O objetivo deste estudo foi investigar as relações entre os parâmetros de halitose e sialometria em pacientes submetidos à radioterapia de cabeça e pescoço, avaliando a presença de saburra, classificada em termos de peso seco, fluxo salivar, teste BANA e halimetria oral e comparar os resultados entre os grupos. Foram examinados 48 pacientes divididos em três grupos. O grupo 1 (\"saúde\") foi constituído de pacientes que haviam terminado o tratamento na Faculdade de Odontologia de Bauru (FOB), sem queixa de halitose e com íntegra saúde oral; o grupo 2 (\"N. O.\") por indivíduos com necessidades odontológicas e o grupo 3 (\"radio\") pacientes que haviam sido submetidos à radioterapia na região de cabeça e pescoço. Foram avaliadas as concentrações bucal de Compostos Sulfurados Voláteis (CSVs) através do monitor portátil de sulfetos HalimeterTM, os valores relacionados à taxa de fluxo salivar em repouso e estimulado, teste BANA com material proveniente da saburra lingual e peso seco da mesma. Os resultados foram analisados utilizando o teste de análise de variância que quantificaram o hálito antes e após a remoção da saburra. As relações entre halimetria bucal, peso seco da saburra, fluxo salivar com e sem estímulo, e a relação entre fluxo salivar em repouso e estimulado foram feitas através do teste de correlação de Pearson. Para verificar correlações entre halimetria bucal inicial e teste BANATM foi utilizado o teste \"t\" de Student. Os resultados mostraram que houve diferença estatisticamente significante entre a halimetria oral nos grupo \"saúde\" e \"radio\" e, nos grupos \"saúde\" e \"N.O.\" Pode-se observar também que houve relação entre a presença de saburra e os níveis de CSVs. Em relação ao fluxo salivar, foi observada uma redução estatisticamente significante entre o grupo \"radio\" e os outros dois. Nas condições dessa pesquisa, foi constatado que a halitose pode ser considerada um efeito adverso da radioterapia, vinculada à hipossalivação e saúde oral deficiente. / The aim of this study was to verify the halitosis parameters in patients who had received head and neck radiotherapy. The degree of halitosis was determined through the presence of tongue coating, classified according to its dry weight; the salivary flow rate, the BANATM test and HalimeterTM oral measurements. A total of 48 subjects were examined, which were divided into three groups. Group 1 was consisted for patients with good oral health and no complains of bad breath; Group 2 consisted of patients with bad oral health condition and Group 3 comprised individuals who had received head and neck radiotherapy. The concentration of Volatile Sulfur Compounds (VSC) was assessed by means of a portable sulfide monitor (HalimeterTM) and the values were correlated to the resting and stimulated salivary flow rate and to the BANATM test with material collected from the tongue coating and its dry weight. Halitosis was quantified before and after the removal of the tongue coating and the data was analyzed by means of the ANOVA test. The correlation among salivary flow rate, weight of the tongue coating and HalimeterTM oral measurements was evaluated by the Pearson test. The results showed a statistically significant difference between group 1 and 3, and between groups 1 and 2. A relationship between the presence of tongue coating and the VSC levels was also demonstrated. In concerning to the salivary flow rate, there was a statistically significant reduction between group 1 and 3, and group 2 and 3. In the accordance of this study, halitosis can be considered a side effect of radiotherapy, tied with the hyposalivation and deficient oral health.

