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Papillary Thyroid Cancer (PTC) accounts for the vast majority of thyroid cancers and comprises more than 90% of neoplasms in the endocrine system. In the last 30 years, the incidence and prevalence of PTC has dramatically risen in developed countries, with a three-fold higher incidence in women than in men. With an overall five-year survival rate of 98.1%, early stage PTC has a favorable prognosis. However, PTC exhibits increased aggressiveness with poor prognosis in men diagnosed with the disease. These striking observations led us to explore the role of androgen and androgen receptor (AR) in this disease. We found an approximately 70% decrease in median AR RNA expression (p Citation Format: Anvita Gupta, Timmy O'Connell, Melanie Jones, Karnika Singh, Monica Schwarcz, JK Rasamny, Dorota Halicka, Jiangwei Li, Codrin Iacob, Nina Suslina, Stimson Schantz, Edward Shin, Zbigniew Darzynkiewicz, Raj Tiwari, Jan Geliebter. Methylation and expression of androgen receptor in Papillary Thyroid Cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4356. doi:10.1158/1538-7445.AM2017-4356

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.

The CYP2E1 gene, whose protein product plays an important role in the metabolism of various carcinogens, exhibits two polymorphisms recognized by the restriction enzymes RsaI and PstI in its transcriptional regulatory region that have been previously implicated in cancer susceptibility. In this study, we have examined these polymorphisms to elucidate CYP2E1 allelic haplotype, examining the prevalence of these CYP2E1 alleles in Caucasians and African Americans and their potential role in risk for oral cancer. In addition to the c1 (RsaI[+]/PstI[−]) and c2 (RsaI[−]/PstI[+]) alleles reported in previous studies, we have identified two new alleles, c3 (RsaI[+]/PstI[+]) and c4 (RsaI[−]/PstI[−]). The prevalence of the c2 and c3 alleles differs between racial groups, with African Americans exhibiting a lower prevalence of the c2 allele (0.003) but a higher prevalence of the c3 allele (0.049) than Caucasians (0.031 for c2 and 0.004 for c3). Of the 570 subjects screened in this study, the c4 allele was observed in one subject, a Caucasian case with the (c4/c4) genotype. A significant increase in the CYP2E1 (c1/c1) genotype was observed in oral cancer cases as compared to frequency-matched controls in subjects who smoked ⩽24 pack-years (P=0.033). No association was observed between CYP2E1 genotype and risk for oral cancer in the heavy-smoking group (i.e. > 24 pack-years). Similar trends were observed for both Caucasians and African Americans. These data suggest that the c1 allele may contribute to increased risk for oral cancer.

Estrogen metabolites have been associated in the pathogenesis of breast and cervical cancer; 16alpha-hydroxyestrone(16alpha-OHE1) demonstrated proliferative effects whereas 2-hydroxyestrone(2-OHE1) had antiproliferative effects. Our study's objective is to demonstrate that head and neck (HN) cancer patients metabolize estrogen differently than healthy controls, which may constitute a risk factor for HN cancer development.Urinary metabolite levels of 2-OHE1 and 16alpha-OHE1 from 50 HN cancer patients and 50 age- and sex-matched controls were measured using enzyme-linked immunosorbent assay (ELISA). Absolute values and 2-/16alpha-OHE1 ratios were calculated. Conditional logistic regression for univariate and multivariate analysis with odds ratio (OR) and 95% confidence interval (CI) were used.Thirty percent (15 of 50) from the case group had a low 2-/16alpha-OHE1 ratio compared with only 4% (2 of 50) in the control group (OR = 11.1; 1.4-91.5, 95% CI) (P0.05). When adjusted for tobacco, OR remained significant at 15.6 (1.1-212.5, 95% CI) (P0.05).HN cancer patients are more likely to express abnormal estrogen metabolism than healthy controls; 2-/16alpha-OHE1 may serve as a potential biological marker of individuals at increased risk of HN cancer.

Near-infrared (NIR) time-resolved and spectroscopic transillumination imaging techniques are used to investigate normal tissues and Warthin's tumor of human parotid glands. The time-sliced imaging arrangement uses 120-fs, 1-kHz repetition-rate, 800-nm pulses from a Ti: sapphire laser and amplifier system for sample illumination and an ultrafast gated intensified camera system (UGICS) for recording two-dimensional (2-D) images using transmitted light. Images recorded with earlier temporal slices (approximately first 100 ps) of transmitted light highlight the tumor, while those recorded with later temporal slices (later than 200 ps) accentuate normal tissues. The spectroscopic imaging arrangement uses 1210-1300 nm tunable output of a Cr: forsterite laser for sample illumination, a Fourier space gate to discriminate against multiple-scattered light, and a NIR area camera to record 2-D images. The tumor region in the specimen appears brighter than the normal region in spectroscopic images recorded with light of different wavelengths. A wavelength-dependent variation in the ratio of light transmission through the tumor to that through the normal parotid gland is observed. Differences in scattering and wavelength-dependent absorption characteristics of normal parotid gland and Warthin's tumor provide a consistent explanation of these observed features. Histopathological analysis of the specimen sheds light on the probable origin of the differences in scattering and absorption characteristics.

