Introdução. Fatores de risco para agravos à saúde se alteram no tempo e no espaço. No que diz respeito ao câncer de cabeça e pescoço (CCP), as associações com tabagismo e consumo de bebidas alcoólicas estão bem estabelecidas. Dados da literatura sugerem que os tipos mais prevalentes de tabaco e álcool numa população estão associados a riscos mais elevados de câncer. No Brasil, poucos estudos epidemiológicos investigaram o efeito de distintos tipos de tabaco e álcool no CCP. Objetivo. Mensurar a razão probabilística de risco para CCP por tipos de tabaco e álcool no consumo não exclusivo (uso de mais de um tipo de tabaco ou bebida alcoólica) e consumo exclusivo (uso de apenas um tipo de tabaco ou bebida alcoólica). Métodos. O presente estudo têm origem em três projetos multicêntricos: Latino-Americano, conduzido de 03/1999 a 12/2001; Genoma Clínico do Câncer realizado de 07/2000 a 08/2011; e o Temático Marcadores de Agressividade em Tumores de Cabeça e Pescoço (GENCAPO), conduzido de 07/2011 a 06/2015. Assim, constituiu-se um estudo caso-controle com dados provenientes de hospitais do Estado de São Paulo. Os casos foram diagnosticados com carcinoma espinocelular de cabeça e pescoço, confirmados histologicamente. Os controles, pacientes com outras doenças que não câncer, foram selecionados em alguns dos hospitais de procedência dos casos. Tanto os casos quanto os controles foram entrevistados por meio de questionários com informações sobre características e hábitos, bem como dados sobre educação e história ocupacional. As associações entre as variáveis tipo de tabaco e tipo de bebidas alcoólicas com CCP, foram estimadas pelo odds ratio (OR) e respectivo intervalo de 95% de confiança (IC 95%) via regressão logística não-condicional, ajustados pelas variáveis de confusão: sexo (feminino, masculino), idade (< 50 anos, 50-59 anos e &#8805; 60 anos), escolaridade (superior, intermediário, analfabeto), ocupação (manual qualificado, manual não qualificado e outros), estudos multicêntricos (Latino-Americano, Genoma Clínico do Câncer e GENCAPO), tabagismo (maços-anos total: Nunca fumaram, <20 maços-ano, &#8805; 20 e < 40 maços-anos e &#8805; 40 maços-anos, para ajuste do efeito do álcool) e consumo de etanol total (Nunca beberam, &#8804; 100 Kg, > 100 e &#8804; 900 e > 900 kg, para ajuste do efeito do tabaco). Resultados. Os riscos decorrentes do tabagismo foram mais expressivos para hipofaringe particularmente, no padrão não-exclusivo e consumo &#8805; 40 maços-ano OR 36,1 (IC95%11,1-117,6); para orofaringe, laringe e cavidade oral, os riscos foram, respectivamente: OR 16,1 (IC95%10,4-24,9); OR 14,2 (IC95% 9,6-21,0); OR 7,4 (IC95% 5,6-10,0). Na condição de consumo exclusivo, para a mesma categoria &#8805; 40 maços-ano para cigarro industrializado, os riscos foram discretamente menos intensos: OR 31,9 (IC95% 9,7-104,3); OR 15,4 (IC95% 9,9-24,0); OR 13,1 (IC95% 8,8-19,5) OR 7,1 (IC95% 5,3-9,6), respectivamente, para hipofaringe, orofaringe, laringe e cavidade oral. No consumo de álcool, foram observadas maiores associações de CCP com as bebidas destiladas. Na condição de consumo exclusivo, para orofaringe o nível de consumo de destilados &#8805; 2000 Kg induziu OR 39,1 (IC 95% 12,7-121,8) em comparação aos que nunca beberam. O uso simultâneo de tabaco e álcool fez aumentar sensivelmente o risco de CCP: OR 10,5 (IC95% 8,5-13,0). Conclusões. Entre os tabagistas com o padrão não-exclusivo de consumo, os maiores riscos foram observados para hipofaringe. Entre os consumidores de bebidas alcoólicas, os destilados conferiram maiores riscos nos dois padrões de consumo. No consumo de cerveja e vinho, as