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SUMMARY Sentinel node (SN) biopsy of head and neck cancer is still considered investigational, and agreement on the width of the surgical sampling has not yet been reached. From May 1999 to Dec 2009, 209 consecutive patients entered a prospective study: 61.7% had primary tumour of the oral cavity and 23.9% of the oropharynx. SN was not found in 26 patients. Based on these data and definitive histopathological analysis, we proposed six hypothetic scenarios to understand the percentage of neck recurrences following different treatments Among patients with identified SN, 54 cases were pN+: 47 in SN and 7 in a different node. Considering the six hypothetic scenarios: "only SN removal", "SN level dissection", "neck dissection from the tumour site to SN level", "selective neck dissection of three levels (SND)", "dissection from level I to IV" and "comprehensive I-V dissection", neck recurrences could be expected in 6.5%, 3.8%, 2.18%, 2.73%, 1.09% and 1.09% of cases, respectively. SN biopsy can be considered a useful tool to personalize the surgical approach to a N0 carcinoma. The minimum treatment of the neck is probably dissection of the levels between the primary tumour and the level containing the SN(s). Outside the framework of a clinical study, the best treatment can still be considered SND.

Scanty data are available on familial risk in oral and pharyngeal cancer. The relationship between oral and pharyngeal cancer and family history of cancer in first-degree relatives was investigated using data from a multicentric case-control study conducted in Italy and Switzerland between 1992 and 2005 on 956 cases aged less than 79 years, with histologically confirmed incident oral and pharyngeal cancer, and 2362 controls admitted to hospital for acute, nonneoplastic conditions. Logistic regression models conditioned on sex, age, study centre, and including terms for education, tobacco smoking, alcohol drinking, and number of siblings were used to estimate the odds ratios (OR) of oral and pharyngeal cancer. The multivariate ORs were similar for a family history of oral and pharyngeal cancer (2.6, 95% confidence interval, CI, 1.5-4.5) and laryngeal cancer (3.8, 95% CI, 2.0-7.2). The OR was 3.1 (95% CI, 2.0-4.8) for oral and pharyngeal cancer and laryngeal cancer combined. The OR was 7.1 (95% CI, 1.3-37.2) for subjects with 2 or more first-degree relatives with oral and pharyngeal/laryngeal cancers. Significant increases in risk were also observed for a family history of melanoma (OR = 5.8; 95% CI, 1.3-26.4) and lung cancer (OR = 1.4; 95% CI, 1.0-2.0). Compared to subjects without family history, nonsmokers, and non or moderate drinkers, the OR was 42.6 for current smokers, heavy drinkers with family history. History of oral and pharyngeal cancer and laryngeal cancer is a strong determinant of oral and pharyngeal cancer risk, independent from tobacco and alcohol. (c) 2007 Wiley-Liss, Inc.

Objective: To provide information on the effects of alcohol and tobacco on laryngeal cancer and its subsites. Methods: This was a case-control study conducted between 1992 and 2000 in northern Italy and Switzerland. A total of 527 cases of incident squamous-cell carcinoma of the larynx and 1297 hospital controls frequency-matched with cases on age, sex, and area of residence were included. Odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were estimated using multiple logistic regression. Results: In comparison with never smokers, ORs were 19.8 for current smokers and 7.0 for ex-smokers. The risk increased in relation to the number of cigarettes (OR = 42.9 for greater than or equal to25 cigarettes/day) and for duration of smoking (OR = 37.2 for greater than or equal to40 years). For alcohol, the risk increased in relation to number of drinks (OR = 5.9 for greater than or equal to56 drinks per week). Combined alcohol and tobacco consumption showed a multiplicative (OR = 177) rather than an additive risk. For current smokers and current drinkers the risk was higher for supraglottis (ORs 54.9 and 2.6, respectively) than for glottis (ORs 7.4 and 1.8) and others subsites (ORs 10.9 and 1.9). Conclusions: Our study shows that both cigarette smoking and alcohol drinking are independent risk factors for laryngeal cancer. Heavy consumption of alcohol and cigarettes determined a multiplicative risk increase, possibly suggesting biological synergy.

