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Supplementary Tables 1-3 from A Sex-Specific Association between a 15q25 Variant and Upper Aerodigestive Tract Cancers

Background: The increasing incidence of oropharyngeal cancer in many developed countries has been attributed to human papillomavirus type 16 (HPV16) infections. Recently, HPV16 E6 serology has been identified as a promising early marker for oropharyngeal cancer. Therefore, characterization of HPV16 E6 seropositivity among individuals without cancer is warranted.Methods: A total of 4,666 controls were pooled from several studies of cancer and HPV seropositivity, all tested within the same laboratory. HPV16 E6 seropositive controls were classified as having (i) moderate [mean fluorescent intensity (MFI) ≥ 484 and Results: Thirty-two (0.7%) HPV16 E6 seropositive controls were identified; 17 (0.4%) with moderate and 15 (0.3%) with high seroreactivity. High HPV16 E6 seroreactivity was associated with former smoking [odds ratio (OR), 5.5; 95% confidence interval (CI), 1.2–51.8], and seropositivity against HPV16 L1 (OR, 4.8; 95% CI, 1.3–15.4); E2 (OR, 7.7; 95% CI, 1.4–29.1); multiple HPV16 proteins (OR, 25.3; 95% CI, 2.6–119.6 for three HPV16 proteins beside E6) and HPV33 E6 (OR, 17.7; 95% CI, 1.9–81.8). No associations were observed with moderate HPV16 E6 seroreactivity.Conclusions: High HPV16 E6 seroreactivity is rare among individuals without diagnosed cancer and was not explained by demographic factors.Impact: Some HPV16 E6 seropositive individuals without diagnosed HPV-driven cancer, especially those with seropositivity against other HPV16 proteins, may harbor a biologically relevant HPV16 infection. Cancer Epidemiol Biomarkers Prev; 24(4); 683–9. ©2015 AACR.

Supplemental Table 1. Study-specific definitions for categorization of tobacco and alcohol use.

Background: Sequence variants located at 15q25 have been associated with lung cancer and propensity to smoke. We recently reported an association between rs16969968 and risk of upper aerodigestive tract (UADT) cancers (oral cavity, oropharynx, hypopharynx, larynx, and esophagus) in women (OR = 1.24, P = 0.003) with little effect in men (OR = 1.04, P = 0.35).Methods: In a coordinated genotyping study within the International Head and Neck Cancer Epidemiology (INHANCE) consortium, we have sought to replicate these findings in an additional 4,604 cases and 6,239 controls from 10 independent UADT cancer case–control studies.Results: rs16969968 was again associated with UADT cancers in women (OR = 1.21, 95% CI = 1.08–1.36, P = 0.001) and a similar lack of observed effect in men [OR = 1.02, 95% CI = 0.95–1.09, P = 0.66; P-heterogeneity (Phet) = 0.01]. In a pooled analysis of the original and current studies, totaling 8,572 UADT cancer cases and 11,558 controls, the association was observed among females (OR = 1.22, 95% CI = 1.12–1.34, P = 7 × 10−6) but not males (OR = 1.02, 95% CI = 0.97–1.08, P = 0.35; Phet = 6 × 10−4). There was little evidence for a sexdifference in the association between this variant and cigarettes smoked per day, with male and female rs16969968 variant carriers smoking approximately the same amount more in the 11,991 ever smokers in the pooled analysis of the 14 studies (Phet = 0.86).Conclusions: This study has confirmed a sex difference in the association between the 15q25 variant rs16969968 and UADT cancers.Impact: Further research is warranted to elucidate the mechanisms underlying these observations. Cancer Epidemiol Biomarkers Prev; 20(4); 658–64. ©2011 AACR.

Head and neck cancer is often diagnosed late and prognosis for most head and neck cancer patients remains poor. To aid early detection, we developed a risk prediction model based on demographic and lifestyle risk factors, human papillomavirus (HPV) serological markers, and genetic markers. A total of 10,126 head and neck cancer cases and 5,254 controls from 5 North American and European studies were included. HPV serostatus was determined by antibodies for HPV16 early oncoproteins (E6, E7) and regulatory early proteins (E1, E2, E4). The data were split into a training set (70%) for model development and a hold-out testing set (30%) for model performance evaluation, including discriminative ability and calibration. The risk models including demographic, lifestyle risk factors and polygenic risk score showed a reasonable predictive accuracy for head and neck cancer overall. A risk model that also included HPV serology showed substantially improved predictive accuracy for oropharyngeal cancer (AUC=0.94, 95%CI=0.92–0.95 in men and AUC=0.92, 95%CI=0.88–0.95 in women). The 5-year absolute risk estimates showed distinct trajectories by risk factor profiles. Based on the UK Biobank cohort, the risks of developing oropharyngeal cancer among 60 years old and HPV16 seropositive in the next 5 years ranged from 5.8% to 14.9% with an average of 8.1% for men, 1.3% to 4.4% with an average of 2.2% for women. Absolute risk was generally higher among individuals with heavy smoking, heavy drinking, HPV seropositivity, and those with higher polygenic risk score. These risk models may be helpful for identifying people at high risk of developing head and neck cancer.

The routine scale and polish is the most commonly performed treatment procedure in general dental practice. With a large proportion of state dental health expenditure in the UK and Ireland being used to provide ‘routine scale and polish’ treatments, it is necessary to establish the true value of this treatment for patients. In this narrative review, we discuss the available evidence regarding provision of the routine scale and polish. Based on the available studies, there is little evidence to support the use of the routine scale and polish alone for the prevention of periodontal disease. CPD/Clinical Relevance: This paper evaluates the evidence surrounding the routine provision of scaling and polishing for the prevention of gingivitis and periodontitis.