diferenças na intensidade das associações com CCP tornaram-se evidentes apenas nas categorias de maior consumo. / Introduction. Risk factors for health problems change over time and space. With regard to head and neck cancer (HNC), associations with smoking and alcohol consumption are well established. Literature data suggest that the most prevalent types of tobacco and alcohol in a population are associated with higher risks of cancer. In Brazil, few epidemiological studies have investigated the effect of different types of tobacco and alcohol on HNC. Objectives. Measure the probabilistic risks for HNC by tobacco and alcohol types in non-exclusive consumption (use of more than one type of tobacco or alcoholic beverage) and exclusive consumption (use of only one type of tobacco or alcoholic beverage). Methods. The present study has origin from three multicentric projects: Latin American, conducted from 03/1999 to 12/2001; Clinical Genome of Cancer performed from 07/2000 to 08/2011; and the Thematic Markers of Aggression in Head and Neck Tumors (GENCAPO), conducted from 07/2011 to 06/2015. Thus, it is a case-control study with data from hospitals in the State of São Paulo. The cases were diagnosed with squamous cell carcinoma of the head and neck, histologically confirmed. The controls, patients with diseases other than cancer, were selected in some of the hospitals where the cases originated. Both cases and controls were interviewed through questionnaires with information on characteristics and habits, as well as data on education and occupational history. Associations between the variables tobacco type and type of alcoholic beverages with HNC were estimated by the odds ratio (OR) and respective 95% confidence interval (CI 95%) through non-conditional logistic regression adjusted for confounding variables: sex (female, male), age (<50 years, 50-59 years and &#8805; 60 years), schooling (upper, intermediate and illiterate), occupation (qualified manual, unqualified manual and others), multicenter studies, smoking (Never smoked, <20 pack-years, &#8805; 20 and <40 pack-years and &#8805; 40 pack-years, to adjust the effect of alcohol) and total ethanol (Never drank, &#8804; 100 kg,> 100 and &#8804; 900 and > 900 kg, to adjust the effect of tobacco). Results. The risks due to smoking were more significant for the hypopharynx, particularly, in the non-exclusive pattern and consumption &#8805; 40 packs per year OR 36,1 (95% CI 11,1-117,6); for oropharynx, larynx and oral cavity, the risks were: OR 16,1 (95% CI, 10,4-24,9); OR 14,2 (95% CI 9,6-21,0); OR 7,4 (95% CI 5,6-10,0). In the exclusive consumption condition, for the same category &#8805; 40 packets per year for industrialized cigarettes, the risks were slightly less intense: OR 31,9 (95% CI 9,7-104,3); OR 15,4 (95% CI 9,9-24,0); OR 13,1 (IC95% 8,8-19,5); OR 7,1 (IC95% 5,3-9,6), respectively, for hypopharynx, oropharynx, larynx and oral cavity. In alcohol consumption, higher associations of HNC with distilled beverages were observed. In the exclusive consumption condition, consumption level of distilled &#8805; 2000 kg induced OR 39,1 (95% CI: 12,7-121,8) for oropharynx. Simultaneous use of tobacco and alcohol increased the risk of HNC: OR 10,5 (95% CI 8,5-13,0). Conclusions. Among smokers with the non-exclusive pattern of consumption, the greatest risks were observed for the hypopharynx. Among the consumers of alcoholic beverages, the distilled conferred greater risks in the two patterns of consumption. In beer and wine consumption, differences in intensity of associations with HNC became evident only in the higher consumption categories.

