Problématique : Bien que le tabac et l’alcool soient les facteurs causaux principaux des cancers épidermoïdes de l’oropharynx, le virus du papillome humain (VPH) serait responsable de l’augmentation récente de l’incidence de ces cancers, particulièrement chez les patients jeunes et/ou non-fumeurs. La prévalence du VPH à haut risque, essentiellement de type 16, est passée de 20% à plus de 60% au cours des vingt dernières années. Certaines études indiquent que les cancers VPH-positifs ont un meilleur pronostic que les VPH- négatifs, mais des données prospectives à cet égard sont rares dans la littérature, surtout pour les études de phase III avec stratification basée sur les risques. Hypothèses et objectifs : Il est présumé que la présence du VPH est un facteur de bon pronostic. L’étude vise à documenter la prévalence du VPH dans les cancers de l’oropharynx, et à établir son impact sur le pronostic, chez des patients traités avec un schéma thérapeutique incluant la chimio-radiothérapie. Méthodologie : Les tumeurs proviennent de cas traités au CHUM pour des cancers épidermoïdes de la sphère ORL à un stade localement avancé (III, IVA et IVB). Elles sont conservées dans une banque tumorale, et les données cliniques sur l’efficacité du traitement et les effets secondaires, recueillies prospectivement. La présence du VPH est établie par biologie moléculaire déterminant la présence du génome VPH et son génotype. Résultats: 255 spécimens ont été soumis au test de génotypage Linear Array HPV. Après amplification par PCR, de l’ADN viral a été détecté dans 175 (68.6%) échantillons tumoraux ; le VPH de type 16 était impliqué dans 133 cas (52.25 %). Conclusion: Une proportion grandissante de cancers ORL est liée au VPH. Notre étude confirme que la présence du VPH est fortement associée à une amélioration du pronostic chez les patients atteints de cancers ORL traités par chimio-radiothérapie, et devrait être un facteur de stratification dans les essais cliniques comprenant des cas de cancers ORL. / Background: HPV is recognised as a good prognostic factor in head and neck (H&N) cancer. However, most of the data is derived from randomised trials with different treatment options or small heterogeneous cohorts. This trial aims to determine the prevalence and prognostic impact of HPV on overall survival (OS), disease-free survival (DFS), local regional control (LRC) and treatment toxicity, in patients with locally advanced SCCHN treated with concomitant platinum-based chemoradiation therapy (CRT) and followed prospectively. Methods: Prospective data on efficacy and toxicity was available for 560 patients treated with CRT. Of these, 270 fixed and paraffin embedded specimens were collected. DNA was extracted from specimens and HPV detection was performed as previously described (Coutlée, J Clin Microbiol, 2006). Analysis was performed using Kaplan-Meier survival curves, Fisher's test for categorical data and log-rank statistics for failure times. Results: Median follow-up was 4.7 years. DNA extraction was successful in 255 cases. HPV prevalence was 68.6%, and 53.3% for HPV-16 specifically. For HPV+ and HPV- respectively, median LRC were 8.9 and 2.2 years (log-rank p = 0.0002), median DFS were 8.9 and 2.1 years (log-rank p=0.0014) and median OS were 8.9 and 3.1 years (log-rank p=0.0002). Survival was statistically significantly different based on HPV genotype, stage, treatment period and chemotherapy regimen. COX adjusted analysis for T, N, age, and treatment remained significant (HR 0.45, p=0.004). Subgroup analysis for genotype, TNM, primary site and chemotherapy regimen will be presented at the meeting. Conclusions: An increasing proportion of oropharyngeal cancer is linked to HPV. This large study with confirms that HPV status is strongly associated with improved prognosis among H&N cancer patients receiving CRT, and should be a stratification factor for clinical trials including H&N cases. Toxicity of CRT is not modified for the HPV population.

