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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. 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. 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.

Human papillomavirus (HPV)–associated oropharyngeal squamous-cell carcinoma differs from oropharyngeal cancers caused by tobacco and other factors. In this study, patients with oropharyngeal cancer were treated with cisplatin plus radiation therapy; the 3-year rate of overall survival was 82.4% among patients with HPV-positive tumors and 57.1% among patients with HPV-negative tumors. HPV status is an independent prognostic factor for survival among patients with oropharyngeal squamous-cell carcinoma. Patients with oropharyngeal cancer were treated with cisplatin plus radiation therapy; the 3-year rate of overall survival was 82.4% among patients with HPV-positive tumors and 57.1% among patients with HPV-negative tumors. HPV status is an independent prognostic factor for survival among patients with oropharyngeal squamous-cell carcinoma. The majority of patients enrolled in therapeutic trials for squamous-cell carcinoma of the head and neck have oropharyngeal squamous-cell carcinoma, which in a subgroup of these patients is caused by infection with human papillomavirus (HPV). 1 This subgroup is defined by the presence of high-risk types of HPV in tumor cells, predominantly HPV type 16 (HPV-16). Expression of viral E6 and E7 oncoproteins that inactivate the tumor-suppressor proteins p53 and the retinoblastoma protein (pRb), respectively, is necessary for malignant behavior of these tumors. 2 Several retrospective case series have shown that among patients with oropharyngeal squamous-cell carcinoma, patients with HPV-positive tumors have . . .

Human papillomaviruses are an important cause of genital warts and cervical cancer. In this large, randomized, placebo-controlled trial, a quadrivalent HPV vaccine given at day 1, month 2, and month 6 was found to significantly reduce the occurrence of cervical intraepithelial neoplasia and vulval or vaginal perianal lesions. No beneficial effect was observed on prevalent lesions. The benefit for prevention of incident lesions associated with HPV-16 and HPV-18 appears to increase with time. A quadrivalent HPV vaccine was found to significantly reduce the occurrence of cervical intraepithelial neoplasia and vulval or vaginal perianal lesions. Anogenital infection with the human papillomavirus (HPV) can cause warts, intraepithelial neoplasia, and invasive cancers. 1 – 6 The majority of HPV-associated diseases are caused by HPV types 6, 11, 16, and 18. HPV types 6 (HPV-6) and 11 (HPV-11) cause most anogenital warts, a portion of the cases of low-grade neoplasia, 5 , 7 – 10 and recurrent respiratory papillomatosis, a rare but potentially life-threatening disease. 11 – 13 HPV type 16 (HPV-16) is the most common cause of invasive cancers of the cervix and other anogenital cancers associated with HPV. 4 , 6 , 14 – 19 HPV type 18 (HPV-18), the second most common cause of cervical cancer, . . .

Infection by carcinogenic human papillomaviruses (HPV) results in precancers [cervical intraepithelial neoplasia (CIN)] and cancers near the ectoendocervical squamocolumnar (SC) junction of the cervix. However, the specific cells targeted by HPV have not been identified and the cellular origin of cervical cancer remains elusive. In this study, we uncovered a discrete population of SC junctional cells with unique morphology and gene-expression profile. We also demonstrated that the selected junctional biomarkers were expressed by a high percentage of high-grade CIN and cervical cancers associated with carcinogenic HPVs but rarely in ectocervical/transformation zone CINs or those associated with noncarcinogenic HPVs. That the original SC junction immunophenotype was not regenerated at new SC junctions following excision, not induced by expression of viral oncoproteins in foreskin keratinocytes, and not seen in HPV-related precursors of the vagina, vulva, and penis further support the notion that junctional cells are the source of cervical cancer. Taken together, our findings suggest that carcinogenic HPV-related CINs and cervical cancers are linked to a small, discrete cell population that localizes to the SC junction of the cervix, expresses a unique gene expression signature, and is not regenerated after excision. The findings in this study uncover a potential target for cervical cancer prevention, provide insight into the risk assessment of cervical lesions, and establish a model for elucidating the pathway to cervical cancer following carcinogenic HPV infection.