Kidney transplantation and head and neck cancer risk: systematic review and meta-analysis Paulo Ricardo Saquete Martins Filho, Aracaju/SE, Brazil, 2013. Background: Kidney transplantation is considered the treatment of choice for end-stage kidney disease, but a wide-ranging excess risk of post-transplant malignancies has been recognized as a complication of long-term immunosuppression. De novo malignancies are important cause of morbidity and mortality in kidney recipients. We performed a systematic review and meta-analysis to determine the risk of head and neck cancer after kidney transplantation. Methods: A systematic search was performed in PUBMED, EMBASE, SCOPUS, and LILACS databases to identify cohort studies reporting on the risk of head and neck cancer in kidney recipients. The assessment of validity of selected studies was performed using the STROBE statement and the Newcastle-Ottawa Scale (NOS) for Cohort Studies. Only studies with NOS ≥ 6 were included in the meta-analysis. Pooled relative risks (RR) were calculated using the Mantel-Haenszel or DerSimonian-Laird method, depending on statistical heterogeneity. To detect publication bias, Egger‟s test, Duval and Tweedie‟s analysis, and leave-one-out sensitivity analysis were conducted. Results: A total of 9 high-quality cohort studies were included in the meta-analysis. The pooled RR of head and neck cancer after kidney transplantation was 8.2 (95% CI 4.0-16.6, p<0.0001). A significant excess risk of cancer was observed in the lip (RR = 43.6, 95% CI 24.2-78.4, p<0.0001). The pooled RR of oral cavity/pharynx and salivary gland was 3.5 (95% CI 2.5-5.0, p<0.0001) and 5.6 (95% CI 1.3-24.0, p = 0.020), respectively. No evidence of publication bias was observed. Conclusion: There is an increased risk of head and neck cancer after kidney transplantation. The head and neck should be examined routinely during the post-transplant surveillance. / Transplante renal e risco de câncer de cabeça e pescoço: revisão sistemática e meta-análise, Paulo Ricardo Saquete Martins Filho, Aracaju/SE, Brasil, 2013. Introdução: O transplante renal é considerado o tratamento de escolha para a doença renal terminal, porém um aumento do risco de câncer pós-transplante tem sido reconhecido como uma complicação da imunossupressão em longo prazo. Malignidades pós-transplante são uma importante causa de morbidade e mortalidade em recipientes renais. Foi realizada uma revisão sistemática e meta-análise para determinar o risco de câncer de cabeça e pescoço após transplante renal. Método: Uma busca sistemática foi realizada nas bases de dados PUBMED, EMBASE, SCOPUS e LILACS para identificar estudos de coorte que estimaram o risco de câncer de cabeça e pescoço após transplante renal. A avaliação da validade dos estudos selecionados foi realizada através da iniciativa STROBE e da Newcastle-Ottawa Scale (NOS) para estudos de coorte. Somente estudos com NOS ≥ 6 foram incluídos na meta-análise. Os riscos relativos (RR) combinados foram calculados através do método de Mantel-Haenszel ou de DerSimonian-Laird, a depender da presença de heterogeneidade estatística. Para detectar viés de publicação, foram utilizados o teste de Egger, a análise de Duval e Tweedie e análise de sensibilidade leave-one-out . Resultados: Um total de 9 estudos de coorte de alta qualidade foram incluídos na meta-análise. O RR combinado do câncer de cabeça e pescoço após transplante renal foi de 8.2 (IC 95%4.0-16.6, p<0.0001). Um significante aumento do risco de câncer foi observado no lábio (RR = 43.6, IC 95% 24.2-78.4, p<0.0001). O RR combinado para o câncer de cavidade oral/faringe e glândulas salivares foi 3.5 (IC 95% 2.5-5.0, p<0.0001) e 5.6 (IC 95% 1.3-24.0, p = 0.020), respectivamente. Não houve evidência de viés de publicação. Conclusão: Há um aumento no risco de câncer de cabeça e pescoço após transplante renal. A região de cabeça e pescoço deve ser examinada rotineiramente durante a vigilância pós-transplante. Palavras-chave: transplante renal; neoplasmas; câncer de cabeça e pescoço; câncer de lábio; câncer oral; meta-análise.