Problématique: Le virus du papillome humain (VPH) est présent dans près de 50% des cancers de l’oropharynx. Le potentiel oncogénique du VPH est encodé dans les oncoprotéines E6 et E7, qui agissent en modulant différents gènes, dont les gènes suppresseurs de tumeur p53 et pRb. Les cellules VPH positives démontrent une altération au niveau de la signalisation de la réponse aux dommages à l’ADN (RDA), un mécanisme de contrôle dans l’arrêt de la croissance des cellules ayant subit des dommages au niveau de leur ADN. Hypothèse et objectifs : Nous croyons que les défauts au niveau de la RDA des cancers VPH positifs peuvent être exploités afin de sensibiliser préférentiellement les cellules cancéreuses aux traitements de radiothérapie. Cette stratégie de recherche nécessite l’élaboration d’un modèle cellulaire de carcinogenèse isogénique pour le cancer de l’oropharynx que nous proposons de développer et de caractériser. L’étude vise à dériver des lignées isogéniques à partir de kératinocytes primaires et cellules épithéliales de l’oropharynx pour ensuite valider la carcinogenèse de notre modèle in vitro & in vivo Méthodologie : Des lignées cellulaires de kératinocytes primaires et de cellules épithéliales de l’oropharynx ont été successivement modifiées par transduction afin de présenter les mutations associées aux cancers de l’oropharynx induits par le VPH. Les cellules ont été modifiées avec des lentivirus codants pour la télomérase (hTERT), les oncogènes E6, E7 et RasV12. Afin de valider la cancérogenèse in vitro de notre modèle, des études d’invasion en matrigel et de croissance sans ancrage en agar mou ont été réalisées. Les populations cellulaires transformées ont été ensuite introduites dans des souris immunodéficientes afin d’évaluer leur tumorogénicité in vivo. Résultats : À partir des plasmides recombinés construits par méthodes de clonage traditionnelle et de recombinaison « Gateway », nous avons produit des lentivirus codants pour la télomérase humaine (hTERT), les oncogènes viraux E6 et E7 et l’oncogène Ras. Les kératinocytes primaires et cellules épithéliales de l’oropharynx ont été infectés successivement par transduction et sélectionnés. Nous avons validé l’expression de nos transgènes par méthode d’immunofluorescence, de Western Blot et de réaction de polymérisation en chaîne quantitative en temps réel (qRT-PCR). Nous avons établi trois lignées des cellules épithéliales de l’oropharynx (HNOE) à partir d’échantillons tissulaires prélevés lors d’amygdalectomie (HNOE42, HNO45, HNOE46). Les cellules transduites avec le lentivirus exprimant le promoteur fort CMV/TO de l’oncogène RasV12 ont présenté un changement morphologique compatible avec une sénescence prématurée induite par l’oncogène Ras. En exprimant des quantités plus faibles du RasV12 mutant, la lignée cellulaire HEKn hTERT-E6-E7 PGK RasV12 a réussi à échapper à la sénescence induite par l’oncogène Ras. La population cellulaire exprimant HEKn hTERT-E6-E7-PGK RasV12 a présenté un phénotype malin en culture et à l’étude d'invasion, mais n’a pas démontré de résultats positifs à l’étude de croissance sans ancrage en agar mou ni en xénogreffe en souris immunodéficientes. Conclusion : Nos résultats démontrent qu’en présence des oncogènes viraux E6 et E7, il y a un troisième mécanisme suppresseur de tumeur qui médie la sénescence induite par l’oncogène Ras. Nous avons identifié que la présence de E6 seule ne suffit pas à immortaliser les kératinocytes primaires humains (HEKn). Nous n’avons pas réussi à créer un modèle in vitro de carcinogenèse pour les cancers de l’oropharynx induits par le VPH. / Background: Human papillomavirus (HPV) is present in almost 50% of all oropharyngeal cancers. The oncogenic potential of HPV is encoded by the E6 and E7 oncoproteins, which act by modulating different genes, including tumour suppressor genes p53 and pRb. The process of inactivation of p53 and pRb is largely responsible for the genomic instability that contributes to malignant transformation of cells. HPV-positive cancer cells show an alteration in their DNA Damage Response (DDR) signalling pathway that allows them to inhibit key tumour suppressor genes and to ignore DNA damage