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High dietary glycaemic index (GI) and glycaemic load (GL) may increase cancer risk. However, limited information was available on GI and/or GL and head and neck cancer (HNC) risk. We conducted a pooled analysis on 8 case-control studies (4081 HNC cases; 7407 controls) from the International Head and Neck Cancer Epidemiology (INHANCE) consortium. We estimated the odds ratios (ORs) and 95% confidence intervals (CIs) of HNC, and its subsites, from fixed- or mixed-effects logistic models including centre-specific quartiles of GI or GL. GI, but not GL, had a weak positive association with HNC (ORQ4 vs. Q1 = 1.16; 95% CI = 1.02–1.31). In subsites, we found a positive association between GI and laryngeal cancer (ORQ4 vs. Q1 = 1.60; 95% CI = 1.30–1.96) and an inverse association between GL and oropharyngeal cancer (ORQ4 vs. Q1 = 0.78; 95% CI = 0.63–0.97). This pooled analysis indicates a modest positive association between GI and HNC, mainly driven by laryngeal cancer.

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.

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.

There have been few published studies on differences between Blacks and Whites in the estimated effects of alcohol and tobacco use on the incidence of head and neck cancer (HNC) in the United States. Previous studies have been limited by small numbers of Blacks. Using pooled data from 13 US case–control studies of oral, pharyngeal, and laryngeal cancers in the International Head and Neck Cancer Epidemiology Consortium, this study comprised a large number of Black HNC cases (n = 975). Logistic regression was used to estimate adjusted odds ratios (OR) and 95% confidence intervals (CI) for several tobacco and alcohol consumption characteristics. Blacks were found to have consistently stronger associations than Whites for the majority of tobacco consumption variables. For example, compared to never smokers, Blacks who smoked cigarettes for > 30 years had an OR 4.53 (95% CI 3.22–6.39), which was larger than that observed in Whites (OR 3.01, 95% CI 2.73–3.33; pinteraction < 0.0001). The ORs for alcohol use were also larger among Blacks compared to Whites. Exclusion of oropharyngeal cases attenuated the racial differences in tobacco use associations but not alcohol use associations. These findings suggest modest racial differences exist in the association of HNC risk with tobacco and alcohol consumption. © 2018, Springer International Publishing AG, part of Springer Nature.

Previous studies on smokeless tobacco use and head and neck cancer (HNC) have found inconsistent and often imprecise estimates, with limited control for cigarette smoking. Using pooled data from 11 US case-control studies (1981-2006) of oral, pharyngeal, and laryngeal cancers (6,772 cases and 8,375 controls) in the International Head and Neck Cancer Epidemiology (INHANCE) Consortium, we applied hierarchical logistic regression to estimate odds ratios and 95% confidence intervals for ever use, frequency of use, and duration of use of snuff and chewing tobacco separately for never and ever cigarette smokers. Ever use (versus never use) of snuff was strongly associated with HNC among never cigarette smokers (odds ratio (OR) = 1.71, 95% confidence interval (CI): 1.08, 2.70), particularly for oral cavity cancers (OR = 3.01, 95% CI: 1.63, 5.55). Although ever (versus never) tobacco chewing was weakly associated with HNC among never cigarette smokers (OR = 1.20, 95% CI: 0.81, 1.77), analyses restricted to cancers of the oral cavity showed a stronger association (OR = 1.81, 95% CI: 1.04, 3.17). Few or no associations between each type of smokeless tobacco and HNC were observed among ever cigarette smokers, possibly reflecting residual confounding by smoking. Smokeless tobacco use appears to be associated with HNC, especially oral cancers, with snuff being more strongly associated than chewing tobacco. © 2016 The Author.

