPV only (aOR 1.38, 95%CI: 1.08-1.75), and multiple HPV (aOR 1.33, 95%CI: 1.06-1.68) prevalence. In analyses stratified by sexual behaviour, CT infection was significantly associated with HPV detection among men reporting ≥2 recent sexual partners, while HSV-2 serostatus was significantly associated with HPV detection in men reporting 0-5 lifetime sexual partners.
Conclusion
In this population, CT infection and HSV-2 serostatus were associated with prevalent genital HPV infection. Future prospective studies should investigate whether these infections influence HPV acquisition and/or persistence.
doi:10.1097/OLQ.0b013e318289c186
PMCID: PMC3904659  PMID: 23680908
Men; genital; sexually transmitted infection; Human papillomavirus; Chlamydia trachomatis; herpes simplex virus type 2
12.  Quadrivalent Human Papillomavirus (HPV) Types 6, 11, 16, 18 Vaccine 
Drugs  2011;71(5):591-602.
The quadrivalent HPV types 6, 11, 16, 18 vaccine (Gardasil®) is a recombinant vaccine comprising purified virus-like particles derived from the L1 capsid proteins of HPV types 6, 11, 16 and 18.
The vaccine was highly immunogenic. Geometric mean titres (GMTs) and seroconversion rates for all four HPV types at month 7 in males aged 10–15 years were noninferior to those in females aged 16–23 years, and those in males aged 9–15 years were noninferior to those in females aged 9–15 years. In addition, GMTs and seroconversion rates in males aged 16–26 years receiving the vaccine were higher than those receiving amorphous aluminium hydroxyphosphate sulfate adjuvant (AAHS) control.
The quadrivalent HPV vaccine was significantly more effective than AAHS control at decreasing the incidence of HPV 6-, 11-, 16- or 18-related external genital lesions (primary endpoint) in a randomized, double-blind, placebo-controlled, multicentre study in males aged 16–26 years. The most common clinical endpoint was HPV 6- and 11-related condyloma; efficacy was robust against these lesions.
The vaccine is also expected to be protective against genital warts in males aged 9–15 years, as the immune response in males of this age group was noninferior to that in males aged 16–26 years.
The quadrivalent HPV vaccine was generally well tolerated in males aged 9–26 years. The most common adverse events reported were injection-site related, and most of these were of mild to moderate severity.
doi:10.2165/11205980-000000000-00000
PMCID: PMC4641443  PMID: 21443282
13.  Associations between CYP19A1 polymorphisms, Native American ancestry, and breast cancer risk and mortality: the Breast Cancer Health Disparities Study 
Cancer causes & control : CCC  2014;25(11):1461-1471.
The cytochrome p450 family 19 gene (CYP19A1) encodes for aromatase, which catalyzes the final step in estrogen biosynthesis and conversion of androgens to estrogens. Genetic variation in CYP19A1 is linked to higher circulating estrogen levels and increased aromatase expression. Using data from the Breast Cancer Health Disparities Study, a consortium of three population-based case–control studies in the United States (n = 3,030 non-Hispanic Whites; n = 2,893 Hispanic/Native Americans (H/NA) and Mexico (n = 1,810), we examined influence of 25 CYP19A1 tagging single-nucleotide polymorphisms (SNPs) on breast cancer risk and mortality, considering NA ancestry. Odds ratios (ORs) and 95 % confidence intervals (CIs) and hazard ratios estimated breast cancer risk and mortality. After multiple comparison adjustment, none of the SNPs were significantly associated with breast cancer risk or mortality. Two SNPs remained significantly associated with increased breast cancer risk in women of moderate to high NA ancestry (≥29 %): rs700518, ORGG 1.36, 95 % CI 1.11–1.67 and rs11856927, ORGG 1.35, 95 % CI 1.05–1.72. A significant interaction was observed for rs2470144 and menopausal status (padj = 0.03); risk was increased in postmenopausal (ORAA 1.22, 95 % CI 1.05–1.14), but not premenopausal (ORAA 0.78, 95 % CI 0.64–0.95) women. The absence of an overall association with CYP19A1 and breast cancer risk is similar to previous literature. However, this analysis provides support that variation in CYP19A1 may influence breast cancer risk differently in women with moderate to high NA ancestry. Additional research is warranted to investigate the how variation in an estrogen-regulating gene contributes to racial/ethnic disparities in breast cancer.