The interaction between environmental exposures and host susceptibility may lead to specific mutational events within head and neck squamous cell carcinoma (HNSCC). Furthermore, this interplay may determine not only the probability of cancer development but also the biologic characteristics of the tumor once it occurs. To better understand the relationship of mutagen sensitivity and tobacco and/or alcohol consumption on HNSCC carcinogenesis, we examined loss of heterozygosity on chromosome 3p in 58 HNSCCs using 10 microsatellite markers. Mutagen sensitivity was determined in vitro by quantitating bleomycin-induced chromatid breaks utilizing peripheral blood lympocytes from respective patients. Forty-six of the 58 invasive cancers showed allelic loss at one or more loci. Consistent with previous investigations, three discrete regions of deletions were identified: 3p13-14.2, 3p21.1-21. 2, and 3p25.1-26.1. The frequency and types of deletions were dependent upon tobacco and alcohol exposures. The distal region of 3p but not the remaining two regions was most frequently influenced by tobacco exposure. In contrast, heavy alcohol use when combined with tobacco use was associated with whole-arm loss of 3p rather than identifiable site-specific damage. Furthermore, this combined influence of alcohol and tobacco exposures on whole-arm loss was most apparent in those patients who expressed mutagen-sensitivity; the odds ratio of whole-arm loss increasing from 2.67 (95% CI 0. 21-33.49) in those individuals who were mutagen resistant to 13.5 (95% CI 1.3-136.0; P = 0.02 by Fisher's exact test) in those who were mutagen sensitive. An assessment of clinical parameters in this population demonstrated that patients with whole-arm loss were more likely to present with cervical lymph node metastases and advanced stage disease than patients with partial losses. Results indicate that various environmental exposures as well as the expression of mutagen sensitivity will influence the types of chromosome 3p allelic losses in head and neck cancers as well as the behavior of disease once it develops.

Screening for head and neck cancer is underutilized. Given that lack of knowledge of the risk factors may partially account for screening underutilization. we surveyed subjective risk and knowledge of risk factors for head and neck cancer among 124 individuals who attended a free. hospital-based head and neck cancer screening. Few participants were current smokers. Most attendees perceived their risk as similar to others of their age and sex. Personal health habits comprised almost all of the risk-decreasing factors, yet less than half of the risk-increasing factors. generated. Personal habits were less frequently endorsed than factors such as pollution and heredity. Those who mentioned a risk behavior, or a family cancer history, reported higher subjective risk. Those who mentioned a personal health habit reported lower subjective risk. Results highlight needed efforts to increase screening among high-risk individuals through targeted education messages.

Combining degenerate oligonucleotide-primed PCR (DOP-PCR) with comparative genomic hybridization (CGH) has made it possible to analyze genomic changes in single cells. Although DOP-PCR-CGH methodology has been reported, the reproducibility of the method has been uncertain. We have developed a reproducible DOP-PCR-CGH protocol by systematically evaluating different labeling methods (including nick translation, PCR incorporation, and random-primed labeling) and different hybridization mixtures (including amplified test DNA vs. amplified reference DNA, termed homo-hybridization; and amplified test DNA vs. unamplified reference DNA or vice versa, termed hetero-hybridization). We have analyzed DNA samples obtained from 16 tissue sources including fresh/frozen normal and tumor samples, formalin fixed and paraffin embedded tumor tissue, and tumor cell lines by using differently labeled probes and hybridization combinations, and we calculated the corresponding rate (CR) of DOP-PCR-CGH with standard CGH. We found that homo-hybridization produced reproducible results with high CRs as compared to standard CGH (91–100% CR, mean 97%); In contrast, hetero-hybridization failed to generate reproducible hybridization with low CRs (57–97% CR, mean 80%; χ2 = 1245.8, P < 0.0001), high background, uneven hybridization, and false deletions or amplifications. In addition, our improved DOP-PCR protocol raised the amplification efficiency at least five times as compared to previously reported protocols, allowing for the detection of genomic imbalances in as little as 12.5 pg of starting DNA. In conclusion, the DOP-PCR-CHG homo-hybridization method, especially when combined with labeling by nick translation, is reliable and reproducible. The method can be used in screening for genomic imbalances using minute amounts of tumor DNA, thereby facilitating CGH application. Genes Chromosomes Cancer 28:395–403, 2000. © 2000 Wiley-Liss, Inc.

Background A complete in vitro multi-stage carcinogenesis model for oral cancer was developed to examine chemopreventive strategies. In the present study, the effects of EGCG [(−)-epigallocatechin-3-gallate], the major constituent of green tea, is being examined to understand mechanisms of action. Methods Effects of EGCG on the cell populations were examined with growth assays, cell cycle analysis, and western blots for retinoblastoma protein (pRB). Results In each cell type, EGCG inhibited growth, with a decrease in efficacy as cells progressed from normal to cancer. A G1 block was induced with an increase in the underphosphorylated form of pRB; EGCG-induced inhibition was not permanent, cells recovered, and no resistance developed. Conclusions Our multistage carcinogenesis model for chemoprevention was effective in defining the chemopreventive value of EGCG. The observation that cancerous oral epithelium was less responsive than normal or dysplastic tissues has implication in the use of this agent, and the mechanisms responsible for this result remain to be defined. © 1998 John Wiley & Sons, Inc. Head Neck20: 528–534, 1998.

Background Our study is a prospective evaluation of unresectable malignant cancers of the head and neck treated with concomitant chemotherapy and radiotherapy (RT) using delayed accelerated fractionation (concomitant boost). Methods Between January 1988 and March 1995, 82 patients with unresectable cancers of the head and neck were enrolled in this phase II study. Of these, 52 patients were treated and followed for a minimum of 3 years and are the subject of this analysis. All patients had T4 lesions and were stage IV according to the American Joint Committee on Staging Criteria (AJCC). Patients received RT with accelerated fractionation to a total of 70 Gy in 6 weeks using a concomitant-boost technique. Concomitant cis platin (100 mg/M2) was given on days 1 and 22 of RT. Twenty-seven patients received mitomycin-C (7.5 mg/M2) on days 1 and 22, and 1 patient received mitomycin-C on day 1. In addition, 27 patients received adjuvant chemotherapy with cis platin and vinblastine. The mean follow-up was 45 months (range, 36–72 months). The minimum follow-up for surviving patients is 3 years. Results At 3 years, the local control rate was 58%. Three-year local control rates for paranasal sinus, nasopharynx, oropharynx, and larynx/hypopharynx were 78%, 78%, 64%, and 100%, respectively. For all patients, the distant-metastasis-free survival was 56%, and the overall survival rate was 36%. Patients with oral cavity cancers experienced worse overall survival versus other sites, 0% versus 47% (p = .03). Salivary cancers also showed worse survival versus other sites, 0% versus 47%, but was not statistically significant. Severe acute complications occurred in 34% of patients. Treatment-related toxicity also resulted in the death of 2 patients. Severe late complications occurred in 7% of patients. Conclusions Treatment of this poor prognostic group of patients with aggressive chemotherapy and RT produced surprisingly good local control and survival. © 1998 John Wiley & Sons, Inc. Head Neck20: 497–503, 1998.