signals. Hypothesis and objectives: We believe that these DDR defects can be exploited to preferentially sensitize cancerous cells to radiotherapy by using a defined cell culture model. We propose to characterize a defined cell culture model for HPV induced oropharyngeal cancer. Derive isogenic cell culture lines from primary skin keratinocytes and oropharyngeal epithelial cells. and to validate the carcinogenesis of our model in vitro and in vivo. Methods: We propose to use primary skin keratinocytes and oropharyngeal epithelial cells which will be sequentially modified by transduction using a Gateway Lentiviral System to present the mutations associated with HPV induced oropharyngeal cancer. The cells will be modified with lentivirus encoding the human telomerase (hTERT), E6, E7 and Ras oncogenes. To validate the in vitro carcinogenesis of our model, we will assess anchorage independent growth and invasiveness by means of soft agar medium and matrigel studies. To assess in vivo tumorigenicity, the transformed cell populations will be introduced into immunodeficient mice. Results: We constructed recombinant lentivector plasmids using traditional cloning and Gateway recombination methods. Using the constructed lentivectors, we generated lentiviruses encoding the catalytic subunit for human telomerase (hTERT), the E6 and E7 viral oncogenes and Ras oncogene. Primary keratinocytes and oropharyngeal epithelial cells were infected successively by transduction with the above-mentioned lentiviruses and then underwent selection. We validated the expression of our transgenes by methods of immunofluorescence, Western blot and real-time quantitative polymerase chain reaction (qRT-PCR). We have successfully established and kept in culture three lines of epithelial oropharyngeal cells (HNOE42, HNOE45, HNOE46) from tissue samples collected during tonsillectomy. Cells transduced with lentivirus expressing CMV/TO, a strong promoter for the RasV12 oncogene, showed morphological changes compatible with premature Ras oncogene induced senescence. Cell line HEKn hTERT-E6-E7 PGK RasV12 managed to escape Ras oncogene induced senescence by expressing lower amount of mutated RasV12. The HEKn hTERT-E6-E7-PGK RasV12 cell line presented a malignant phenotype in culture and on matrigel invasion assay. However, soft agar assay for anchorage independent cell growth and xenograft assay in immunodeficient mice were both negative for tumorigenicity. Conclusion: Our results demonstrate that in the presence of E6 and E7, a third tumor suppressor mechanism mediates Ras oncogene induced senescence. Furthermore, we have found that the presence of E6 alone is not sufficient to immortalize primary human keratinocytes (HEKn). We have not managed to create an in vitro carcinogenesis cell culture model for HPV induced oropharyngeal cancer.

O selênio é um micronutriente essencial que apresenta ação antioxidante por meio de selenoproteínas, como a glutationa peroxidase 1 (GPX1). O polimorfismo PRO198LEU no gene em questão tem sido relacionado ao aumento do risco para alguns tipos de câncer, como o de mama e pulmão. Atualmente, o câncer de cabeça e pescoço é um importante problema de saúde pública no mundo e, inclusive, no Brasil. O objetivo do presente estudo foi avaliar eventual associação entre o polimorfismo GPX1 PRO198LEU e risco de câncer epidermóide da cavidade oral e orofaringe, bem como possível interação com utilização de tabaco e ingestão de álcool. O genótipo para o polimorfismo GPX1 PRO198LEU foi determinado pela técnica de PCR-RFLP (Reação em cadeia da polimerase - Polimorfismo no comprimento do fragmento de restrição) e seqüenciamento do DNA em 175 pacientes com câncer epidermóide da cavidade oral e orofaringe (grupo caso) integrantes de parte da casuística do Projeto Genoma Clínico do Câncer de Cabeça e Pescoço, e em 203 indivíduos sem a doença, internados nas enfermarias do Hospital Heliópolis (grupo controle). A freqüência do alelo de referência e do polimórfico foi de 0,72 e 0,28, respectivamente, em ambos os grupos. A freqüência dos genótipos encontrou-se em equilíbrio de Hardy-Weinberg nos grupos caso e controle. Não houve diferença estatisticamente