Les traitements des cancers des VADS reposent sur la chirurgie, la radiothérapie, et la chimiothérapie. Malgré ces traitements, la survie globale des patients à 5 ans est de l’ordre de 50%. Les causes d’échec thérapeutique sont dues au profil de résistance des tumeurs. Le ciblage de l’axe EGFR/mTOR/HIF-1 par une combinaison de rapalogues et d’anti-EGFR a montré son efficacité sur certaines tumeurs solides. L’objet de ce travail de thèse a été de caractériser l’impact d’une combinaison de drogues à faibles doses sur des lignées cellulaires des VADS au moyen d’une approche pharmacologique et moléculaires. Nos résultats montrent que la combinaison de la rapamycine (5nM) au cetuximab (2,5μg/ml) diminue la survie clonogénique des cellules et permet une inhibition du facteur de transcription HIF-1α. Cette combinaison de drogue améliore l’efficacité de la radiothérapie. En revanche, l’induction de HIF-2a induite par le traitement provoque la résistance des cellules aux traitements par, et une rechute rapide des tumeurs in vivo. L’inhibition de HIF-2 permet une inhibition de la survie cellulaire d’environ 100% dans un modèle résistant. / Management of HNSCC relies on surgery, radiotherapy, and chemotherapy. Despite these treatments, the 5 years overall survival of patient is lower than 50%. Main causes of therapeutic failure are due to the profile of resistance of tumors. The efficacy of a combination rapalogues and anti-EGFR therapies in targeting the EGFR/mTOR/HIF-1 axis in solid tumors was shown previously. In this PhD work, we have evaluated the impact of a low-dose drug combination on head and neck cancer cells lines with a pharmacological and molecular approach. We show that the combination of rapamycine (5nM) and cetuximab (2,5μg/ml) efficiently inhibits the HIF-1 transcription factor and impairs cell clonogenic survival. The efficacy of radiation therapy is improved by this drug combination. However, cell resistance to the treatment is acquired via the induction of HIF-2 in our resistant model cell line. This induction is associated with more tumor relapse in tumors mice xenograft. The inhibition of HIF-2 achieves a dramatic drop of cell clonogenic survival to < 1%.

Les cancers des voies aéro-digestives supérieures, liés à la consommation d'alcool et de tabac mais également à l'HPV-16, ont un pronostic médiocre malgré les traitements actuels. Le développement de nouvelles stratégies innovantes dans des modèles précliniques adaptés est ainsi nécessaire. Nous avons préalablement développé une stratégie vaccinale ADN permettant l'auto-assemblage in vivo de pseudo-particules virales non infectieuses exprimant l'oncoprotéine E7 de l'HPV-16 (pVLP-E7). Nous avons notamment montré que l'injection de pVLP-E7 en intradermique (ID) était capable d'induire de bonnes réponses anti-tumorales dans un modèle murin de cancer obtenu en injectant dans le flanc des cellules d'une lignée exprimant les antigènes E6 et E7 de l'HPV-16, mais qu'il était nécessaire d'ajouter des adjuvants de types agoniste de TLR 7 et 9 dans des tumeurs avancées. Afin de tester de nouvelles voies vaccinales dans un modèle pertinent, nous avons développé un modèle orthotopique intrabuccal présentant des caractéristiques anatomiques et inflammatoires plus proches des cancers observés chez l'homme que le modèle ectopique. Dans ce modèle, nous avons testé une voie vaccinale muqueuse intrajugale qui a montré de meilleures réponses T CD8+ spécifiques en comparaison à la voie ID. Nous avons montré que ce type de vaccination en association à des adjuvants, était efficace dans des tumeurs établies, en lien avec une infiltration intratumorale et ganglionnaire de lymphocytes T CD8+ spécifique, permettant également une protection lors de rechallenge tumoral. Cette stratégie apparaît donc prometteuse dans le traitement de ces cancers fréquemment récidivants. / Head and neck squamous cell cancer (HNSCC) associated with alcohol and tobacco consumption, and recently with human papillomavirus-16 (HPV-16), have bad prognosis despite current therapies. Development of innovative vaccine strategies and adequate pre-clinical tumor models are required to better evaluate HNSCCs. We developed a DNA vaccination that creates non-infectious virus-like particles, which express HPV-16 E7 oncoprotein (pVLP-E7). Results showed that pVLP-E7 induced an E7-specific immune response in vivo and in vitro. Moreover, using an ectopic model of HNSCC that expresses E6/E7 (TC-1), we found that pVLP-E7 intradermic (ID) immunizations induced anti-tumoral responses at early stages. For larger established tumors, pVLP-E7 vaccines were only efficient when administered with TLR-7 and TLR-9 agonists. In an orthotopic model that shares anatomical and inflammatory features with human HNSCC we observed that intra-cheek (IC) infusion of either TC-1 or NR-S1 cells into mice elicited higher numbers of inflammatory infiltrates in the tumor compared to ectopic models. Using this orthotopic IC model, we found that mucosal IC pVLP-E7 vaccination elicited better vaccine-specific CD8+ T-cell responses than ID administration in naive and tumor-bearing mice. Furthermore, pVLP-E7 IC immunizations in combination with TLR agonists led to rejection of established tumors and long-term protection, both of which were associated with E7-specific CD8+ T cell infiltration in tumors and lymph nodes. Our findings demonstrate that pVLP-E7 IC vaccination with adjuvants is efficient against these tumor models and together provides a valuable therapeutic strategy for HNSCCs.

