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Background: Effective screening for oropharyngeal cancer is lacking. Four oncogenic HPV clearance definitions were explored to understand long-term natural history for persistent oncogenic oral HPV (oncHPV), the precursor of oropharyngeal cancer., Methods: Prospective multicenter cohort of participants living with/at-risk for HIV, with oral rinse and gargle samples collected every 6 to 12 months for up to 10 years and tested for oncHPV. HPV clearance definitions included 1 (clear1), 2 (clear2), 3 (clear3) consecutive negatives, or being negative at last two visits (clearlast)., Results: Median time to clearance of oncHPV exceeded 2 years for conservative definitions (clear3: 2.38, clearlast: 2.43), but not lenient (clear1: 0.68, clear2: 1.15). By clear3, most incident infections cleared at 2, 5, 8 years (55.1%, 75.6%, 79.1%), contrary to prevalent infections (37.1%, 52.5%, 59.5%, respectively). In adjusted analysis, prevalent oncHPV, older age, male sex, and living with HIV were associated with reduced clearance. Of 1,833 subjects screened, 13.8% had prevalent oncHPV and 47.5% of those infections persisted ≥5 years, representing 6.5% of persons screened. Two men with prevalent oral HPV16 developed incident oropharyngeal cancer [IR = 1.62 per 100 person-years; 95% confidence interval (CI), 0.41-6.4]. Many with oral HPV16 persisted ≥5 years (and/or developed HPV-oropharyngeal cancer) among those with 2 (72.2%), ≥2 of first 3 (65.7%), or 3 (80.0%) consecutive positive oHPV16 tests, but not after 1 (39.4%)., Conclusions: In our 10-year study, most incident infections cleared quickly. However, half of prevalent oncHPV persisted ≥5 years, suggesting increased risk with persistent oncHPV at >2 visits., Impact: We identified groups with persistent oncHPV at increased risk of oropharyngeal cancer and contextualized risk levels for those with oral HPV16 infection., (©2024 American Association for Cancer Research.)

Background: Human papillomavirus (HPV)-related oropharyngeal cancer screening is being explored in research studies, but strategies to identify an appropriate population are not established. The authors evaluated whether a screening population could be enriched for participants with oncogenic HPV biomarkers using risk factors for oral HPV., Methods: Participants were enrolled at Johns Hopkins Hospitals and Mount Sinai Icahn School of Medicine. Eligible participants were either men aged 30 years or older who had two or more lifetime oral sex partners and a personal history of anogenital dysplasia/cancer or partners of patients who had HPV-related cancer. Oral rinse and serum samples were tested for oncogenic HPV DNA, RNA, and E6 or E7 antibodies, respectively. Participants with any biomarker were considered at-risk., Results: Of 1108 individuals, 7.3% had any oncogenic oral HPV DNA, and 22.9% had serum antibodies for oncogenic HPV E6 or E7. Seventeen participants (1.5%) had both oral and blood biomarkers. HPV type 16 (HPV16) biomarkers were rarer, detected in 3.7% of participants, including 20 with oral HPV16 DNA and 22 with HPV16 E6 serum antibodies (n = 1 had both). In adjusted analysis, living with HIV (adjusted odds ratio, 2.65; 95% CI, 1.60-4.40) and older age (66-86 vs. 24-45 years; adjusted odds ratio, 1.70; 95% CI, 1.07-2.70) were significant predictors of being at risk. Compared with the general population, the prevalence of oral HPV16 (1.8% vs. 0.9%), any oncogenic oral HPV DNA (7.3% vs. 3.5%), and HPV16 E6 antibodies (2.2% vs. 0.3%) was significantly elevated., Conclusions: Enrichment by the eligibility criteria successfully identified a population with higher biomarker prevalence, including HPV16 biomarkers, that may be considered for screening trials. Most in this group are still expected to have a low risk of oropharyngeal cancer., (© 2023 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Background: Human papillomavirus-related oropharyngeal cancer (HPV-OPC) incidence is increasing, but the natural history of the precursor-oral HPV-has not been well described., Methods: This observational cohort study of people living with HIV and at-risk HIV uninfected people evaluated participants semiannually using 30-second oral rinse and gargle specimens over 7 years. Initially, 447 participants were followed for 4 years as part of the Persistent Oral Papillomavirus Study, and a subset of 128 who showed persistent infections at the last Persistent Oral Papillomavirus Study visit had an additional visit, as part of the Men and Women Understanding Throat HPV Study, on average 2.5 years later. Extracted DNA from oral rinse and gargle specimens was amplified using polymerase chain reaction and type specification of 13 oncogenic HPV types. Risk factors for oncogenic oral HPV clearance were evaluated using Cox models., Results: The majority of oncogenic oral HPV infections cleared quickly, with a median time to clearance of 1.4 years (interquartile range = 0.5-3.9 years). After 7 years of follow-up, 97% of incident and 71% of prevalent infections had cleared. Lower HPV-16 viral load was statistically significantly associated with clearance (per 10-fold decrease in copy number: adjusted hazard ratio [aHR] = 2.51, 95% confidence interval [CI] = 1.20 to 5.26; P = .01). Adjusted analyses showed that oncogenic oral HPV clearance was lower among prevalent than incident-detected infections (aHR = 0.44, 95% CI = 0.35 to 0.55), among men than women (aHR = 0.74, 95% CI = 0.60 to 0.91), for older participants (aHR per 10 years increasing age = 0.81, 95% CI = 0.74 to 0.89), and among people living with HIV (aHR = 0.76, 95% CI = 0.60 to 0.95). One participant who had oral HPV-16 consistently detected at 10 study visits over 4.5 years was subsequently diagnosed with HPV-OPC., Conclusions: This prospective study of oncogenic oral HPV infection is the longest and largest quantification of oral HPV-16 infections to date., (© The Author(s) 2020. Published by Oxford University Press.)

