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Head and neck squamous cell carcinoma (HNSCC) is attributable to carcinogen and oncogenic virus exposure and rates are driven by the prevalence, intensity, and duration of exposures. Recent dramatic shifts in human behavior have resulted in substantial heterogeneity in HNSCC incidence trends over calendar time. For example, changes in sexual behavior during the 1900s likely increased exposure to oral human papillomavirus (HPV) infection and, consequently, rates of HPV-positive HNSCC. Shifting rate-ratios for HPV-positive versus negative HNSCC determine the HPV attributable fraction (AF), best measured by direct tumor testing for HPV DNA and RNA. Potential high efficacy of HPV vaccines against oral HPV infections will affect future incidence trends, depending on calendar time of introduction, male and female coverage, and herd protection. Accurate estimates of HPV AF for all cancers, including HNSCC, may inform HPV immunization policy and surveillance of effectiveness.

Objectives The role of HPV in oral cavity cancers was investigated using two markers of viral exposure. Materials and methods HPV DNA and p16INK4a expression were evaluated in tumor tissue from a U.S. population-based sample of 122 invasive oral cavity cancer cases. Results HPV DNA was detected in 38 of 122 (31%) oral cavity tumors. Seven genotypes were detected including HPV 16, which was found in 22% of tumors. p16INK4a was expressed in 30% of tumors and was poorly correlated with HPV DNA detection (Kappa Conclusions Based on both HPV DNA and p16INK4a, HPV is etiologically linked to a limited subset of oral cavity cancers. However, the role of HPV in oral cavity cancer may vary widely by subsite and may have increased over time, similar to trends observed for oropharyngeal cancer.

Rectal squamous cell carcinoma (SCC) is a rare tumor with unresolved etiology. Human immunodeficiency virus-infected individuals and solid organ transplant recipients experience >30-fold and approximately 3-fold elevated rates of rectal SCC, respectively, suggesting immunosuppression plays a role.1 Human immunodeficiency virus-infected homosexual men have >60-fold higher rates of rectal SCC, similar to anal SCC. These patterns, which differ from the more common rectal adenocarcinoma (AdCA), raise the possibility of shared etiology between rectal and anal SCC, with human papillomavirus type 16 (HPV16) being a likely candidate.2.

Highlights • The prognostic value of pretreatment blood counts is investigated. • This is also done for the nadir neutrophil & lymphocyte levels during radiotherapy. • The impact of treatment modality (IMPT and IMRT) on these nadir levels is examined. • Pretreatment neutrophilia and leukocytosis were associated with worse outcomes. • Treatment modality did not affect blood counts during radiotherapy., Introduction Peripheral blood count components are accessible and evidently predictive in other cancers but have not been explored in oropharyngeal carcinoma. We examine if there is an association between the use of intensity-modulated radiotherapy (IMRT) or intensity-modulated proton therapy (IMPT) and lymphopenia, as well as if there is an association between baseline neutrophilia, baseline leukocytosis and lymphocyte nadir in oropharyngeal cancer. Materials and Methods Analysis started with 150 patients from a previous case to case study design, which retrospectively identified adults with oropharyngeal carcinoma, 100 treated with IMRT in 2010-2012 and 50 treated with IMPT in 2011–2014. Pretreatment leukocyte, neutrophil, lymphocyte, and hemoglobin levels were extracted, as were neutrophil and lymphocyte nadir levels during radiotherapy. We retained 137 patients with recorded pre-treatment leukocyte and neutrophil levels for associated analysis and 114 patients with recorded lymphocyte levels during radiation and associated analysis. Multivariate survival analyses were done with Cox regression. Results The radiotherapy type (IMRT vs. IMPT) was not associated with lymphopenia (grade 3 P > .99; grade 4 P = .55). In univariate analyses, poor overall survival was associated with pretreatment neutrophilia (hazard ratio [HR] 5.58, 95% confidence interval [CI] 1.99–15.7, P = .001), pretreatment leukocytosis (HR 4.85, 95% CI 1.73–13.6, P = .003), grade 4 lymphopenia during radiotherapy (HR 3.28, 95% CI 1.14–9.44, P = .03), and possibly smoking status >10 pack-years (HR 2.88, 95% CI 1.01–8.18, P = .05), but only T status was possibly significant in multivariate analysis (HR 2.64, 95% CI 0.99–7.00, P = .05). Poor progression-free survival was associated with pretreatment leukocytosis and T status in univariate analysis, and pretreatment neutrophilia and advanced age on multivariate analysis. Conclusions Treatment modality did not affect blood counts during radiotherapy. Pretreatment neutrophilia, pretreatment leukocytosis, and grade 4 lymphopenia during radiotherapy were associated with worse outcomes after, but establishing causality will require additional work with increased statistical power.