Head and neck cancer is the fifth most common cancer worldwide with an estimated annual global incidence of over 500 000 cases. These malignant tumours develop in the mucosal linings of the upper respiratory tract or in the salivary glands. The most common sites are in the oral cavity and larynx. Treatment modalities comprising surgery and chemoradiotherapy have improved significantly during the last 20 years, but not the long-term survival of patients. The aim of this thesis was to study the different factors affecting tumour growth in head and neck cancer that may have clinical implications in the future. Factors involving apoptosis, cell cycle activity, inflammation, and enzyme activity were of special interest. The results of the thesis indicate that patients with malignant salivary gland tumours having the lowest level of actively replicating cells have the best prognosis. The largest amount of replicating cells in tongue cancer specimens was found in the peripheral areas of tumour nests. Metallothionein, a protein that can hinder apoptosis, was found in excess in the same areas, whereas apoptosis activity was considerably lower. Taken together, these results indicate that the most aggressive cancer cells are found in the peripheral areas of tumours where apoptosis may be hindered. The expression of the death receptor Fas was higher in tongue cancer specimens than in normal mucosa. The expression of this receptor was studied further in two cell lines established from oral cancers. When a low dose of cisplatin was added to cell cultures, the Fas expression was enhanced in both cell lines and, furthermore, the Fas-induced apoptosis was increased in one of the cell lines. The results show that a common chemotherapeutic drug given in a low, less toxic dose may enhance receptor-mediated apoptosis of cancer cells. Malignant solid tumours are often distinguished by an increased proteolytic activity resulting in invasive growth, neo-angiogenesis, and metastases. This activity is conducted by enzymes that are secreted from tumour cells, or from normal cells in the tumour microenvironment. The regulation of enzyme secretion may be mediated by cytokines, small signalling molecules also present in cancer tissue. The results of this thesis show that two cytokines can synergistically induce enzyme secretion (matrix metalloproteinase-1 and -9) from oral cancer cells. Cytokine tumour necrosis factor-alpha and hepatocyte growth factor added alone to cell cultures strongly stimulated secretion of these enzymes. Thus, the tested cytokines, which are commonly secreted by fibroblasts and immune cells, may promote tumour growth. This thesis has contributed to an increased understanding of factors affecting tumour growth in head and neck cancer. The upcoming cancer therapies will be based on the increasing knowledge of these and other aberrant cellular mechanisms that may vary between different cancer forms.