doi:10.1007/s10552-014-0448-5
PMCID: PMC4435673  PMID: 25088806
CYP19A1 polymorphisms; Native American ancestry; Breast cancer risk; Breast cancer mortality
14.  Prospective Study of Seroreactivity to JC virus T-Antigen and Risk of Colorectal Cancers and Adenomas 
John Cunningham virus (JCV) is a common polyomavirus classified as a possible carcinogen by the International Agency for Research on Cancer. JCV may play a role in colorectal carcinogenesis, although we previously reported no association between JCV capsid antibodies and colorectal cancer (CRC). No studies have examined the role of seroreactivity to JCV T-antigen (T-Ag) oncoprotein in CRC. A case-control study nested within a community-based prospective cohort (CLUE II) was conducted. In 1989, 25,080 residents of Washington County, Maryland were enrolled in CLUE II, completing baseline questionnaires and providing blood samples. At follow-up, 257 incident CRC cases were identified by linkage to population-based cancer registries through 2006 and matched to controls on age, sex, race, and date of blood draw. One hundred and twenty three colorectal adenoma cases were identified through self-report during follow-up and matched to controls on age, sex, race, date of blood draw, and CRC screening. Baseline serum samples were tested for seroreactivity to JCV T-Ag. Associations between JCV T-Ag seroreactivity and CRC/adenomas were evaluated using conditional logistic regression models. Overall, seroreactivity to JCV T-Ag was not statistically significantly associated with either the risk of CRC (OR =1.34, 95% CI=0.89-2.01) or adenoma (OR =1.30, 95% CI=0.70-2.42), while a borderline association with CRC was observed among women (OR=1.82, 95% CI=1.00-3.31). Our past evaluation of JCV capsid seropositivity, combined with current findings, do not support a notable etiologic role for JCV infection in CRC.
doi:10.1158/1055-9965.EPI-14-0370
PMCID: PMC4221292  PMID: 25128403
JC virus; T-antigen; colon cancer; colorectal cancer; adenomas
15.  Physicians’ Human Papillomavirus Vaccine Recommendations in the Context of Permissive Guidelines for Male Patients: A National Study 
Background
Little is known about physicians’ human papillomavirus (HPV) vaccine recommendations for males while the Advisory Committee on Immunization Practices’ (ACIP) permissive guidelines for male vaccination were in effect. The purpose of this study was to examine and explore factors associated with U.S. physicians’ HPV vaccine recommendations to early (ages 11–12), middle (13–17), and late adolescent/young adult (18–26) males.
Methods
Nationally representative samples of family physicians and pediatricians were selected in 2011 (n=1,219). Physicians reported the frequency with which they recommended HPV vaccine to male patients (“always” [>75% of the time] vs. other) for each age group. Statistically significant predictors of vaccine recommendation were identified using multivariable logistic regression.
Results
The prevalence of physicians reporting they “always” recommended HPV vaccination for males was 10.8% for ages 11–12, 12.9% for ages 13–17, and 13.2% for ages 18–26. Pediatrician specialty and self-reported early adoption of new vaccines were significantly associated with recommendation for all patient age groups. Additionally, physician race and patient payment method were associated with physician recommendations to patients ages 11–12, and patient race was associated with recommendations to ages 13–17 and 18–26.
Conclusions
Less than 15% of physicians surveyed reported “always” recommending HPV vaccine to male patients following national guidelines for permissive vaccination. Vaccine financing may have affected physicians’ vaccine recommendations.
Impact
If these recommendation practices continue following the ACIP’s routine recommendation for males in October 2011, then interventions designed to increase recommendations should target family physicians and possibly utilize early adopters to encourage support of HPV vaccination guidelines.
doi:10.1158/1055-9965.EPI-14-0344
PMCID: PMC4184998  PMID: 25028456
cancer vaccines; human papillomavirus; HPV vaccines; males; physicians
16.  Seroprevalence of Human Papillomavirus (HPV) Type 6 and 16 Vary by Anatomic Site of HPV Infection in Men 
Background
It is largely unknown if anti-HPV serum antibody responses vary by anatomic site of infection in men.
