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Head and neck squamous cell carcinoma (HNSCC) was the 7th most common malignancy worldwide in 2018 and despite therapeutic advances, the overall survival rate for oral squamous cell carcinoma (OSCC; ∼50%) has remained unchanged for decades. The most common types are OSCC and oropharyngeal squamous cell carcinoma (OPSCC, survival rate ∼85%). Tobacco smoking is a major risk factor of HNSCC. In the developed world, the incidence of OSCC is declining as a result of tobacco cessation programs. However, OPSCC, which is also linked to human papillomavirus (HPV) infection, is on the rise and now ranks as the most common HPV-related cancer. The current state of knowledge indicates that HPV-associated disease differs substantially from other types of HNSCC and distinct biological differences between HPV-positive and HPV-negative HNSCC have been identified. Although risk factors have been extensively discussed in the literature, there are multiple clinically relevant questions that remain unanswered and even unexplored. Moreover, existing approaches (e.g., tobacco cessation, vaccination, and chemoprevention) to manage and control this disease remain a challenge. Thus, in this review, we discuss potential future basic research that can assist in a better understanding of disease pathogenesis which may lead to novel and more effective preventive strategies for OSCC and OPSCC., (©2020 American Association for Cancer Research.)

Background: Evidence suggests that natural antibodies developed after HPV16 infection may protect some women but not men against subsequent HPV16 reacquisition. Less is known whether antibodies developed following HPV16 infection are protective among men who have sex with men (MSM). Methods: Four hundred seventy-five MSM from the Human Papillomavirus Infection in Men (HIM) study were tested for serum antibodies to HPV16 L1 using enzyme-linked immunosorbent assays, and for anal and genital HPV16 DNA using PCR consensus primer system (PGMY 09/11). Adjusted Cox regression was used to evaluate whether baseline HPV16 seropositivity impacts subsequent genital or anal HPV16 DNA. Results: The risk of subsequent genital HPV16 [aHR = 1.05, 95% confidence interval (CI) = 0.66-1.68] and anal HPV16 infections among MSM (aHR = 2.34, 95% CI = 0.92-5.98) was similar or nonsignificantly higher in HPV16-seropositive than HPV16-seronegative MSM. The risk of genital HPV16 was also similar between HPV16-seronegative and HPV16-seropositive MSM in the highest tertile of HPV16 antibody levels and when restricting to those with new sex partners during follow-up ( P > 0.20). Among the 118 MSM who were HPV16 seropositive, 90% remained HPV16 seropositive up to 4 years later. When tested together, MSM with the highest antibody titers (top tertile) had similar levels to females (mean = 130.3 vs. 134.5 EU/mL, P = 0.84). Conclusions: Despite years of HPV16 seropositivity persistence and antibody titers comparable with females, this study suggested no evidence of HPV16 natural antibodies protecting against subsequent genital or anal HPV16 infection in MSM. Impact: This could help partially explain the high incidence of genital and anal HPV16 infection and related anal cancer seen in middle-aged and older MSM. Cancer Epidemiol Biomarkers Prev; 27(4); 496-502. ©2018 AACR ., (©2018 American Association for Cancer Research.)

Naturally induced serum antibodies against human papillomavirus (HPV) may affect risks of subsequent incident genital infections by HPV 6, 11, 16, or 18 in men. In this study, we examined the hypothesis by following 4,123 healthy men every 6 months (median follow-up time, 4.1 years). HPV antibodies were measured at baseline using a virus-like particle-based ELISA assay. Genital HPV genotypes were detected using Roche Linear Array. Incidence proportions and 6-month persistence proportions were calculated at 6-month intervals. Kaplan-Meier curves and Cox models were used to assess genotype-specific cumulative incidence and HRs, respectively. HPV 6, 11, 16, and 18 seroprevalence was 8.1%, 13.9%, 12.7%, and 10.8%, respectively. Significantly higher rates of incident infections were observed for HPV 16 among baseline-seropositive men [adjusted HR, 1.37; 95% confidence interval (CI), 1.01-1.86], with similar but nonsignificant HRs for 6-month persistent infections. Risk of persistent HPV 18 infection was significantly lower among seropositive men in the unadjusted model (HR, 0.22; 95% CI, 0.06-0.91), but not in the adjusted model (HR, 0.19; 95% CI, 0.03-1.37). Incident and 6-month persistent infections for HPV 6 and 11 did not differ by baseline serostatus. Baseline serostatus among men was not associated with a reduction in subsequent incident genital HPV 6, 11, and 16 infections. However, protection against persistent HPV18 infections was observed in unadjusted models. Our research suggests a need of further studies to examine the potentially protective effects of naturally induced HPV18 antibodies in men. Cancer Res; 76(20); 6066-75. ©2016 AACR., Competing Interests: ARG and SLS receive research funding from Merck. ARG is a member of their Speaker’s Bureau. LLV and ARG are consultants of Merck for HPV vaccines. None of the other authors have conflicts of interest to report., (©2016 American Association for Cancer Research.)