L’intelligibilité de la parole est un véritable enjeu dans la prise en charge des personnes présentant un trouble de la production de la parole pathologique (TPPP). L’usage de ce terme, avec un sens commun recouvrant le domaine de la compréhension, et un sens restreint répondant à la mesure du transfert d’information linguistique dans un contexte de test, entretient une ambigüité ; ambigüité qui entrave le développement des concepts de prise en charge. L’objectif de ce travail de thèse est, à travers trois groupes d’expériences autour de la notion d’intelligibilité, de proposer un cadre conceptuel pouvant servir à organiser la prise en charge des TPPP et à identifier les questions de recherche fondamentale impliquées dans la problématique de l’intelligibilité dans les TPPP.L’objectif principal du premier groupe d’expériences est d’étudier la place de l’intelligibilité dans les stratégies cognitives sous-jacentes à la perception de la parole pathologique. La méthode utilisée est une catégorisation libre..La deuxième série d’expériences est consacrée à la manière dont un groupe d’experts réalise une tâche de jugement de sévérité comparée à une tâche de jugement d’intelligibilité. Le troisième groupe d’expériences cherche à déterminer les cibles les plus efficaces dans la prise en charge des TPPP. Elle repose sur l’hypothèse suivante : la conservation d’une perception juste d’un phonème ou d’une syllabe malgré sa distorsion pathologique permet de déterminer sa contribution à l’intelligibilité et participe à la définition de la notion de robustesse perceptive. Pour tester cette hypothèse, une méthode d’analyse du taux de perception obtenu par un jury d’auditeurs, en fonction du degré de vraisemblance issu d’un système automatique de reconnaissance a été formalisée. Les résultats de ces expériences, interprétées sous l’éclairage croisé des théories sur la perception et de la production de la parole et des modèles de santé, nous ont permis de proposer une définition des différents concepts dans la perspective de la classification internationale du fonctionnement. / The intelligibility of speech is a real challenge for the management of speech disorders. The use of this word, with a common meaning of comprehension and, a specific meaning in a context of test, of measurement of the information transfer, carries some ambiguity, which could hinder the concept of management.The purpose of this work is to propose a conceptual framework for the management of pathological speech production (PSP) through three kinds of experiments. The aim of the first set of experiments is to study the place of the intelligibility within the underlying cognitive strategies of the perception of pathological speech.A free classification method is used with a corpus of sentences read by 33 speakers: 20 patients with speech disorders (a pathological speech production due to neurological diseases or sequellae of cancer or malformative lesions) and 13 normal subjects. The second set of experiments studies the way an expert group performs evaluation of severity compared to evaluation of intelligibility. During an off line experiment, the corpus of the previous study filled by a corpus of different sentences by speaker, was presented to 5 judges (logopedists and phoniatriciansThe third group of experiments looks for the most efficient targets for managing speech disorders. It‘s based on the following assumption: the preservation of a correct perception of a phoneme or a syllable, despite its pathological distortion, allows to determine its contribution to intelligibility and participates to the notion of perceptive robustness. For testing this assumption, was proposed a method of analysis by the identification score (obtained by a jury of listeners) function of the degree of” plausibility (obtained by an automatic system for speech recognition). The outcome of these experiments, adopting the points of view of some perception theories of SD mixed with health models allow us to precise the definition of the main concepts in the prospect of the international classification of functioning.

Head and neck cancers are etiologically associated with smoking and alcohol consumption. Part of these tumors is induced by HPV and their incidence is increasing in the last decade. Patients with virally induced tumors have better prognosis even though they are usually diagnosed with tumors in advanced stage. One of the possible explanations may be better stimulation of the immune system by viral antigens. Macrophages are cells of the innate immune system which belong to professional phagocytes. They are called TAM upon infiltration to the tumor where they represent heterogeneous group of cells. Two main phenotypes are antitumor M1 and protumor M2 macrophages. TAMs are a major component of tumor microenvironment of many types of tumors, one of them are also head and neck cancers. In my thesis I focused on the immunohistochemical detection of M1 and M2 macrophages in the head and neck tumors of viral and non-viral etiology and at the same time RT-qPCR analyses of gene expression of macrophage-associated and/or immunosuppressive genes IDO1, ARG1, CD163, NOS2 a PTGS2 was performed. My data showed that HPV- negative tumors had higher number of M2 macrophages with typical markers CD163, ARG1 and PTGS2. It is known that patients with these tumors have worse prognosis of the disease. Due to high...