Importance: Human papillomavirus (HPV) infection is found in about 40% of women who survive allogeneic hematopoietic stem cell transplant and can induce subsequent neoplasms., Objective: To determine the safety and immunogenicity of the quadrivalent HPV vaccine (HPV-6, -11, -16, and -18) in clinically stable women post-allogeneic transplant compared with female healthy volunteers., Interventions: Participants received the quadrivalent HPV vaccine in intramuscular injections on days 1 and 2 and then 6 months later., Design, Setting, and Participants: This prospective, open-label phase-1 study was conducted in a government clinical research hospital and included clinically stable women posttransplant who were or were not receiving immunosuppressive therapy compared with healthy female volunteers age 18 to 50 years who were followed up or a year after first receiving quadrivalent HPV vaccination. The study was conducted from June 2, 2010, until July 19, 2016. After all of the results of the study assays were completed and available in early 2018, the analysis took place from February 2018 to May 2019., Main Outcomes and Measures: Anti-HPV-6, -11, -16, and -18-specific antibody responses using L1 virus-like particle enzyme-linked immunosorbent assay were measured in serum before (day 1) and at months 7 and 12 postvaccination. Anti-HPV-16 and -18 neutralization titers were determined using a pseudovirion-based neutralization assay., Results: Of 64 vaccinated women, 23 (35.9%) were receiving immunosuppressive therapy (median age, 34 years [range, 18-48 years]; median 1.2 years posttransplant), 21 (32.8%) were not receiving immunosuppression (median age, 32 years [range, 18-49 years]; median 2.5 years posttransplant), and 20 (31.3%) were healthy volunteers (median age, 32 years [range, 23-45 years]). After vaccine series completion, 18 of 23 patients receiving immunosuppression (78.3%), 20 of 21 not receiving immunosuppression (95.2%), and all 20 volunteers developed antibody responses to all quadrivalent HPV vaccine types (P = .04, comparing the 3 groups). Geometric mean antibody levels for each HPV type were higher at months 7 and 12 than at baseline in each group (all geometric mean ratios >1; P < .001) but not significantly different across groups. Antibody and neutralization titers for anti-HPV-16 and anti-HPV-18 correlated at month 7 (Spearman ρ = 0.92; P < .001 for both). Adverse events were mild and not different across groups., Conclusions and Relevance: Treatment with the HPV vaccination was followed by strong, functionally active antibody responses against vaccine-related HPV types and no serious adverse events. These findings suggest that HPV vaccination may be safely administered to women posttransplant to potentially reduce HPV infection and related neoplasia., Trial Registration: ClinicalTrials.gov Identifier: NCT01092195.

Performance of commercially available human papillomavirus (HPV) assays (approved for cervical HPV detection) is unknown for detecting HPV-related oropharyngeal cancer (HPV-OPC). Assays for detection of HPV DNA [ELISA (DEIA) and Cobas], and RNA (Aptima) in oral rinse samples, and serum HPV oncogene antibodies were evaluated. Sensitivity and specificity of each test was explored among HPV-OPC cases and controls. Biomarker prevalence was evaluated among 294 "at-risk" people (screening) and 133 "high-risk" people [known to previously have oral oncogenic HPV (oncHPV) DNA and/or HPV16 E6/E7 antibodies detected]. HPV16 E6 antibodies had the best overall test performance with sensitivity of 88%, compared with oral HPV16 DNA sensitivity of 51% by DEIA and 43% by Cobas (each P < 0.001). Specificity was comparable in each of these tests (≥98%). When positivity for any oncHPV type was compared with HPV16 for the same test, sensitivity was comparable (60% vs. 51%, 40% vs. 43%, and 92% vs. 88% for DEIA, Cobas, and E6 antibodies, respectively), but specificity was reduced (93%-97%). Aptima had poor sensitivity (23%). Sensitivity decreased when cotesting HPV16 oral rinse DNA and E6 antibodies (37%-48%), or multiple E antibodies (69%-72%). HPV16 DNA were detected in ∼2% of the at-risk by either DEIA or Cobas and up to 15% of the high-risk population. HPV16 E6 seroprevalence was 2.3% and 2.4% in the at-risk and high-risk populations, respectively. Oral rinse HPV testing had moderate-to-poor sensitivity for HPV-OPC, suggesting many true positives would be missed in a potential screening scenario. HPV16 E6 serum antibody was the most promising biomarker evaluated., (©2019 American Association for Cancer Research.)

Background: Oropharyngeal cancer incidence is rapidly rising due to human papillomavirus (HPV) type 16 infection. The dearth of data on effectiveness of national female-only vaccination programs in preventing oral HPV infection and potential herd immunity in unvaccinated males has resulted in considerable controversy regarding the need to vaccinate males, especially in countries with high female vaccination coverage., Methods: Subjects aged 0-65 years undergoing tonsillectomy for nonmalignant indications were recruited in 6 hospitals in the United Kingdom. Oral samples were collected as follows: oral rinse, tongue base, and pharyngeal wall brushes, then tonsil tissue (tonsillectomy). Vaccination data were obtained from regional health authorities. All samples were centrally tested for HPV DNA by polymerase chain reaction., Results: Of 940 subjects, 243 females and 69 males were aged 12-24 years (median age, 18.6 years), with 189 (78%) females and no males vaccinated against HPV. Overall, oropharyngeal HPV-16 prevalence was significantly lower in vaccinated versus unvaccinated females (0.5% vs 5.6%, P = .04). In contrast, prevalence of any oropharyngeal HPV type was similar in vaccinated and unvaccinated females (19% vs 20%, P = .76). Oropharyngeal HPV-16 prevalence in unvaccinated males was similar to vaccinated females (0% vs 0.5%, P > .99), and lower than unvaccinated females (0% vs 5.6%, P = .08)., Conclusions: Our findings indicate that the UK female-only vaccination program is associated with significant reductions in oropharyngeal HPV-16 infections. These are also the first data to suggest potential herd immunity from female-only vaccination against oropharyngeal HPV infection in contemporaneously aged males., (© The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America.)

An assistive robotic manipulator (ARM) can provide independence and improve the quality of life for patients suffering from tetraplegia. However, to properly control such device to a satisfactory level without any motor functions requires a very high performing brain-computer interface (BCI). Steady-state visual evoked potentials (SSVEP) based BCI are among the best performing. Thus, this study investigates the design of a system for a full workspace control of a 7 degrees of freedom ARM. A SSVEP signal is elicited by observing a visual stimulus flickering at a specific frequency and phase. This study investigates the best combination of unique frequencies and phases to provide a 16-target BCI by testing three different systems off line. Furthermore, a fourth system is developed to investigate the impact of the stimulating monitor refresh rate. Experiments conducted on two subjects suggest that a 16-target BCI created by four unique frequencies and 16-unique phases provide the best performance. Subject 1 reaches a maximum estimated ITR of 235 bits/min while subject 2 reaches 140 bits/min. The findings suggest that the optimal SSVEP stimuli to generate 16 targets are a low number of frequencies and a high number of unique phases. Moreover, the findings do not suggest any need for considering the monitor refresh rate if stimuli are modulated using a sinusoidal signal sampled at the refresh rate.