Recent results indicate that genome-wide association studies (GWAS) have the potential to explain much of the heritability of common complex phenotypes, but methods are lacking to reliably identify the remaining associated single nucleotide polymorphisms (SNPs). We applied stratified False Discovery Rate (sFDR) methods to leverage genic enrichment in GWAS summary statistics data to uncover new loci likely to replicate in independent samples. Specifically, we use linkage disequilibrium-weighted annotations for each SNP in combination with nominal p-values to estimate the True Discovery Rate (TDR = 1−FDR) for strata determined by different genic categories. We show a consistent pattern of enrichment of polygenic effects in specific annotation categories across diverse phenotypes, with the greatest enrichment for SNPs tagging regulatory and coding genic elements, little enrichment in introns, and negative enrichment for intergenic SNPs. Stratified enrichment directly leads to increased TDR for a given p-value, mirrored by increased replication rates in independent samples. We show this in independent Crohn's disease GWAS, where we find a hundredfold variation in replication rate across genic categories. Applying a well-established sFDR methodology we demonstrate the utility of stratification for improving power of GWAS in complex phenotypes, with increased rejection rates from 20% in height to 300% in schizophrenia with traditional FDR and sFDR both fixed at 0.05. Our analyses demonstrate an inherent stratification among GWAS SNPs with important conceptual implications that can be leveraged by statistical methods to improve the discovery of loci., Author Summary Modern genome-wide association studies (GWAS) have failed to identify large portions of the genetic basis of common, complex traits. Recent work suggested this could be because many genetic variants, each with individually small effects, compose their genetic architecture, limiting the power of GWAS. Moreover, these variants appear more abundantly in and near genes. Using genome annotations, summary statistics from several of the largest GWAS, and established statistical methods for quantifying distributions of test statistics, we show a consistency across studies. Namely, we show that, across all assessed traits, the test statistics resulting from SNPs that are related to the 5′ UTR of genes show the largest abundance of associations, while SNPs related to exons and the 3′UTR are also enriched. SNPs related to introns are only moderately enriched, and intergenic SNPs show a depletion of associations relative to the average SNP. This enrichment corresponds directly to increased replication across independent samples and can be incorporated a priori into statistical methods to improve discovery and prediction. Our results contribute to on-going debates about the functional nature of the genetic architecture of complex traits and point to avenues for leveraging existing GWAS data for discovery in future GWA and sequencing studies.

Background: Genome-wide association studies (GWAS) require large sample sizes to obtain adequate statistical power, but\ud it may be possible to increase the power by incorporating complementary data. In this study we investigated the feasibility\ud of automatically retrieving information from the medical literature and leveraging this information in GWAS.\ud Methods: We developed a method that searches through PubMed abstracts for pre-assigned keywords and key concepts,\ud and uses this information to assign prior probabilities of association for each single nucleotide polymorphism (SNP) with the\ud phenotype of interest - the Adjusting Association Priors with Text (AdAPT) method. Association results from a GWAS can\ud subsequently be ranked in the context of these priors using the Bayes False Discovery Probability (BFDP) framework. We\ud initially tested AdAPT by comparing rankings of known susceptibility alleles in a previous lung cancer GWAS, and\ud subsequently applied it in a two-phase GWAS of oral cancer.\ud Results: Known lung cancer susceptibility SNPs were consistently ranked higher by AdAPT BFDPs than by p-values. In the\ud oral cancer GWAS, we sought to replicate the top five SNPs as ranked by AdAPT BFDPs, of which rs991316, located in the\ud ADH gene region of 4q23, displayed a statistically significant association with oral cancer risk in the replication phase (perrare-allele\ud log additive p-value [ptrend] = 2.561023\ud ). The combined OR for having one additional rare allele was 0.83 (95% CI:\ud 0.76–0.90), and this association was independent of previously identified susceptibility SNPs that are associated with overall\ud UADT cancer in this gene region. We also investigated if rs991316 was associated with other cancers of the upper\ud aerodigestive tract (UADT), but no additional association signal was found.\ud Conclusion: This study highlights the potential utility of systematically incorporating prior knowledge from the medical\ud literature in genome-wide analyses using the AdAPT methodology. AdAPT is available online (url: http://services.gate.ac.uk/\ud lld/gwas/service/config).