Toporcov, Tatiana Natasha Znaor, Ariana Zhang, Zuo-Feng Yu, Guo-Pei Winn, Deborah M Wei, Qingyi Vilensky, Marta Vaughan, Thomas Thomson, Peter Talamini, Renato Szeszenia-Dabrowska, Neonila Sturgis, Erich M Smith, Elaine Shangina, Oxana Schwartz, Stephen M Schantz, Stimson Rudnai, Peter Richiardi, Lorenzo Ramroth, Heribert Purdue, Mark P Olshan, Andrew F Eluf-Neto, Jose Muscat, Joshua Moyses, Raquel Ajub Morgenstern, Hal Menezes, Ana McClean, Michael Matsuo, Keitaro Mates, Dana Macfarlane, Tatiana V Lissowska, Jolanta Levi, Fabio Lazarus, Philip La Vecchia, Carlo Lagiou, Pagona Koifman, Sergio Kjaerheim, Kristina Kelsey, Karl Holcatova, Ivana Herrero, Rolando Healy, Claire Hayes, Richard B Franceschi, Silvia Fernandez, Leticia Fabianova, Eleonora Daudt, Alexander W Curioni, Otavio Alberto Maso, Luigino Dal Curado, Maria Paula Conway, David I Chen, Chu Castellsague, Xavier Canova, Cristina Cadoni, Gabriella Brennan, Paul Boccia, Stefania Antunes, Jose Leopoldo Ferreira Ahrens, Wolfgang Agudo, Antonio Boffetta, Paolo Hashibe, Mia Lee, Yuan-Chin Amy Filho, Victor Wunsch eng FIRCA TW01500/TW/FIC NIH HHS/ K07CA104231/CA/NCI NIH HHS/ P01CA068384/CA/NCI NIH HHS/ P30ES010126/ES/NIEHS NIH HHS/ P50CA90388/CA/NCI NIH HHS/ R01CA048996/CA/NCI NIH HHS/ R01CA100264/CA/NCI NIH HHS/ R01CA30022/CA/NCI NIH HHS/ R01CA51845/CA/NCI NIH HHS/ R01CA61188/CA/NCI NIH HHS/ R01DA11386/DA/NIDA NIH HHS/ R01DE012609/DE/NIDCR NIH HHS/ R01DE11979/DE/NIDCR NIH HHS/ R01DE13110/DE/NIDCR NIH HHS/ R01DE13158/DE/NIDCR NIH HHS/ R01ES11740/ES/NIEHS NIH HHS/ R03CA113157/CA/NCI NIH HHS/ R03CA77954/CA/NCI NIH HHS/ R03DE016611/DE/NIDCR NIH HHS/ R21ES011667/ES/NIEHS NIH HHS/ T32CA09142/CA/NCI NIH HHS/ U01CA96134/CA/NCI NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. England 2015/01/24 06:00 Int J Epidemiol. 2015 Feb;44(1):169-85. doi: 10.1093/ije/dyu255. Epub 2015 Jan 22.; International audience; BACKGROUND: Increasing incidence of head and neck cancer (HNC) in young adults has been reported. We aimed to compare the role of major risk factors and family history of cancer in HNC in young adults and older patients. METHODS: We pooled data from 25 case-control studies and conducted separate analyses for adults 45 years old ('older adults', 17700 cases and 22 704 controls). Using logistic regression with studies treated as random effects, we estimated adjusted odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: The young group of cases had a higher proportion of oral tongue cancer (16.0% in women; 11.0% in men) and unspecified oral cavity / oropharynx cancer (16.2%; 11.1%) and a lower proportion of larynx cancer (12.1%; 16.6%) than older adult cases. The proportions of never smokers or never drinkers among female cases were higher than among male cases in both age groups. Positive associations with HNC and duration or pack-years of smoking and drinking were similar across age groups. However, the attributable fractions (AFs) for smoking and drinking were lower in young when compared with older adults (AFs for smoking in young women, older women, young men and older men, respectively, = 19.9% (95% CI=9.8%, 27.9%), 48.9% (46.6%, 50.8%), 46.2% (38.5%, 52.5%), 64.3% (62.2%, 66.4%); AFs for drinking=5.3% (-11.2%, 18.0%), 20.0% (14.5%, 25.0%), 21.5% (5.0%, 34.9%) and 50.4% (46.1%, 54.3%). A family history of early-onset cancer was associated with HNC risk in the young [OR=2.27 (95% CI=1.26, 4.10)], but not in the older adults [OR=1.10 (0.91, 1.31)]. The attributable fraction for family history of early-onset cancer was 23.2% (8.60% to 31.4%) in young compared with 2.20% (-2.41%, 5.80%) in older adults. CONCLUSIONS: Differences in HNC aetiology according to age group may exist. The lower AF of cigarette smoking and alcohol drinking in young adults may be due to the reduced length of exposure due to the lower age. Other characteristics, such as those that are inherited, may play a more important role in HNC in young adults compared with older adults.

Evidence for the possible effect of vitamin E on head and neck cancers (HNCs) is limited.Methods:We used individual-level pooled data from 10 case-control studies (5959 cases and 12 248 controls) participating in the International Head and Neck Cancer Epidemiology (INHANCE) consortium to assess the association between vitamin E intake from natural sources and cancer of the oral cavity/pharynx and larynx. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using unconditional logistic regression models applied to quintile categories of nonalcohol energy-adjusted vitamin E intake.Results:Intake of vitamin E was inversely related to oral/pharyngeal cancer (OR for the fifth vs the first quintile category=0.59, 95% CI: 0.49-0.71; P for trend

Evidence of associations between single nutrients and head and neck cancer (HNC) is still more limited and less consistent than that for fruit and vegetables. However, clarification of the protective mechanisms of fruit and vegetables is important to our understanding of HNC etiology. We investigated the association between vitamin C intake from natural sources and cancer of the oral cavity/pharynx and larynx using individual-level pooled data from ten case-control studies (5959 cases and 12248 controls) participating in the International Head and Neck Cancer Epidemiology (INHANCE) consortium. After harmonization of study-specific exposure information via the residual method, adjusted odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were estimated using unconditional multiple logistic regression models on quintile categories of ’non-alcohol energy-adjusted’ vitamin C intake. In the presence of heterogeneity of the estimated ORs among studies, we derived those estimates from generalized linear mixed models. Higher intakes of vitamin C were inversely related to oral and pharyngeal (OR=0.54, 95% CI: 0.45–0.65, for the fifth quintile category versus the first one, p for trend