High-risk human papillomavirus (HPV) is now recognised as the principal cause of the increasing incidence rates of oropharyngeal squamous cell carcinoma (OPSCC) in some parts of the world. The primary risk factor for developing HPV-related OPSCC is oral HPV-infection and the majority of oral HPV-infections are acquired by oral sex. Progression into an OPSCC includes persistent infection with evasion of immune response in the microenvironment, the activation of viral early genes (E6, E7) in basal epithelial cells, the deregulation of cell cycle and the accumulation of chromosomal instability. Patients affected by HPV-related OPSCC tend to be younger and have better outcomes. This observation has lead current research to evaluate treatment de-escalation options to reduce long-term associated morbidity. Moreover, a different molecular profile for HPV-related OPSCC has been described, opening new options for targeted therapy and immunotherapy approaches. This paper comprehensively reviews our accumulated knowledge regarding the role of HPV in OPSCC spanning from infection to cancer development, including its clinical diagnosis, management and preventive strategies.

Summary Background Patients with platinum-refractory recurrent or metastatic squamous cell carcinoma of the head and neck have few treatment options and poor prognosis. Nivolumab significantly improved survival of this patient population when compared with standard single-agent therapy of investigator's choice in Checkmate 141; here we report the effect of nivolumab on patient-reported outcomes (PROs). Methods CheckMate 141 was a randomised, open-label, phase 3 trial in patients with recurrent or metastatic squamous cell carcinoma of the head and neck who progressed within 6 months after platinum-based chemotherapy. Patients were randomly assigned (2:1) to nivolumab 3 mg/kg every 2 weeks (n=240) or investigator's choice (n=121) of methotrexate (40–60 mg/m 2 of body surface area), docetaxel (30–40 mg/m 2 ), or cetuximab (250 mg/m 2 after a loading dose of 400 mg/m 2 ) until disease progression, intolerable toxicity, or withdrawal of consent. On Jan 26, 2016, the independent data monitoring committee reviewed the data at the planned interim analysis and declared overall survival superiority for nivolumab over investigator's choice therapy (primary endpoint; described previously). The protocol was amended to allow patients in the investigator's choice group to cross over to nivolumab. All patients not on active therapy are being followed for survival. As an exploratory endpoint, PROs were assessed at baseline, week 9, and every 6 weeks thereafter using the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire–Core 30 (QLQ-C30), the EORTC head and neck cancer-specific module (EORTC QLQ-H&N35), and the three-level European Quality of Life–5 Dimensions (EQ-5D) questionnaire. Differences within and between treatment groups in PROs were analysed by ANCOVA among patients with baseline and at least one other assessment. All randomised patients were included in the time to clinically meaningful deterioration analyses. Median time to clinically meaningful deterioration was analysed by Kaplan-Meier methods. CheckMate 141 was registered with ClinicalTrials.org, number NCT02105636. Findings Patients were enrolled between May 29, 2014, and July 31, 2015, and subsequently 361 patients were randomly assigned to receive nivolumab (n=240) or investigator's choice (n=121). Among them, 129 patients (93 in the nivolumab group and 36 in the investigator's choice group) completed any of the PRO questionnaires at baseline and at least one other assessment. Treatment with nivolumab resulted in adjusted mean changes from baseline to week 15 ranging from −2·1 to 5·4 across functional and symptom domains measured by the EORTC QLQ-C30, with no domains indicating clinically meaningful deterioration. By contrast, eight (53%) of the 15 domains in the investigator's choice group showed clinically meaningful deterioration (10 points or more) at week 15 (change from baseline range, −24·5 to 2·4). Similarly, on the EORTC QLQ-H&N35, clinically meaningful worsening at week 15 was seen in no domains in the nivolumab group and eight (44%) of 18 domains in the investigator's choice group. Patients in the nivolumab group had a clinically meaningful improvement (according to a difference of 7 points or greater) in adjusted mean change from baseline to week 15 on the EQ-5D visual analogue scale, in contrast to a clinically meaningful deterioration in the investigator's choice group (7·3 vs −7·8). Differences between groups were significant and clinically meaningful at weeks 9 and 15 in favour of nivolumab for role functioning, social functioning, fatigue, dyspnoea, and appetite loss on the EORTC QLQ-C30 and pain and sensory problems on the EORTC QLQ-H&N35. Median time to deterioration was significantly longer with nivolumab versus investigator's choice for 13 (37%) of 35 domains assessed across the three questionnaires. Interpretation In this exploratory analysis of CheckMate 141, nivolumab stabilised symptoms and functioning from baseline to weeks 9 and 15, whereas investigator's choice led to clinically meaningful deterioration. Nivolumab delayed time to deterioration of patient-reported quality-of-life outcomes compared with single-agent therapy of investigator's choice in patients with platinum-refractory recurrent or metastatic squamous cell carcinoma of the head and neck. In view of the major unmet need in this population and the importance of maintaining or improving quality of life for patients with recurrent or metastatic squamous cell carcinoma of the head and neck, these data support nivolumab as a new standard-of-care option in this setting. Funding Bristol-Myers Squibb.