International audience; Raman spectroscopy can provide a rapid, label-free, nondestructive measurement of the chemical fingerprint of a sample and has shown potential for cancer screening and diagnosis. Here we report a protocol for Raman microspectroscopic analysis of different exfoliative cytology samples (cervical, oral and lung), covering sample preparation, spectral acquisition, preprocessing and data analysis. The protocol takes 2 h 20 min for sample preparation, measurement and data preprocessing and up to 8 h for a complete analysis. A key feature of the protocol is that it uses the same sample preparation procedure as commonly used in diagnostic cytology laboratories (i.e., liquid-based cytology on glass slides), ensuring compatibility with clinical workflows. Our protocol also covers methods to correct for the spectral contribution of glass and sample pretreatment methods to remove contaminants (such as blood and mucus) that can obscure spectral features in the exfoliated cells and lead to variability. The protocol establishes a standardized clinical routine allowing the collection of highly reproducible data for Raman spectral cytopathology for cancer diagnostic applications for cervical and lung cancer and for monitoring suspicious lesions for oral cancer.

Nutritional immunity is the sequestration of bioavailable trace metals such as iron, zinc and copper by the host to limit pathogenicity by invading microorganisms. As one of the most conserved activities of the innate immune system, limiting the availability of free trace metals by cells of the immune system serves not only to conceal these vital nutrients from invading bacteria but also operates to tightly regulate host immune cell responses and function. In the setting of chronic lung disease, the regulation of trace metals by the host is often disrupted, leading to the altered availability of these nutrients to commensal and invading opportunistic pathogenic microbes. Similarly, alterations in the uptake, secretion, turnover and redox activity of these vitally important metals has significant repercussions for immune cell function including the response to and resolution of infection. This review will discuss the intricate role of nutritional immunity in host immune cells of the lung and how changes in this fundamental process as a result of chronic lung disease may alter the airway microbiome, disease progression and the response to infection.

Recent advances in DNA sequencing technology have facilitated rapid advances in the analysis of the human microbiome and its role in human disease. Several studies have now shown that OSCC and some oral premalignant conditions are associated with alterations in the oral microbiome. These studies raise questions regarding the role of the oral microbiome in the progression of oral malignancies and whether microbiome change is a significant risk factor in the development of oral cancer. This short review summarises current knowledge in the field and highlights questions that require further investigation.

The potential of Raman microspectroscopy of exfoliated cells has been demonstrated for oral cancer diagnosis. In this study, brush biopsies were collected from the buccal mucosa/tongue of healthy donors (n = 31) and from oral mucosal dysplastic lesions (n = 31 patients). Raman spectra were acquired and subjected to partial least squares-discriminant analysis (PLS-DA). The patient samples could be differentiated from healthy donor samples with 96% sensitivity and 95% specificity. Furthermore, PLS-DA models were developed based on cytopathological and histopathological assessment. Low and high grade dysplasia could be discriminated with 64% sensitivity and 65% specificity based on cytopathological assessment, while 81% sensitivity and 86% specificity could be achieved when histopathological assessment was within six months of the brush biopsy sampling. Therefore, this explorative study has successfully demonstrated that Raman spectroscopy may have a role in monitoring patients with dysplasia and may reduce the need for multiple biopsies.

Although several oropharyngeal cancer (OPC) susceptibility loci have been identified, most previous studies lacked detailed information on human papillomavirus (HPV) status. We conduct a genome-wide analysis by HPV16 serology status in 4,002 oral cancer cases (OPC and oral cavity cancer (OCC)) and 5,256 controls. We detect four susceptibility loci pointing to a distinct genetic predisposition by HPV status. Our most notable finding in the HLA region, that is now confirmed to be specific of HPV(+)OPC risk, reveal two independent loci with strong protective effects, one refining the previously reported HLA class II haplotype association. Antibody levels against HPV16 viral proteins strongly implicate the protective HLA variants as major determinants of humoral response against L1 capsid protein or E6 oncoprotein suggesting a natural immune response against HPV(+)OPC promoted by HLA variants. This indicates that therapeutic vaccines that target E6 and attenuate viral response after established HPV infections might protect against HPV(+)OPC., Genetic susceptibility loci for oropharyngeal cancer have been reported but these studies have not always examined human papillomavirus (HPV) status. Here, the authors perform genome-wide analysis taking into account HPV16 serology status and report two independent loci in the HLA region, suggesting the protective role of HLA variants against HPV infection.

BackgroundThe association between socioeconomic disadvantage (low education and/or income) and head and neck cancer is well established, with smoking and alcohol consumption explaining up to three-quarters of the risk. We aimed to investigate the nature of and explanations for head and neck cancer risk associated with occupational socioeconomic prestige (a perceptual measure of psychosocial status), occupational socioeconomic position and manual-work experience, and to assess the potential explanatory role of occupational exposures.MethodsPooled analysis included 5818 patients with head and neck cancer (and 7326 control participants) from five studies in Europe and South America. Lifetime job histories were coded to: (1) occupational social prestige—Treiman’s Standard International Occupational Prestige Scale (SIOPS); (2) occupational socioeconomic position—International Socio-Economic Index (ISEI); and (3) manual/non-manual jobs.ResultsFor the longest held job, adjusting for smoking, alcohol and nature of occupation, increased head and neck cancer risk estimates were observed for low SIOPS OR=1.88 (95% CI: 1.64 to 2.17), low ISEI OR=1.74 (95% CI: 1.51 to 1.99) and manual occupations OR=1.49 (95% CI: 1.35 to 1.64). Following mutual adjustment by socioeconomic exposures, risk associated with low SIOPS remained OR=1.59 (95% CI: 1.30 to 1.94).ConclusionsThese findings indicate that low occupational socioeconomic prestige, position and manual work are associated with head and neck cancer, and such risks are only partly explained by smoking, alcohol and occupational exposures. Perceptual occupational psychosocial status (SIOPS) appears to be the strongest socioeconomic factor, relative to socioeconomic position and manual/non-manual work.