significante (p>0,05) quanto à distribuição do genótipo para o polimorfismo GPX1PRO198LEU entre casos (50% PRO/PRO; 43% PRO/LEU e 7% LEU/LEU) e controles (51% PRO/PRO; 43% PRO/LEU e 6% LEU/LEU), não se verificando associação entre esse polimorfismo e risco para o câncer epidermóide da cavidade oral e orofaringe (Odds ratio = 1,02; 95% IC = 0,68-1,53; p = 0,51; homozigotos polimórficos e heterozigotos agrupados comparados a homozigotos de referência). Além disso, a utilização de tabaco ou ingestão de álcool não modificou a ausência de associação entre o polimorfismo GPX1 PRO198LEU e o câncer em questão (Utilização de tabaco maior que 20 pack years: Odds ratio = 0,94; 95% IC = 0,53-1,70; p = 0,49; Ingestão de álcool maior que 80g de etanol/dia: Odds ratio = 0,80; IC = 0,46-1,39; p = 0,26). Conclui-se que esse polimorfismo não aumenta o risco para o câncer epidermóide da cavidade oral e orofaringe. / Selenium is an essential micronutrient that presents antioxidant activity through selenoproteins such as glutathione peroxidase 1 (GPX1). PRO198LEU polymorphism in this gene has been associated with increased risk for some cancer types such as breast and lung cancers. Currently head and neck cancer is a major public health problem in the world and in Brazil. The aim of this study was to evaluate a possible association between GPX1 PRO198LEU polymorphism and risk of oral cavity and oropharyngeal squamous cell cancer. GPX1 PRO198LEU polymorphism genotype was determined by PCR-RFLP method (Polymerase chain reaction-Restriction fragment length polymorphism) and DNA sequencing in 175 patients with oral cavity and oropharyngeal squamous cell cancer (case group) from the Head and Neck Cancer Clinical Genome Project, and in 203 cancer-free individuals, hospitalized in the wards of Heliopolis Hospital (control group). The frequency of reference and polymorphic allele was 0.72 and 0.28, respectively, in both groups. The genotype distribution was in Hardy-Weinberg equilibrium in case and control groups. There was no statistically significant difference (p> 0.05) on the distribution of genotype for the GPX1 PRO198LEU polymorphism between cases (50% PRO/PRO, 43% PRO/LEU and 7% LEU/ LEU) and controls (51% PRO/PRO, 43% PRO/LEU and 6% LEU/LEU) and there was no association between this polymorphism and risk for oral cavity and oropharyngeal squamous cell cancer (odds ratio = 1.02, 95% CI = 0.68 to 1,53; p = 0.51; polymorphic homozygotes and heterozygotes combined compared with reference homozygotes). Furthermore, the use of tobacco or alcohol intake did not change the lack of association between the GPX1 PRO198LEU polymorphism and cancer risk (use of tobacco greater than 20 pack years: odds ratio = 0.94, 95% CI = 0.53 to 1,70, p = 0.49; alcohol intake greater than 80g etanol/day: Odds ratio = 0.80, CI = 0.46 to 1.39, p = 0.26). We conclude that this polymorphism does not increase the risk of oral cavity and oropharyngeal squamous cell cancer.

Die chirurgische und strahlentherapeutische Behandlung oropharyngealer Tumoren führt häufig zu einer Beeinträchtigung des Schluckens und Sprechens. Das Ziel dieser Arbeit ist die Untersuchung des Schweregrades der Schluck- und Sprechprobleme bei Patienten, die wegen Tumoren der Regio tonsillaris nach unterschiedlichen Operationsmethoden behandelt wurden. 54 Patienten mit oropharyngealen Tumoren (unterteilt nach den Operationsmethoden: A: Tumortonsillektomie; B: Oropharynxteilresektion mit primärem Wundverschluß; C: Oro-pharynxteilresektion mit plastischer Rekonstruktion) wurden mittels Befragung, mit einem standarisierten Fragebogen, einem kompletten HNO-Status inklusive transnasaler Endo-skopie, mit drei unterschiedlichen Sprachverständlichkeitstests und einer Röntgenkine-matographie untersucht. Die besten funktionellen Resultate (sowohl der Schluck- als auch der Sprechfunktion) zeigten sich in Gruppe A, während sich in den Gruppen B und C deutlich schlechtere Ergebnisse fanden. Zwischen den Gruppen B und C ließen sich nur geringe Unterschiede feststellen. Die statistische Analyse konnte eine positive Korrelation der Ergebnisse innerhalb der Sprach-verständlichkeitstests sowie der drei Tests untereinander nachweisen. Die