Background. Tongue cancer is seen with increasing frequency in young individuals. There is controversy concerning the clinical course and outcome for oral tongue cancer in young patients. Methods. A retrospective review of 36 patients under 40 years of age with squamous cell carcinoma of the tongue was performed. These patients were matched to an older population. The 5-year disease-free survival; rates of local, regional, and distant failure; and rate of second primary tumor were determined for both populations. Results. The 5-year disease-free survival for the young patients was 62% versus 69% in the older population (p =.30). Ten of 36 (28%) of younger patients recurred locally versus five of 36 (14%) of the older patients (p =.11). ). Nine of 36 (25%) younger patients recurred regionally in the younger group versus six of 36 (17%) patients in the older group (p=.25). Sixteen of 36 (44%) of the younger patients had locoregional failure versus eight of 36 (22%) of the older patients (p

BACKGROUND Two competing concepts, field cancerization and micrometastatic lesions, have been postulated to account for the high frequency of second primary tumors and multicentric dysplasia in patients with head and neck carcinoma. METHODS To provide insight into this process, the authors examined histologically normal mucosa and dysplastic tissue adjacent to invasive tumor for loss of heterozygosity (LOH) at three commonly deleted loci. Tissues from 21 patients with carcinoma of the oral cavity and oropharynx were identified and verified by a pathologist to contain histologically normal mucosa, dysplasia, and adjacent invasive squamous cell carcinoma. Each specimen was analyzed for LOH at D9S171 (9p21), D3S1007 (3p21.3-22), and D3S1228 (3p14). RESULTS Of the 21 patients, 19 had adequate DNA for analysis. Seventeen patients were heterozygous at one or both of the 3p sites and LOH occurred in 6 of 17 invasive tumor specimens, 1 of 17 dysplasia specimens, and in none of the mucosal specimens. LOH at 9p21 occurred in 11 of 13 informative specimens of invasive tumor, 8 of 13 dysplasia specimens, and 6 of 13 normal mucosa specimens. However, one case that did not have 9p deletion in the tumor demonstrated LOH in the mucosa and two cases had LOH in both the tumor and mucosa but with deletion of the opposite allele. CONCLUSIONS These data suggest that 9p21 but not 3p14 or 3p21 deletions occur in the absence of histologic changes. In two cases preinvasive and invasive lesions that apparently were an example of histologic progression contained disparate genetic events, calling into question the use of adjacent dysplasia as a model for premalignant lesions. Cancer 1998;82:1376-80. © 1998 American Cancer Society.

An in vitro model for oral cancer was used to examine the growth inhibitory effects of chemopreventive agents when used singly and in combination. The model consists of primary cultures of normal oral epithelial cells, newly established cell lines derived from dysplastic leukoplakia and squamous cell carcinoma. Two naturally occurring substances, (-)-epigallocatechin-3-gallate (EGCG) from green tea and curcumin from the spice turmeric were tested. Cells were treated singly and in combination and effects on growth determined in 5-day growth assays and by cell cycle analysis. Effective dose 50s and the combination index were calculated with the computerized Chou-Talalay method which is based on the median-effect principle. Agents were shown to differ in their inhibitory potency. EGCG was less effective with cell progression; the cancer cells were more resistant than normal or dysplastic cells. In contrast, curcumin was equally effective regardless of the cell type tested. Cell cycle analysis indicated that EGCG blocked cells in G1, whereas curcumin blocked cells in S/G2M. The combination of both agents showed synergistic interactions in growth inhibition and increased sigmoidicity (steepness) of the dose-effect curves, a response that was dose and cell type dependent. Combinations allowed for a dose reduction of 4.4-8.5-fold for EGCG and 2.2-2.8-fold for curcumin at ED50s as indicated by the dose reduction index (DRI). Even greater DRI values were observed above ED50 levels. Our results demonstrate that this model which includes normal, premalignant and malignant oral cells can be used to analyse the relative potential of various chemopreventive agents. Two such naturally-occurring agents, EGCG and curcumin, were noted to inhibit growth by different mechanisms, a factor which may account for their demonstrable interactive synergistic effect.

Background Deletion of 9p21 is a common event in many human tumors, including head and neck squamous cell carcinoma (HNSCC). The gene CDKN2, which encodes the protein p16, a cyclin-dependent kinase-4 inhibitor, maps to 9p21. The role of CDKN2 as the tumor suppressor gene in these neoplasms is unclear. The role of loss of heterozygosity (LOH) as a prognostic tool has not been described in HNSCC. Methods We performed deletion mapping using Southern and PCR-based LOH analysis and prospective survival analysis. Results We demonstrate that LOH of 9p and, specifically, the interferon (IFN) gene cluster correlates with recurrence of HNSCC. We also demonstrate two separate areas of deletion on 9p, one centromeric to IFNβ and telomeric to CDKN2 and the other centromeric to CDKN2 and telomeric to the polymorphic marker D9S19. All the deletions involve either the markers IFNα and/or D9S171 and D9S126 but not necessarily CDKN2. Conclusions These results suggest another tumor suppressor gene (TSG) may be involved in HNSCC carcinogenesis and may play a role in aggressive disease as manifest by local, regional, or distant recurrence. © 1998 John Wiley & Sons, Inc. Head Neck20: 113–118, 1998.

Head and neck cancer represents a paradigm for the prevention of environmentally induced diseases. Etiologic factors, including tobacco and alcohol, have been well established. Furthermore, disease development may depend not only upon such exposures but also upon a genetically defined susceptibility to exposure-induced DNA damage. As discussed in this review, the ability to identify etiologic factors, both external and host related, will lead to improved identification of individuals at risk. The development of novel strategies for cancer prevention will be promoted, among which lifestyle alteration will arguably play the most significant role. Therefore, this review places special emphasis on the translation of the understanding of disease into more effective behavioral modification strategies.