Methods
This study assessed type-specific anti-HPV serum antibody prevalence associated with corresponding HPV DNA detection in the external genitalia and the anal canal of 1587 heterosexual men and 199 men who have sex with men (MSM).
Results
We observed that HPV 6 and 16 seroprevalence was higher in the presence of same HPV type infection in the anal canal compared to the presence in the external genitalia only, and among MSM compared to heterosexual men. Seropositivity to HPV 6 was strongly associated with HPV 6 DNA detection in the anal canal but not in the external genitalia alone among both heterosexual men (Adjusted Prevalence Ratio (APR), anal+/genital+ vs. anal-/genital-: 4.2 [95% CI: 11.7-10.5]; anal+/genital- vs. anal-/genital-: 7.9 [95% CI: 3.7-17.0]) and MSM (APR, anal+/genital+ vs. anal-/genital-: 5.6 [95% CI: 2.7-11.9]; anal+/genital- vs. anal-/genital-: 3.2 [95% CI: 2.1-4.9]). Similar associations between seropositivity to HPV 16 and anal HPV 16 DNA detection were only observed in MSM (anal+/genital+ vs. anal-/genital-: 3.1 [95% CI: 2.0-5.0]; anal+/genital- vs. anal-/genital-: 2.2 [95% CI: 1.3-3.5]).
Conclusion
Our data demonstrated that seroprevalence varied by anatomic site of HPV infection, suggesting differences in epithelium type present at these anatomic sites may be relevant.
Impact
Our finding is instrumental in advancing our understanding of immune mechanism involved in anatomic site-specific antibody response.
doi:10.1158/1055-9965.EPI-12-0483
PMCID: PMC3466057  PMID: 22761306
Human Papillomavirus (HPV); heterosexual men; men who have sex with men (MSM); seroprevalence; external genitalia; anal canal
17.  Prevention of Invasive Cervical Cancer in the United States: Past, Present, and Future 
Over the past several decades, invasive cervical cancer (ICC) incidence in the United States has declined dramatically. Much of this decline has been attributed to widespread use of cytology screening followed by treatment of precancerous lesions. Despite available technologies to prevent ICC and screening programs targeting high-risk women, certain populations in the United States experience disproportionately high rates of ICC (e.g., racial/ethnic minorities and rural women). Limited access to and use of screening/follow-up services underlie this disparity. The licensure of the human papillomavirus (HPV) vaccine in 2006 introduced an additional method of ICC prevention. Unfortunately, dissemination of the vaccine to age-eligible females has been lower than expected (32% have received all 3 recommended doses). Decreasing the burden of HPV infection and HPV-related diseases in the United States will require greater dissemination of the HPV vaccine to adolescents and young adults, along with successful implementation of revised ICC screening guidelines that incorporate HPV and cytology cotesting. While a future without ICC is possible, we will need a comprehensive national health care program and innovative approaches to reduce ICC burden and disparities.
doi:10.1158/1055-9965.EPI-11-1158
PMCID: PMC3556792  PMID: 22556273
18.  Race and prevalence of human papillomavirus infection among men residing in Brazil, Mexico, and the United States 
HPV causes anal, penile and oropharyngeal cancers in men. Genital HPV prevalence in men appears to vary by world region with men residing in Asia having among the lowest prevalence. Unfortunately, there is little information on prevalence of HPV infection in men by race. The purpose of this study was to examine HPV prevalence by race across three countries. 3,909 men ages 18–70 years enrolled in an ongoing prospective cohort study of the natural history of HPV in men (The HIM Study) were included in the analysis. Participants completed risk factor questionnaires and samples were taken from the penile epithelium and scrotum for HPV detection. HPV testing of the combined DNA extract was conducted using PCR and genotyping. Asian/Pacific Islanders had the lowest HPV prevalence of 42.2% compared to Blacks (66.2%), and Whites (71.5%). The Asian/Pacific Islander race was strongly protective in univariate analysis (prevalence ratio(PR)= 0.59; 95% confidence interval(CI):0.48 – 0.74) and multivariate analysis for any HPV infection (PR= 0.65; 95% CI:0.52 – 0.8). Stratified analysis by lifetime number of female partners also showed strong inverse associations with the Asian/Pacific Islander race. We consistently observed the lowest prevalence of HPV infection among Asian/Pacific Islanders with moderate inverse associations even after various adjustments for potential confounding factors. Unmeasured behavioral factors, sexual mixing with low risk women, and/or race-specific differences in the frequency of germline variations among immune regulating genes may underlie these associations. Further studies among Asian populations that incorporate measures of immuno-genetics are needed to understand this phenomenon.