Purpose: Individuals with tetraplegia depend on alternative interfaces in order to control computers and other electronic equipment. Current interfaces are often limited in the number of available control commands, and may compromise the social identity of an individual due to their undesirable appearance. The purpose of this study was to implement an alternative computer interface, which was fully embedded into the oral cavity and which provided multiple control commands., Methods: The development of a wireless, intraoral, inductive tongue computer was described. The interface encompassed a 10-key keypad area and a mouse pad area. This system was embedded wirelessly into the oral cavity of the user. The functionality of the system was demonstrated in two tetraplegic individuals and two able-bodied individuals Results: The system was invisible during use and allowed the user to type on a computer using either the keypad area or the mouse pad. The maximal typing rate was 1.8 s for repetitively typing a correct character with the keypad area and 1.4 s for repetitively typing a correct character with the mouse pad area., Conclusion: The results suggest that this inductive tongue computer interface provides an esthetically acceptable and functionally efficient environmental control for a severely disabled user. Implications for Rehabilitation New Design, Implementation and detection methods for intra oral assistive devices. Demonstration of wireless, powering and encapsulation techniques suitable for intra oral embedment of assistive devices. Demonstration of the functionality of a rechargeable and fully embedded intra oral tongue controlled computer input device.

Background: Oral human papillomavirus (HPV) infection and related oropharyngeal cancer are uncommon in lower-income countries, particularly compared to HPV-associated cervical cancer. However, little is known about the natural history of oral HPV in less-developed settings and how it compares to the natural history of cervical HPV., Methods: Three hundred fifty women aged 22 to 33 years from the Costa Rica Vaccine Trial provided exfoliated cells from the cervical and oral regions at 2 visits 2 years apart. Samples from both visits were tested for 25 characterized α HPV types by the SPF10 PCR-DNA enzyme immunoassay-LiPA25 version 1 system. Risk factors for oral HPV persistence were calculated utilizing generalized estimating equations with a logistic link., Results: Among the 82 women with characterized α oral HPV DNA detected at baseline, 14 persisted and were detected 2 years later (17.6%; 95% confidence interval [CI], 10.9-28.5%) and was similar to the persistence of α cervical HPV (40/223; 17.7%; 95% CI, 13.1-23.9%; P = 0.86). Acquisition of new α oral HPV type was low; incident infection (1.7%; 95% CI, 0.6-3.7%)., Conclusions: Oral HPV DNA is uncommon in young women in Latin America, and often appears to clear within a few years at similar rates to cervical HPV.

HPV-positive oropharyngeal cancer patients experience significantly lower locoregional recurrence and higher overall survival in comparison with HPV-negative patients, especially among those who received radiation therapy. The goal of the present study is to investigate the molecular mechanisms underlying the differential radiation sensitivity between HPV-negative and HPV-positive head and neck squamous cell carcinoma (HNSCC). Here, we show that HPV-negative HNSCC cells exhibit increased glucose metabolism as evidenced by increased production of lactate, while HPV-positive HNSCC cells effectively utilize mitochondrial respiration as evidenced by increased oxygen consumption. HPV-negative cells express HIF1α and its downstream mediators of glucose metabolism such as hexokinase II (HKII) and carbonic anhydrase IX (CAIX) at higher levels, while the expression level of cytochrome c oxidase (COX) was noticeably higher in HPV-positive HNSCC. In addition, the expression levels of pyruvate dehydrogenase kinases (PDKs), which inhibit pyruvate dehydrogenase activity, thereby preventing entry of pyruvate into the mitochondrial tricarboxylic acid (TCA) cycle, were much higher in HPV-negative HNSCC compared to those in HPV-positive cells. Importantly, a PDK inhibitor, dichloroacetate, effectively sensitized HPV-negative cells to irradiation. Lastly, we found positive interactions between tonsil location and HPV positivity for COX intensity and COX/HKII index ratio as determined by immunohistochemical analysis. Overall survival of patients with HNSCC at the tonsil was significantly improved with an increased COX expression. Taken together, the present study provides molecular insights into the mechanistic basis for the differential responses to radiotherapy between HPV-driven vs . spontaneous or chemically induced oropharyngeal cancer., Competing Interests: CONFLICTS OF INTEREST Contributing authors do not have any conflict of interest to disclose.