Background: This prospective study was conducted to assess changes in quality of life (QoL) of patients who undergo a partial laryngectomy (PLE). Methods: The European Organization for Research and Treatment of Cancer questionnaires QLQ-C30 and QLQ-H&N35 were used pre-procedure (n=218), one week (n=159), three months (n=122) and one year after PLE (n=88). Changes over time were analyzed with the Wilcoxon-signed-rank-test and the Holm-Bonferroni-method, and interpreted regarding clinical relevance. Results: Most subscales worsened one week post-procedure, but many recovered to baseline level after one year. Dyspnea and cognitive functioning deteriorated over time, with worst scores recorded after one year. Financial difficulties and fatigue increased after surgery and maintained that level throughout the follow-up period; sticky saliva remained worse than at baseline, despite some improvements over time. Conclusions: The discovered limitations of QoL should be observed more closely during follow-up treatment, and patients should be informed about these potential eaffects before PLE.:1 Einführung ........................................................................................................... 3 1.1 Das Larynxkarzinom ......................................................................................... 3 1.2 Therapiemöglichkeiten des Larynxkarzinoms ................................................... 4 1.3 Lebensqualität ................................................................................................... 5 1.4 Methodik bei der Evaluierung von Lebensqualität ............................................. 7 1.5 Lebensqualität bei Krebspatienten .................................................................... 8 1.6 Lebensqualität nach Therapie von Kopf-Hals-Tumoren .................................. 10 2 Zielstellung der Studie ....................................................................................... 13 3 Publikation ......................................................................................................... 14 4 Zusammenfassung ............................................................................................ 37 4.1 Einführung....................................................................................................... 38 4.2 Methoden ........................................................................................................ 39 4.3 Ergebnisse ...................................................................................................... 39 4.4 Diskussion....................................................................................................... 41 5 Literaturverzeichnis ............................................................................................ 44 6 Anlagen ............................................................................................................. 49 6.1 Darstellung des eigenen Beitrags ................................................................... 49 6.2 Selbstständigkeitserklärung ............................................................................ 50

Regionäre Metastasten verschlechtern die Prognose von Patienten mit einem Kopf-Hals-Karzinom deutlich. So verringert sich die 5-Jahresüberlebensrate bei einer Metastasierung in die regionären Lymphknoten um etwa 50%. Die Daten von 672 Patienten mit einem Plattenepithelkarzinom des Oropharynx, Hypopharynx oder Larynx der Jahre 2005 bis 2009 wurden retrospektiv ausgewertet. Bei 270 Patienten mit einem Primärtumor der Tonsille (n=82), des Oropharynx (excl. Tonsille) (n=70), des Hypopharynx (n=33), der Supraglottis (n=42) oder der Glottis (n=43) wurde eine ipsilaterale (n=47) oder bilaterale (n=223) Neck dissection im Rahmen der Primärtherapie durchgeführt. Dabei wurden bei 61% der ipsilateralen und 49% der kontralateralen Neck dissections die Level en bloc reseziert und konnten im Falle einer Metastasierung nicht in die levelbezogene Auswertung eingeschlossen werden. Die Level, in welche die Tumoren bevorzugt metastasieren, wurden evaluiert und tumorspezifische Parameter (Tumorlokalisation, pT-Kategorie) auf ihren möglichen Einfluss auf die Parameter der Metastasierung (pN-Kategorie, Seitenlokalisation, Anzahl, Größe und Level der Lymphknotenmetastasen) getestet. In allen untersuchten Tumorlokalisationen lagen die meisten Lymphknotenmetastasen im ipsi- und kontralateralen Level II. Bei Angabe der Sublevel lagen die Metastasen vor allem in Level IIA. Ipsilateral konnten Lymphknotenmetastasen in allen fünf Leveln und kontralateral in den Leveln II, III und V nachgewiesen werden. Verschiedene Metastasierungswege und Levelkombinationen der Lymphknotenmetastasen zeigen, dass die regionäre Metastasierung keinen starren Gesetzmäßigkeiten folgt. Die Metastasierungsrate und die Seitenlokalisation der Lymphknotenmetastasen unterschieden sich signifikant je nach Lokalisation des Primärtumors. Die Anzahl der ipsilateralen histopathologisch nachgewiesenen Lymphknoten zeigte eine statistisch signifikante Korrelation zum Nachweis von Lymphknotenmetastasen. Eine zunehmende Metastasierung mit steigender pT Kategorie wurde bei den Glottistumoren nachgewiesen, nicht aber bei den Tumoren der anderen Lokalisationen. Die Ausdehnung des Primärtumors (pT-Kategorie) lässt keine Rückschlüsse auf die Parameter regionärer Metastasen (Seitenlokalisation, Anzahl, Größe und Level der Lymphknotenmetastasen) zu.