doi:10.1002/ijc.27397
PMCID: PMC3458422  PMID: 22161806
19.  Dietary Consumption of Antioxidant Nutrients and Risk of Incident Cervical Intraepithelial Neoplasia 
Gynecologic oncology  2010;118(3):289-294.
Objective
Women with human papillomavirus (HPV) infections are at risk for developing squamous intraepithelial lesions (SIL) of the cervix; however, other factors are required for infections to progress to SIL. We hypothesize that consumption of fruits and vegetables high in antioxidant nutrients may prevent, in part, the development of HPV-associated SIL.
Methods
This study is a nested case-control study of 265 HPV-positive women (93 SIL cases and 172 cytologically normal controls) in the Ludwig-McGill Cohort Study, Sao Paulo, Brazil. Diet was assessed by a self-administered food frequency questionnaire. The association between food and nutrient intake of antioxidants and incident SIL was determined by logistic regression and multinomial regression when comparing LSIL and HSILs.
Results
Higher reported consumption of papaya was inversely associated with risk of SIL (p trend=0.01) and strongest for ≥1 time/week (adjusted odds ratios (AORs)=0.19; 95%CI, 0.08-0.49). Risk of SIL was reduced among women reporting consumption of oranges ≥1 time/week (AOR=0.32; 95%CI, 0.12-0.87; p-trend = 0.02). Nutrient intakes of ß-cryptoxanthin and α-carotene were marginally protective against SIL.
Conclusions
Frequent consumption of fruits high in antioxidant nutrients appears to be associated with reduced risk of incident SIL among Brazilian women.
doi:10.1016/j.ygyno.2010.05.022
PMCID: PMC3691953  PMID: 20691333
cervical cancer; cervical intraepithelial neoplasia; human papillomavirus; diet; antioxidant nutrient
20.  Case–Control Study of Cutaneous Human Papillomavirus Infection in Basal Cell Carcinoma of the Skin 
Genus-β human papillomavirus (HPV) DNA has been detected in basal cell carcinoma (BCC) tumors, but most epidemiologic studies have not observed associations between genus-β HPV seropositivity and BCC. A clinic-based case–control study was conducted to investigate cutaneous HPV infection in BCC. BCC cases (n = 224) were recruited from a dermatology clinic, and controls (n = 300) were patients who were screened negative for skin cancer. Antibodies against cutaneous HPV types in genera α, β, γ, mu, and nu were measured, and tumors from a subset of BCC cases (n = 195) were tested for HPV DNA. Overall associations were observed between BCC and seropositivity for HPV types in genus-α (odds ratio (OR) = 1.61; 95% confidence interval (CI) = 1.11–2.35), γ (OR = 1.78; 95% CI = 1.22–2.60), and mu (OR = 1.56; 95% CI = 1.06–2.30). BCC cases with β-HPV DNA in their tumors were more likely to be β-HPV seropositive than controls (OR = 1.76; 95% CI = 1.03–3.01), with type-specific associations observed for HPV8 and HPV23, whereas no association was observed between β-HPV seropositivity and β-HPV DNA–negative BCC. No concordance between seropositivity and tumor DNA status was observed for HPV types in genera α and γ. In conclusion, the combined serology and tumor DNA results suggest that β HPV types may have a role in BCC. Additional studies of BCC that assess HPV types in multiple genera are needed.
doi:10.1038/jid.2012.478
PMCID: PMC4545594  PMID: 23303448
21.  Case–control Study of Merkel Cell Polyomavirus Infection and Cutaneous Squamous Cell Carcinoma 
Background
Merkel cell polyomavirus (MCV) DNA has been reported in 0% to 25% of squamous cell carcinomas (SCC) occurring in immunocompetent individuals. We conducted the first serologic case–control study of MCV and SCC.