Background: Previous Costa Rica Vaccine Trial (CVT) reports separately demonstrated vaccine efficacy against HPV16 and HPV18 (HPV16/18) infections at the cervical, anal, and oral regions; however, the combined overall multisite efficacy (protection at all three sites) and vaccine efficacy among women infected with HPV16 or HPV18 prior to vaccination are less known., Methods: Women age 18 to 25 years from the CVT were randomly assigned to the HPV16/18 vaccine (Cervarix) or a hepatitis A vaccine. Cervical, oral, and anal specimens were collected at the four-year follow-up visit from 4186 women. Multisite and single-site vaccine efficacies (VEs) and 95% confidence intervals (CIs) were computed for one-time detection of point prevalent HPV16/18 in the cervical, anal, and oral regions four years after vaccination. All statistical tests were two-sided., Results: The multisite woman-level vaccine efficacy was highest among "naïve" women (HPV16/18 seronegative and cervical HPV high-risk DNA negative at vaccination) (vaccine efficacy = 83.5%, 95% CI = 72.1% to 90.8%). Multisite woman-level vaccine efficacy was also demonstrated among women with evidence of a pre-enrollment HPV16 or HPV18 infection (seropositive for HPV16 and/or HPV18 but cervical HPV16/18 DNA negative at vaccination) (vaccine efficacy = 57.8%, 95% CI = 34.4% to 73.4%), but not in those with cervical HPV16 and/or HPV18 DNA at vaccination (anal/oral HPV16/18 VE = 25.3%, 95% CI = -40.4% to 61.1%). Concordant HPV16/18 infections at two or three sites were also less common in HPV16/18-infected women in the HPV vaccine vs control arm (7.4% vs 30.4%, P < .001)., Conclusions: This study found high multisite vaccine efficacy among "naïve" women and also suggests the vaccine may provide protection against HPV16/18 infections at one or more anatomic sites among some women infected with these types prior to HPV16/18 vaccination., (Published by Oxford University Press 2015. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Two commercial HPV tests target the same 65 bp fragment of the human papillomavirus genome (designated SPF10): the original HPV SPF10 PCR-DEIA-LiPA25 system, version 1, (LiPA25) and the INNO-LiPA HPV Genotyping Extra (INNO-LiPA). The original SPF10 LiPA25 system was designed to have high analytical sensitivity and applied in HPV vaccine and epidemiology studies worldwide. But due to apparent similarities, this test can be easily confused with INNO-LiPA, a more recent assay of which the intended use, i.e., epidemiological or clinical, is currently unclear. The aim was to compare the analytical sensitivity of SPF10 LiPA25 to that of INNO-LiPA on the level of general HPV detection and genotyping. HPV testing by both assays was performed on the same DNA isolated from cervical swab (n = 365) and biopsy (n = 42) specimens. In cervical swabs, SPF10 LiPA25 and INNO-LiPA identified 35.3% and 29.3% multiple infections, 52.6% and 51.5% single infections, and no HPV type in 12.1% and 19.2%, respectively. Genotyping results were 64.7% identical, 26.0% compatible and 9.3% discordant between both methods. SPF10 LiPA25 detected significantly more genotypes (p < 0.001). The higher analytical sensitivity of SPF10 LiPA25 was confirmed by the MPTS123 genotyping assay. HPV positivity by the general probes in SPF10 DEIA was significantly higher (87.9%) than by those on INNO-LiPA (77.0%) (kappa = 0.592, p < 0.001). In cervical biopsies, SPF10 LiPA25 and INNO-LiPA identified 21.4% and 9.5% multiple types, 76.2% and 81.0% single types, and no type in 2.4% and 9.5%, respectively. Between both tests, the identification of genotypes was 76.3% identical, 14.3% compatible and 9.5% discordant. Overall, significantly more genotypes were detected by SPF10 LiPA25 (kappa = 0.853, p = 0.022). HPV positivity was higher by the SPF10 DEIA (97.6%) than by the INNO-LiPA strip (92.9%). These results demonstrate that SPF10 LiPA25 is more suitable for HPV genotyping in epidemiologic and vaccine-related studies, due to its higher analytical sensitivity., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Background: Vaccine efficacy (VE) against vulvar human papillomavirus (HPV) infection has not been reported and data regarding its epidemiology are sparse., Methods: Women (n = 5404) age 22-29 present at the 4-year study visit of the Costa Rica Vaccine Trial provided vulvar and cervical samples. A subset (n = 1044) was tested for HPV DNA (SPF10/LiPA25 version 1). VE against 1-time detection of vulvar HPV16/18 among HPV vaccinated versus unvaccinated women was calculated and compared to the cervix. Prevalence of and risk factors for HPV were evaluated in the control arm (n = 536)., Results: Vulvar HPV16/18 VE (54.1%; 95% confidence interval [CI], 4.9%-79.1%) was comparable to cervix (45.8%; 95% CI, 6.4%-69.4%). Vulvar and cervical HPV16 prevalence within the control arm was 3.0% and 4.7%, respectively. Independent risk factors for vulvar HPV were similar to cervix and included: age (adjusted odds ratio [aOR] 0.5 [95% CI, .3-.9] ≥28 vs 22-23]); marital status (aOR 2.3 [95% CI, 1.5-3.5] single vs married/living-as-married); and number of sexual partners (aOR 3.6 [95% CI, 1.9-7.0] ≥6 vs 1)., Conclusions: In this intention-to-treat analysis, VE against vulvar and cervical HPV16/18 were comparable 4 years following vaccination. Risk factors for HPV were similar by anatomic site., Clinical Trials Registration: NCT00128661., (Published by Oxford University Press on behalf of the Infectious Diseases Society of America 2014. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

The publisher regrets that this article has been temporarily removed. A replacement will appear as soon as possible in which the reason for the removal of the article will be specified, or the article will be reinstated. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy., (Copyright © 2014. Published by Elsevier B.V. All rights reserved.)

Purpose: Poorer survival from head and neck squamous cell carcinoma (HNSCC) in African Americans (AA) may be due to disparity in the prevalence of Human Papillomavirus (HPV) but earlier studies often failed to control other etiological factors. We aimed to elucidate whether racial disparities in HPV prevalence and overall survival were due to confounding from smoking or alcohol use., Materials and Methods: 385 patients with SCC of the mouth, pharynx, nose, or larynx who had surgical resection at Wayne State University affiliated hospitals were identified through a population-based cancer registry. Formalin fixed paraffin embedded tissue blocks were used to determine the presence of HPV DNA and its genotype using a sensitive broad-spectrum PCR technique. Patients' demographics, tumor characteristics and vital status were obtained through record linkage with the registry data and smoking and alcohol information was abstracted from medical record. Cox's proportional hazard model and unconditional logistic regression models were employed to analyze the overall survival and tumor HPV-positivity, respectively., Results: HPV positivity in oropharyngeal cancer was substantially lower in AA than in other racial groups (odds ratio 0.14, 95% confidence interval (CI) 0.05-0.37) and adjustment for smoking or alcohol did not change this association. However, a significantly increased hazard ratio of death in AA oropharyngeal cancer patients (univariable hazard ratio (HR) 2.55, 95% CI 1.42-4.59) decreased to almost unity (HR 1.49, 95% CI 0.75-2.93) after adjustment for HPV and smoking., Conclusions: Lower HPV prevalence in AA largely accounts for their poorer survival from oropharyngeal cancer, but not other HNSSC., (© 2014.)

Background: Little is known about the epidemiology of oral human papillomavirus (HPV) in Latin America., Methods: Women (N = 5838) aged 22-29 in the control and vaccine arms of an HPV-16/18 vaccine trial in Costa Rica had oral, cervical, and anal specimens collected. Samples were tested for alpha mucosal HPV types (SPF10/LiPA25 version 1); a subset of oral samples (n = 500) was tested for cutaneous HPV types in the genera alpha, beta, gamma, mu, and nu., Results: In the control arm (n = 2926), 1.9% of women had an oral alpha mucosal HPV detected, 1.3% had carcinogenic HPV, and 0.4% had HPV-16; similar patterns for non-16/18 HPV types were observed in the vaccine arm. Independent risk factors for any oral alpha mucosal HPV among women in the control arm included marital status (adjusted odds ratio [AOR], 3.2; 95% confidence interval [CI], 1.8-5.7 for single compared to married/living as married), number of sexual partners (AOR, 2.4; 95% CI, 1.0-6.1 for ≥4 partners compared to 0-1 partners), chronic sinusitis (AOR, 3.1; 95% CI, 1.5-6.7), and cervical HPV infection (AOR, 2.6; 95% CI, 1.4-4.6). Detection of beta HPV was common (18.6%) and not associated with sexual activity., Conclusions: Unlike cutaneous HPV types, alpha mucosal HPV types were uncommon in the oral region and were predominately associated with sexual behavior. Clinical Trials Registration. NCT00128661.