Arbeit zeigt, daß durch Oropharynxteilresektionen mit primärem Wundverschluß und mit plastischer Rekonstruktion annähernd gleichwertige Resultate erzielt werden, obwohl der operationsbedingte Gewebedefekt vor plastischer Rekonstruktion deutlich größer ist. Diese Ergebnisse widersprechen einigen Literaturangaben, die schlechtere funktionelle Ergebnisse nach plastischer Rekonstruktion beschreiben. Die Arbeit zeigt außerdem, daß sich die drei verwendeten Sprachverständlichkeitstests für die Untersuchung der beeinträchtigten Sprech-funktion nach operativer Behandlung oropharyngealer Tumoren eignen. / The surgical and radiotherapeutical treatment of oropharyngeal tumors often results in swallowing and speech malfunction. The purpose of this study is to investigate the severity of swallowing and speech malfunction in patients with tumors of the tonsillar region, which were treated by different surgical strategies. 54 Patients with oropharyngeal tumors (seperated according to the surgical strategy: A: radical tonsillectomy; B: partial oropharyngectomy and primary closure; C: partial oropharyngectomy and plastic reconstruction) were investigated by interrogation, a standardized questionaire, a full otorhinolaryngological examination including transnasal endoscopy, three different speech tests and a radiographic swallow examination. The best functional results (regarding swallow- as well as speech function) were found in group A. The functional results in group B and C were distinctly worse, but only minimal differences could be found between these two groups. Statistical analysis confirmed a positive correlation of the results of the three speech tests and beetween the three speech tests. The study shows very similar functional results after partial oropharyngectomy with primary closure and partial oropharyngectomy with plastic reconstruction, although the tissue defect before plastic reconstruction was distinctly greater. These results differ from some results in the literature, which describe worse functional results after plastic reconstruction. The study also shows the usability of the three speech tests to assess variant degrees of speech malfunction after surgical and radiotherapeutical treatment of oropharyngeal tumors.

O selênio é um micronutriente essencial que apresenta ação antioxidante por meio de selenoproteínas, como a glutationa peroxidase 1 (GPX1). O polimorfismo PRO198LEU no gene em questão tem sido relacionado ao aumento do risco para alguns tipos de câncer, como o de mama e pulmão. Atualmente, o câncer de cabeça e pescoço é um importante problema de saúde pública no mundo e, inclusive, no Brasil. O objetivo do presente estudo foi avaliar eventual associação entre o polimorfismo GPX1 PRO198LEU e risco de câncer epidermóide da cavidade oral e orofaringe, bem como possível interação com utilização de tabaco e ingestão de álcool. O genótipo para o polimorfismo GPX1 PRO198LEU foi determinado pela técnica de PCR-RFLP (Reação em cadeia da polimerase - Polimorfismo no comprimento do fragmento de restrição) e seqüenciamento do DNA em 175 pacientes com câncer epidermóide da cavidade oral e orofaringe (grupo caso) integrantes de parte da casuística do Projeto Genoma Clínico do Câncer de Cabeça e Pescoço, e em 203 indivíduos sem a doença, internados nas enfermarias do Hospital Heliópolis (grupo controle). A freqüência do alelo de referência e do polimórfico foi de 0,72 e 0,28, respectivamente, em ambos os grupos. A freqüência dos genótipos encontrou-se em equilíbrio de Hardy-Weinberg nos grupos caso e controle. Não houve diferença estatisticamente significante (p>0,05) quanto à distribuição do genótipo para o polimorfismo GPX1PRO198LEU entre casos (50% PRO/PRO; 43% PRO/LEU e 7% LEU/LEU) e controles (51% PRO/PRO; 43% PRO/LEU e 6% LEU/LEU), não se verificando associação entre esse polimorfismo e risco para o câncer epidermóide da cavidade oral e orofaringe (Odds ratio = 1,02; 95% IC = 0,68-1,53; p = 0,51; homozigotos polimórficos e heterozigotos agrupados comparados a homozigotos de referência). Além disso, a utilização de tabaco ou ingestão de álcool não modificou a ausência de associação entre o polimorfismo GPX1 PRO198LEU e o