Food and nutrition play an important role in head and neck cancer (HNC) etiology; however, the role of carotenoids remains largely undefined. We explored the relation of HNC risk with the intake of carotenoids within the International Head and Neck Cancer Epidemiology Consortium. We pooled individual-level data from 10 case-control studies conducted in Europe, North America, and Japan. The analysis included 18,207 subjects (4414 with oral and pharyngeal cancer, 1545 with laryngeal cancer, and 12,248 controls), categorized by quintiles of carotenoid intake from natural sources. Comparing the highest with the lowest quintile, the risk reduction associated with total carotenoid intake was 39% (95% CI 29-47%) for oral/pharyngeal cancer and 39% (95% CI 24-50%) for laryngeal cancer. Intakes of β-carotene equivalents, β-cryptoxanthin, lycopene, and lutein plus zeaxanthin were associated with at least 18% reduction in the rate of oral and pharyngeal cancer (95% CI 6-29%) and 17% reduction in the rate of laryngeal cancer (95% CI 0-32%). The overall protective effect of carotenoids on HNC was stronger for subjects reporting greater alcohol consumption (p&nbsp

Leoncini, Emanuele Ricciardi, Walter Cadoni, Gabriella Arzani, Dario Petrelli, Livia Paludetti, Gaetano Brennan, Paul Luce, Daniele Stucker, Isabelle Matsuo, Keitaro Talamini, Renato La Vecchia, Carlo Olshan, Andrew F Winn, Deborah M Herrero, Rolando Franceschi, Silvia Castellsague, Xavier Muscat, Joshua Morgenstern, Hal Zhang, Zuo-Feng Levi, Fabio Dal Maso, Luigino Kelsey, Karl McClean, Michael Vaughan, Thomas L Lazarus, Philip Purdue, Mark P Hayes, Richard B Chen, Chu Schwartz, Stephen M Shangina, Oxana Koifman, Sergio Ahrens, Wolfgang Matos, Elena Lagiou, Pagona Lissowska, Jolanta Szeszenia-Dabrowska, Neonila Fernandez, Leticia Menezes, Ana Agudo, Antonio Daudt, Alexander W Richiardi, Lorenzo Kjaerheim, Kristina Mates, Dana Betka, Jaroslav Yu, Guo-Pei Schantz, Stimson Simonato, Lorenzo Brenner, Hermann Conway, David I Macfarlane, Tatiana V Thomson, Peter Fabianova, Eleonora Znaor, Ariana Rudnai, Peter Healy, Claire Boffetta, Paolo Chuang, Shu-Chun Lee, Yuan-Chin Amy Hashibe, Mia Boccia, Stefania eng Netherlands 2013/11/26 06:00 Eur J Epidemiol. 2014 Jan;29(1):35-48. doi: 10.1007/s10654-013-9863-2. Epub 2013 Nov 24.; International audience; Several epidemiological studies have shown a positive association between adult height and cancer incidence. The only study conducted among women on mouth and pharynx cancer risk, however, reported an inverse association. This study aims to investigate the association between height and the risk of head and neck cancer (HNC) within a large international consortium of HNC. We analyzed pooled individual-level data from 24 case-control studies participating in the International Head and Neck Cancer Epidemiology Consortium. Odds ratios (ORs) and 95 % confidence intervals (CIs) were estimated separately for men and women for associations between height and HNC risk. Educational level, tobacco smoking, and alcohol consumption were included in all regression models. Stratified analyses by HNC subsites were performed. This project included 17,666 cases and 28,198 controls. We found an inverse association between height and HNC (adjusted OR per 10 cm height = 0.91, 95 % CI 0.86-0.95 for men; adjusted OR = 0.86, 95 % CI 0.79-0.93 for women). In men, the estimated OR did vary by educational level, smoking status, geographic area, and control source. No differences by subsites were detected. Adult height is inversely associated with HNC risk. As height can be considered a marker of childhood illness and low energy intake, the inverse association is consistent with prior studies showing that HNC occur more frequently among deprived individuals. Further studies designed to elucidate the mechanism of such association would be warranted.