Background: Human papillomavirus (HPV) infection, particularly with type 16, causes a growing fraction of oropharyngeal cancers, whose incidence is increasing, mainly in developed countries. In a double-blind controlled trial conducted to investigate vaccine efficacy (VE) of the bivalent HPV 16/18 vaccine against cervical infections and lesions, we estimated VE against prevalent oral HPV infections 4 years after vaccination., Methods and Findings: A total of 7,466 women 18-25 years old were randomized (1∶1) to receive the HPV16/18 vaccine or hepatitis A vaccine as control. At the final blinded 4-year study visit, 5,840 participants provided oral specimens (91·9% of eligible women) to evaluate VE against oral infections. Our primary analysis evaluated prevalent oral HPV infection among all vaccinated women with oral and cervical HPV results. Corresponding VE against prevalent cervical HPV16/18 infection was calculated for comparison. Oral prevalence of identifiable mucosal HPV was relatively low (1·7%). Approximately four years after vaccination, there were 15 prevalent HPV16/18 infections in the control group and one in the vaccine group, for an estimated VE of 93·3% (95% CI = 63% to 100%). Corresponding efficacy against prevalent cervical HPV16/18 infection for the same cohort at the same visit was 72·0% (95% CI = 63% to 79%) (p versus oral VE = 0·04). There was no statistically significant protection against other oral HPV infections, though power was limited for these analyses., Conclusions: HPV prevalence four years after vaccination with the ASO4-adjuvanted HPV16/18 vaccine was much lower among women in the vaccine arm compared to the control arm, suggesting that the vaccine affords strong protection against oral HPV16/18 infection, with potentially important implications for prevention of increasingly common HPV-associated oropharyngeal cancer. ClinicalTrials.gov, Registry number NCT00128661.

Liquid-based methods for the collection, transportation, and storage of cervical cells are cumbersome and expensive and involve laborious DNA extraction. An FTA cartridge is a solid carrier device, easier to handle and allowing simple DNA elution for human papillomavirus (HPV) testing. HPV-DNA results from cervical specimens collected in PreservCyt medium (Hologic, Inc.) and the indicating FTA elute cartridge were compared in an area where transportation and storage may affect the performance of the test. Cervical cells from 319 young adult women enrolled in the Costa Rica Vaccine Trial were collected by a nurse using a Cervex brush (Roberts), which was placed on the FTA cartridge and subsequently rinsed in 20 ml of PreservCyt medium. Two 0.5-ml PreservCyt aliquots were frozen for HPV-PCR testing; the FTA cartridges were kept at room temperature. HPV-DNA detection and typing was performed using SPF(10) PCR/DEIA (DNA enzyme immunoassay detection of amplimers)/LiPA(25) system. The percent agreement, agreement among positives, and kappas were estimated. Positivity was higher for FTA compared to PreservCyt specimens (54.5% versus 45.8%, P < 0.001). For oncogenic types, the overall agreement was 0.92, the agreement between positives was 0.74, and the kappa was 0.79. For individual HPV types, the overall agreement ranged from 0.97 to 1.00. We did not observe reduced cytology adequacy when specimen collection for cytology was preceded by FTA collection for HPV testing. HPV-DNA detection from FTA cartridges is broadly comparable to detection from PC medium. The higher HPV detection observed for FTA-collected specimens should be explored further. FTA cartridges could provide a simpler and more cost-effective method for cervical cell collection, storage, and transportation for HPV-DNA detection in research settings in developing countries.

Background: Anal cancer is caused by human papillomavirus (HPV), yet little is known about anal HPV infection among healthy young women., Methods: A total of 2017 sexually active women in the control arm of an HPV-16/18 vaccine trial had a single anal specimen collected by a clinician at the 4-year study visit. Samples were tested for HPV by SPF(10) PCR/DEIA/LiPA(25), version 1., Results: A total of 4% of women had HPV-16, 22% had oncogenic HPV, and 31% had any HPV detected in an anal specimen. The prevalence of anal HPV was higher among women who reported anal intercourse, compared with those who did not (43.4% vs 28.4%; P< .001). Among women who reported anal intercourse, cervical HPV (adjusted odds ratio [aOR], 5.3 [95% confidence interval {CI}, 3.4-8.2]), number of sex partners (aOR, 2.2 [95% CI, 1.1-4.6] for ≥ 4 partners), and number of anal intercourse partners (aOR, 1.9 [95% CI, 1.1-3.3] for ≥ 2 partners) were independent risk factors for anal HPV detection. Among women who reported no anal intercourse, cervical HPV (aOR, 4.7 [95% CI, 3.7-5.9]), number of sex partners (aOR, 2.4 [95% CI, 1.7-3.4] for ≥ 4 partners), and report of anal fissures (aOR, 2.3 [95% CI, 1.1-4.8]) were associated with an increased odds of anal HPV detection., Conclusion: Anal HPV is common among young women, even those who report no anal sex, and was associated with cervical HPV infection. Anal fissures in women who report never having had anal intercourse may facilitate HPV exposure., Clinical Trials Registration: NCT00128661.

Elucidation of the role of human papillomavirus (HPV) in the etiology and prognosis of squamous carcinomas of the head and neck (HNSCC) is essential to optimize prevention and treatment strategies for this disease. We analyzed 385 HNSCC tissue blocks identified through a population-based cancer registry in Metropolitan Detroit for HPV DNA using a broad-spectrum PCR technique (SPF10-LiPA25) to correlate with patient and tumor characteristics and overall survival. Overall, HPV DNA (any type) was detected in 29.4% of all HNSCC, but it was significantly more prevalent (50.6%) in oropharyngeal sites (N=81), where 90% of HPV were type 16, than in other sites. HPV prevalence (any type) in oropharyngeal sites was highest in patients with a negative smoking indicator, Caucasians and in regional tumor stage. Likewise, only in oropharyngeal sites did patients overall positive to HPV show significantly better survival compared with HPV-negative patients, notably among those who had been irradiated. The best and the worst survival from cancer in oropharyngeal sites were found, respectively, among HPV-positive patients with negative smoking indicator and among HPV-negative patients with positive smoking indicator. The results of this study revealed that the presence of HPV DNA was associated with patients' specific characteristics and better overall survival exclusively in oropharyngeal sites. To define the fraction of HNSCC preventable by HPV vaccination or amenable to less aggressive treatment, however, tobacco exposure and HPV markers other than DNA presence need to be taken into account., (Copyright © 2011 UICC.)