HPV-positive oropharynx cancer is frequently characterized as a disease of never-smokers due to higher HPV prevalence in oropharynx tumors among never-smokers than ever-smokers. We sought to estimate the burden (incidence rates and case counts) of HPV-positive oropharynx cancers among never, former, and current smokers in the US population by combining data from several sources.We decomposed the SEER population-level incidence of oropharynx cancers into rates among never-, former-, and current-smokers using a formula based upon rate ratios (RR) for the smoking-oropharynx cancer association (NIH-AARP cohort study) and smoking prevalence in the U.S. population (NHANES 2007/2008). These rates were multiplied by smoking strata-specific HPV prevalence in oropharynx cancer patients (RTOG0129) to estimate incidence of HPV-positive and HPV-negative oropharynx cancers, which were applied to the US population of smokers to calculate annual case counts. Analyses were conducted overall and gender-stratified.The incidence of HPV-positive oropharynx cancers was significantly higher among ever versus never-smokers in the US population aged 20+ years during 2007/2008 (RR=1.81; 95%CI=1.32-2.47), including significantly higher incidence in current smokers (RR=2.26; 95%CI=1.60-3.21) and former smokers (RR=1.38; 95%CI=1.02-1.85). Of the estimated 6677 (5418 in men and 1259 in women) annually incident HPV-positive oropharynx cancers in the U.S during 2007/2008, 63.3% arose among ever smokers and 36.7% among never-smokers (p0.001). In both men and women, incidence rates and annual cases of HPV-positive oropharynx cancers were higher in ever smokers versus never smokers.The population-level burden of HPV-positive oropharynx cancers is significantly higher among ever-smokers than never-smokers in the U.S.

Introduction Human Papillomavirus (HPV) 16 E6 serum antibodies are common in people with HPV-related oropharyngeal cancers (HPV-OPC), but not the general population. We explored HPV16 seroprevalence in people with and without oral HPV16 infection, the cause of HPV-OPC. Methods Oral rinse samples were collected semiannually and tested for 36 types of HPV DNA by PCR. HPV16 E6 serum antibodies were tested at the visit of first oral HPV detection in participants with prevalent (n = 54), or incident (n = 39) oral HPV16 DNA; or at baseline in matched participants with no oral HPV16 DNA (n = 155) using multiplex serology assay. Predictors of seropositivity were examined using logistic regression. Results HPV16 E6 seropositivity (7.5% vs 0.7%; p = 0.005) but not seropositivity to the other HPV16 antigens, was significantly more common in those with than without oral HPV16 infection. There were only 8 HPV16 E6 seropositive participants, but oral HPV16 DNA remained a strong predictor of E6 seropositivity after adjustment for other risk factors (aOR = 14.6 95%CI, 1.7–122.5). Seroprevalence was similar in those with prevalent (7.4%; 4/54), and incident (7.7%; 3/39) oral HPV16 infection (p = 1.00). E6 seroprevalence was associated with reduced oral HPV16 clearance, but was not statistically significant (HR = 0.65 95% CI, 0.16–2.70). Seropositive participants were primarily male (87.5%), HIV-positive (75.0%; median CD4 cell-count of 840) and had oral HPV16 DNA (87.5%). History of an HPV-related cancer (0/8) or HPV-related anogenital dysplasia (1/8) was rare, and 4 participants had recent screening showing no anogenital dysplasia. Discussion HPV16 E6 seropositivity was higher among people with than without oral HPV16 infection, despite no known anogenital disease in these participants.