BACKGROUND: A feasibility chemoprevention trial of green tea and oral leukoplakia has been conducted. The purpose is to demonstrate the success and pitfalls of conducting such a population-based trial within Indian rural villages.METHODS: Two dosages of green tea were utilized: 3.6 g per day and 5.4 g per day. Compliance was measured using tea package counts and by measuring the blood concentration of the active anticancer compound in green tea, (-)-epigallo-catechin-3-gallate (EGCG).RESULTS: Following a 3-year planning period, 13 villages were visited, and 1,203 tobacco users were interviewed in order to identify 64 participants suitable for trial inclusion. Of the subsequently 28 consenting individuals entered, 23 remained on protocol for the entire 6-month duration, Overall compliance was excellent, with participants consuming approximately 80% of prescribed packets.CONCLUSIONS: These results provide a basis for continuing international collaborative efforts in conducting population-based chemoprevention trials against head and neck cancer. (C) 1997 by Excerpta Medics, Inc.

The development of head and neck cancer may depend not only on exposure to environmental carcinogens but also on a genetically based susceptibility to carcinogen-induced damage. This thesis presents a case-control study that demonstrates the significance of mutagen sensitivity, a measure of an individual's intrinsic DNA repair capacity against free radical damage, as a risk factor for the disease. As part of the case-control analysis, 167 previously untreated patients and 177 age- and sex-matched healthy controls were assessed for various lifestyle factors including tobacco and alcohol habits, occupational exposures, and diet. Mutagen sensitivity expressed by each individual was determined by quantifying bleomycin-induced chromosomal breaks within peripheral blood lymphocytes in vitro. Consistent with our initial observations and those of others, mutagen hypersensitivity was strongly associated with increased risk of head and neck cancer (odds ratio, 4.95; 95% confidence interval, 2.67 to 9.17) after adjusting for age, sex, and race. Low intake of vitamins C and E was also associated with an increased risk of disease and was interactive with mutagen sensitivity in risk estimates. Individuals with both a low intake of various antioxidants and increased chromosomal sensitivity to oxidant-induced DNA damage were at greatest risk. This study supports the concept that the risk of head and neck cancer is determined by a balance of factors that either enhance or protect against free radical oxygen damage, including innate capacities for DNA repair.

Cyclooxygenase may be important in the pathogenesis of smoking-related cancer because it activates carcinogens and catalyzes prostaglandin biosynthesis. We determined the effects of benzo[a]pyrene (B[a]P), a polycyclic aromatic hydrocarbon in tobacco smoke, on cyclooxygenase-2 (Cox-2) mRNA, protein and synthesis of prostaglandin E2 (PGE2) in normal and transformed oral epithelial cells. Treatment with B[a]P caused a dose-dependent increase in production of PGE2, with a maximal increase of approximately 100%. Enhanced synthesis of PGE2 was associated with increased amounts of Cox-2 protein. B[a]P also caused a two-fold increase in Cox-2 mRNA in both normal and transformed cells. Transient transfections with a Cox-2 promoter construct showed that B[a]P-mediated induction of Cox-2 mRNA reflected increased transcription. Levels of Cox-1 were unaffected by B[a]P. B[e]P did not affect the synthesis of PGE2 or amounts of Cox-2. These data are important because B[a]P-mediated induction of Cox-2 may predispose to carcinogenesis by enhancing the production of mutagens and the synthesis of prostaglandins.

Background and Objective The objective of this study was to examine the question of whether unique spectral patterns were associated with cell proliferation and could be identified by comparing the fluorescence pattern of slow to rapid growing cells. Study Design/Materials and Methods: Three in vitro model systems, (A431 cells inhibited by EGF, serum-starved 3T3 fibroblasts, and normal oral epithelial cells exposed to TGFβ), were analyzed using fluorescence spectroscopy. Growth status was monitored by cell number, 3H-thymidine incorporation, and flow cytometry. Results The excitation spectra (λex 240–430 nm, λem 450 nm) effectively distinguished slow and rapid growing cells in all three systems. Statistical analysis of the ratios of the main broad peak (320–350 nm) to a point on the down-slope of the curve at 370 nm was statistically significant. Ratios in the emission scan (λex 340 nm, λem 360–660 nm) could separate slow and rapid growing A431 and oral epithelial cells (P=0.0001 and P=0.023, respectively), but not slow and fast growing 3T3 cells (P=0.56). Conclusion Innate cellular fluorescence has the potential to discriminate proliferating and nonproliferating cell populations. Lasers Surg. Medicine 20:319–331, 1997. © 1997 Wiley-Liss, Inc.

Effective chemoprevention of aerodigestive tumors could have far-reaching effects. Aerodigestive cancer accounts for one-third of all cancer deaths in the United States and is the most common cancer in some areas of the world. Prognosis is poor, and a reduced quality of life remains in those who do survive. To date, there have been no effective chemopreventive agents, but many new compounds hold promise. The concepts of field carcinogenesis and multi step carcinogenesis underpin the development of chemopreventive agents for aerodigestive tract tumors. Important risk factors are tobacco use, alcohol consumption, dietary habits, genetic susceptibility, socioeconomic status, and the interaction of these. Two promising areas for surrogate biomarker development are tissue autofluorescence and DNA repair. Numerous chemoprevention trials have shown that antioxidant compounds are effective in reversing precursor lesions. Studies of the effects of chemopreventive agents on second primary tumors are ongoing. Finally, large-scale trials of the anti-oxidant beta carotene have been disappointing; they have shown that among heavy smokers and possibly heavy alcohol consumers beta carotene increases risk for lung cancer incidence and mortality. These findings underline the critical need to better understand specific mechanisms of action at a particular tissue site, and under various conditions, such as heavy smoking. Novel agents are under development: epigallacatchin gallate, or green tea, curcumin, and a new emphasis on folic acid. Studies to date show that targeting susceptible subgroups, by means of genetic or lifestyle factors, and all ethnic groups will facilitate the goals of chemoprevention studies.