Field cancerisation (FC) is potentially an underlying cause of poor treatment outcomes of oral squamous cell carcinoma (OSCC). To explore the phenomenon using Raman microspectroscopy, brush biopsies from the buccal mucosa, tongue, gingiva and alveolus of healthy donors (n = 40) and from potentially malignant lesions (PML) of Dysplasia Clinic patients (n = 40) were examined. Contralateral normal samples (n = 38) were also collected from the patients. Raman spectra were acquired from the nucleus and cytoplasm of each cell, and subjected to partial least squares-discriminant analysis (PLS-DA). High discriminatory accuracy for donor and PML samples was achieved for both cytopalmic and nuclear data sets. Notably, contralateral normal (patient) samples were also accurately discriminated from donor samples and contralateral normal samples from patients with multiple lesions showed a similar spectral profile to PML samples, strongly indicating a FC effect. These findings support the potential of Raman microspectroscopy as a screening tool for PML using oral exfoliated cells.

This study demonstrates the efficacy of Raman micro-spectroscopy of oral cytological samples for differentiating dysplastic, potentially malignant lesions from those of normal, healthy donors. Cells were collected using brush biopsy from healthy donors (n = 20) and patients attending a Dysplasia Clinic (n = 20). Donors were sampled at four different sites (buccal mucosa, tongue, alveolus, gingiva), to ensure matched normal sites for all lesions, while patient samples were taken from clinically evident, histologically verified dysplastic lesions. Spectra were acquired from the nucleus and cytoplasm of individual cells of all samples and subjected to partial least squares-discriminant analysis. Discriminative sensitivities of 94% and 86% and specificity of 85% were achieved for the cytoplasm and nucleus, respectively, largely based on lipidic contributions of dysplastic cells. Alveolar/gingival samples were differentiated from tongue/buccal samples, indicating that anatomical site is potentially a confounding factor, while age, gender, smoking and alcohol consumption were confirmed not to be.

Objectives:\ud \ud To test the performance of an oral cancer prognostic 13-gene signature for the prediction of survival of patients diagnosed with HPV-negative and p16-negative oral cavity cancer.\ud Materials and Methods:\ud \ud Diagnostic formalin-fixed paraffin-embedded oral cavity cancer tumor samples were obtained from the Fred Hutchinson Cancer Research Center/University of Washington, University of Calgary, University of Michigan, University of Utah, and seven ARCAGE study centers coordinated by the International Agency of Research on Cancer. RNA from 638 Human Papillomavirus (HPV)-negative and p16-negative samples was analyzed for the 13 genes using a NanoString assay. Ridge-penalized Cox regressions were applied to samples randomly split into discovery and validation sets to build models and evaluate the performance of the 13-gene signature in predicting 2-year oral cavity cancer-specific survival overall and separately for patients with early and late stage disease.\ud Results:\ud \ud Among AJCC stage I/II patients, including the 13-gene signature in the model resulted in substantial improvement in the prediction of 2-year oral cavity cancer-specific survival. For models containing age and sex with and without the 13-gene signature score, the areas under the Receiver Operating Characteristic Curve (AUC) and partial AUC were 0.700 vs. 0.537 (p < 0.001), and 0.046 vs. 0.018 (p < 0.001), respectively. Improvement in predicting prognosis for AJCC stage III/IV disease also was observed, but to a lesser extent.\ud Conclusions:\ud \ud If confirmed using tumor samples from a larger number of early stage oral cavity cancer patients, the 13-gene signature may inform personalized treatment of early stage HPV-negative and p16-negative oral cavity cancer patients.

Background Alcohol is a well-established risk factor for head and neck cancer (HNC). This study aims to explore the effect of alcohol intensity and duration, as joint continuous exposures, on HNC risk. Methods Data from 26 case-control studies in the INHANCE Consortium were used, including never and current drinkers who drunk ≤10 drinks/day for ≤54 years (24234 controls, 4085 oral cavity, 3359 oropharyngeal, 983 hypopharyngeal and 3340 laryngeal cancers). The dose-response relationship between the risk and the joint exposure to drinking intensity and duration was investigated through bivariate regression spline models, adjusting for potential confounders, including tobacco smoking. Results For all subsites, cancer risk steeply increased with increasing drinks/day, with no appreciable threshold effect at lower intensities. For each intensity level, the risk of oral cavity, hypopharyngeal and laryngeal cancers did not vary according to years of drinking, suggesting no effect of duration. For oropharyngeal cancer, the risk increased with durations up to 28 years, flattening thereafter. The risk peaked at the higher levels of intensity and duration for all subsites (odds ratio = 7.95 for oral cavity, 12.86 for oropharynx, 24.96 for hypopharynx and 6.60 for larynx). Conclusions Present results further encourage the reduction of alcohol intensity to mitigate HNC risk.

Introduction: Various established occupational lung carcinogens are also suspected risk factors for laryngeal cancer. However, individual studies are often inadequate in size to investigate this relatively rare outcome. Other limitations include imprecise exposure assessment and inadequate adjustment for confounders. Methods: This study applied a quantitative job exposure matrix (SYN-JEM) for four established occupational lung carcinogens to five case-control studies within the International Head and Neck Cancer Epidemiology Consortium. We used occupational histories for 2256 laryngeal cancer cases and 7857 controls recruited from 1989 to 2007. We assigned quantitative exposure levels for asbestos, respirable crystalline silica, chromium-VI, and chromium-VI and nickel combined (to address highly correlated exposures) via SYN-JEM. We assessed effects of occupational exposure on cancer risk for males (asbestos, respirable crystalline silica, chromium-VI, and chromium-VI and nickel combined) and females (asbestos and respirable crystalline silica), adjusting for age, study, tobacco smoking, alcohol consumption, and asbestos exposure where relevant. Results: Among females, odds ratios (ORs) were increased for ever versus never exposed. Among males, P values for linear trend were 90th percentile cumulative exposure (OR = 1.3, 95% confidence interval [CI] = 1.0, 1.6), respirable crystalline silica at 30+ years duration (OR = 1.4, 95% CI = 1.2, 1.7) and 75th-90th percentile cumulative exposure (OR = 1.4, 95% CI = 1.1, 1.8), chromium-VI at >75th percentile cumulative exposure (OR = 1.9, 95% CI = 1.2, 3.0), and chromium-VI and nickel combined at 20-29 years duration (OR = 1.5, 95% CI = 1.1, 2.2). Conclusions: These findings support hypotheses of causal links between four lung carcinogens (asbestos, respirable crystalline silica, chromium-VI, and nickel) and laryngeal cancer.