Wyss, Annah Hashibe, Mia Chuang, Shu-Chun Lee, Yuan-Chin Amy Zhang, Zuo-Feng Yu, Guo-Pei Winn, Deborah M Wei, Qingyi Talamini, Renato Szeszenia-Dabrowska, Neonila Sturgis, Erich M Smith, Elaine Shangina, Oxana Schwartz, Stephen M Schantz, Stimson Rudnai, Peter Purdue, Mark P Eluf-Neto, Jose Muscat, Joshua Morgenstern, Hal Michaluart, Pedro Jr Menezes, Ana Matos, Elena Mates, Ioan Nicolae Lissowska, Jolanta Levi, Fabio Lazarus, Philip La Vecchia, Carlo Koifman, Sergio Herrero, Rolando Hayes, Richard B Franceschi, Silvia Wunsch-Filho, Victor Fernandez, Leticia Fabianova, Eleonora Daudt, Alexander W Dal Maso, Luigino Curado, Maria Paula Chen, Chu Castellsague, Xavier de Carvalho, Marcos Brasilino Cadoni, Gabriella Boccia, Stefania Brennan, Paul Boffetta, Paolo Olshan, Andrew F eng R03 CA113157/CA/NCI NIH HHS/ R24 HD041025/HD/NICHD NIH HHS/ T32-CA09330/CA/NCI NIH HHS/ T32ES007018/ES/NIEHS NIH HHS/ Meta-Analysis Research Support, N.I.H., Extramural 2013/07/03 06:00 Am J Epidemiol. 2013 Sep 1;178(5):679-90. doi: 10.1093/aje/kwt029. Epub 2013 Jun 30.; International audience; Cigar and pipe smoking are considered risk factors for head and neck cancers, but the magnitude of effect estimates for these products has been imprecisely estimated. By using pooled data from the International Head and Neck Cancer Epidemiology (INHANCE) Consortium (comprising 13,935 cases and 18,691 controls in 19 studies from 1981 to 2007), we applied hierarchical logistic regression to more precisely estimate odds ratios and 95% confidence intervals for cigarette, cigar, and pipe smoking separately, compared with reference groups of those who had never smoked each single product. Odds ratios for cigar and pipe smoking were stratified by ever cigarette smoking. We also considered effect estimates of smoking a single product exclusively versus never having smoked any product (reference group). Among never cigarette smokers, the odds ratio for ever cigar smoking was 2.54 (95% confidence interval (CI): 1.93, 3.34), and the odds ratio for ever pipe smoking was 2.08 (95% CI: 1.55, 2.81). These odds ratios increased with increasing frequency and duration of smoking (Ptrend

Background: In addition to influences of exposure to carcinogenic compounds, the development of cancer may depend on an individual intrinsic cancer susceptibility. Biomarkers for cancer susceptibility can be powerful additions to epidemiologic analyses. Purpose: This multicenter, case-control analysis combines previously published data and new data to substantiate the value of mutagen sensitivity as a biomarker of susceptibility to head and neck squamous cell carcinoma and, more importantly, to gain insight into the interaction between susceptibility and exposure to carcinogens. Methods: Mutagen sensitivity (mean number of chromatid breaks per cell of cultured lymphocytes treated with bleomycin in the late S-G2 phase of the cell cycle) was determined in 313 patients with head and neck cancer and in 334 control subjects at two major U.S. medical institutions and one European institution, yielding a unique study population. The ages of the case and control subjects, as well as their history of use of tobacco and alcohol, were also recorded. The relationships between variables were analyzed by use of Student's t tests, Spearman's rank correlations, and multiple linear regression. For estimation of cancer risk, crude odds ratios (ORs) were measured and multiple logistic regression was performed. All P values were based on two-sided tests. Results: There were no differences across institutions in the distribution of mutagen sensitivity (Kruskal-Wallis test) for both case subjects and control subjects. Values for case subjects were consistently and significantly (P

Li, Qian Chuang, Shu-Chun Eluf-Neto, Jose Menezes, Ana Matos, Elena Koifman, Sergio Wunsch-Filho, Victor Fernandez, Leticia Daudt, Alexander W Curado, Maria Paula Winn, Deborah M Franceschi, Silvia Herrero, Rolando Castellsague, Xavier Morgenstern, Hal Zhang, Zuo-Feng Lazarus, Philip Muscat, Joshua McClean, Michael Kelsey, Karl T Hayes, Richard B Purdue, Mark P Schwartz, Stephen M Chen, Chu Benhamou, Simone Olshan, Andrew F Yu, Guopei Schantz, Stimson Ferro, Gilles Brennan, Paul Boffetta, Paolo Hashibe, Mia eng K07CA104231/CA/NCI NIH HHS/ P01CA068384/CA/NCI NIH HHS/ P30ES010126/ES/NIEHS NIH HHS/ P50CA90388/CA/NCI NIH HHS/ R01CA048896/CA/NCI NIH HHS/ R01CA078609/CA/NCI NIH HHS/ R01CA100679/CA/NCI NIH HHS/ R01CA51845/CA/NCI NIH HHS/ R01CA61188/CA/NCI NIH HHS/ R01DA11386/DA/NIDA NIH HHS/ R01DE012609/DE/NIDCR NIH HHS/ R01DE13158/DE/NIDCR NIH HHS/ R03 CA113157-01/CA/NCI NIH HHS/ R03 CA113157-02/CA/NCI NIH HHS/ R03 DE016611/DE/NIDCR NIH HHS/ R03 DE016611-01/DE/NIDCR NIH HHS/ R03 DE016611-02/DE/NIDCR NIH HHS/ R03CA113157/CA/NCI NIH HHS/ R03CA77954/CA/NCI NIH HHS/ R21ES011667/ES/NIEHS NIH HHS/ R24 HD050924/HD/NICHD NIH HHS/ T32CA09142/CA/NCI NIH HHS/ U01CA96134/CA/NCI NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't 2011/12/17 06:00 Int J Cancer. 2012 Oct 1;131(7):1686-99. doi: 10.1002/ijc.27405. Epub 2012 Jan 27.; International audience; To investigate the potential role of vitamin or mineral supplementation on the risk of head and neck cancer (HNC), we analyzed individual-level pooled data from 12 case-control studies (7,002 HNC cases and 8,383 controls) participating in the International Head and Neck Cancer Epidemiology consortium. There were a total of 2,028 oral cavity cancer, 2,465 pharyngeal cancer, 874 unspecified oral/pharynx cancer, 1,329 laryngeal cancer and 306 overlapping HNC cases. Odds ratios (OR) and 95% confidence intervals (CIs) for self reported ever use of any vitamins, multivitamins, vitamin A, vitamin C, vitamin E, and calcium, beta-carotene, iron, selenium and zinc supplements were assessed. We further examined frequency, duration and cumulative exposure of each vitamin or mineral when possible and stratified by smoking and drinking status. All ORs were adjusted for age, sex, race/ethnicity, study center, education level, pack-years of smoking, frequency of alcohol drinking and fruit/vegetable intake. A decreased risk of HNC was observed with ever use of vitamin C (OR = 0.76, 95% CI = 0.59-0.96) and with ever use of calcium supplement (OR = 0.64, 95% CI = 0.42-0.97). The inverse association with HNC risk was also observed for 10 or more years of vitamin C use (OR = 0.72, 95% CI = 0.54-0.97) and more than 365 tablets of cumulative calcium intake (OR = 0.36, 95% CI = 0.16-0.83), but linear trends were not observed for the frequency or duration of any supplement intake. We did not observe any strong associations between vitamin or mineral supplement intake and the risk of HNC.