Background: Round 1 data of human papillomavirus (HPV) FOCAL, a three-arm, randomised trial, which aims to establish the efficacy of HPV DNA testing as a primary screen for cervical cancer, are presented. Methods: The three arms are: Control arm – liquid based cytology with atypical squamous cells of unknown significance (ASC-US) triage with hrHPV testing; Intervention Arm – hrHPV at entry with liquid-based cytology (LBC) triage of hrHPV positives, with exit screen at 4 years; Safety check arm – hrHPV at entry with LBC triage of hrHPV positives with exit screen at 2 years. Results: A total of 6154 women were randomised to the control arm and 12 494 to the HPV arms (intervention and safety check). In the HPV arm, the baseline cervical intraepithelial neoplasia (CIN)2+ and CIN3+ rate was 9.2/1000 (95%CI; 7.4, 10.9) and 4.8/1000 (95%CI; 3.6, 6.1), which increased to 16.1/1000 (95%CI 13.2, 18.9) for CIN2+ and to 8.0/1000 (95%CI; 5.9, 10.0) for CIN3+ after subsequent screening of HPV-DNA-positive/cytology-negative women. Detection rate in the control arm remained unchanged after subsequent screening of ASC-US-positive/hrHPV DNA-negative women at 11.0/1000 for CIN2+ and 5.0/1000 for CIN3+. Conclusion: After subsequent screening of women who were either hrHPV positive/cytology negative or ASC-US positive/HPV negative, women randomised to the HPV arms had increased CIN2+ detection compared with women randomised to the cytology arm.

Human-papillomavirus (HPV) testing is more sensitive, but less specific, than conventional cytology for detecting high-grade cervical intraepithelial neoplasia (CIN). We assessed whether HPV testing with triage by p16-INK4A overexpression can increase specificity while maintaining sensitivity. HPV-positive women were enrolled between June 10, 2003, and Dec 31, 2004 in a multicentre randomised controlled trial, which compared stand-alone HPV testing by Hybrid Capture 2 (experimental group) with conventional cytology, were referred for colposcopy. In seven of nine centres, cytospin preparations from these women were tested for p16-INK4A overexpression by immunostaining. The sensitivity and specificity for CIN grade 2 or more, determined at blind review of histology, were calculated for these women. We also estimated the relative sensitivity and relative referral to colposcopy that would have been obtained by HPV testing with p16-INK4A triage compared with conventional cytology. This trial is registered as a Standard Randomised Controlled Trial, number ISRCTN81678807. 24 661 women were randomly assigned to the experimental group. 1137 women (74% of those undergoing colposcopy in relevant centres), including 50 with CIN2 and 42 with CIN3 or cancer, had valid p16-INK4A immunostaining. For the endpoint of CIN2+, sensitivity and specificity of p16-INK4A (deemed positive with any number of stained cells—except endocervical, metaplastic, and atrophic cells if morphologically normal) in HPV-positive women of any age were 88% (81 of 92; 95% CI 80–94) and 61% (633 of 1045; 57–64), respectively. In the 35–60-year age group, the relative sensitivity of HPV testing and p16-INK4A triage versus conventional cytology for CIN2+ was 1·53 (95% CI 1·15–2·02) and relative referral was 1·08 (0·96–1·21). In the 25–34-year age group, relative sensitivity was 3·01 (1·82–5·17) and relative referral was 1·15 (0·96–1·37). In the latter age group, when 5% or more stained cells were deemed positive, the corresponding values were 2·06 (1·20–3·68) and 0·58 (0·46–0·73), respectively. HPV testing with p16-INK4A triage produces a significant increase in sensitivity compared with conventional cytology, with no substantial increase in referral to colposcopy. European Union, Italian Ministry of Health, Regional Health Administrations of Piemonte, Tuscany, Veneto, and Emilia-Romagna, and Public Health Agency of Lazio Region.

Background Anti-EGFR-based therapies have limited success in HNSCC patients. Predictive biomarkers are greatly needed to identify the patients likely to be benefited from these targeted therapies. Here, we present the prognostic and predictive association of biomarkers in HPV-negative locally advanced (LA) HNSCC patients. Methods Treatment-naive tumour tissue samples of 404 patients, a subset of randomised Phase 3 trial comparing cisplatin radiation (CRT) versus nimotuzumab plus cisplatin radiation (NCRT) were analysed to evaluate the expression of HIF1α, EGFR and pEGFR by immunohistochemistry and EGFR gene copy change by FISH. Progression-free survival (PFS), locoregional control (LRC) and overall survival (OS) were estimated by Kaplan–Meier method. Hazard ratios were estimated by Cox proportional hazard models. Results Baseline characteristics of the patients were balanced between two treatment groups (CRT vs NCRT) and were representative of the trial cohort. The median follow-up was of 39.13 months. Low HIF1α was associated with better PFS [HR (95% CI) = 0.62 (0.42–0.93)], LRC [HR (95% CI) = 0.56 (0.37–0.86)] and OS [HR (95% CI) = 0.63 (0.43–0.93)] in the CRT group. Multivariable analysis revealed HIF1α as an independent negative prognostic biomarker. For patients with high HIF1α, NCRT significantly improved the outcomes [PFS:HR (95% CI) = 0.55 (0.37–0.82), LRC:HR (95% CI) = 0.55 (0.36–0.85) and OS:HR (95% CI) = 0.54 (0.36–0.81)] compared to CRT. While in patients with low HIF1α, no difference in the clinical outcomes was observed between treatments. Interaction test suggested a predictive value of HIF1α for OS ( P  = 0.008). Conclusions High HIF1α expression is a predictor of poor clinical response to CRT in HPV-negative LA-HNSCC patients. These patients with high HIF1α significantly benefited with the addition of nimotuzumab to CRT. Clinical trial registration Registered with the Clinical Trial Registry of India (Trial registration identifier—CTRI/2014/09/004980).