With the aim to dissect the effect of adult height on head and neck cancer (HNC), we use the Mendelian randomization (MR) approach to test the association between genetic instruments for height and the risk of HNC. 599 single nucleotide polymorphisms (SNPs) were identified as genetic instruments for height, accounting for 16% of the phenotypic variation. Genetic data concerning HNC cases and controls were obtained from a genome-wide association study. Summary statistics for genetic association were used in complementary MR approaches: the weighted genetic risk score (GRS) and the inverse-variance weighted (IVW). MR-Egger regression was used for sensitivity analysis and pleiotropy evaluation. From the GRS analysis, one standard deviation (SD) higher height (6.9 cm; due to genetic predisposition across 599 SNPs) raised the risk for HNC (Odds ratio (OR), 1.14; 95% Confidence Interval (95%CI), 0.99–1.32). The association analyses with potential confounders revealed that the GRS was associated with tobacco smoking (OR = 0.80, 95% CI (0.69–0.93)). MR-Egger regression did not provide evidence of overall directional pleiotropy. Our study indicates that height is potentially associated with HNC risk. However, the reported risk could be underestimated since, at the genetic level, height emerged to be inversely associated with smoking.

Head and neck cancer (HNC) is a preventable malignancy that continues to cause substantial morbidity and mortality worldwide. Using data from the ARCAGE and Rome studies, we investigated the main predictors of survival after larynx, hypopharynx and oral cavity (OC) cancers. We used the Kaplan-Meier method to estimate overall survival, and Cox proportional models to examine the relationship between survival and sociodemographic and clinical characteristics. 604 larynx, 146 hypopharynx and 460 OC cancer cases were included in this study. Over a median follow-up time of 4.6 years, nearly 50% (n = 586) of patients died. Five-year survival was 65% for larynx, 55% for OC and 35% for hypopharynx cancers. In a multivariable analysis, we observed an increased mortality risk among older (≥71 years) versus younger (≤50 years) patients with larynx/hypopharynx combined (LH) and OC cancers [HR = 1.61, 95% CI 1.09-2.38 (LH) and HR = 2.12, 95% CI 1.35-3.33 (OC)], current versus never smokers [HR = 2.67, 95% CI 1.40-5.08 (LH) and HR = 2.16, 95% CI 1.32-3.54 (OC)] and advanced versus early stage disease at diagnosis [IV versus I, HR = 2.60, 95% CI 1.78-3.79 (LH) and HR = 3.17, 95% CI 2.05-4.89 (OC)]. Survival was not associated with sex, alcohol consumption, education, oral health, p16 expression, presence of HPV infection or body mass index 2 years before cancer diagnosis. Despite advances in diagnosis and therapeutic modalities, survival after HNC remains low in Europe. In addition to the recognized prognostic effect of stage at diagnosis, smoking history and older age at diagnosis are important prognostic indicators for HNC.

Vibrational spectroscopy, based on either infrared absorption or Raman scattering, has attracted increasing attention for biomedical applications. Proof of concept explorations for diagnosis of oral potentially malignant disorders and cancer are reviewed, and recent advances critically appraised. Specific examples of applications of Raman microspectroscopy for analysis of histological, cytological and saliva samples are presented for illustrative purposes, and the future prospects, ultimately for routine, chairside in vivo screening are discussed.

Objectives: \ud This study aimed at re-evaluating the strength and shape of the dose-response relationship between the combined (or joint) effect of intensity and duration of cigarette smoking and the risk of head and neck cancer (HNC). We explored this issue considering bivariate spline models, where smoking intensity and duration were treated as interacting continuous exposures.\ud \ud Materials and Methods: \ud We pooled individual-level data from 33 case-control studies (18,260 HNC cases and 29,844 controls) participating in the International Head and Neck Cancer Epidemiology (INHANCE) consortium. In bivariate regression spline models, exposures to cigarette smoking intensity and duration (compared with never smokers) were modeled as a linear piecewise function within a logistic regression also including potential confounders. We jointly estimated the optimal knot locations and regression parameters within the Bayesian framework.\ud \ud Results: \ud For oral-cavity/pharyngeal (OCP) cancers, an odds ratio (OR) >5 was reached after 30 years in current smokers of ∼20 or more cigarettes/day. Patterns of OCP cancer risk in current smokers differed across strata of alcohol intensity. For laryngeal cancer, ORs >20 were found for current smokers of ≥20 cigarettes/day for ≥30 years. In former smokers who quit ≥10 years ago, the ORs were approximately halved for OCP cancers, and ∼1/3 for laryngeal cancer, as compared to the same levels of intensity and duration in current smokers.\ud \ud Conclusion: \ud Referring to bivariate spline models, this study better quantified the joint effect of intensity and duration of cigarette smoking on HNC risk, further stressing the need of smoking cessation policies.