Chuang, Shu-Chun Jenab, Mazda Heck, Julia E Bosetti, Cristina Talamini, Renato Matsuo, Keitaro Castellsague, Xavier Franceschi, Silvia Herrero, Rolando Winn, Deborah M La Vecchia, Carlo Morgenstern, Hal Zhang, Zuo-Feng Levi, Fabio Dal Maso, Luigino Kelsey, Karl McClean, Michael D Vaughan, Thomas Lazarus, Philip Muscat, Joshua Ramroth, Heribert Chen, Chu Schwartz, Stephen M Eluf-Neto, Jose Hayes, Richard B Purdue, Mark Boccia, Stefania Cadoni, Gabriella Zaridze, David Koifman, Sergio Curado, Maria Paula Ahrens, Wolfgang Benhamou, Simone Matos, Elena Lagiou, Pagona Szeszenia-Dabrowska, Neonilla Olshan, Andrew F Fernandez, Leticia Menezes, Ana Agudo, Antonio Daudt, Alexander W Merletti, Franco Macfarlane, Gary J Kjaerheim, Kristina Mates, Dana Holcatova, Ivana Schantz, Stimson Yu, Guo-Pei Simonato, Lorenzo Brenner, Hermann Mueller, Heiko Conway, David I Thomson, Peter Fabianova, Eleonora Znaor, Ariana Rudnai, Peter Healy, Claire M Ferro, Gilles Brennan, Paul Boffetta, Paolo Hashibe, Mia eng K07CA104231/CA/NCI NIH HHS/ P01CA068384/CA/NCI NIH HHS/ P30 CA015704/CA/NCI NIH HHS/ P30ES010126/ES/NIEHS NIH HHS/ P50CA90388/CA/NCI NIH HHS/ R01 CA100679/CA/NCI NIH HHS/ R01 CA100679-09/CA/NCI NIH HHS/ R01 ES014843/ES/NIEHS NIH HHS/ R01CA048996/CA/NCI NIH HHS/ R01CA078609/CA/NCI NIH HHS/ R01CA100679/CA/NCI NIH HHS/ R01CA30022/CA/NCI NIH HHS/ R01CA51845/CA/NCI NIH HHS/ R01CA61188/CA/NCI NIH HHS/ R01DA11386/DA/NIDA NIH HHS/ R01DE012609/DE/NIDCR NIH HHS/ R01DE13158/DE/NIDCR NIH HHS/ R03CA113157/CA/NCI NIH HHS/ R03CA77954/CA/NCI NIH HHS/ R03DE016611/DE/NIDCR NIH HHS/ R21ES011667/ES/NIEHS NIH HHS/ R24 HD050924/HD/NICHD NIH HHS/ T32CA09142/CA/NCI NIH HHS/ U01CA96134/CA/NCI NIH HHS/ Research Support, N.I.H., Extramural Research Support, N.I.H., Intramural Research Support, Non-U.S. Gov't Netherlands 2011/11/01 06:00 Cancer Causes Control. 2012 Jan;23(1):69-88. doi: 10.1007/s10552-011-9857-x. Epub 2011 Oct 29.; International audience; We investigated the association between diet and head and neck cancer (HNC) risk using data from the International Head and Neck Cancer Epidemiology (INHANCE) consortium. The INHANCE pooled data included 22 case-control studies with 14,520 cases and 22,737 controls. Center-specific quartiles among the controls were used for food groups, and frequencies per week were used for single food items. A dietary pattern score combining high fruit and vegetable intake and low red meat intake was created. Odds ratios (OR) and 95% confidence intervals (CI) for the dietary items on the risk of HNC were estimated with a two-stage random-effects logistic regression model. An inverse association was observed for higher-frequency intake of fruit (4th vs. 1st quartile OR = 0.52, 95% CI = 0.43-0.62, p (trend) < 0.01) and vegetables (OR = 0.66, 95% CI = 0.49-0.90, p (trend) = 0.01). Intake of red meat (OR = 1.40, 95% CI = 1.13-1.74, p (trend) = 0.13) and processed meat (OR = 1.37, 95% CI = 1.14-1.65, p (trend) < 0.01) was positively associated with HNC risk. Higher dietary pattern scores, reflecting high fruit/vegetable and low red meat intake, were associated with reduced HNC risk (per score increment OR = 0.90, 95% CI = 0.84-0.97).