Human papillomavirus (HPV) is the cause of a distinct subset of oropharyngeal cancer rising in incidence in the United States and other developed countries. This increased incidence, combined with the strong effect of tumor HPV status on survival, has had a profound effect on the head and neck cancer discipline. The multidisciplinary field of head and neck cancer is in the midst of re-evaluating evidence-based algorithms for clinical decision making, developed from clinical trials conducted in an era when HPV-negative cancer predominated. This article reviews relationships between tumor HPV status and gender, cancer incidence trends, overall survival, treatment response, racial disparities, tumor staging, risk stratification, survival post disease progression, and clinical trial design.

Current radiation therapy (RT) treatment schedules for head and neck squamous cell carcinoma (HNSCC) are derived from a combination of rigorous radiobiology and data from prospective clinical trials. Human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC) is now appreciated to be biologically distinct from the traditional type of HNSCC resulting from tobacco and alcohol use. Remarkably high 5-year survival rates, not previously observed in the head and neck cancer patient population, are observed among patients with HPV-positive OPSCC when treated with platinum-based chemoradiation therapy (CRT). Additionally, the patient population afflicted with HPV-positive OPSCC is younger, healthier, and far more likely to be alive to deal with the long-term consequences of therapy. Clinicians who treat HPV-positive OPSCC are now faced with the problem that current treatment paradigms were developed in an era when the traditional HNSCC patient (tobaccoand alcohol-related) predominated. This has led to an appropriate re-examination of treatment paradigms as applied to the HPV-positive OPSCC patient, as well as a new appreciation for the problem of chronic toxicity. We note that it is provocative (and frightening) to “mess with success.” For this reason, the proposition of dose deescalation (of chemotherapy and/or RT) or substitution with

Summary Background Although human papillomavirus detection in cervical lymph nodes of head and neck squamous cell cancers (HNSCC) of unknown primary site (UP) is indicative of a primary tumor of the oropharynx (OP), localization can remain elusive. Therefore, we investigated ultrasonography (US) for the identification of the primary tumor. Methods Eligible cases had HNSCC of UP after evaluation by a head and neck surgical oncologist. Controls were healthy volunteers. Transcervical and intraoral ultrasonography was performed by a standard protocol using convex (3.75–6.0 MHz and 5–7.5 MHz) transducers. US findings were compared with operative examination (exam under anesthesia, direct laryngoscopy) and biopsies. The primary outcome of interest was the presence or absence of a lesion on US. Results 10 cases and 20 controls were enrolled. PET/CT scans were negative/nonspecific (9), or suspicious (1) for a primary lesion. On US, predominantly hypoechoic (9 of 10) lesions were visualized consistent with base of tongue ( n = 7) or tonsil ( n = 3) primary tumors. On operative examination, 5 of 10 were appreciated. Two additional primaries were confirmed with biopsies “directed” by preoperative US. This represents an overall diagnostic rate of 70%, which is 20% higher than our detection rate for 2008–2010. The three cases in which a suspicious lesion was visualized on US, yet remained UP despite further interventions, could represent false positives, misclassification or operator variability. No lesions were suspected among the controls. Conclusion Ultrasound has promise for detection of UPs of the OP and therefore warrants further investigation.