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 Amplification of the cyclin D1 (CCND1) gene, which encodes a cell cycle regulating protein, has been described in several solid tumors including head and neck squamous cell carcinoma (HNSCC). While correlations between CCND1 amplification and tumor behavior have been suggested, no investigation has focused on risk factor exposure as a potential cause of CCND1 alteration. Methods Southern blotting was used to identify CCND1 amplification in 57 previously untreated HNSCC tumor specimens. Tissue from 27 cases was analyzed for CCND1 mRNA expression by Northern blot analysis. Results In 13/57 (23%) cases, a 2–5 fold amplification of CCND1 was found. CCND1 mRNA expression was higher in amplified than in non-amplified tumors and supported an association between CCND1 amplification and increased expression of CCND1 mRNA. No correlation was found between CCND1 amplification or CCND1 expression and clinical or pathological parameters. However, analysis of risk factor exposure revealed that patients with greater tobacco exposure were more likely to have tumors with CCND1 amplification (p = .037). Also, tobacco exposure was correlated with CCND1 expression in tumors. Conclusion Tobacco exposure is a well-known risk factor for HNSCC. CCND1 amplification and alterations in expression may be causally related to tobacco carcinogen exposure and lead to a loss of cell cycle regulation. HEAD & NECK 1996;18:512–521 © 1996 John Wiley & Sons, Inc.

PURPOSE We report our experience with simultaneous resection of residual masses above and below the diaphragm in patients with metastatic nomseminomatous germ cell tumor (NSGCT) of the testis. MATERIALS AND METHODS Twenty-four patients underwent simultaneous resection of residual postchemotherapy masses in the retroperitoneum and chest, including three who also had radical neck dissection. All had been heavily pretreated with chemotherapy and five had undergone previous retroperitoneal lymph node dissections (RPLNDs). RESULTS The combined procedure was performed with no mortality and low morbidity. The median length of the procedure was 5 hours 45 minutes, median blood loss 500 mL, and median length of hospital stay 9 days. Complications included one patient with chylous ascites and one with a prolonged air leak, both of which resolved with conservative management. Eighteen patients had similar pathologic findings in all sites: 13 with necrosis only and five with teratoma only. Six patients had discordant pathology in the abdomen and chest, including one with viable tumor in the chest only and two with viable tumor in the abdomen only. The overall actuarial 5-year survival rate for all patients was 79%. CONCLUSION Simultaneous resection of neck, chest, and abdominal residual masses after chemotherapy for germ cell tumors is both a feasible and safe alternative to staged excision in selected patients who require surgical intervention at multiple sites and fulfills the objective of rendering patients disease-free in a single operative procedure.

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

The purpose of a cancer staging system is to encompass all attributes of a tumor that define its life history. We propose a biological staging system which incorporates all of the phases of the natural history of head and neck cancer beginning with the earliest cellular changes extending through the early phase of invasion to the occurrence of metastasis and, finally, culminating in therapeutically refractory disease. This temporally structured system recognizes the importance of constitutional predisposition, and the impact of environmental factors. The intent is to augment the AJCC/UICC staging system and use this system to provide a framework which will easily incorporate current and future advances in basic science, prevention, therapy and palliation which will improve the quality and quantity of life for patients.

Polarized light propagating through the tissue retains the polarization information. The temporal profiles of the degree of polarization of the output light depends on the wavelength of the light and the type of the tissue that it propagates.

A method has been established for the routine culture for normal oral epithelial (NOE) cells based on simple methodology and commercially available materials. Normal mucosa was obtained from surgical resections of cancer patients, oropharyngeal mucosa, or pediatric tonsillectomies, anterior tonsillar pillar. NOE cells were allowed to outgrow using explant outgrowth techniques on whole mucosa or the dispased epithelial component. Outgrowth in AmnioMax-C100 medium (Gibco) followed by cell passaging in KGM (Clonetics) using Primaria (Falcon) tissue culture dishes produced reproducible growth, a reflection of a high rate of cell proliferation. Using this technique, cells maintain log phase growth for 2 cell passages, a minimum of 10–20 population doublings, and over 108 cells can be easily obtained from most specimens, if desired. The growth potential of NOE cells from individual clinical specimens can be predicted by cell size on a particle counter. If the mean population diameter is approximately 15 μm or less, cells exhibit good log phase growth whereas if the diameter is greater than 16 um, growth is poor. NOE cells cultured by this method show typical epithelial morphology, have desmosomal junctions, rest on an extracellular matrix, are positive for cytokeratin expression and are growth inhibited by TGF-β, a normal inhibitory growth regulator. In summary, using this technique, epithelial cells from human oral mucosa can be easily generated in sufficient quantity and quality for cell biological, biochemical and molecular studies.

To identify alterations in the biochemical composition and histoarchitectural structure of the lining epithelium that signal malignant transformation in carcinogen-exposed upper aerodigestive mucosa by quantitation of native cellular fluorescent properties.Case series.Head and Neck Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY.Thirty-one patients with previously untreated mucosal neoplasias of the oral cavity and pharynx were studied by means of a hand-held fiberoptic probe attached to a xenon lamp-based fluorescent spectrometer. Fluorescence analyses of the lesions and contralateral normal sites were performed in each patient on the basis of specific emission and excitation wavelengths. Differences between normal tissue and neoplastic mucosa were tested for statistical significance by paired t test and Hotelling's T2 test.The ratios of fluorescence intensities of neoplastic mucosa and contralateral normal sites were significantly different in three of the four fluorescence scans (excitation of 300 nm and emission of 320 to 580 nm; excitation of 340 nm and emission of 360 to 660 nm; and excitation of 200 to 360 nm and emission of 380 nm) when analyzed individually (P.05). The ratios in the scans with excitation of 240 to 430 nm and emission of 450 nm were not significantly different. All four scans, when analyzed together, demonstrated significant differences between normal and neoplastic tissues (P.01).Neoplastic mucosa of the upper aerodigestive tract within an individual patient will express native cellular fluorescent properties in vivo that differ from those of normal upper aerodigestive epithelia. This may represent a noninvasive screening method for head and neck squamous cell cancers.