In 20-40% of cervical intra-epithelial neoplasia (CIN) and in 4-8% of cervical carcinoma tissue specimens, multiple HPV genotypes have been detected. Whole tissue section (WTS) PCR does not determine how the individual types relate causally to complex and multiple CIN. Our objective was to determine whether laser capture micro-dissection (LCM) with HPV PCR genotyping (LCM-PCR) could accurately recover type-specific HPV DNA from epithelial cells in individual areas of CIN and normal epithelium, and whether one or more viruses are present in one lesion. For that, histologically selected samples of CIN and normal epithelium were isolated by LCM and analysed by the SPF(10) PCR/LiPA(25) (version 1) HPV genotyping system for 25 HPV genotypes. HPV genotypes detected in 756 areas of CIN (grade 1, 2 or 3) by LCM-PCR were compared with results obtained by WTS-PCR in 60 cases (74 biopsies). We showed that when a single HPV type is detected by WTS-PCR, that type was almost always (94%; 29/31) recovered by LCM-PCR from CIN. When multiple HPV types were present by WTS-PCR, their distribution within histological sections could be mapped by LCM-PCR. Association of a single HPV type with a discrete area of CIN was found for 93% (372/399) of LCM fragments analysed by PCR. We found colliding CIN lesions associated with separate HPV types and only 62% (61/99) of HPV types detected by WTS-PCR were found in CIN by LCM-PCR. Therefore, the LCM-PCR technique was found very accurate for high-resolution HPV genotyping and for assigning an individual HPV type to an area of CIN. At LCM level, in cervical biopsy sections with multiple HPV infections, the relation between HPV types and CIN lesions is often complex. Almost every HPV type found in CIN by LCM-PCR is associated with a biological separate independent CIN lesion-one virus, one lesion., (Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.)

Expression of the betapapillomavirus (betaPV) E6/E7 genes has been shown to impair both keratinocyte differentiation and apoptosis. Especially late-terminal keratinocyte differentiation shares certain aspects with apoptosis, such as fragmentation of DNA and activation of caspases. Here we investigated the disruption of keratinocyte differentiation in organotypic skin (raft) cultures of primary (PHK) and immortalized (N/TERT) human keratinocytes, in particular by human papillomavirus (HPV)8. Immunohistochemical analysis of HPV5 and HPV8 E6/E7-expressing PHK revealed thickening of the rafts and complete absence of stratum corneum formation, even after 18 days of culture. This phenotype was confirmed in N/TERT raft cultures. When expressed separately, the aberrant morphology was observed only in rafts expressing E6, not E7. Immunofluorescence analysis of HPV8 E6 PHK rafts showed an increase in number and size of Filaggrin- and Caspase-14-positive cells in the granular layer. In raft lysates analyzed by western-blot, the presence of pro-Caspase-14 in the differentiated keratinocytes was confirmed, but in the HPV8 E6 rafts none of the Caspase-14 subunits were detected. In conclusion, in the raft system, HPV8 E6 prevented late-terminal keratinocyte differentiation resulting in an accumulation of Filaggrin and pro-Caspase-14-positive cells in the absence of stratification. This differentiation arrest was accompanied by the failure to express Caspase-14 subunits, suggesting absence of Caspase-14 activation and probable abrogation of Filaggrin maturation in HPV8 E6-expressing keratinocytes., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Background: Anal cancer remains rare (incidence of about 1·5 per 100,000 women yearly), but rates are increasing in many countries. Human papillomavirus (HPV) 16 and 18 infections cause most cases of anal cancer. We assessed efficacy of an AS04-adjuvanted HPV 16 and HPV 18 vaccine against anal infection with HPV 16, HPV 18, or both (HPV 16/18)., Methods: Women from Costa Rica were registered between June 28, 2004, and Dec 21, 2005, in a randomised double-blind controlled trial that was designed to assess vaccine efficacy against persistent cervical HPV 16/18 infections and associated precancerous lesions. Eligible women were residents of Guanacaste and selected areas of Puntarenas, Costa Rica, age 18-25 years, in good general health, willing to provide informed consent, and were not pregnant or breastfeeding. Participants were randomly assigned (1:1) to receive an HPV vaccine (Cervarix, GlaxoSmithKline, Rixensart, Belgium) or a control hepatitis A vaccine (modified preparation of Havrix, GlaxoSmithKline, Rixensart, Belgium). Vaccines were administered in three 0·5 mL doses at enrolment, 1 month, and 6 months. Women, selected at the final blinded study visit 4 years after vaccination, provided anal specimens for assessment of vaccine efficacy against anal HPV 16/18 infection. Prevalence of anal HPV 16/18 infections, reported as vaccine efficacy, was the primary endpoint of the study described here. Vaccine efficacy against cervical HPV 16/18 infection in the same women at the 4-year visit was used as a comparator. Analyses were done in a restricted cohort of women who were negative for both cervical HPV 16 and HPV 18 DNA and who were HPV 16 and HPV 18 seronegative before enrolment (HPV naive), and also in the full cohort of women who provided an anal specimen. Investigators were masked to group assignment. This study is registered at ClinicalTrials.gov, number NCT00128661., Findings: All women who attended the final blinded study visit and consented to anal specimen collection were included in the analysis (4210 of 6352 eligible women). In the full cohort, vaccine efficacy against prevalent HPV 16/18 infection measured one-time, 4 years post vaccination was lower at the anus (62·0%, 95% CI 47·1-73·1) compared with the cervix (76·4%, 67·0-83·5; p for interaction by anatomical site 0·031). In the restricted cohort, vaccine efficacy against anal HPV 16/18 infection was 83·6% (66·7-92·8), which was similar to vaccine efficacy against cervical HPV 16/18 infection (87·9%, 77·4-94·0). Safety issues were not addressed in the current analysis. Additional safety data will be published later in a separate article., Interpretation: The AS04-adjuvanted vaccine affords strong protection against anal HPV infection, particularly among women more likely to be HPV naive at enrolment., Funding: National Cancer Institute with contributions from the National Institutes of Health Office of Research on Women's Health. Vaccine was provided by GlaxoSmithKline Biologicals., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Background: Lung cancer kills more than 1 million people worldwide each year. Whereas several human papillomavirus (HPV)-associated cancers have been identified, the role of HPV in lung carcinogenesis remains controversial., Methods: We selected 450 lung cancer patients from an Italian population-based case-control study, the Environment and Genetics in Lung Cancer Etiology. These patients were selected from those with an adequate number of unstained tissue sections and included all those who had never smoked and a random sample of the remaining patients. We used real-time polymerase chain reaction (PCR) to test specimens from these patients for HPV DNA, specifically for E6 gene sequences from HPV16 and E7 gene sequences from HPV18. We also tested a subset of 92 specimens from all never-smokers and a random selection of smokers for additional HPV types by a PCR-based test for at least 54 mucosal HPV genotypes. DNA was extracted from ethanol- or formalin-fixed paraffin-embedded tumor tissue under strict PCR clean conditions. The prevalence of HPV in tumor tissue was investigated., Results: Specimens from 399 of 450 patients had adequate DNA for analysis. Most patients were current (220 patients or 48.9%) smokers, and 92 patients (20.4%) were women. When HPV16 and HPV18 type-specific primers were used, two specimens were positive for HPV16 at low copy number but were negative on additional type-specific HPV16 testing. Neither these specimens nor the others examined for a broad range of HPV types were positive for any HPV type., Conclusions: When DNA contamination was avoided and state-of-the-art highly sensitive HPV DNA detection assays were used, we found no evidence that HPV was associated with lung cancer in a representative Western population. Our results provide the strongest evidence to date to rule out a role for HPV in lung carcinogenesis in Western populations.