Methods
Patients with histologically confirmed cutaneous SCC (n = 173) were recruited from a university dermatology clinic. Controls were individuals who screened negative for and had no history of skin or other cancers (n = 300). Levels of antibodies against capsid antigens for MCV and another polyomavirus, JC virus (JCV), were determined by fluorescent bead-based multiplex serology. Fresh-frozen tumor tissues were obtained from 145 SCC cases and tested for MCV DNA by multiplexed PCR. Associations between MCV seroreactivity and SCC were estimated by ORs and 95% CIs calculated using logistic regression with adjustment for age and sex.
Results
MCV DNA was detected in SCC tumor tissues from 55 (38%) of 145 cases. A statistically significant association was observed between MCV seropositivity and MCV DNA-positive SCC (OR = 2.49, 95% CI = 1.03–6.04), with an almost four-fold association observed when comparing those with MCV antibodies in the fourth versus first quartiles (OR = 3.93, 95% CI = 1.43–10.76, Ptrend = 0.01). No significant associations were observed between MCV seropositivity and MCV DNA-negative SCC (OR = 1.38, 95% CI = 0.76–2.48) or between JCV seropositivity and MCV DNA-positive or DNA-negative SCC.
Conclusion
Past exposure to MCV may be a risk factor for SCC.
Impact
Understanding the role of viral infections in the development of nonmelanoma skin cancer could lead to novel prevention strategies.
doi:10.1158/1055-9965.EPI-11-0764
PMCID: PMC4543303  PMID: 22016472
22.  Case–Control Study of Cutaneous Human Papillomaviruses in Squamous Cell Carcinoma of the Skin 
Background
Cutaneous human papillomavirus (HPV) infection may be a risk factor for squamous cell carcinoma (SCC) of the skin.
Methods
To investigate the association between cutaneous HPV and SCC, a case–control study was conducted, including 173 SCC cases from a university dermatology clinic and 300 controls that screened negative for skin cancer. Serum antibodies against cutaneous HPV types in genera alpha, beta, gamma, mu, and nu were measured. Tumor tissue from 159 SCC cases was tested for the presence of DNA for genus-beta HPV types. Using logistic regression ORs and 95% confidence intervals (CI) were estimated for the associations between SCC and cutaneous HPV infection, adjusting for age and sex. The Bonferroni method was used to account for multiple comparisons.
Results
SCC was positively associated with seropositivity to any genus-beta HPV type (OR, 1.93; 95% CI, 1.23–3.02), particularly with types in species-1 (OR, 1.86; 95% CI, 1.22–2.85). Type-specific associations with SCC were observed for HPV 8 (OR, 1.80; 95% CI, 1.14–2.84), 17 (OR, 1.59; 95% CI, 1.02–2.49) and HPV 10 from genus-alpha (OR, 2.24; 95% CI, 1.04–4.85). None of the type-specific associations remained statistically significant after correction for multiple comparisons. When DNA-positive SCC cases were compared with controls, strong serologic associations were observed for HPVs 5 (OR, 3.48; 95% CI, 1.27–9.59), 17 (OR, 3.36; 95% CI, 1.29–8.72), and 24 (OR, 3.79; 95% CI, 1.24–11.5).
Conclusion
Genus-beta HPV infections were associated with SCC in our study population.
Impact
Identifying the role of cutaneous HPV infection in SCC may lead to improved characterization of high-risk individuals and the development of novel prevention strategies.
doi:10.1158/1055-9965.EPI-12-0032
PMCID: PMC4543310  PMID: 22707711
23.  Male Human Papillomavirus Prevalence and Association With Condom Use in Brazil, Mexico, and the United States 
The Journal of Infectious Diseases  2012;205(8):1287-1293.
Background. Reported associations of condom use and human papillomavirus (HPV) infection have been inconsistent. We investigated self-reported frequency of condom use and detection of genital HPV among men.
Methods. A cross-sectional analysis was conducted in men aged 18–70 years from Brazil, Mexico, and the United States. Men completed questionnaires on sexual history, condom use, and sociodemographic characteristics. Among 2621 men reporting recent vaginal sex, prevalence of any HPV, any oncogenic type, and nononcogenic types only was estimated by frequency of condom use (“always” or “not always”). Multivariable models were used to estimate prevalence ratios (PRs) for HPV according to frequency of condom use.