Background : Change in epithelial thickness is part of the neoplastic transformation process of the upper aerodigestive tract. The quantitation of native cellular fluorescence (NCF) may represent a noninvasive means of distinguishing such a change. Patients and methods : Nineteen patients with squamous neoplasms and 12 surgical specimens from cancer patients were analyzed for NCF using a hand-held fiber optic probe attached to a fluorescent spectrometer. Tumors and normal sites were analyzed for fluorescence, and tissue samples were obtained. Ratios of intensities of various emitted wavelengths were computed to quantitate and compare various spectral patterns. These ratios were then correlated with mucosal thickness. Results : The 330 nm peak in the excitation scan (λEx 200 to 360 nm, λEm 380 nm) was lost in the tumors compared with the normal sites. The 390 nm peak in the emission scan (λEx 340 nm, λEm 360 to 660 nm) was also lost. The 290 nm/330 nm ratio in the in-vivo excitation scan (λEx 200 to 360 nm, λEm 380 nm) correlated with changes in epithelial thickness. The 390/450 ratio in the emission scan (λEx 340 nm, λEm 360 to 660 nm) correlated negatively with the mean epithelial thickness. Conclusions : Native cellular fluorescence analysis can identify changes in neoplastic tissues, including changes in epithelial thickness.

beta-carotene and other antioxidant nutrients, such as vitamin E, are well suited for widespread preventive use because they are nontoxic and easily given in supplement form. Intervention trials designed to show a reduction of cancer incidence in the general population are logistically and practically impossible for most types of cancer, including cancer of the oral cavity. Thus evidence for chemoprevention must be indirect, using laboratory and animal models, epidemiologic surveys, and trials showing reversal of premalignant lesions or cancer prevention in high-risk groups. In several animal models, beta-carotene and other antioxidant nutrients inhibit oral carcinogenesis. Epidemiologic studies consistently relate low intake of these nutrients with high cancer risk. Smokers have lower beta-carotene levels in plasma and oral mucosal cells than nonsmokers. Eight clinical trials have now shown that beta-carotene and vitamin E produce regression of oral leukoplakia, but chemoprevention studies in oral leukoplakia have limitations, which we review. All available evidence supports a significant role for antioxidant nutrients in preventing oral cancer.

Background. Patients with head and neck cancer who continue to smoke after diagnosis and treatment are more likely than patients who quit to experience tumor recurrence and second primary malignancies. Therefore, information about patients' smoking status and the factors associated with continued tobacco use are important considerations in the comprehensive care patients with head and neck cancer. Methods. Study participants were 144 patients with newly diagnosed squamous cell carcinomas of the upper aerodigestive tract who underwent surgical treatment, with or without postoperative radiotherapy or chemotherapy, 3-15 months before assessment of their postoperative tobacco use. Results. Among the 74 patients who had smoked in the year before diagnosis, 35% reported continued tobacco use after surgery. Compared with patients who abstained from smoking, patients who continued to use tobacco were less likely to have received postoperative radiotherapy, to have had less extensive disease, to have had oral cavity disease, and to have had higher levels of education. Hierarchical regression analysis indicated that most of the explained variance in smoking status could be accounted for on the first step of analysis by disease site. Interest in smoking cessation was high, and most patients made multiple attempts to quit. Conclusions. Although the diagnosis of a tobacco-related malignancy clearly represents a strong catalyst for smoking cessation, a sizable subgroup of patients continue to smoke. Patients with less severe disease who undergo less extensive treatment are particularly at risk for continued tobacco use. These data highlight the importance of developing smoking cessation interventions designed to meet the demographic, disease, treatment, and tobacco-use characteristics of this patient population. Cancer 1995;75:569-76.

Background The purpose of this article was to present the Beth Israel Medical Center experience using high-dose-rate intraoperative radiotherapy (HDR-IORT) in the management of recurrent head and neck cancer. Methods We conducted a retrospective review of all patients with locally or regionally recurrent head and neck cancer who underwent HDR-IORT at our institution between 2001 and 2010. Results Seventy-six patients were identified who underwent treatment to a total of 87 sites after gross-total resection. The 2-year estimate of in-field tumor control was found to be 62%. Median overall survival was 19 months with 42% of the patients surviving at least 2 years. Significantly longer survival was found for patients achieving in-field control versus infield progression (33 months vs 17 months, respectively; p = .01). Conclusion HDR-IORT is well tolerated and associated with encouraging in-field disease control. In-field control is associated with improved survival. Further study is warranted to more fully investigate HDR-IORT in the salvage setting. © 2013 Wiley Periodicals, Inc. Head Neck, 2013

To study non-cancer-related mortality rates over time and examine the possible causes for several major deaths in patients with oral cavity and oropharyngeal (OC/OP) cancer.Retrospective cohort analysis using the Surveillance, Epidemiology, and End Results (SEER) cancer registry data of the National Cancer Institute.Cause-specific mortality rates during the first year after diagnosis of OC/OP cancer were calculated for 4 cohorts (1980-1984, 1990-1994, 2000-2003, and 2004-2007). The percentage changes over time were calculated. Standardized mortality ratios (SMRs) for suicide, cardiovascular disease, and pneumonia were calculated and compared with patient demographic and clinical characteristics.We analyzed data for 32,487 patients in 4 cohorts. From 1980-1984 to 2004-2007, mortality from suicide increased by 406.2% (P = .01), cardiovascular disease-related and pneumonia-related mortality decreased by 45.9% (P.001) and 42.9% (P = .009), respectively, and rates of other non-cancer-related deaths did not change. Compared with the general population, patients diagnosed as having OC/OP cancer were at a significantly higher risk of mortality from suicide (SMR, 7.8; 95% CI, 4.6-12.4; P.001), cardiovascular disease (SMR, 2.4; 95% CI, 2.1-2.7; P.001), and pneumonia (SMR, 8.9; 95% CI, 6.8-11.5; P.001) during the first year after cancer diagnosis. Risk factors for increased mortality included age of 55 to 64 years, marital status (including never married, divorced, or separated), advanced tumor stage (including regional and distant disease), treatment with radiotherapy alone, and pharyngeal tumor location.Suicide rates have significantly increased in patients with OC/OP cancer since 1980 to 1984. Although cardiovascular disease-and pneumonia-related deaths have significantly decreased over time, they remain higher than the general US population. Increased knowledge of risk factors associated with non-cancer-related mortality in OC/OP cancer may lead to early intervention and enhanced overall survival.