Introduction: \ud Oral Medicine focuses on care for patients with chronic, recurrent and medically related disorders of the orofacial region that are distinct from diseases of the periodontal and tooth tissues, with an emphasis on non‐surgical management. At present, there are no shared outcomes for Oral Medicine to define the standards to be achieved before new graduates become registered dentists engaged with ongoing professional development.\ud \ud Curriculum: \ud We present a consensus undergraduate curriculum in Oral Medicine agreed by representatives from 18 Dental Schools in the United Kingdom and Republic of Ireland. The scope of Oral Medicine practice includes conditions involving the oral mucosa, salivary glands, neurological system or musculoskeletal tissues that are not directly attributable to dental (tooth and periodontium) pathology. Account is taken of the priorities for practice and learning opportunities needed to support development of relevance to independent clinical practice. The outcomes triangulate with the requirements set out by the respective regulatory bodies in the UK and Republic of Ireland prior to first registration and are consistent with the framework for European undergraduate dental education and greater harmonisation of dental education.\ud \ud Conclusions: \ud This curriculum will act as a foundation for an increasingly shared approach between centres with respect to the outcomes to be achieved in Oral Medicine. The curriculum may also be of interest to others, such as those responsible for the training of dental hygienists and dental therapists. It provides a platform for future collective developments with the overarching goal of raising the quality of patient care.

Oral leukoplakia presents as a white patch on the oral mucosa and is recognized as having significant malignant potential. Although colonization of these patches with Candida albicans is common, little is known about the bacterial microbiota of these patches. In the current study we analyzed the microbiome of oral leukoplakia in 36 patients compared to healthy mucosal tissue from the same patients and healthy control subjects to determine if specific microbial enrichments could be identified early in the malignant process that could play a role in the progression of the disease. This was carried out by sequence analysis of the V1–V2 region of the bacterial 16S rRNA gene using the Illumina MiSeq. Oral leukoplakia exhibited increased abundance of Fusobacteria and reduced levels of Firmicutes (Metastats P < 0.01). Candida colonization was also more prevalent in leukoplakia patients relative to healthy controls (P = 0.025). Bacterial colonization patterns on oral leukoplakia were highly variable and five distinct bacterial clusters were discerned. These clusters exhibited co-occurrence of Fusobacterium, Leptotrichia, and Campylobacter species (Pearson P < 0.01), which is strikingly similar to the microbial co-occurrence patterns observed on colorectal cancers (Warren et al., 2013). Increased abundance of the acetaldehydogenic microorganism Rothia mucilaginosa was also apparent on oral leukoplakias from lingual sites (P 0.0012). Severe dysplasia was associated with elevated levels of Leptotrichia spp. and Campylobacter concisus (P < 0.05). Oral leukoplakia exhibits an altered microbiota that has similarities to the microbiome of colorectal cancer.

Objectives HPV16-positive oropharyngeal cancer (OPC) patients experience better outcomes compared to HPV16-negative patients. Currently, strategies for treatment de-escalation are based on HPV status, smoking history and disease stage. However, the appropriate cut-point for smoking and the role of other non-clinical factors in OPC survival remains uncertain. Materials and Methods We examined factors associated with OPC outcome in 321 patients recruited in a large European multi-center study. Seropositivity for HPV16 E6 was used as a marker of HPV16 positive cancer. Hazard ratios (HR) and confidence intervals (CI) were estimated using Cox proportional models adjusted for potential confounders. Results Overall 5-year survival following OPC diagnosis was 50%. HPV16-positive OPC cases were at significantly lower risk of death (aHR = 0.51, 95% CI: 0.32–0.80). A significant effect on OPC survival was apparent for female sex (aHR 0.50: 95% CI: 0.29–0.85) and being underweight at diagnosis (aHR: 2.41, 95% CI: 1.38–4.21). A 10 pack year smoking history was not associated with overall survival. Higher stage at diagnosis appeared as the only factor significantly associated with OPC recurrence (aHR: 4.88, 95% CI: 2.12–11.21). Conclusion This study confirms that HPV16 status is an independent prognostic factor for OPC survival while female sex lowers risk of death and being underweight at diagnosis increases the risk of death. Smoking was not an independent predictor of OPC survival.

The International Head and Neck Cancer Epidemiology (INHANCE) consortium is a collaboration of research groups leading large epidemiology studies to improve the understanding of the causes and mechanisms of head and neck cancer. The consortium includes investigators of 35 studies who have pooled their data on 25 500 patients with head and neck cancer (i.e., cancers of the oral cavity, oropharynx, hypopharynx, and larynx) and 37 100 controls. The INHANCE analyses have confirmed that tobacco use and alcohol intake are key risk factors of these diseases and have provided precise estimates of risk and dose response, the benefit of quitting, and the hazard of smoking even a few cigarettes per day. Other risk factors include short height, lean body mass, low education and income, and a family history of head and neck cancer. Risk factors are generally similar for oral cavity, pharynx, and larynx, although the magnitude of risk may vary. Some major strengths of pooling data across studies include more precise estimates of risk and the ability to control for potentially confounding factors and to examine factors that may interact with each other. The INHANCE consortium provides evidence of the scientific productivity and discoveries that can be obtained from data pooling projects. © 2015 John Wiley & Sons A/S.

Low socioeconomic status has been reported to be associated with head and neck cancer risk. However, previous studies have been too small to examine the associations by cancer subsite, age, sex, global region and calendar time and to explain the association in terms of behavioral risk factors. Individual participant data of 23,964 cases with head and neck cancer and 31,954 controls from 31 studies in 27 countries pooled with random effects models. Overall, low education was associated with an increased risk of head and neck cancer (OR = 2.50; 95% CI = 2.02 – 3.09). Overall one-third of the increased risk was not explained by differences in the distribution of cigarette smoking and alcohol behaviors; and it remained elevated among never users of tobacco and nondrinkers (OR = 1.61; 95% CI = 1.13 – 2.31). More of the estimated education effect was not explained by cigarette smoking and alcohol behaviors: in women than in men, in older than younger groups, in the oropharynx than in other sites, in South/Central America than in Europe/North America and was strongest in countries with greater income inequality. Similar findings were observed for the estimated effect of low versus high household income. The lowest levels of income and educational attainment were associated with more than 2-fold increased risk of head and neck cancer, which is not entirely explained by differences in the distributions of behavioral risk factors for these cancers and which varies across cancer sites, sexes, countries and country income inequality levels.