Although distant metastases occur in a minority of papillary thyroid carcinoma (PTC) patients, their impact on disease course and survival rates is profound, with aggregate 10-yr survival rates of 40% (1). Limited treatment options further complicate management of metastatic PTC. Radioiodine (RAI) remains the standard of care for most distant metastases in PTC. Of particular concern, however, is the significant prevalence of PTC metastases unable to trap RAI; such metastases are termed RAI-refractory (RAIR). Because thyroid cancer loses differentiated features of normal thyroid tissue, one feature commonly lost is sodium iodide symporter expression, which is the entire basis for the use of RAI therapy in thyroid malignancies. This phenomenon can occur in a heterogeneous manner: in a given patient, RAI uptake can vary between individual metastases, and it can even vary within a metastasis at the cellular level. Because radiation dose to the tumor and successful outcome of RAI therapy are directly correlated, this has a significant negative impact on the ability to treat metastatic disease. One recent study on RAIR metastases' impact on survival (1) showed that 23% of PTC patients had distant metastases that were unable to trap RAI at all, whereas another 23% of PTC patients had distant metastases that trapped RAI but were nonetheless unable to achieve remission (both groups were designated as RAIR). Ten-year survival rates (among all differentiated thyroid cancers) were decreased to 10% for the patients with no RAI uptake and 29% for those with metastases that trapped RAI but did not achieve remission, compared with the 92% 10-yr survival rate of metastatic thyroid cancer patients with RAI uptake who achieved remission (1). The large disparity between survival rates of these groups underscores the extraordinary impact of RAIR metastases in PTC prognosis. Given the high prevalence of BRAFV600E mutations (and other activating mutations in the RET-Ras-Raf-MAPK pathway) in PTC and RAIR metastatic PTC, one experimental therapy that has been studied is the use of synthetic tyrosine kinase inhibitors (TKI), such as sorafenib, to block this pathway (2). Originally developed as specific inhibitors of BRAFV600E, these drugs have since been shown to have a less specific range of targets. These compounds are approved by the U.S. Food and Drug Administration for the treatment of unresectable hepatocellular carcinoma, gastrointestinal stromal tumors, and advanced renal cell carcinoma. Recently, phase II clinical trials have shown that sorafenib had significant efficacy against RAIR metastatic thyroid cancers, including PTC; sorafenib has since moved forward to phase III clinical trials. These drugs are currently being used off-label at cancer centers for the treatment of RAIR metastatic thyroid malignancies (2, 3). Although treatment of RAIR metastatic thyroid cancer with sorafenib in clinical trials has yielded some positive results thus far, concerns have been raised regarding several aspects of TKI treatment. The first is the disparity in response according to the site of the metastases. Lung metastases were more responsive than those in lymph nodes, and bone metastases are highly refractory to sorafenib treatment (2, 3). Additionally, there were several adverse side effects resulting from sorafenib treatment. These ranged from mild to severe and included diarrhea, hypertension, fatigue, weight loss/anorexia, thyroiditis, and hand-foot reaction syndrome; in some cases, the side effects were severe enough to warrant discontinuation or reduction of therapy. More dangerous side effects reported included pericardial effusion and reversible neutropenia (2, 3). Perhaps most distressing, however, was the subsequent development of new primary cancers in a subset of patients receiving sorafenib therapy. Cabanillas et al. (3) reported that 27% of their patients developed squamous cell carcinoma of the skin or inflammation of actinic keratoses; this trend has been observed in other clinical studies dealing with sorafenib (4). This effect (as well as the lack of responsiveness of some tumors to sorafenib) has been speculated to be the result of the TKI ability to activate CRAF (another member of the RAF family of kinases, with functions similar to BRAF) in cells with wild-type BRAF or mutant RAS, which in turn gives rise to continued activation of MAPK signaling (2, 5). Furthermore, BRAFV600E has been shown to confer antiapoptotic phenotypes to PTC cells (and transformed thyroid cells) via ERK-independent interactions with the mitochondria. Treatment of the cells with sorafenib and the MEK inhibitor U0126 was unable to induce responsiveness to apoptotic stimuli, despite inhibiting ERK signaling; this phenomenon may further explain the ineffectiveness of sorafenib on some metastatic thyroid tumors (6). Given the apparent shortcomings of both conventional RAI and experimental TKI like sorafenib, we propose that inhibitors of other molecular targets be explored in clinical trials. One attractive target is the urokinase plasminogen activator (uPA) and the uPA receptor (uPAR) system, a key mediator of tumor invasion. uPAR converts pro-uPA to its active form, which then cleaves plasminogen to plasmin. Plasmin can then degrade extracellular matrix components, a prerequisite for tumor invasion and metastasis (7). Previous work by our group has shown that uPAR and uPA are consistently up-regulated in PTC tissue, and the degree of up-regulation positively correlates with metastasis. Furthermore, we have demonstrated that inhibition of uPA and uPAR significantly reduces degradative and invasive potential of BRAFV600E-positive PTC cells (8). Finally, our group has also shown that uPAR (which we showed was induced by BRAFV600E-induced ERK hyperactivity) mediates focal adhesion kinase/phosphatidylinositol 3-kinase/Akt signaling, which coordinates various functions critical to metastatic behavior, including migration, invasion, and proliferation in BRAFV600E-positive PTC cells (9). Our data corroborate studies showing similar importance of this system in other malignancies (7). Given the importance of the uPA/uPAR system in PTC invasion and metastasis, we submit that uPA/uPAR inhibitors are attractive alternatives in the treatment of metastatic PTC, especially RAIR disease. Potent, orally bioavailable inhibitors of uPA have recently been developed and may hold great potential for the treatment of any metastatic tumor expressing this marker, including PTC (10, 11). One such agent, designed by Wilex (Mesupron, WX-671), is currently being studied in clinical trials for other cancers. In cellular and animal models, Mesupron has been shown to effectively inhibit tumor growth and metastatic spread. Early clinical studies in head and neck carcinoma revealed that Mesupron achieved therapeutic concentrations in tumor tissue while causing no significant side effects, beyond minor gastrointestinal effects (10). This lack of serious side effects corroborates early studies demonstrating the normal life spans/phenotypes of uPA/uPAR-knockout mice (7). A phase II clinical trial in nonmetastatic pancreatic cancer has yielded further promising results. In this trial, addition of Mesupron to conventional chemotherapy (gemcitabine) was well tolerated, causing no specific toxicities (beyond those attributed to gemcitabine) and improving response rates (partial or complete remissions), progression-free survival, and overall survival rates (12). Additionally, a phase II clinical trial in HER2/neu-negative metastatic breast cancer is currently ongoing (13). Mesupron (and other uPA/uPAR system inhibitors) would enable the direct inhibition of a system that is a significant contributor to biological processes underlying the metastatic phenotype of PTC (proteolysis, invasion, and migration, growth and proliferation), as well as metastatic phenotypes of other thyroid malignancies. Furthermore, it would avoid therapy-limiting side effects and the potential risk of skin cancer development seen in sorafenib and other TKI. We therefore advocate that clinical trials involving such inhibitors of the uPA/uPAR system be explored for the treatment of metastatic PTC (particularly RAIR cases) and other thyroid cancers.