Betapapillomavirus (betaPV) infections are often associated with squamous-cell carcinoma (SCC) and the prevalence of betaPV infections in (immunosuppressed) SCC patients is known to be high. The distribution and possible associated factors of betaPV infections in the general population, however, are largely unknown. To address this issue, betaPV infection was studied in 1405 SCC-free immunocompetent (n=845) and immunosuppressed (n=560) individuals from six countries of different latitudes. A standard study protocol was used to obtain information about age, sex, UV-irradiation and skin type, and from all participants eyebrow hairs were collected for detection and genotyping of 25 established betaPV types using the PM-PCR reverse hybridization assay (RHA) method. The frequency of betaPV-positive participants ranged from 84 to 91% in the immunocompetent population with HPV23 as the most prevalent type, and from 81 to 98% in the immunosuppressed population with HPV23 as the most or the second most prevalent type. The median number of infecting betaPV types ranged from four to six in the immunocompetent and from three to six in the immunosuppressed population. Increasing age in the immunocompetent participants and (duration of) immunosuppression in the immunosuppressed patients were associated with betaPV infection. In both groups, sex, skin phototype, sunburns and sun-exposure were not consistently associated with betaPV infection. This study demonstrates that betaPV infections are also highly prevalent in SCC-free individuals, with similar HPV types prevailing in both immunocompetent and immunosuppressed persons. Age and (duration of) immunosuppression were identified as betaPV infection-associated factors, whereas characteristics related to sun exposure and skin type were not.

Epidemiological studies have shown an association between infections by specific betapapillomaviruses, such as human papillomavirus (HPV) types 5 and 8, and cutaneous squamous cell carcinoma (SCC). The role of betapapillomaviruses in the development of cutaneous SCC is, however, still enigmatic. The ability to inhibit UVB-induced apoptosis, as demonstrated for HPV5 in vitro, may be important in this respect, as survival of DNA-damaged and mutated cells increases the risk of transformation. The aim of this study was to assess whether inhibition of UVB-induced apoptosis is a general property of betapapillomaviruses and to identify apoptotic factors that are potentially involved in this process. Primary human keratinocytes transduced with E6 and E7 of selected betapapillomaviruses (HPV5, HPV8, HPV15, HPV20, HPV24 and HPV38) were characterized and subjected to UVB irradiation. HPV8- and HPV20-expressing keratinocytes in particular showed fewer signs of apoptosis, as demonstrated by lower levels of active caspase 3, less enzymic caspase activity and less DNA fragmentation. The observed inhibition of UVB-induced apoptosis was mediated by E6 and coincided with reduced steady-state expression of the pro-apoptotic protein Bax. In conclusion, E6 of HPV8 and HPV20 reduces the apoptotic responses upon UVB irradiation when expressed in primary human keratinocytes. Infections with HPV8 and HPV20 may therefore augment the carcinogenic effect of UV radiation and potentially contribute to oncogenic transformation of the skin.

Infections with human papillomaviruses (HPVs) belonging to the genus Betapapillomavirus have been linked to the development of non-melanoma skin cancer. Although persistence is expected, systematic investigation of this aspect of betapapillomavirus (beta-PV) infection has not been conducted. This study investigated the prevalence and persistence of 25 known beta-PV types in the skin of immunocompetent individuals. Over a 2 year period, eight consecutive plucked eyebrow hair samples taken from 23 healthy individuals were analysed for the presence of beta-PV DNA. Using a recently published general beta-PV PCR and genotyping method, 61% of the individuals were beta-PV DNA positive for one or more types at intake, whereas during follow-up this percentage rose to 96%. HPV23 was the most frequently detected beta-PV type. Type-specific beta-PV DNA was detected over 6 months or longer in 74% of the individuals. In 57% of the individuals, DNA from multiple beta-PV types was detected simultaneously for 6 months or longer. When the detection intervals of all beta-PV type-specific infections in the study population were considered, a substantial proportion, 48%, lasted at least half a year. The consistent beta-PV patterns found over time in most individuals strongly suggested that beta-PV DNA detection in plucked eyebrow hairs reveals true beta-PV infection. If the minimum interval of detection was set at 6 months, persistent beta-PV infections were found in the majority of the study population (74%).

Human papillomavirus can be detected by amplification of viral DNA. A novel one-step PCR (PM-PCR) was evaluated for amplification of a 117-bp fragment from the E1 region. It permitted ultrasensitive detection of all 25 known human papillomavirus genotypes from the beta-papillomavirus genus. The intra- and intertypic sequence variations of the 77-bp interprimer region were studied. Genotype-specific probes as well as general probes were selected for the 25 established beta-papillomavirus types, and a reverse hybridization assay (RHA) was developed (PM-PCR RHA method). The analytical sensitivity of the PM-PCR RHA method was 10 to 100 viral genomes. The one-step PM-PCR turned out to be more sensitive than the previously described nested MaHa-PCR for beta-papillomavirus detection. The PM-PCR RHA method was able to detect and identify beta-papillomavirus types in frozen patient material as well as in poorly amplifiable material such as formalin-fixed, paraffin-embedded skin biopsy specimens. Inter- and intralaboratory variability experiments showed that the reproducibility of the assay was very high. In conclusion, the one-step PM-PCR together with the RHA allows extremely sensitive, specific, and reproducible detection of beta-papillomavirus DNA as well as reliable identification of beta-papillomavirus genotypes in both fresh and paraffin-embedded patient material.

Separately, actinic keratosis (AK) and cutaneous squamous cell carcinoma (SCC) have been associated with cutaneous human papillomavirus (HPV) infections. To further explore the association between HPV infection and SCC development, we determined markers of cutaneous HPV infection within a single population in persons with precursor lesions (AK), cancerous lesions (SCC), and without. Serum and plucked eyebrow hairs were collected from 57 tumor-free controls, 126 AK, and 64 SCC cases. Presence of HPV L1 and E6 seroreactivity and viral DNA were determined for HPV types 5, 8, 15, 16, 20, 24, and 38. Significant positive associations with increasing severity of the lesions (controls, AK, and SCC, respectively) were observed for overall HPV L1 seropositivity (13%, 26%, and 37%) and for HPV8 (4%, 17%, and 30%). In parallel, the proportion of L1 seropositive individuals against multiple HPV types increased from 14% to 39% and 45%. The overall E6 seroreactivity, however, tended to decline with AK and SCC, especially for HPV8 (21%, 11%, and 2%). HPV DNA positivity was most prevalent in the AK cases (54%) compared with the SCC cases (44%) and the tumor-free controls (40%). Among all participants, there was a positive trend between overall HPV DNA positivity and L1 seropositivity, but not E6 seropositivity. Taken together, our data suggest that cutaneous HPV infections accompanied by detectable HPV DNA in eyebrow hairs and HPV L1 seropositivity, but not E6 seropositivity, are associated with an increased risk of AK and SCC.