We conducted a genome-wide association study of oral cavity and pharyngeal cancer in 6,034 cases and 6,585 controls from Europe, North America and South America. We detected eight significantly associated loci (P < 5 × 10(-8)), seven of which are new for these cancer sites. Oral and pharyngeal cancers combined were associated with loci at 6p21.32 (rs3828805, HLA-DQB1), 10q26.13 (rs201982221, LHPP) and 11p15.4 (rs1453414, OR52N2-TRIM5). Oral cancer was associated with two new regions, 2p23.3 (rs6547741, GPN1) and 9q34.12 (rs928674, LAMC3), and with known cancer-related loci-9p21.3 (rs8181047, CDKN2B-AS1) and 5p15.33 (rs10462706, CLPTM1L). Oropharyngeal cancer associations were limited to the human leukocyte antigen (HLA) region, and classical HLA allele imputation showed a protective association with the class II haplotype HLA-DRB1*1301-HLA-DQA1*0103-HLA-DQB1*0603 (odds ratio (OR) = 0.59, P = 2.7 × 10(-9)). Stratified analyses on a subgroup of oropharyngeal cases with information available on human papillomavirus (HPV) status indicated that this association was considerably stronger in HPV-positive (OR = 0.23, P = 1.6 × 10(-6)) than in HPV-negative (OR = 0.75, P = 0.16) cancers. Genotyping performed at the Center for Inherited Disease Research (CIDR) was funded through the U.S. National Institute of Dental and Craniofacial Research (NIDCR) grant 1X01HG007780-0. Genotyping for shared controls with the Lung OncoArray initiative was funded through the grant X01HG007492-0. Corina Lesseur undertook this work during the tenure of a Postdoctoral Fellowship awarded by the International Agency for Research on Cancer. The funders did not participate in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. We acknowledge all of the participants involved in this research and the funders and support. We thank Dr. Leticia Fernandez (Instituto Nacional de Oncologia y Radiobiologia, La Habana, Cuba) for her contribution to the IARC ORC multicenter study. We are also grateful to Sergio Koifman (Escola Nacional de Saúde Pública, Rio de Janeiro, Brazil) for his contribution to the IARC Latin America multicenter study (Sergio Koifman passed away in May 2014) and to Xavier Castellsagué from the ARCAGE Barcelona Center who recently passed away (June 2016). The University of Pittsburgh head and neck cancer case-control study is supported by National Institutes of Health grants P50 CA097190 and P30 CA047904. The Carolina Head and Neck Cancer Study (CHANCE) was supported by the National Cancer Institute (R01-CA90731). The Head and Neck Genome Project (GENCAPO) was supported by the Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) (Grant numbers 04/12054-9 and 10/51168-0). The authors thank all the members of the GENCAPO team. The HN5000 study was funded by the National Institute for Health Research (NIHR) under its Programme Grants for Applied Research scheme (RP-PG-0707-10034), the views expressed in this publication are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. The Toronto study was funded by the Canadian Cancer Society Research Institute (020214) and the National Cancer Institute (U19 CA148127) and the Cancer Care Ontario Research Chair. The alcohol-related cancers and genetic susceptibility study in Europe (ARCAGE) was funded by the European Commission’s 5th Framework Program (QLK1-2001-00182), the Italian Association for Cancer Research, Compagnia di San Paolo/FIRMS, Region Piemonte, and Padova University (CPDA057222).The Rome Study was supported by the Associazione Italiana per la Ricerca sul Cancro (AIRC) IG 2011 10491 and IG2013 14220 to SB, and Fondazione Veronesi to SB. The IARC Latin American study was funded by the European Commission INCO-DC programme (IC18-CT97-0222), with additional funding from Fondo para la Investigacion Cientifica y Tecnologica (Argentina) and the Fundação de Amparo à Pesquisa do Estado de São Paulo (01/01768-2). The IARC Central Europe study was supported by European Commission’s INCO-COPERNICUS Program (IC15-CT98-0332), NIH/National Cancer Institute grant CA92039, and the World Cancer Research Foundation grant WCRF 99A28.The IARC Oral Cancer Multicenter study was funded by: grant S06 96 202489 05F02 from Europe against Cancer; Grants FIS 97/0024, FIS 97/0662, and BAE 01/5013 from Fondo de Investigaciones Sanitarias, Spain; UICC Yamagiwa-Yoshida Memorial International Cancer Study; National Cancer Institute of Canada; Italian Association for Research on Cancer; and the Pan American Health Organization. The coordination of EPIC study is financially supported

Circumorificial plasmacytosis is a rare plasma cell proliferative disorder of the orificial mucous membranes. The etiology is unknown, and there are no reported effective treatments to date. We report three cases of idiopathic circumorificial plasmacytosis with varying clinical presentations and responses to treatment, including a first reported case of resolution with adalimumab therapy.

BACKGROUND: Although smoking and HPV infection are recognized as important risk factors for oropharyngeal cancer, how their joint exposure impacts on oropharyngeal cancer risk is unclear. Specifically, whether smoking confers any additional risk to HPV-positive oropharyngeal cancer is not understood.METHODS: Using HPV serology as a marker of HPV-related cancer, we examined the interaction between smoking and HPV16 in 459 oropharyngeal (and 1445 oral cavity and laryngeal) cancer patients and 3024 control participants from two large European multi-centre studies. Odds ratios and credible intervals [CrI], adjusted for potential confounders, were estimated using Bayesian logistic regression.RESULTS: Both smoking [odds ratio (OR [CrI]: 6.82 [4.52, 10.29]) and HPV seropositivity (OR [CrI]: 235.69 [99.95, 555.74]) were independently associated with oropharyngeal cancer. The joint association of smoking and HPV seropositivity was consistent with that expected on the additive scale (synergy index [CrI]: 1.32 [0.51, 3.45]), suggesting they act as independent risk factors for oropharyngeal cancer.CONCLUSIONS: Smoking was consistently associated with increase in oropharyngeal cancer risk in models stratified by HPV16 seropositivity. In addition, we report that the prevalence of oropharyngeal cancer increases with smoking for both HPV16-positive and HPV16-negative persons. The impact of smoking on HPV16-positive oropharyngeal cancer highlights the continued need for smoking cessation programmes for primary prevention of head and neck cancer.