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).

Mutations of the tumor-suppressor gene TP53 and amplification of CCND1 gene have been reported to occur frequently in head and neck squamous cell carcinomas (HNSQCC). In experimental systems, TP53 mutations have been shown to lead to genomic instability, including an increased propensity for gene amplification. We have examined 16 HNSQCC cell lines for the association between TP53 over-expression/mutation and CCND1 amplification. p53 over-expression was detected in 50% of the cell lines by immunohistochemistry using the monoclonal antibody (MAb) PAb1801. TP53 mutations were also detected in 50% of the cell lines by analysis of single-strand conformation polymorphism (SSCP) and DNA sequencing of exons 4 through 9. Six cell lines showed TP53 mutations and over-expression of the protein, 2 cell lines showed TP53 mutations but no p53 expression, and 2 cell lines showed over-expression of p53 protein but no TP53 gene mutations. CCND1 amplification was found in 38% of the cell lines by Southern blot analysis. Only 1 cell line showed both TP53 mutation and CCND1 amplification, whereas 7 of 8 cell lines with TP53 mutations had no CCND1 amplification. pRb expression was detected by Western blot analysis, and the level of pRb did not correlate with either CCND1 amplification or TP53 mutation. Our findings suggest that TP53 mutation and CCND1 amplification are common genetic alterations in HNSQCC and that the occurrence of either genetic event may be sufficient to abrogate normal cell cycle control.

Factors controlling glutathione metabolism may govern sensitivity to chemotherapeutic agents such as cisplatin. Using a battery of cell lines derived from previously untreated head and neck squamous cell carcinomas, we examined cisplatin resistance relative to (a) glutathione-S-transferase (GST)-pi gene amplification and expression, (b) basal and inducible GST-total and GST-pi enzymatic activity, and (c) cellular levels of reduced glutathione (GSH). Using Southern blot analysis and northern blot hybridization, no relationship between GST-pi gene amplification, mRNA expression and drug resistance could be identified. Despite the capacity of cisplatin to induce GST enzyme activity, the response was variable and unrelated to cisplatin responsiveness. However, an inverse relationship between GSH levels and cisplatin sensitivity was identified. To further clarify these effects, cells were treated with S-allyl cysteine (SAC), a thioallyl derivative isolated from garlic (Allium sativum), which altered cellular GSH in a biphasic manner. Pretreatment with SAC to lower cellular GSH levels followed by exposure to cisplatin significantly enhanced the cytotoxic effects of cisplatin, while SAC alone had no effect on cell growth.

Clonal chromosomal abnormalities were characterized in nine cell lines established from squamous cell carcinomas of the head and neck. Aneuploidy was a common feature; one cell line was near-diploid, three were near-triploid, four were near-tetraploid, and one cell line showed extensive variation in chromosome numbers. Consistent numerical abnormalities included loss of the sex chromosomes in six cell lines, losses of chromosomes 2 and 21 in six and five cell lines, respectively, and gain of chromosome 20 in five cell lines. Recurrent structural rearrangements included del(10)(q22-q26) (seven cell lines), i(5)(p10) (six cell lines), i(8)(q10) (six cell lines), add(19)(q13) (six cell lines), del(4)(q21-q31.3) (five cell lines), i(3)(q10) (four cell lines), del(12)(p11.1-p12) (four cell lines), and add (18)(q21-q23) (four cell lines). Other changes were noted in lower frequencies. Loss of specific regions on chromosomes 2, 3p, 4q, 5q, 8p, 10q, 12p, 18q, 19q, and 21 suggests that they may represent sites of putative tumor suppressor genes, loss of which may play a role in the pathogenesis of squamous cell carcinomas of the head and neck. Alternatively, gain of chromosomal region 3q, 5p, and 8q due to isochromosome formation suggests that more than one mechanism is involved in malignant transformation. Cytogenetic evidence of gene amplification was found in two cell lines; as an hsr(11)(q 13) in one and as dmins in the other. The clonal karyotypes of four cell lines were compared with those of their respective primary tumors. In all cell lines, clonal evolution had occurred, with loss of some rearrangements present in the primary tumors or the gain of additional abnormalities.

The capacity to identify subclinical neoplastic disease of the upper aerodigestive tract (UADT) using tissue autofluorescent spectroscopy would significantly contribute to cancer screening. Rats received N-nitrosomethyl benzylamine (NMBA), a carcinogen shown to cause esophageal malignancies. Following sacrifice at early weekly intervals, gross assessment of esophageal mucosa of NMBA-exposed rats was indistinguishable from saline-treated controls. Histopathologic evaluation, however, revealed NMBA-induced preneoplastic changes in the epithelium. Concurrent with these changes, the NMBA-exposed rats demonstrated specific alterations in autofluorescence. These results demonstrate that NMBA-induced esophageal premalignancy can be distinguished by autofluorescent properties. The capacity to detect alterations in autofluorescence may allow more sensitive screening of UADT mucosa at risk for cancer development.