câncer em questão (Utilização de tabaco maior que 20 pack years: Odds ratio = 0,94; 95% IC = 0,53-1,70; p = 0,49; Ingestão de álcool maior que 80g de etanol/dia: Odds ratio = 0,80; IC = 0,46-1,39; p = 0,26). Conclui-se que esse polimorfismo não aumenta o risco para o câncer epidermóide da cavidade oral e orofaringe. / Selenium is an essential micronutrient that presents antioxidant activity through selenoproteins such as glutathione peroxidase 1 (GPX1). PRO198LEU polymorphism in this gene has been associated with increased risk for some cancer types such as breast and lung cancers. Currently head and neck cancer is a major public health problem in the world and in Brazil. The aim of this study was to evaluate a possible association between GPX1 PRO198LEU polymorphism and risk of oral cavity and oropharyngeal squamous cell cancer. GPX1 PRO198LEU polymorphism genotype was determined by PCR-RFLP method (Polymerase chain reaction-Restriction fragment length polymorphism) and DNA sequencing in 175 patients with oral cavity and oropharyngeal squamous cell cancer (case group) from the Head and Neck Cancer Clinical Genome Project, and in 203 cancer-free individuals, hospitalized in the wards of Heliopolis Hospital (control group). The frequency of reference and polymorphic allele was 0.72 and 0.28, respectively, in both groups. The genotype distribution was in Hardy-Weinberg equilibrium in case and control groups. There was no statistically significant difference (p> 0.05) on the distribution of genotype for the GPX1 PRO198LEU polymorphism between cases (50% PRO/PRO, 43% PRO/LEU and 7% LEU/ LEU) and controls (51% PRO/PRO, 43% PRO/LEU and 6% LEU/LEU) and there was no association between this polymorphism and risk for oral cavity and oropharyngeal squamous cell cancer (odds ratio = 1.02, 95% CI = 0.68 to 1,53; p = 0.51; polymorphic homozygotes and heterozygotes combined compared with reference homozygotes). Furthermore, the use of tobacco or alcohol intake did not change the lack of association between the GPX1 PRO198LEU polymorphism and cancer risk (use of tobacco greater than 20 pack years: odds ratio = 0.94, 95% CI = 0.53 to 1,70, p = 0.49; alcohol intake greater than 80g etanol/day: Odds ratio = 0.80, CI = 0.46 to 1.39, p = 0.26). We conclude that this polymorphism does not increase the risk of oral cavity and oropharyngeal squamous cell cancer.

Introdução. Há evidências de que a desigualdade social pode influenciar o prognóstico do câncer quando foram comparadas as taxas de sobrevida segundo o status socioeconômico, entretanto isso ainda não foi estudado no Brasil. Objetivo. Analisar a desigualdade social na determinação da sobrevida específica em um, três e cinco anos, de pacientes diagnosticados com câncer de boca e orofaringe em São Paulo. Metodologia. Utilizou-se a coorte de base hospitalar do grupo de pesquisa Genoma Clínico do Câncer de Cabeça e Pescoço (GENCAPO), à qual foram aplicados novos critérios de exclusão. Assim, foram analisados dados demográficos, socioeconômicos, comportamentais, sintomas autorreferidos e de condições clínicas de 1.154 pacientes, com diagnóstico de malignidade nas regiões de boca (C00.3-C06) e orofaringe (C09-C10), arrolados de 2001 a 2009 e acompanhados por cinco anos. A desigualdade social foi aferida pela escolaridade e a ocupação. As probabilidades acumuladas de sobrevida específica em um, três e cinco anos foram calculadas pelo método de Kaplan-Meier e as diferenças entre as curvas de sobrevida, pelo teste de Log-rank. A regressão de Cox univariada e múltipla possibilitou a análise dos fatores associados à sobrevida - Hazard Ratio (HR) com IC95%. Resultados. As probabilidades acumuladas de sobrevida específica em um, três e cinco anos para câncer de boca e orofaringe, foram de 74,72%, 49,86 e 42,46%, respectivamente. Baixa escolaridade (HR=1,25; IC95%=1,03-1,51) e realização de trabalhos manuais (HR=1,37; IC95%=1,05-1,78) foram associados à menor probabilidade de sobrevivência em cinco anos na análise não ajustada. A cor da pele preta/parda, tumor de tamanho T3 ou T4 e comprometimento de linfonodos foram fatores independentemente associados à menor sobrevida específica por câncer de boca e