Oral Diseases (2011) 17, 696–704 Objectives: Orofacial granulomatosis has mostly been described in reports of very small numbers of cases. Few large case groups have been described. The aim of this study was to describe the demographics, symptoms, clinical features and laboratory findings in a large cohort of cases. Subjects and Methods: Clinical and laboratory data for 119 cases of orofacial granulomatosis who attended oral medicine clinics in Dublin, Ireland, were examined for demographic characteristics at the time of first presentation. The male/female ratio was approximately 1:1, with a median age (and range) of 28 (5–84) years. Results: Symptoms had been present for a median duration of 12 weeks. A food association was suspected by 30% of patients. The predominant complaint was lip swelling (77%) with only 15% reporting facial swelling, while 8% complained of both. Almost all patients had clinical evidence of lip or facial swelling (95%). Other common extra-oral manifestations were lip fissuring (30%), angular cheilitis (28%) and perioral erythema (28%). Common intra-oral manifestations were cobblestoning of the buccal mucosa (63%), ulcers (36%), granulomatous gingivitis (33%), mucosal tags (29%) and fissured tongue (17%). Over half of the biopsies (56%) performed were reported as typical of orofacial granulomatosis. Conclusion: This is one of the largest cohorts of orofacial granulomatosis patients to have been described in detail.

The technical aspects of dentistry need to be practised with insight into the spectrum of human diseases and illnesses and how these impact upon individuals and society. Application of this insight is critical to decision-making related to the planning and delivery of safe and appropriate patient-centred healthcare tailored to the needs of the individual. Provision for the necessary training is included in undergraduate programmes, but in the United Kingdom and Ireland there is considerable variation between centres without common outcomes. In 2009 representatives from 17 undergraduate dental schools in the United Kingdom and Ireland agreed to move towards a common, shared approach to meet their own immediate needs and that might also be of value to others in keeping with the Bologna Process. To provide a clear identity the term 'Clinical Medical Sciences in Dentistry' was agreed in preference to other names such as 'Human Disease' or 'Medicine and Surgery'. The group was challenged to define consensus outcomes. Contemporary dental education documents informed, but did not drive the process. The consensus curriculum for undergraduate Clinical Medical Sciences in Dentistry teaching agreed by the participating centres is reported. Many of the issues are generic and it includes elements that are likely to be applicable to others. This document will act as a focus for a more unified approach to the outcomes required by graduates of the participating centres and act as a catalyst for future developments that ultimately aim to enhance the quality of patient care.

J Oral Pathol Med (2011) 40: 10–13 Background: Food-associated allergies, especially to benzoates and cinnamon-related compounds, have been associated with orofacial granulomatosis and both standard and urticarial patch testing have been used to detect such allergies. Elimination diets have also been shown to be effective in some patients. Objectives: To compare the results of standard and urticarial patch testing in a cohort of patients with orofacial granulomatosis. Materials and methods: Records of 120 cases seen in two hospitals were retrieved and examined for patch test details. Results: Standard patch testing was much less likely to detect allergy to benzoates and cinnamon compounds (7%) than urticarial tests (55%). All urticarial tests that were positive had shown a reaction by 60 min. Conclusions: Both standard and urticarial patch tests are required to detect food allergies in orofacial granulomatosis. The difficulties of patient self-recording of urticarial tests can be eliminated by retaining patients in the testing unit for professional reading of patches at 60 min.

The incidence of cancers of the upper aerodigestive tract (UADT) is increasing throughout the world. To date the increases have been proportionally greatest among young people. Several reports have suggested that they often do not have a history of tobacco smoking or heavy alcohol consumption. Objectives were to determine the contribution of lifestyle factors to the etiology of UADT cancers occurring in those aged less than 50 years. A case-control study was conducted in 10 European countries. Cases were cancers of the oral cavity and pharynx, larynx and esophagus, and hospital or population controls were age and sex matched. RESULTS: There were 356 cases younger than 50 years and 419 controls. Risk was strongly related to current smoking [odds ratio (OR) 5.5 95% ; confidence interval (CI) (3.3, 9.2)], and risk increased with number of pack-years smoked. Risk was also related to alcohol consumption for both current (OR 1.8 ; 0.97, 3.3) and past (OR 3.4 ; 1.6, 7.4) drinkers, and risk increased with number of drink-years. Persons frequently consuming fruits and vegetables were at significantly reduced risk. Risk factors already identified as being important for UADT cancers in adults are also important influences on risk in younger adults. The implication of these results is that the public health message in preventing UADT cancers remains the same to young and old alike.

Cancers of the upper aerodigestive tract (UADT) include those of the oral cavity, pharynx (other than nasopharynx), larynx, and esophagus. Tobacco smoking and consumption of alcoholic beverages are established causes of UADT cancers, whereas reduced intake of vegetables and fruits are likely causes. The role of genetic predisposition and possible interactions of genetic with exogenous factors, however, have not been adequately studied. Moreover, the role of pattern of smoking and drinking, as well as the exact nature of the implicated dietary variables, has not been clarified. To address these issues, the International Agency for Research on Cancer initiated in 2002 the alcohol-related cancers and genetic susceptibility (ARCAGE) in Europe project, with the participation of 15 centers in 11 European countries. Information and biological data from a total of 2304 cases and 2227 controls have been collected and will be used in a series of analyses. A total of 166 single nucleotide polymorphisms of 76 genes are being studied for genetic associations with UADT cancers. We report here the methodology of the ARCAGE project, main demographic and lifestyle characteristics of the cases and controls, as well as the distribution of cases by histology and subsite. About 80% of cases were males and fewer than 20% of all cases occurred before the age of 50 years. Overall, the most common subsite was larynx, followed by oral cavity, oropharynx, esophagus and hypopharynx. Close to 90% of UADT cancers were squamous cell carcinomas. A clear preponderance of smokers and alcohol drinkers among UADT cases compared with controls was observed.