Background Thyroid cancer, as with other types of cancer, is dependent on angiogenesis for its continued growth and development. Interestingly, estrogen has been shown to contribute to thyroid cancer aggressiveness in vitro, which is in full support of the observed increased incidence of thyroid cancer in women over men. Provided that estrogen has been observed to contribute to increased angiogenesis of estrogen responsive breast cancer, it is conceivable to speculate that estrogen also contributes to angiogenesis of estrogen responsive thyroid cancer. Methods In this study, three human thyroid cancer cells (B-CPAP, CGTH-W-1, ML-1) were treated with estrogen alone or estrogen and anti-estrogens (fulvestrant and 3,3′-diindolylmethane, a natural dietary compound) for 24 hours. The cell culture media was then added to human umbilical vein endothelial cell (HUVECs) and assayed for angiogenesis associated events. Vascular endothelial growth factor (VEGF) levels were also quantified in the conditioned media so as to evaluate if it is a key player involved in these observations. Results Conditioned medium from estrogen treated thyroid cancer cells enhanced phenotypical changes (proliferation, migration and tubulogenesis) of endothelial cells typically observed during angiogenesis. These phenotypic changes observed in HUVECs were determined to be modulated by estrogen induced secretion of VEGF by the cancer cells. Lastly, we show that VEGF secretion was inhibited by the anti-estrogens, fulvestrant and 3,3′-diindolylmethane, which resulted in diminished angiogenesis associated events in HUVECs. Conclusion Our data establishes estrogen as being a key regulator of VEGF secretion/expression in thyroid cells which enhances the process of angiogenesis in thyroid cancer. These findings also suggest the clinical utility of anti-estrogens as anti-angiogenic compounds to be used as a therapeutic means to treat thyroid cancer. We also observed that 3,3′-diindolylmethane is a promising naturally occurring anti-estrogen which can be used as a part of therapeutic regimen to treat thyroid cancer.

Edefonti, V Hashibe, M Ambrogi, F Parpinel, M Bravi, F Talamini, R Levi, F Yu, G Morgenstern, H Kelsey, K McClean, M Schantz, S Zhang, Z Chuang, S Boffetta, P La Vecchia, C Decarli, A eng CA100679/CA/NCI NIH HHS/ CA78609/CA/NCI NIH HHS/ P50CA90388/CA/NCI NIH HHS/ R01CA51845/CA/NCI NIH HHS/ R01DA11386/DA/NIDA 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/ Meta-Analysis Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't England 2011/11/30 06:00 Ann Oncol. 2012 Jul;23(7):1869-80. doi: 10.1093/annonc/mdr548. Epub 2011 Nov 28.; International audience; BACKGROUND: The association between dietary patterns and head and neck cancer has rarely been addressed. PATIENTS AND METHODS: We used individual-level pooled data from five case-control studies (2452 cases and 5013 controls) participating in the International Head and Neck Cancer Epidemiology consortium. A posteriori dietary patterns were identified through a principal component factor analysis carried out on 24 nutrients derived from study-specific food-frequency questionnaires. Odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were estimated using unconditional logistic regression models on quintiles of factor scores. RESULTS: We identified three major dietary patterns named 'animal products and cereals', 'antioxidant vitamins and fiber', and 'fats'. The 'antioxidant vitamins and fiber' pattern was inversely related to oral and pharyngeal cancer (OR=0.57, 95% CI 0.43-0.76 for the highest versus the lowest score quintile). The 'animal products and cereals' pattern was positively associated with laryngeal cancer (OR=1.54, 95% CI 1.12-2.11), whereas the 'fats' pattern was inversely associated with oral and pharyngeal cancer (OR=0.78, 95% CI 0.63-0.97) and positively associated with laryngeal cancer (OR=1.69, 95% CI 1.22-2.34). CONCLUSIONS: These findings suggest that diets rich in animal products, cereals, and fats are positively related to laryngeal cancer, and those rich in fruit and vegetables inversely related to oral and pharyngeal cancer.

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.

An assay employing the UV-mimetic mutagen 4-nitroquinoline-1-oxide (4NQO) to estimate a person's UV-sensitivity was developed. This sensitivity may be translated into an individual's susceptibility to acquire cutaneous malignancies. We used cytogenetic recordings on cultured lymphocytes from 103 normal individuals, 62 melanoma patients, and 71 patients with head and neck cancer. The frequency of chromosome damage (chromatid breaks) caused by exposure to 4NQO was used to measure sensitivity. Preliminary results showed that a significantly higher proportion of melanoma patients was 4NQO sensitive compared to the other two groups, whose 4NQO sensitivity was statistically not different. Although a number of theoretical and technical problems remain to be resolved and a great deal of additional information (especially clinical and epidemiological) is needed, it appears that 4NQO sensitivity may be effectively employed as a biological marker for identification of individuals at risk for melanoma (and possibly other cutaneous neoplasms as well).

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.

Evidence from several laboratories suggests that HPV plays a role in the etiology of squamous cell carcinomas of the oral cavity. A multifactorial risk factor profile for the development of oral cancer may include HPV in addition to well-established risk factors such as tobacco and alcohol use. The prevalence of oral carcinomas reported to be associated with HPV has varied widely due to differences in the sensitivity of the assay used for HPV detection. The aims of this study were: (1) to ascertain the prevalence of HPV DNA in oral squamous cell carcinomas using the most sensitive technique available, the polymerase chain reaction; (2) to determine the type of HPV in the tumors; and 3) to correlate the virologic data with other risk factor data obtained from patients' records. Fourteen (78%) of 18 primary tumors, 6 (67%) of 9 normal epithelial tissues from the patients and 5 (100%) of 5 neck metastases were HPV DNA-positive. Of the 14 HPV DNA-positive primary tumors, specific typing revealed HPV 16 in 2, HPV 18 in 2, HPV 16 and 18 in 5, HPV 6/11, 16 and 18 in 4, and HPV 6/11 in 1. HPV types in the normal or metastatic tissue were usually the same as those in the respective primary tumor. There was no significant association between HPV presence and any of 12 factors or patient characteristics studied.