Background: A randomised trial to ascertain whether women who do not attend for cervical screening are more likely to respond to the opportunity to collect a self-sample for human papillomavirus (HPV) testing, or to a further invitation to attend for cervical screening. Methods: The study was carried out in a Primary Care Trust (PCT) in London between June 2009 and December 2009. In total, 3000 women were randomly selected from persistent non-responders (i.e., who had not responded to at least two invitations to attend for screening). The women were randomised on a 1 : 1 basis to either receive an HPV self-sampling kit or a further invitation to attend for cervical cytology. The main outcome measures were (1) percentage of women attending for cervical cytology compared with those returning a self-sample HPV test or attending for cytology subsequent to receiving the kit and (2) percentage of those testing positive for HPV who attended further investigation. Results: The total response in the self-sampling group for screening was 10.2%. Of the 1500 women in the control group sent a further invitation for cervical screening, 4.5% attended for cytology screening. This difference is highly statistically significant ( P <0.0001). Of the 8 women who tested positive for HPV, 7 attended for a cervical smear and had a concurrent colposcopy. Three of these (43%) had high-grade disease (defined as CIN 2+), with one found to have an invasive cancer (stage 1b) and one CIN 3. Conclusions: The value of this intervention relies on the detection of high-grade CIN and early stage cancer with a good prognosis. The relatively high yield of abnormalities found is consistent with that expected among a hard to reach and relatively high-risk group of women. Our study suggests that self-sampling could increase participation among non-responders in England, but further work is needed to ascertain whether the low response rate seen here is likely to be representative of the rest of the country. Other studies are needed to investigate the response to self-sampling in different demographic and geographic settings.

Human papillomaviruses (HPVs) are oncogenic viruses causing most cervical cancers. Highly prevalent in young, sexually active women, only a minority of HPV infections persist. To better characterize the immuno-modulatory impact of early HPV infections, we measured changes in a panel of 20 cytokines in cervicovaginal samples collected from young women who were tested for HPV and self-reported for genital inflammation and infection symptoms. Multi-factor statistical analyses revealed that increased IL-1Alpha and IL-12/IL-23p40 concentrations were associated with HPV infection and that macrophage inflammatory proteins were associated in particular with high-risk HPV infections. ClinicalTrials.gov identifier NCT02946346

Background: In Italy, cervical cancer screening programmes actively invite women aged 25–64 years. Programmes are hindered by low participation. Methods: A sample of non-responder women aged 35–64 years, belonging to three different programmes (in Rome, Florence and Teramo), was randomly split into four arms: two control groups received standard recall letters to perform either Pap-test (first group) or human papillomavirus (HPV) test (second group) at the clinic. A third arm was sent letters offering a self-sampler for HPV testing, to be requested by phone, whereas a fourth group was directly sent the self-samplers home. Results: Compliance with standard recall was 13.9% (N619). Offering HPV test at the clinic had a nonsignificant effect on compliance (N616, relative risk (RR)=1.08; 95% CI=0.82–1.41). Self-sampler at request had the poorest performance, 8.7% (N622, RR=0.62; 95% CI=0.45–0.86), whereas direct mailing of the self-sampler registered the highest compliance: 19.6% (N616, RR=1.41; 95% CI=1.10–1.82). This effect on compliance was observed only in urban areas, Florence and Rome (N438, RR=1.69; 95% CI=1.24–2.30), but not in Abruzzo (N178, RR=0.95; 95% CI=0.61–1.50), a prevalently rural area. Conclusions: Mailing self-samplers to non-responders may increase compliance as compared with delivering standard recall letters. Nevertheless, effectiveness is context specific and the strategy costs should be carefully considered.