We investigated the association between occupational history and upper aerodigestive tract (UADT) cancer risk in the ARCAGE European case-control study. The study included 1,851 patients with incident cancer of the oral cavity, oropharynx, hypopharynx, larynx or esophagus and 1,949 controls. We estimated odds ratios (OR) and 95% confidence intervals (CI) for ever employment in 283 occupations and 172 industries, adjusting for smoking and alcohol. Men (1,457 cases) and women (394 cases) were analyzed separately and we incorporated a semi-Bayes adjustment approach for multiple comparisons. Among men, we found increased risks for occupational categories previously reported to be associated with at least one type of UADT cancer, including painters (OR = 1.74, 95% CI: 1.01-3.00), bricklayers (1.58, 1.05-2.37), workers employed in the erection of roofs and frames (2.62, 1.08-6.36), reinforced concreters (3.46, 1.11-10.8), dockers (2.91, 1.05-8.05) and workers employed in the construction of roads (3.03, 1.23-7.46), general construction of buildings (1.44, 1.12-1.85) and cargo handling (2.60, 1.17-5.75). With the exception of the first three categories, risks both increased when restricting to long duration of employment and remained elevated after semi-Bayes adjustment. Increased risks were also found for loggers (3.56, 1.20-10.5) and cattle and dairy farming (3.60, 1.15-11.2). Among women, there was no clear evidence of increased risks of UADT cancer in association with occupations or industrial activities. This study provides evidence of an association between some occupational categories and UADT cancer risk among men. The most consistent findings, also supported by previous studies, were obtained for specific workers employed in the construction industry. © 2011 UICC.

Background: The study aimed to investigate the role of medical history (skin warts, Candida albicans, herpetic lesions, heartburn, regurgitation) and medication use (for heartburn; for regurgitation; aspirin) in the aetiology of upper aerodigestive tract (UADT) cancer. Methods: A multicentre (10 European countries) case-control study [Alcohol-Related CAncers and GEnetic susceptibility (ARCAGE) project]. Results: There were 1779 cases of UADT cancer and 1993 controls. History of warts or C. albicans infection was associated with a reduced risk [odds ratio (OR) 0.80, 95% confidence interval (CI) 0.68-0.94 and OR 0.73, 95% CI 0.60-0.89, respectively] but there was no association with herpetic lesions, heartburn, regurgitation or medication for related symptoms. Regurgitation was associated with an increased risk for cancer of the oesophagus (OR 1.47, 95% CI 0.98-2.21). Regular aspirin use was not associated with risk of UADT cancer overall but was associated with a reduced risk for cancer of oesophagus (OR 0.51, 95% CI 0.28-0.96), hypopharynx (OR 0.53, 95% CI 0.28-1.02) and larynx (OR 0.74, 95% CI 0.54-1.01). Conclusions: A history of some infections appears to be a marker for decreased risk of UADT cancer. The role of medical history and medication use varied by UADT subsites with aspirin use associated with a decreased risk of oesophageal cancer and suggestive of a decreased risk of hypopharyngeal and laryngeal cancers.

Genome-wide association studies (GWAS) have been successful in identifying common genetic variation involved in susceptibility to etiologically complex disease. We conducted a GWAS to identify common genetic variation involved in susceptibility to upper aero-digestive tract (UADT) cancers. Genome-wide genotyping was carried out using the Illumina HumanHap300 beadchips in 2,091 UADT cancer cases and 3,513 controls from two large European multi-centre UADT cancer studies, as well as 4,821 generic controls. The 19 top-ranked variants were investigated further in an additional 6,514 UADT cancer cases and 7,892 controls of European descent from an additional 13 UADT cancer studies participating in the INHANCE consortium. Five common variants presented evidence for significant association in the combined analysis (p≤5×10−7). Two novel variants were identified, a 4q21 variant (rs1494961, p = 1×10−8) located near DNA repair related genes HEL308 and FAM175A (or Abraxas) and a 12q24 variant (rs4767364, p = 2×10−8) located in an extended linkage disequilibrium region that contains multiple genes including the aldehyde dehydrogenase 2 (ALDH2) gene. Three remaining variants are located in the ADH gene cluster and were identified previously in a candidate gene study involving some of these samples. The association between these three variants and UADT cancers was independently replicated in 5,092 UADT cancer cases and 6,794 controls non-overlapping samples presented here (rs1573496-ADH7, p = 5×10−8; rs1229984-ADH1B, p = 7×10−9; and rs698-ADH1C, p = 0.02). These results implicate two variants at 4q21 and 12q24 and further highlight three ADH variants in UADT cancer susceptibility.

Genome-wide association studies (GWAS) have been successful in identifying common genetic variation involved in susceptibility to etiologically complex disease. We conducted a GWAS to identify common genetic variation involved in susceptibility to upper aero-digestive tract (UADT) cancers. Genome-wide genotyping was carried out using the Illumina HumanHap300 beadchips in 2,091 UADT cancer cases and 3,513 controls from two large European multi-centre UADT cancer studies, as well as 4,821 generic controls. The 19 top-ranked variants were investigated further in an additional 6,514 UADT cancer cases and 7,892 controls of European descent from an additional 13 UADT cancer studies participating in the INHANCE consortium. Five common variants presented evidence for significant association in the combined analysis (p

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 (P het) = 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; P het = 6 × 10-4). There was little evidence for a sex difference 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.©2011 AACR.