Background Tumor-specific neoantigens provide personalized targets for immunotherapy. Vaccines against epitopes predicted by in silico approaches very rarely induce CD4+ and CD8+ ex vivo T cell responses regardless of formulation. ATLAS selects neoantigens for vaccine inclusion using ex vivo screening of all patient-specific mutations to identify pre-existing CD4+ or CD8+ T cell responses and to exclude inhibitory peptides that suppress immunity and accelerate tumor progression. Preliminary data suggest that the inhibitory peptide profile may predict tumor response to immunotherapy. Methods GEN-009-101 is a phase I/IIa study testing safety, immunogenicity and clinical activity in immune responsive tumors. After next-generation tumor sequencing and ATLAS testing of autologous leukocytes, up to 20 stimulatory synthetic long peptides adjuvanted with poly-ICLC make each personalized vaccine. The immunogenicity pilot has enrolled 9 patients in remission to receive GEN-009 monotherapy. Results 4 patients have participated to the primary immunogenicity readout at day 50 (some data pending). The 17 doses given across patients have induced only mild local discomfort and no DLT. ATLAS results show high interpatient variability. Vaccination has generated immune responses against 94% of administered peptides, and both CD8+ and CD4+ responses in a 44hr ex vivo fluorospot assay. Ten-day in vitro stimulation (IVS) assays result in broader immune responses.Table1178PDTablePTTumor TypeSomatic Mutations/MbATLAS NeoantigensPost-vaccination Response*StimulatoryInhibitoryex vivo CD4/CD8IVS CD4/CD8Total Positive1NSCLC1.256010% / 40%100% / 20%100%2Bladder3.1516450% / 38%63% / 50%88%3Melanoma28.69199416% / 38%75% / TBDTBD4Bladder3.53181TBDTBDTBD5NSCLC3.5616955% / 45%TBDTBD*number of positive peptides/total peptides immunized Conclusions GEN-009 is a neoantigen vaccine that identifies tumor specific immune targets from the individual patient's repertoire. Immunogenicity data show that ATLAS can, with very high frequency, identify relevant neoantigens and exclude suppressive peptides. Clinical vaccination with PD-1 blockade is in process. Clinical trial identification NCT03633110, issued 6-Aug-2018. Legal entity responsible for the study Genocea Biosciences. Funding Genocea Biosciences. Disclosure P. Twardowski: Advisory / Consultancy, Speaker Bureau / Expert testimony: Bayer; Speaker Bureau / Expert testimony: Janssen; Speaker Bureau / Expert testimony: Pfizer; Speaker Bureau / Expert testimony: Astellas; Speaker Bureau / Expert testimony: Sanofi; Advisory / Consultancy: Bristol-Myers Squibb. M.L. Johnson: Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Genentech / Roche; Advisory / Consultancy: Celgene; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Boehringer Ingelheim; Advisory / Consultancy, Research grant / Funding (institution): Sanofi; Advisory / Consultancy, Research grant / Funding (institution): Mirati; Advisory / Consultancy, Research grant / Funding (institution): LOXO; Advisory / Consultancy: Calithera; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Merck; Advisory / Consultancy: Araxes Pharma; Advisory / Consultancy: Mersana Therapeutics ; Advisory / Consultancy, Research grant / Funding (institution): BeiGene; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Incyte; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Pfizer; Advisory / Consultancy, Research grant / Funding (institution): Guardant Health; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Bristol-Myers Squibb; Advisory / Consultancy: Ribon Therapeutics ; Research grant / Funding (institution), Travel / Accommodation / Expenses: AbbVie; Travel / Accommodation / Expenses: Astellas; Research grant / Funding (institution), Travel / Accommodation / Expenses, Spouse / Financial dependant: Clovis; Spouse / Financial dependant: Otsuka Pharmaceuticals; Research grant / Funding (institution): BerGenBio; Research grant / Funding (institution): Lilly; Research grant / Funding (institution), Travel / Accommodation / Expenses: EMD Serono; Research grant / Funding (institution): Janssen; Research grant / Funding (institution): Genmab; Research grant / Funding (institution): Stemcentrix; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Checkpoint Therapeutics; Research grant / Funding (institution): Array Biopharma; Research grant / Funding (institution): Regeneron; Research grant / Funding (institution): Apexigen; Research grant / Funding (institution): Tarveda; Research grant / Funding (institution): Adaptimmune; Research grant / Funding (institution): Syndax; Research grant / Funding (institution): Neovia; Research grant / Funding (institution): Hengrui Therapeutics, INC; Research grant / Funding (institution), Travel / Accommodation / Expenses: Daiichi - Sankyo; Research grant / Funding (institution): Lycera; Research grant / Funding (institution): G1 Therapeutics; Research grant / Funding (institution): Dynavax; Research grant / Funding (institution): Cytomx; Research grant / Funding (institution): Birdie; Research grant / Funding (institution): Corvus; Research grant / Funding (institution): Genocea; Research grant / Funding (institution): Gritstone; Research grant / Funding (institution): Amgen; Research grant / Funding (institution): Kadmon; Research grant / Funding (institution): Acerta; Research grant / Funding (institution): Takeda; Research grant / Funding (institution): Shattuck Labs; Research grant / Funding (institution): GlaxoSmithKline; Travel / Accommodation / Expenses: Exelixis; Travel / Accommodation / Expenses: Sysmex Inostics; Travel / Accommodation / Expenses: Vapotherm. M. Stein: Advisory / Consultancy, Research grant / Funding (institution): Merck Sharp & Dohme; Advisory / Consultancy: Exelixis; Research grant / Funding (institution): Oncoceutics; Research grant / Funding (institution): Janssen Oncology; Research grant / Funding (institution): Medivation/Astellas; Research grant / Funding (institution): Advaxis; Research grant / Funding (institution): Suzhou Kintor Pharmaceuticals; Research grant / Funding (institution): Harpoon; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Genocea; Research grant / Funding (institution): Lilly; Research grant / Funding (institution): Nektar; Research grant / Funding (institution): Seattle Genetics; Research grant / Funding (institution): Xencor. M.L. Gillison: Advisory / Consultancy: Amgen; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Aspyrian; Advisory / Consultancy: Celgene; Advisory / Consultancy: Britsol-Myers Squibb; Advisory / Consultancy: GlaxoSmithKline; Advisory / Consultancy: Genocea; Advisory / Consultancy: Lilly; Advisory / Consultancy: NewLink; Advisory / Consultancy: Bayer; Advisory / Consultancy: Roche; Advisory / Consultancy: Genentech; Advisory / Consultancy: Ventana; Advisory / Consultancy: Biomimetix. L. McNeil: Shareholder / Stockholder / Stock options, Full / Part-time employment: Genocea. L. Dowal: Shareholder / Stockholder / Stock options, Full / Part-time employment: Genocea. D. DeOliveira: Shareholder / Stockholder / Stock options, Full / Part-time employment: Genocea. M. Jain: Shareholder / Stockholder / Stock options, Full / Part-time employment: Genocea. J. Price: Shareholder / Stockholder / Stock options, Full / Part-time employment: Genocea. R. Hernandez: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment: Genocea. A. DeCillis: Advisory / Consultancy: Genocea; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Exelixis; Advisory / Consultancy: Pyramid; Advisory / Consultancy: Daiichi Sankyo. N. Singh: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment, Officer / Board of Directors: Genocea. T. Davis: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment, Officer / Board of Directors: Genocea. J. Flechtner: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment, Officer / Board of Directors: Genocea. R.B. Cohen: Advisory / Consultancy, Research grant / Funding (institution): Genocea; Advisory / Consultancy, Research grant / Funding (institution): Innate Biopharma; Advisory / Consultancy, Research grant / Funding (institution): HEAT Biologics; Advisory / Consultancy: Cantargia; Advisory / Consultancy: Tmunity; Research grant / Funding (institution): Arrys; Research grant / Funding (institution): Celldex. All other authors have declared no conflicts of interest.