Due to its role in the synthesis and repair of DNA, folate may protect against the development of cervical cancer. Prospective data on the possible association between folate and cervical cancer have been lacking. There is also a paucity of prospective evidence concerning the possible associations between cervical cancer and vitamin B12, which shares pathways with folate, and homocysteine, a marker of low B vitamin concentrations. A nested case-control study was conducted to prospectively evaluate the associations between cervical cancer and serum concentrations of folate, vitamin B12, and homocysteine. Among a community-based cohort of women who donated blood in 1974 for a serum bank in Washington County, Maryland, 39 cases of cervical cancer diagnosed between 1975 and mid-1990 were included in the study (13 cases of invasive cervical cancer and 26 cases of carcinoma in situ). Two controls were matched to each case by age, race, and sex. Stored serum from the cases and controls was assayed for folate, B12, and homocysteine concentrations. For folate, adjusted odds ratios were 1.0, 0.62, and 0.60 for the low to high thirds of the serum concentrations, respectively, a trend in the protective direction that was not statistically significant (P for trend = 0.42). Overall, the results for vitamin B12 tended to mimic those for folate, whereas the associations for homocysteine tended to be in the opposite direction. None of the results of this study were statistically significant, but patterns of the associations are in accord with hypothesized mechanistic pathways concerning B vitamins and cervical cancer.

Serum samples from 194 cases and 217 controls participating in a case-control study of invasive cervical cancer in Brazil were examined for antibodies to human papillomavirus (HPV) 16 virus-like particles (VLPs) by ELISA. The prevalence of antibody in cases and controls was 47.4 versus 24.4% (P < 0.001). The prevalence was higher in women who had HPV-16 DNA in the genital tract (54.2%) than in those with other HPVs (36.8%) or no HPVs (44.8%), but the differences were not statistically significant. Among cases and controls, HPV-16 VLP antibodies were associated with a greater number of lifetime sexual partners (chi2 for trend, P < 0.001). Among controls, age was inversely associated with HPV-16 VLP seroreactivity (chi2 for trend, P = 0.019). The sera were previously tested for antibodies to HPV-16 E6 and E7 oncoproteins; there was no correlation between antibody titers to HPV-16 E6 or E7 and VLPs. The HPV-16 serological assays were compared as screening tests for invasive cervical cancer. The sensitivity and specificity estimates were 47.4 and 75.6% for HPV-16 VLP serology, 63.4 and 89.9% for either HPV-16 E6 or E7 serology, and 53.6 and 93.6% for high titers of either HPV-16 E6 or E7 or VLP antibodies. The utility of HPV-16 VLP ELISA as a screening test for invasive cervical cancer is limited by a high seroprevalence in women with probable prior exposure to HVP 16 but without disease.

Our objective was to examine whether past infection with human papillomavirus (HPV)-16, as determined by an antibody assay, is a risk factor for subsequent cervical cancer. Incident cases of in situ or invasive cervical cancer occurring between 1975 and 1990 in a cohort of over 11,000 healthy women in Washington County, MD, were identified. The baseline sera of cases and of matched controls, collected in 1974, were examined for IgG antibodies reactive with virus-like particles of HPV-16, a cancer-associated HPV, and HPV-6, a low-risk HPV. Postdiagnosis sera of 11 cases were also assessed similarly. Fourteen cases of invasive and 28 cases of in situ cervical cancer and 83 matched controls were evaluated. The main outcome measure was the risk of cervical cancer in women who had HPV-16 or HPV-6 antibodies in prediagnostic sera. Antibodies to HPV-16 but not to HPV-6 were a marker for subsequent occurrence of cervical cancer. Case sera were reactive more often and more strongly with HPV-16 virus-like particles than were sera of matched controls. The presence of antibodies to HPV-16 was significantly associated with an increased risk of cervical cancer (odds ratio, 3.9; 95% confidence limits, 1.4, 10.7); high antibody levels to HPV-16 were associated with an even greater risk of cervical cancer (odds ratio = 7.5, 95% confidence limits 1.5, 36.3). The association with cervical cancer was strengthened after adjustment for smoking and years of education. In tests of 11 pairs of pre- and postdiagnostic sera, HPV-16 antibodies did not decline markedly over a 7-13-year time period, and seroconversion to HPV-16 appeared to have occurred in 2 cases. The serological data indicate that HPV-16 infection is associated with future risk of cervical cancer and strengthen the evidence for the etiological role of HPVs in cervical cancer.

Masked sera from 194 cases and 217 controls participating in a case-control study of cervical cancer in Brazil were examined for antibodies to human papillomavirus (HPV) 16 E6 and E7 by radioimmunoprecipitation assay. Radiolabeled full-length E6 and E7 proteins expressed by in vitro transcription and translation in rabbit reticulocyte lysate were used as antigens. The antibody prevalences in cases and controls were: 54.1% versus 6% for E6; 30.4% versus 4.6% for E7; 63.4% versus 10.1% for either E6 or E7; and 21.1% versus 0.5% for both E6 and E7. The corresponding odds ratios were 35 ([95% confidence interval (CI)], 15-83), 10 (95% CI, 4-25), 28 (95% CI, 13-61) and 87 (95% CI, 10-736). The most marked contrast between cases and controls was observed for sera with high antibody titers (cpm > 6000) with an odds ratio of 239 (95% CI, 29-1946) for E6 or E7. Seroreactivity in cases was partially type specific; women who had HPV-16 DNA in the genital tract had higher antibody prevalence rates than those who were negative for HPV DNA. Reactivity to the E6 protein was associated with the stage of disease; the antibody prevalence was 62.7% in cases with stages II-IV and 31.0% in cases with stage I (P < 0.005). HPV-16 serology and HPV polymerase chain reaction were compared as markers for invasive cervical cancer.(ABSTRACT TRUNCATED AT 250 WORDS)