Introduction: In the European Union, there are 180,000 new cases of upper aerodigestive tract (UADT) cancer cases per year - more than half of whom will die of the disease. Socioeconomic inequalities in UADT cancer incidence are recognised across Europe. We aimed to assess the components of socioeconomic risk both independently and through their influence on the known behavioural risk factors of smoking, alcohol consumption and diet. Patients and methods: A multicentre case-control study with 2198 cases of UADT cancer and 2141 controls from hospital and population sources was undertaken involving 14 centres from 10 countries. Personal interviews collected information on demographics, lifetime occupation history, smoking, alcohol consumption and diet. Socioeconomic status was measured by education, occupational social class and Unemployment. Odds ratios (ORs) and 95% confidence intervals (CIs) were computed using Unconditional logistic regression. Results: When controlling for age, sex and centre significantly increased risks for UADT cancer were observed for those with low versus high educational attainment OR = 1.98 (95% CI 1.67, 2.36). Similarly, for occupational socioeconomic indicators - comparing the lowest versus highest International Socio-Economic index (ISEI) quartile for the longest occupation gave OR = 1.60 (1.28, 2.00); and for unemployment OR = 1.64 (1.24, 2.17). Statistical significance remained for low education when adjusting for smoking, alcohol and diet behaviours OR = 1.29 (1.06, 1.57) in the multivariate analysis. Inequalities were observed only among men but not among women and were greater among those in the British Isles and Eastern European countries than in Southern and Central/Northern European countries, Associations were broadly consistent for subsite and source of controls (hospital and community). Conclusion: Socioeconomic inequalities for UADT cancers are only observed among men and are not totally explained by smoking, alcohol drinking and diet. (C) 2009 Elsevier Ltd. All rights reserved.

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. European Journal of Cancer Prevention 18:76-84 © 2009 Wolters Kluwer Health.

The aim of this prospective, randomized, double-blind study was to compare the efficacy of parecoxibfor postoperative analgesia after endoscopic turbinate and sinus surgery, with the non-selective non-steroid anti-inflammatory drug (NSAID), ketorolac.A total of 50 patients with an ASA physical status I-II, receiving functional endoscopic sinus surgery (FESS) and endoscopic turbinectomy after local infiltration with 1% mepivacaine, were randomly assigned to receive intravenous administration of either 40 mg parecoxib (N.=25) or 30 mg ketorolac (N.=25), 15 min before the discontinuation of anaesthesia and then every 8 h postoperatively. A blinded observer recorded the incidence and severity of pain upon admission to the postanesthesia care unit (PACU), as well as 10, 20, and 30 min after PACU admission. Thereafter, observations continued every 1 h for the first 6 h, and then 12 h and 24 h after surgery.The area under the curve of the visual analogue scale (AUCVAS) calculated during the study period was 635 (26-1 413) in the Parecoxib group and 669 (28-1 901) in the Ketorolac group (P=0.54). Rescue morphine analgesia was required by 12 patients (48%) in the Parecoxib group and 11 patients (44%) in the Ketorolac group (P0.05); while mean morphine consumption was 5 +/- 2.5 mg and 5 +/- 2.0 mg in Ketorolac and Parecoxib groups, respectively (P0.05). No differences in the incidence of side effects were recorded between the two groups. Patient satisfaction was similarly high in both groups, and all patients were discharged uneventfully 24 h after surgery.In patients undergoing endoscopic nasal surgery and local infiltration with 1% mepivacaine, parecoxib administered before discontinuing general anesthesia is as effective in treating early postoperative pain as ketorolac.

Alcohol is an important risk factor for upper aerodigestive cancers and is principally metabolized by alcohol dehydrogenase (ADH) enzymes. We have investigated six ADH genetic variants in over 3, 800 aerodigestive cancer cases and 5, 200 controls from three individual studies. Gene variants rs1229984 (ADH1B) and rs1573496 (ADH7) were significantly protective against aerodigestive cancer in each individual study and overall (P = 10(-10) and 10(-9), respectively). These effects became more apparent with increasing alcohol consumption (P for trend = 0.0002 and 0.065, respectively). Both gene effects were independent of each other, implying that multiple ADH genes may be involved in upper aerodigestive cancer etiology.