The incidence of thyroid cancer is four to five times higher in women than in men, suggesting a role for estrogen (E₂) in the pathogenesis of thyroid proliferative disease (TPD) that comprises cancer and goiter. The objective of this study was to investigate the antiestrogenic activity of 3,3'-diindolylmethane (DIM), a bioactive compound derived from cruciferous vegetables, in patients with TPD.In this limited phase I clinical trial study, patients found to have TPD were administered 300 mg of DIM per day for 14 days. Patients subsequently underwent a total or partial thyroidectomy, and tissue, urine, and serum samples were collected. Pre- and post-DIM serum and urine samples were analyzed for DIM levels as well as estrogen metabolites. DIM levels were also determined in thyroid tissue samples.DIM was detectable in thyroid tissue, serum, and urine of patients after 14 days of supplementation. Urine analyses revealed that DIM modulated estrogen metabolism in patients with TPD. There was an increase in the ratio of 2-hydroxyestrones (C-2) to 16α-hydroxyestrone (C-16), consistent with antiestrogenic activity that results in more of C-2 product compared with C-16.Our data suggest that DIM enhances estrogen metabolism in TPD patients and can potentially serve as an antiestrogenic dietary supplement to help reduce the risk of developing TPD. The fact that DIM is detected in thyroid tissue implicates that it can manifest its antiestrogenic activity in situ to modulate TPD.

Papillary thyroid carcinoma (PTC) is the most common endocrine and thyroid malignancy. The urokinase plasminogen activator receptor (uPAR) plays an important role in cancer pathogenesis, including breakdown of the extracellular matrix, invasion, and metastasis. Additionally, there is increasing evidence that uPAR also promotes tumorigenesis via the modulation of multiple signaling pathways. BRAFV600E, the most common initial genetic mutation in PTC, leads to ERK1/2 hyperphosphorylation, which has been shown in numerous cancers to induce uPAR. Treatment of the BRAFV600E-positive PTC cell line, BCPAP, with the MEK/ERK inhibitor U0126 reduced uPAR RNA levels by 90%. siRNA-mediated down-regulation of uPAR in BCPAP cells resulted in greatly decreased activity in the focal adhesion kinase (FAK)/phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway. This phenomenon was concurrent with drastically reduced proliferation rates and decreased clonigenic survival, as well as demonstrated senescence-associated nuclear morphology and induction of b-galactosidase activity. uPAR-knockdown BCPAP cells also displayed greatly reduced migration and invasion rates, as well as a complete loss of the cells' ability to augment their invasiveness following plasminogen supplementation. Taken together, these data provide new evidence of a novel role for uPAR induction (as a consequence of constitutive ERK1/2 activation) as a central component in PTC pathogenesis, and highlight the potential of uPAR as a therapeutic target.