At present, human papillomavirus (HPV) infection is chiefly known for its causal relationship with cervical cancer. Apart from genital types, the papillomavirus family consists of numerous human cutaneous types. The majority belongs to the so-called epidermodysplasia-verruciformis(EV)-HPV types that are potentially involved in skin cancer development. Non-melanoma skin cancers, especially cutaneous squamous cell carcinoma contain HPV DNA (30-60%). In immune-suppressed organ transplant recipients this percentage increases up to 90. Recent epidemiological studies show a statistically significant association between EV-HPV infection and squamous cell carcinoma. In addition recent experimental studies show specific EV-HPV types have a potential to transform cells that is comparable to high-risk genital HPV types. These data indicate that cutaneous HPV infections and squamous cell carcinoma development are associated.

Epidemiological studies, which address the role of human papillomavirus (HPV) in the pathogenesis of (pre)malignant cutaneous lesions, focus on the HPV B1 subgroup comprising the so-called epidermodysplasia verruciformis (EV)-associated HPV types. To detect and type HPV DNA in human materials, Polymerase Chain Reaction (PCR)-based assays are used. In this chapter, a nested, broad-spectrum PCR method using a mixture of primers and a type-specific PCR using specific primers are described. The broad-spectrum PCR detects the B1 subgroup of HPV types. HPV typing is performed by sequence analysis of the PCR product. The type-specific PCR detects and types HPV 5a, 8, 15, 17, 20, 24, 36, and 38. These HPV types are representative of the B1 subgroup, because they are evenly distributed over the phylogenetic tree of the B1 subgroup.

Ultraviolet radiation (UVR) is associated with an increased risk of squamous cell carcinoma (SCC), which is in part due to immunomodulation. In addition, human papilloma virus (HPV), especially the epidermodysplasia verruciformis (EV)-associated types, may be involved. In view of the capacity of UVR to impair host resistance to infections, we investigated the relationship between solar exposure and the prevalence of cutaneous HPV. In a case-control study on skin cancer (320 controls and 156 patients) a lifetime-retrospective questionnaire on sun exposure was administered. The presence of DNA of HPV types 5, 8, 15, 20, 24, and 38 in plucked eyebrow hair and type-specific seroreactivity were assessed and analyzed in relation to estimated exposure. Sunburn episodes in the past, especially at age 13-20 y, appeared to be associated with an enhanced risk of EV-HPV DNA positivity. In contrast, a higher lifetime sun exposure was associated with a lower risk of HPV infection. These results indicate that UVR at erythematogenic doses increases the risk of EV-HPV infection, possibly due to impaired host resistance to HPV and/or a direct effect of UVR on viral replication. The favorable association between lifetime sun exposure and HPV prevalence, however, underscores the enigmatic role of HPV in skin carcinogenesis.

A role for cutaneous human papillomaviruses (HPV) has been proposed in the development of skin cancer. Well-designed epidemiologic studies to demonstrate an association between HPV infection and skin cancer are extremely rare. To identify HPV infection as a potential risk factor, we investigated the association between the presence of HPV DNA in eyebrow hairs and a history of cutaneous squamous cell carcinoma. A case-control study was designed consisting of 155 immunocompetent individuals with a history of squamous cell carcinoma and 371 controls without skin cancer. DNA extracted from plucked eyebrow hairs collected from the study population was analyzed with a cutaneous HPV subgroup polymerase chain reaction and newly designed HPV type specific polymerase chain reactions for HPV 2, 5, 8, 15, 16, 20, 24, and 38. HPV DNA was detected in 63.1% of the total study population. The presence of HPV DNA was associated with age (p=0.0002) and male sex (p=0.02), but not with sun exposure, skin type, and smoking. After adjustment for age and sex, the presence of HPV DNA in eyebrow hairs was associated with a history of squamous cell carcinoma (odds ratio 1.7, 95% confidence interval 1.1; 2.7). HPV type specific analysis revealed that no HPV type stood out. The high-risk mucosal type HPV 16 and the skin wart type HPV 2 were rarely found in this study (<0.2%). The positive association found between the presence of HPV DNA in eyebrow hairs and a history of squamous cell carcinoma warrants further research into the role that HPV infection plays in the development of cutaneous squamous cell carcinoma.

DNA from epidermodysplasia verruciformis-related human papillomavirus (EV-HPV) types is frequently found in nonmelanoma skin cancer (squamous and basal cell carcinoma). Epidemiological studies that investigate the relation between EV-HPV infection and nonmelanoma skin cancer are scarce. We designed a case-control study in which we looked for HPV infection in 540 cases with a history of skin cancer and 333 controls. By measuring seroreactivity to L1 virus-like particles of EV-HPV types 5, 8, 15, 20, 24, and 38 and the genital type HPV16 and by estimating the skin cancer relative risk among HPV seropositives, we analyzed whether EV-HPV serorecognition is associated with nonmelanoma skin cancer. Seroreactivity to five of the six EV-HPV types tested (HPV5, 8, 15, 20, and 24) was significantly increased in the squamous cell carcinoma cases. After adjusting for age and sex, the estimated squamous cell carcinoma relative risk was significantly increased in HPV8 and HPV38 seropositives [odds ratio (OR) = 14.7 (95% confidence interval (CI), 1.6-135) and OR = 3.0 (95% CI, 1.1-8.4), respectively]. The estimated relative risk for nodular and superficial multifocal basal cell carcinoma was also significantly increased in the HPV8 seropositives [OR = 9.2 (95% CI, 1.1-78.2) and OR = 17.3 (95% CI, 2.1-143), respectively] and in the HPV20 seropositives [OR = 3.2 (95% CI 1.3-7.9) and OR = 3.4 (95% CI 1.2-9.5), respectively]. The relative risk of developing malignant melanoma was not increased among HPV seropositives, and no associations were found for HPV16. Restricted analyses among the HPV seropositives only, to exclude distortion by interindividual differences in seroresponsiveness, underscored the significance of our findings. Restricted analyses among patients with skin cancer only, however, revealed that EV-HPV seropositivity was not significantly more present in patients with nonmelanoma skin cancer than in those with melanoma skin cancer. Taken together, our results indicate that EV-HPV serorecognition is nonspecifically associated with nonmelanoma skin cancer and suggest that EV-HPV-directed seroresponses are induced upon skin cancer formation, rather than upon infection.