orofaringe em um, três e cinco anos. Disfagia e dificuldade respiratória foram associados à menor sobrevida específica em um ano. Em três anos, observou-se também a otalgia e em cinco anos, a dificuldade de deglutição. Conclusões. Foi identificada associação entre a desigualdade social, menor escolaridade e trabalho manual, à menor sobrevida em 5 anos. Esses fatores, na análise ajustada pelas características demográficas, tiveram sua associação potencialmente explicada pela cor da pele preta/parda. / Introduction. There is evidence that social inequality may influence the prognosis of cancer when comparing survival rates according to socioeconomic status, but this has not been studied in Brazil. Aim. To evaluate social inequality in the determination of one, three and five years specific survival of patients diagnosed with oral and oropharyngeal cancer in São Paulo. Methodology. A hospital-based cohort of the research group \"Clinical Genome of Head and Neck Cancer\" (GENCAPO) was used, applying new exclusion criteria. Demographic, socioeconomic, behavioral, selfreported symptoms and clinical conditions characteristics of 1,154 patients, diagnosed with malignancy in the mouth (C00.3-C06) and oropharynx (C09-C10) regions, included from 2001 to 2009 and followed up for five years, were analyzed. Social inequality was measured by schooling and occupation. The cumulative probabilities of one, three, and five years specific survival were calculated by the Kaplan-Meier method and differences between the survival curves by the log-rank test. Univariate and Multiple Cox Regression allowed to analyze the factors associated with survival - Hazard Ratio (HR) with 95% CI. Results. The accumulated probabilities of one, three and five years specific survival for oral and oropharyngeal cancer were 74.72%, 49.86 and 42.46%, respectively. Low schooling (HR = 1.25, 95% CI = 1.03-1.51) and manual work (HR = 1.37, 95% CI = 1.05-1.78) were associated with a lower survival probability at five years in the unadjusted analysis. Dysphagia and breathing difficulties were associated with lower one year specific survival. At three years, it was also observed earache, and at five years, swallowing difficulty. Conclusions. An association among social inequality, lower schooling and manual labor, with the lowest survival at 5 years, was identified. These results were potentially explained by black/brown skin color in the adjusted analysis for demographic characteristics.

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La candidose oro-pharyngée (COP) est l’infection opportuniste la plus répandue chez les patients infectés au VIH-1. Un modèle de COP chez la souris transgénique (Tg) exprimant une partie du génome du VIH-1 (CD4C/HIVMutA) est maintenant disponible. Grâce à ce modèle, il est possible d’étudier les perturbations quantitatives et fonctionnelles des macrophages exprimant les gènes nef, rev et env du VIH-1 dans le contexte d’une COP. Cette étude démontre que la présence du transgène n’influence pas le pourcentage des macrophages dans la muqueuse buccale et le petit intestin, malgré le fait que la charge buccale de C. albicans soit significativement plus élevée chez les souris Tg. Cependant, l’expression du transgène cause une diminution de la production de H2O2 par les macrophages, ainsi que l’augmentation de la production de la cytokine proinflammatoire IL-6 et de la chimiokine MCP-1. / Oro-pharyngeal candidiasis (OPC) is the most common opportunistic infection in HIV-1 infected patients. An OPC model using transgenic mice (CD4C/HIVMutA) expressing selected genes of the HIV-1 genome is now available. Using this model, it is now possible to study potential quantitative and functional disturbances in macrophages expressing the nef, rev and env genes of HIV-1 in the context of OPC. This study shows that transgene expression does not affect quantitative percentage values of macrophages in the oral mucosa and the small intestine, although burdens of C. albicans loads are increased in Tg mice. Transgene expression does induce diminished H2O2 production in macrophages, while increasing production of the proinflammatory cytokine IL-6 and the chemokine MCP-1.