Background Oral human papillomavirus (HPV) infection is the principal underlying cause of a dramatic increase in oropharyngeal cancer. Dentistry can play an important role in developing clinical algorithms for secondary prevention. Methods The authors conducted this cross-sectional pilot study with practices of The National Dental Practice-Based Research Network. The authors evaluated the feasibility and acceptability of screening and testing procedures as judged by practitioners and patients. The authors used tablet devices for patient screening, obtaining consent, and administering a confidential oral HPV risk factor survey. Results Most patients (85%) were comfortable being asked about their cigarette use and their sexual behavior (69%) and were interested in participating again (79%). More than 90% of practitioners were comfortable with study procedures except the extra time required for patient participation (75% comfortable). There were no problems with oral rinse collection as reported by patients or practitioners. Conclusions It is feasible in community dental offices to collect oral rinses for HPV detection and to ask patients explicit questions about sexual history when using a tablet device for confidentiality. Practical Implications Discussing high-risk types of HPV and appropriately assessing that risk are a challenge for oral health care professionals. These results are positive from a research perspective but do not address the advisability of routine HPV screening in dentistry.

Infection with human papillomavirus (HPV) is recognized as one of the major causes of infection-related cancer worldwide, as well as the causal factor in other diseases. Strong evidence for a causal etiology with HPV has been stated by the International Agency for Research on Cancer for cancers of the cervix uteri, penis, vulva, vagina, anus and oropharynx (including base of the tongue and tonsils). Of the estimated 12.7 million new cancers occurring in 2008 worldwide, 4.8% were attributable to HPV infection, with substantially higher incidence and mortality rates seen in developing versus developed countries. In recent years, we have gained tremendous knowledge about HPVs and their interactions with host cells, tissues and the immune system; have validated and implemented strategies for safe and efficacious prophylactic vaccination against HPV infections; have developed increasingly sensitive and specific molecular diagnostic tools for HPV detection for use in cervical cancer screening; and have substantially increased global awareness of HPV and its many associated diseases in women, men, and children. While these achievements exemplify the success of biomedical research in generating important public health interventions, they also generate new and daunting challenges: costs of HPV prevention and medical care, the implementation of what is technically possible, socio-political resistance to prevention opportunities, and the very wide ranges of national economic capabilities and health care systems. Gains and challenges faced in the quest for comprehensive control of HPV infection and HPV-related cancers and other disease are summarized in this review. The information presented may be viewed in terms of a reframed paradigm of prevention of cervical cancer and other HPV-related diseases that will include strategic combinations of at least four major components: 1) routine introduction of HPV vaccines to women in all countries, 2) extension and simplification of existing screening programs using HPV-based technology, 3) extension of adapted screening programs to developing populations, and 4) consideration of the broader spectrum of cancers and other diseases preventable by HPV vaccination in women, as well as in men. Despite the huge advances already achieved, there must be ongoing efforts including international advocacy to achieve widespread-optimally universal-implementation of HPV prevention strategies in both developed and developing countries. This article summarizes information from the chapters presented in a special ICO Monograph 'Comprehensive Control of HPV Infections and Related Diseases' Vaccine Volume 30, Supplement 5, 2012. Additional details on each subtopic and full information regarding the supporting literature references may be found in the original chapters. (C) 2013 Elsevier Ltd. All rights reserved.

Poster-Abstract

Background Oral HPV infection elevates risk of oropharyngeal cancer, but its natural history is unknown. Natural history studies necessitate validation of an automated, high-throughput method for HPV genomic DNA detection in oral rinse samples (ORS). Objectives To compare agreement of oral HPV detection in ORS processed by a magnetic-bead based automated platform to a previous gold-standard, manual protein-precipitation method. Agreement was compared to that of repeat sampling and repeat HPV testing. Study design HIV-infected individuals ( n =100) provided two ORS collected 15min apart. DNA was isolated from equal aliquots by either a protein-precipitation based (Puregene, Qiagen) or magnetic bead-based (QIAsymphony™ SP, Qiagen) method. HPV DNA was detected and type-specified by consensus primer PCR and reverse line blot hybridization. The kappa statistic was used to assess overall agreement (OA) and agreement on a positive test (Ps+). Results The DNA purification methods had very high agreement for categorizing an individual as HPV infected (OA=0.95; Ps+=0.94) as well as for detection of HPV type-specific infection (OA=0.99; Ps+=0.88) in ORS. Agreement for detection of HPV type-specific infection was greater than that observed with repeat oral rinse sampling (OA=0.99, Ps+=0.76) but comparable to inter-assay agreement (OA=1.00, Ps+=0.90). Conclusions HPV detection in ORS processed with a magnetic-bead based automated platform will facilitate large natural history studies of oral HPV infection necessary to evaluate the potential use of oral HPV detection in oral cancer screening.

DNA vaccines have emerged as an attractive approach for antigen-specific cancer immunotherapy. We have previously linked Mycobacterium tuberculosis heat shock protein 70 (HSP70) to human papillomavirus type 16 (HPV-16) E7 in the context of a DNA vaccine. Vaccination with DNA encoding E7/HSP70 has generated a dramatic increase of E7-specific CD8+ T cell precursors and a strong antitumor effect against E7-expressing tumor (TC-1) in vaccinated mice. The success of our strategy has led to two phases I/II clinical trial proposals in patients with HPV-16 associated high-grade squamous intraepithelial lesion (HSIL) of the cervix and in patients with advanced HPV-associated head and neck squamous cell carcinoma (HNSCC). To translate our HPV DNA vaccines into the clinical domain, the efficacy of pNGVL4a-Sig/E7(detox)/HSP70 DNA vaccine and of various routes of administrations were assessed in mice. Our results indicated that pNGVL4a-Sig/E7(detox)/HSP70 DNA vaccine administered via gene gun generated the highest number of E7-specific CD8+ T cells. In addition, DNA vaccination via gene gun required the least dose to generate similar or slightly better antitumor effects compared to needle intramuscular (i.m.) and biojector administrations. Thus, our data suggest that DNA vaccination via gene gun represents the most potent regimen for DNA administration.