Galeone, Carlotta Tavani, Alessandra Pelucchi, Claudio Turati, Federica Winn, Deborah M Levi, Fabio Yu, Guo-Pei Morgenstern, Hal Kelsey, Karl Dal Maso, Luigino Purdue, Mark P McClean, Michael Talamini, Renato Hayes, Richard B Franceschi, Silvia Schantz, Stimson Zhang, Zuo-Feng Ferro, Gilles Chuang, Shu-Chun Boffetta, Paolo La Vecchia, Carlo Hashibe, Mia eng CA100679/CA/NCI NIH HHS/ CA78609/CA/NCI NIH HHS/ P50CA90388/CA/NCI NIH HHS/ R01 CA100679-08/CA/NCI NIH HHS/ R01 CA100679-09/CA/NCI NIH HHS/ R01CA51845/CA/NCI NIH HHS/ R01DA11386/DA/NIDA NIH HHS/ R03 CA113157-01/CA/NCI NIH HHS/ R03 CA113157-02/CA/NCI NIH HHS/ R03CA113157/CA/NCI NIH HHS/ R03CA77954/CA/NCI NIH HHS/ R21ES011667/ES/NIEHS NIH HHS/ T32CA09142/CA/NCI NIH HHS/ U01CA96134/CA/NCI NIH HHS/ Research Support, N.I.H., Extramural Research Support, N.I.H., Intramural Research Support, Non-U.S. Gov't 2010/06/24 06:00 Cancer Epidemiol Biomarkers Prev. 2010 Jul;19(7):1723-36. doi: 10.1158/1055-9965.EPI-10-0191. Epub 2010 Jun 22.; International audience; BACKGROUND: Only a few studies have explored the relation between coffee and tea intake and head and neck cancers, with inconsistent results. METHODS: We pooled individual-level data from nine case-control studies of head and neck cancers, including 5,139 cases and 9,028 controls. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (95% CI), adjusting for potential confounders. RESULTS: Caffeinated coffee intake was inversely related with the risk of cancer of the oral cavity and pharynx: the ORs were 0.96 (95% CI, 0.94-0.98) for an increment of 1 cup per day and 0.61 (95% CI, 0.47-0.80) in drinkers of >4 cups per day versus nondrinkers. This latter estimate was consistent for different anatomic sites (OR, 0.46; 95% CI, 0.30-0.71 for oral cavity; OR, 0.58; 95% CI, 0.41-0.82 for oropharynx/hypopharynx; and OR, 0.61; 95% CI, 0.37-1.01 for oral cavity/pharynx not otherwise specified) and across strata of selected covariates. No association of caffeinated coffee drinking was found with laryngeal cancer (OR, 0.96; 95% CI, 0.64-1.45 in drinkers of >4 cups per day versus nondrinkers). Data on decaffeinated coffee were too sparse for detailed analysis, but indicated no increased risk. Tea intake was not associated with head and neck cancer risk (OR, 0.99; 95% CI, 0.89-1.11 for drinkers versus nondrinkers). CONCLUSIONS: This pooled analysis of case-control studies supports the hypothesis of an inverse association between caffeinated coffee drinking and risk of cancer of the oral cavity and pharynx. IMPACT: Given widespread use of coffee and the relatively high incidence and low survival of head and neck cancers, the observed inverse association may have appreciable public health relevance.

The human microsomal epoxide hydrolase (EH) gene contains polymorphic alleles which are associated with altered EH activity and may be linked to increased risk for tobacco-related cancers. The objective was to examine the role of EH polymorphisms in orolaryngeal cancer risk. The prevalence of the EH codons 113 and 139 polymorphisms were examined in 81 African American and 142 Caucasian incident orolaryngeal cancer patients and 335 controls frequency-matched on age, sex, and race. In Caucasians, a significant risk increase was observed for subjects with the EH(113Tyr) variant (OR=2.1, 95% CI=1.1-4.0) and predicted high-activity EH genotypes in heavy-smokers (>or=35 pack-years; OR=3.4, 95% CI=1.2-9.6). A significant association between predicted high EH activity genotypes and orolaryngeal cancer risk was observed in Caucasian subjects with the GSTM1 null (OR=3.5, 95% CI=1.3-9.3) but not GSTM [+] (OR=0.9, 95%CI=0.4-2.1) genotype. These results suggest that EH polymorphisms play an important role in risk for orolaryngeal cancer in Caucasians.

Native cellular fluorescence (NCF) represents the innate capacity of tissues to absorb and emit light of specified wavelengths. Recent advances in optical engineering and computer technology have provided the, opportunity to measure NCF characteristics of various tissues in vivo. This report will briefly review the current status of NCF analysis of various neoplastic tissues. The status of investigations involving the upper aerodigestive tract will be discussed. Though initial results demonstrate that neoplastic tissues can be discriminated from normal mucosa by NCF analysis, the biologic basis of this difference remains uncertain. This report will also emphasize that the ability to screen for cancer in aerodigestive mucosa may be enhanced through the assessment of multiple emission and excitation wavelengths. The true nature of the cellular fluorophores responsible for these mucosal spectral characteristics should be more fully defined in coming years.