Contexte : Le rôle de l’exposition professionnelle aux solvants dans la survenue de cancers des voies aéro-digestives supérieures (VADS), suggéré dans quelques études, n’a été que peu examiné, malgré leur utilisation très répandue en milieu de travail. Objectif : L’objectif de cette thèse état d’évaluer les associations entre les expositions professionnelles aux solvants et le risque de cancer des VADS. Méthodes : Ce travail est basé sur les données de l’étude Icare, une large étude cas-témoins en population générale conduite en France entre 2001-2007. L’analyse a été restreinte aux hommes et a porté sur 1857 cas de carcinome épidermoïde de la cavité buccale, du pharynx et du larynx, et 2780 témoins. L’histoire professionnelle détaillée ainsi que les consommations de tabac et d’alcool ont été recueillies par questionnaire. Les expositions aux solvants ont été évaluées à l’aide de matrices emplois-expositions et incluaient cinq solvants chlorés (perchloroéthylène, trichloroéthylène, chlorure de méthylène, chloroforme, tétrachlorure de carbone), cinq solvants pétroliers (benzène ; essences carburant ; gazole, fiouls et kérosène ; essences spéciales ; white spirits) et cinq solvants oxygénés (cétones et esters ; alcools ; éther éthylique ; éthylène glycol ; tétrahydrofurane). Les odds-ratios ajustés sur les consommations de tabac et d’alcool et d’autres facteurs de confusion potentiels, et les intervalles de confiances à 95% ont été estimés par régression logistique. Résultats : Aucune association significative n’a été mise en évidence entre exposition professionnelle aux solvants chlorés, pétroliers et oxygénés étudiés et le risque de cancer de l’ensemble des VADS. Dans l’analyse par localisation, le risque de cancer du larynx augmentait significativement avec l’exposition cumulée au perchloroéthylène. Des risques élevés de cancer de l’hypopharynx, bien que non significatifs, étaient observés pour les hommes exposés à des niveaux élevés de chlorure de méthylène, de white spirits et de tétrahydrofurane. Une association entre exposition au tétrahydrofurane et cancer de la cavité buccale était également suggérée. Aucune association claire n’était observée pour les autres solvants, quelle que soit la localisation de cancer. Conclusion : Des associations positives ont été observées avec plusieurs solvants spécifiques. Toutefois, dans l’ensemble, nos résultats ne sont pas en faveur d’un rôle majeur de l’exposition aux solvants dans la survenue de cancer des VADS. / Background : The role of occupational exposure to solvents in the risk of head and neck cancer has been suggested in some studies but has been few investigated, despite their widespread use in the workplace. Objective: The objective of this thesis was to examine the associations between occupational exposure to solvents and the risk of head and neck cancer. Methods: This work is based on data from the ICARE study, a large population-based case-control study conducted in France between 2001 and 2007. The analysis was restricted to men and included 1,857 cases of squamous cell carcinoma of the oral cavity, pharynx and larynx and 2,780 controls. Detailed occupational lifetime as well as alcohol and tobacco consumptions were collected by questionnaires. Exposure to solvents was assessed by job exposure matrices and included five chlorinated solvents (perchloroethylene, trichloroethylene, methylene chloride, chloroform, carbon tetrachloride), five petroleum-based solvents (benzene; gasoline; diesel, fuels and kerosene; special petroleum products; white spirits) and five oxygenated solvents (ketones and esters; alcohols; diethyl ether; ethylene glycol; tetrahydrofuran). Odds-ratios adjusted for smoking, alcohol drinking and other potential confounders and 95% confidence intervals were estimated with logistic models. Results: No significant association was found between occupational exposure to chlorinated, petroleum-based and oxygenated solvents and the risk of head and neck cancer overall. In subsite analysis, the risk of laryngeal cancer increased with cumulative exposure to perchloroethylene. Non-significantly elevated risks of hypopharyngeal cancer were found in men exposed to high cumulative levels of methylene chloride, white spirits and tetrahydrofuran. An association between exposure to tetrahydrofuran and oral cavity cancer was also suggested. No other clear association was found for the other solvents under study, for any cancer site. Conclusion: Although positive associations were observed for several solvents, overall the results do not suggest a substantial role of exposure to solvents in head and neck cancer risk.