The management of advanced cancers of the larynx and hypopharynx has become increasingly complex as different treatment modalities including surgery, radiation, and chemotherapy have been combined with the goal of improving local disease control and disease-specific survival. A union of 17 comprehensive cancer centers in the United States, the National Comprehensive Cancer Network (NCCN), was formed in 1995 to promote state-of-the-art cancer care. To achieve this goal, multidisciplinary panels of experts from member institutions have created disease-specific practice guidelines for the evaluation and treatment of cancer patients, including head and neck cancers. 47 These guidelines, intended to help clarify and standardize care of patients with head and neck cancers, were based, where possible, on the findings of multicenter randomized, controlled trials. Many decision points in patient management have not been evaluated to date in such trials, however, and therefore data from phase II trials and case series also influenced the treatment guidelines. Although detailed analysis of surgical methods and radiation techniques is beyond the scope of this article, the evolving laryngeal preservation strategies for patients with advanced, resectable hypopharyngeal or laryngeal (including supraglottic and glottic) cancers are reviewed, using the relevant sections of the NCCN practice guidelines as a framework for discussion. Until recently in the United States, the conventional therapy given patients with locally advanced laryngeal (T3 or T4) or hypopharyngeal (T2, T3, or T4) cancers has been total laryngectomy with neck dissection followed by postoperative radiation therapy. 54 Unfortunately, patients treated with laryngectomy suffer a complete loss of voice and sometimes impairment of swallowing function, leading to decreased overall quality of life in many aspects, including nutrition, social functioning, and personal hygiene. These problems motivated the development of laryngeal-preservation approaches. Organ-preservation approaches have included induction chemotherapy followed in responding patients by radiation and primary radiation therapy alone with surgery reserved for treatment failures. After resectable, advanced laryngeal or hypopharyngeal cancer has been diagnosed, patients and their treating physicians must choose among three primary treatment modalities that are currently available. The NCCN practice guidelines present these three options as surgery, induction chemotherapy, or definitive radiation therapy (Figs. 1, 2, and 3). Many factors contribute to the decision-making process, including patient preference, performance status, tumor location and stage, and the treatment practices of the patient's physicians. Recently, the Department of Veterans Affairs (VA) and the European Organization for Research and Treatment of Cancer (EORTC) reported two landmark randomized, controlled trials in patients with advanced, resectable laryngeal or hypopharyngeal cancer. These two large trials compared primary surgical management with a laryngeal preservation approach of induction chemotherapy followed by definitive radiation. The trials demonstrated that overall survival was comparable in the two treatment groups. 16,37 Moreover, laryngeal preservation was enjoyed by one half to two thirds of the surviving patients in the chemotherapy plus radiation therapy group but by none of the primary laryngectomy patients at 5 years. Given that data from these two important trials served as a foundation for the critical decision point of choosing primary therapy shown in the NCCN guidelines, an understanding of the treatment algorithms requires careful consideration of the findings in these two trials.

Does Age Matter? Survival Outcomes With the Addition of Concurrent Chemotherapy for Elderly Head and Neck Cancer Patients Undergoing Definitive Radiation Using the National Cancer Data Base A. Amini, B. Jones, J. McDermott, A. Jimeno, D.W. Bowles, D. Raben, and S. Karam; Department of Radiation Oncology, University of Colorado Denver, Aurora, CO, Department of Medical Oncology, University of Colorado Denver, Aurora, CO

Human Papillomavirus (HPV) and Overall Survival (OS) After Progression of Oropharyngeal Squamous Cell Carcinoma (OPSCC) Management of Recurrent Head-and-Neck Squamous Cell Carcinoma C. Fakhry, Q. Zhang, P. Nguyen-Tân, D. Rosenthal, A. El-Naggar, A. Garden, D. Soulieres, J. Harris, Q. Le, and M. Gillison; Johns Hopkins Medical Institution, Baltimore, MD, Radiation Therapy Oncology Group Statistical Center, Philadelphia, PA, CHUM Hospital Notre Dame, Montreal, QC, Canada, University of Texas MD Anderson Cancer Center, Houston, TX, Stanford University Medical Center, Stanford, CA, Ohio State University Medical Center, Columbus, OH