Problématique : Bien que le tabac et l’alcool soient les facteurs causaux principaux des cancers épidermoïdes de l’oropharynx, le virus du papillome humain (VPH) serait responsable de l’augmentation récente de l’incidence de ces cancers, particulièrement chez les patients jeunes et/ou non-fumeurs. La prévalence du VPH à haut risque, essentiellement de type 16, est passée de 20% à plus de 60% au cours des vingt dernières années. Certaines études indiquent que les cancers VPH-positifs ont un meilleur pronostic que les VPH- négatifs, mais des données prospectives à cet égard sont rares dans la littérature, surtout pour les études de phase III avec stratification basée sur les risques. Hypothèses et objectifs : Il est présumé que la présence du VPH est un facteur de bon pronostic. L’étude vise à documenter la prévalence du VPH dans les cancers de l’oropharynx, et à établir son impact sur le pronostic, chez des patients traités avec un schéma thérapeutique incluant la chimio-radiothérapie. Méthodologie : Les tumeurs proviennent de cas traités au CHUM pour des cancers épidermoïdes de la sphère ORL à un stade localement avancé (III, IVA et IVB). Elles sont conservées dans une banque tumorale, et les données cliniques sur l’efficacité du traitement et les effets secondaires, recueillies prospectivement. La présence du VPH est établie par biologie moléculaire déterminant la présence du génome VPH et son génotype. Résultats: 255 spécimens ont été soumis au test de génotypage Linear Array HPV. Après amplification par PCR, de l’ADN viral a été détecté dans 175 (68.6%) échantillons tumoraux ; le VPH de type 16 était impliqué dans 133 cas (52.25 %). Conclusion: Une proportion grandissante de cancers ORL est liée au VPH. Notre étude confirme que la présence du VPH est fortement associée à une amélioration du pronostic chez les patients atteints de cancers ORL traités par chimio-radiothérapie, et devrait être un facteur de stratification dans les essais cliniques comprenant des cas de cancers ORL. / Background: HPV is recognised as a good prognostic factor in head and neck (H&N) cancer. However, most of the data is derived from randomised trials with different treatment options or small heterogeneous cohorts. This trial aims to determine the prevalence and prognostic impact of HPV on overall survival (OS), disease-free survival (DFS), local regional control (LRC) and treatment toxicity, in patients with locally advanced SCCHN treated with concomitant platinum-based chemoradiation therapy (CRT) and followed prospectively. Methods: Prospective data on efficacy and toxicity was available for 560 patients treated with CRT. Of these, 270 fixed and paraffin embedded specimens were collected. DNA was extracted from specimens and HPV detection was performed as previously described (Coutlée, J Clin Microbiol, 2006). Analysis was performed using Kaplan-Meier survival curves, Fisher's test for categorical data and log-rank statistics for failure times. Results: Median follow-up was 4.7 years. DNA extraction was successful in 255 cases. HPV prevalence was 68.6%, and 53.3% for HPV-16 specifically. For HPV+ and HPV- respectively, median LRC were 8.9 and 2.2 years (log-rank p = 0.0002), median DFS were 8.9 and 2.1 years (log-rank p=0.0014) and median OS were 8.9 and 3.1 years (log-rank p=0.0002). Survival was statistically significantly different based on HPV genotype, stage, treatment period and chemotherapy regimen. COX adjusted analysis for T, N, age, and treatment remained significant (HR 0.45, p=0.004). Subgroup analysis for genotype, TNM, primary site and chemotherapy regimen will be presented at the meeting. Conclusions: An increasing proportion of oropharyngeal cancer is linked to HPV. This large study with confirms that HPV status is strongly associated with improved prognosis among H&N cancer patients receiving CRT, and should be a stratification factor for clinical trials including H&N cases. Toxicity of CRT is not modified for the HPV population.

This study explores the effects of surgical reconstruction and nerve repair on sensorimotor function and quality of life (QOL) for patients with base of tongue (BOT) cancer compared to healthy, age-matched adults. Sensations were tested on the anterior two-thirds of the oral tongue for two-point discrimination, light touch, taste, temperature, form and texture on 30 patients with BOT reconstruction with radial forearm free-flap and on 30 controls. Results indicated sensation for the unaffected tongue side and affected side with lingual nerve intact was comparable to controls, with poorer sensory outcomes for nerve repair. However, lingual nerves repaired with reanastomosis provided superior results to cable-grafting and severed nerves. Patients had decreased motor function only when the hypoglossal and lingual nerves were affected. Patients' QOL responses on the UW-QOL and EORTC QLQ-H&N35 revealed involvement of lingual and hypoglossal nerves resulted in poorer QOL outcomes. QOL interviews revealed additional problematic issues in this population not identified by standardized questionnaires. / Speech-Language Pathology