OBJECTIVE: To examine all studies reporting prevalences of oral lichen planus (OLP) for epidemiological validity and to extract prevalence data from the valid papers. DESIGN: Computer based literature searches were carried out using the MeSH headings 'lichen planus, oral and (prevalence or incidence)' and were supplemented by manual searching. MAIN OUTCOME MEASURES: Each paper was examined for five criteria: clinic-based or population study, adequate demographic description (by sex and age group) of the population, adequate demographic description of the sample (if the population was sampled), adequate demographic description of the OLP cases identified, and histological confirmation of the clinical diagnosis. RESULTS: Forty-five relevant papers were identified, 21 clinic-based and 24 population studies. All but one of the population studies was deficient. One study, while having some defects, was probably sufficiently valid to permit the findings to be regarded as useful. An overall age-standardized prevalence of 1.27% (0.96% in men and 1.57% in women) can be calculated from this study. CONCLUSIONS: There appears to be only one usable prevalence study of OLP. Other large-scale studies are required in other populations. Such studies need to distinguish between OLP and lichenoid reactions.

Adhesion molecules are known to play a crucial role in the recruitment of inflammatory cells to sites of inflammation. In this study endothelial cell and keratinocyte adhesion molecule expression in recurrent oral ulcers (ROU) (n = 13) was compared with that found in normal oral mucosa (NOM) (n = 11) and experimentally induced ulcers (EIU) (n = 5) by using immunohistochemistry. Significantly greater expression of both vascular cell adhesion molecule- (VCAM-1) and E-selectin was demonstrated on vasculature in ROU compared with that found in both NOM and EIU. Induction of keratinocyte intercellular adhesion molecule-1 (ICAM-1) was also a prominent feature of ROU. The expression of VCAM-1 and E-selectin on blood vessels in ROU is likely to be important in the accumulation of lymphocytes that characterise early aphthous lesions. The induction of keratinocyte ICAM-1 may facilitate lymphocyte invasion of the epithelium in ROU, which may ultimately result in ulcer formation.

The current Ebola outbreak in West Africa is a global health emergency with implications for all healthcare professionals. This article will review the clinical features, transmission and oral manifestations of Ebola virus infection, and discuss the implications of the current outbreak for dental practices in Ireland. Guidance for managing suspected cases and contacts is also provided.Although Ebola is an alarming disease with a very high mortality rate, it is extremely unlikely that the dental team will encounter a new presentation of Ebola or that it will pose a significant transmission risk. The dental team should be aware of the Health Protection Surveillance Centre (HPSC) Algorithm for Ebola Virus Disease Risk Assessment, and it should be followed as necessary. It is advised to defer dental treatment for 21 days after possible exposure to the Ebola virus.

Background The benefit of patch testing patients with oral lichenoid lesions (OLL) is still debated. Objective We assessed the results of patch testing in patients with multiple amalgams and multiple OLL, where the etiology of the oral mucosal disease was unclear. Methods Patients referred from an oral medicine clinic were patch tested to the British Society of Cutaneous Allergy standard series, dental and materials series, and, in 1 patient, the dental methacrylate series also. Patients' responses to amalgam removal were assessed during a mean follow-up of 2.6 (range, 0-4.75) years. Results Thirty-one patients with OLL were referred for patch testing. Ten (32%) patients tested positively to mercury. Eight patients with positive reactions to mercury had amalgam removal, with complete or partial resolution of the OLL in all cases (100%). Conclusions Patients with OLL of unclear etiology adjacent to large amalgam restorations should be investigated for delayed contact hypersensitivity. Removal of amalgams in patients with positive patch test reactions to mercury results in improvement or resolution of the OLL in most patients.

Background: The increasing incidence of oropharyngeal cancer in many developed countries has been attributed to human papillomavirus type 16 (HPV16) infections. Recently, HPV16 E6 serology has been identified as a promising early marker for oropharyngeal cancer. Therefore, characterization of HPV16 E6 seropositivity among individuals without cancer is warranted. Methods: A total of 4,666 controls were pooled from several studies of cancer and HPV seropositivity, all tested within the same laboratory. HPV16 E6 seropositive controls were classified as having (i) moderate [mean fluorescent intensity (MFI) ≥ 484 and Results: Thirty-two (0.7%) HPV16 E6 seropositive controls were identified; 17 (0.4%) with moderate and 15 (0.3%) with high seroreactivity. High HPV16 E6 seroreactivity was associated with former smoking [odds ratio (OR), 5.5; 95% confidence interval (CI), 1.2–51.8], and seropositivity against HPV16 L1 (OR, 4.8; 95% CI, 1.3–15.4); E2 (OR, 7.7; 95% CI, 1.4–29.1); multiple HPV16 proteins (OR, 25.3; 95% CI, 2.6–119.6 for three HPV16 proteins beside E6) and HPV33 E6 (OR, 17.7; 95% CI, 1.9–81.8). No associations were observed with moderate HPV16 E6 seroreactivity. Conclusions: High HPV16 E6 seroreactivity is rare among individuals without diagnosed cancer and was not explained by demographic factors. Impact: Some HPV16 E6 seropositive individuals without diagnosed HPV-driven cancer, especially those with seropositivity against other HPV16 proteins, may harbor a biologically relevant HPV16 infection. Cancer Epidemiol Biomarkers Prev; 24(4); 683–9. ©2015 AACR.