Results. The prevalence of any HPV was 70.5%; any oncogenic type, 34%, and nononcogenic types only, 22.2%. The adjusted PR for always vs not always using condoms was 0.87 (95% confidence interval [CI], .77–.97) for all countries combined. The association was stronger in the United States (PR, 0.70; CI, .55–.90) than in Brazil (PR, 0.84; CI, .71–1.01) or Mexico (PR, 1.05; CI, .89–1.25) (P for interaction = .025).
Conclusions. HPV prevalence was high even among those who reported always using condoms, and its associations with always using condoms varied among countries.
doi:10.1093/infdis/jis181
PMCID: PMC3308908  PMID: 22396601
24.  Genetic variants in interleukin genes are associated with breast cancer risk and survival in a genetically admixed population: the Breast Cancer Health Disparities Study 
Carcinogenesis  2014;35(8):1750-1759.
Summary
These data support the associations between IL genes and breast cancer risk and mortality in a large admixed population.
Interleukins (ILs) are key regulators of immune response. Genetic variation in IL genes may influence breast cancer risk and mortality given their role in cell growth, angiogenesis and regulation of inflammatory process. We examined 16 IL genes with breast cancer risk and mortality in an admixed population of Hispanic/Native American (NA) (2111 cases and 2597 controls) and non-Hispanic white (NHW) (1481 cases and 1585 controls) women. Adaptive Rank Truncated Product (ARTP) analysis was conducted to determine gene significance and lasso (least absolute shrinkage and selection operator) was used to identify potential gene by gene and gene by lifestyle interactions. The pathway was statistically significant for breast cancer risk overall (P ARTP = 0.0006), for women with low NA ancestry (P ARTP = 0.01), for premenopausal women (P ARTP = 0.02), for estrogen receptor (ER)+/progesterone receptor (PR)+ tumors (P ARTP = 0.03) and ER−/PR− tumors (P ARTP = 0.02). Eight of the 16 genes evaluated were associated with breast cancer risk (IL1A, IL1B, IL1RN, IL2, IL2RA, IL4, IL6 and IL10); four genes were associated with breast cancer risk among women with low NA ancestry (IL1B, IL6, IL6R and IL10), two were associated with breast cancer risk among women with high NA ancestry (IL2 and IL2RA) and four genes were associated with premenopausal breast cancer risk (IL1A, IL1B, IL2 and IL3). IL4, IL6R, IL8 and IL17A were associated with breast cancer-specific mortality. We confirmed associations with several functional polymorphisms previously associated with breast cancer risk and provide support that their combined effect influences the carcinogenic process.
doi:10.1093/carcin/bgu078
PMCID: PMC4123645  PMID: 24670917
25.  Prevalent Serum Antibody Is Not a Marker of Immune Protection against Acquisition of Oncogenic HPV16 in Men 
Cancer research  2011;72(3):676-685.
In women, naturally induced anti–human papilloma virus (HPV) serum antibodies are a likely marker of host immune protection against subsequent HPV acquisition and progression to precancerous lesions and cancers. However, it is unclear whether the same is the case in men. In this study, we assessed the risk of incident genital infection and 6-month persistent genital infection with HPV16 in relation to baseline serostatus in a cohort of 2,187 men over a 48-month period. Genital swabs were collected every 6 months and tested for HPV presence. Incidence proportions by serostatus were calculated at each study visit to examine whether potential immune protection attenuated over time. Overall, incidence proportions did not differ statistically between baseline seropositive and seronegative men at any study visit or over the follow-up period. The risk of incident and 6-month persistent infection was not associated with baseline serostatus or baseline serum antibody levels in the cohort. Our findings suggest that baseline HPV seropositivity in men is not associated with reduced risk of subsequent HPV16 acquisition. Thus, prevalent serum antibodies induced by prior infection may not be a suitable marker for subsequent immune protection against genital HPV16 acquisition in men.
doi:10.1158/0008-5472.CAN-11-0751
PMCID: PMC3474343  PMID: 22123925

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