Os avanços na compreensão da biologia das neoplasias de cabeça e pescoço têm aberto novas direções na ciência. As pesquisas estão sendo direcionadas para o desenvolvimento de terapias com alvos moleculares específicos, os quais são úteis tanto na predição dos tratamentos, quanto na seleção de pacientes que podem responder a uma determinada terapia com base nas alterações moleculares dos tumores. As proteínas hnRNP K e SET, recentemente identificadas como superexpressas em câncer de cabeça e pescoço, representam um novo e atrativo alvo terapêutico para esse tipo de câncer. As mitocôndrias também tem sido objeto de estudo, pois participam nos processos de morte celular por apoptose, e estão envolvidas na sobrevivência celular. Neste estudo avaliamos os efeitos in vitro e in vivo em carcinoma oral e em célula não-tumoral, de novos compostos com alvo-específico (hnRNP K e SET) ou com ação na mitocôndria, para aplicação tanto como antitumoral, como citoprotetor. A citotoxicidade dos compostos foi avaliada pelo método de resazurina nas linhagens tumorais de carcinoma de células escamosas de cabeça e pescoço (HN13, HN12, HN6 e CAL27). Os compostos 11 e 17, alvos específicos da proteína hnRNP K, apresentaram baixa citotoxicidade; o peptídeo OP449, alvo específico da proteína SET, e o composto YV-241, com ação na mitocôndria, apresentaram alta citotoxicidade, com valores de IC50 5,11 e 7,77 ?M, respectivamente. OP449 alterou as proteínas reguladas por SET e reduziu a proliferação das células tumorais no modelo de xenoenxerto ortotópico em camundongo BALB/ c nude; os resultados, porém, não foram significativos. A associação de OP449 com FTY720 promoveu um efeito sinérgico significativo (CID<0,7) na linhagem celular HN12 e reduziu os tumores do xenoenxerto no dorso em camundongos BALB/c nude. O composto YV-241 alterou o potencial de membrana mitocondrial das células tumorais e aumentou o número de mitocôndrias, observado por microscopia eletrônica de transmissão e por microscopia confocal, reduziu proteínas envolvidas com vias de sinalização de sobrevivência, proliferação, ciclo celular e angiogênese, e induziu apoptose com o envolvimento da mitocôndria. Além disso, o composto reduziu os tumores do modelo de xenoenxerto. O possível efeito citoprotetor do composto JM-E-H foi observado na linhagem NOK-SI, por meio da regulação da via de sinalização de HIF-1?. Portanto, OP449 + FTY720 e o composto YV-241 apresentam potencial terapêutico contra carcinoma oral, e o composto JM-E-H, potencial efeito citoprotetor / Advances in understanding the biology of head and neck cancer have opened new directions in science. Research is being directed at the development of therapies with specific molecular targets that are useful in predicting treatments or in selecting patients who may respond to a particular molecular therapy based on molecular changes of the tumors. The hnRNP K and SET proteins, recently identified as overexpressed in head and neck cancer, represent a new and attractive therapeutic target for this type of cancer. Mitochondria have also been the object of study, since they participate in the processes of cell death by apoptosis, and are involved in cell survival. In this work we evaluated the in vitro and in vivo effects in oral carcinoma and non-tumor cell of new compounds with specific target (hnRNP K and SET) or with action in mitocondria, for application either as antitumor or cytoprotectant. The cytotoxicity of the compounds was evaluated by the resazurin method in head and neck squamous cell carcinoma cell lines (HN13, HN12, HN6 and CAL27). Compounds 11 and 17, specific targets of hnRNP K protein, showed low cytotoxicity; the peptide OP449, specific target of SET protein, and compound YV-241, acting on mitochondria, showed high cytotoxicity, with IC50 values of 5.11 and 7. 77?M, respectively. OP449 altered SET-regulated proteins and decreased proliferation of tumor cells in the orthotopic xenograft model in BALB/c nude mouse. The results, however, were not significant. The association of OP449 with FTY720 caused a significant synergistic effect (CID <0.7) on HN12 cell line, and decreased the xenograft tumors. The YV-241 compound altered mitochondrial membrane potential of tumor cells and increased the number of mitochondria, observed by transmission electron microscopy and by confocal microscopy, reduced proteins involved with signaling pathways for survival, proliferation, cell cycle and angiogénesis, and induced apoptosis with the involvement of mitochondria. In addition,the compound reduced tumors of the xenograft model. The possible cytoprotective effect of the compound JM-E-H was observed in the NOK-SI lineage through the regulation of HIF-1? signaling pathway. Therefore, OP449 + FTY720 and compound YV-241 show therapeutic potential against oral carcinoma, and the compound JM-E-H, potential cytoprotective effect

Made available in DSpace on 2016-08-10T10:38:45Z (GMT). No. of bitstreams: 1 Cristiana da Costa Luciano.pdf: 1987242 bytes, checksum: 2f3402c7b9c457e5f89de59897be59ea (MD5) Previous issue date: 2012-11-14 / The head and neck cancer is the fifth most common in Brazil, being the most predominant histology type the squamous cell carcinoma. Radiation therapy is a procedure for treatment with the efficacy variable, and may play an important role in controlling tumor growth. Faced with this therapy, the patient is exposed to ionizing radiation that can cause adverse effects resulting cessation of treatment. The objective was to evaluate the association of polymorphisms of TP53 and ATM genes in patients with head and neck cancer with adverse effects on normal tissues presented as a result of radiotherapy. Materials: The DNA was extracted 54 samples of peripheral blood of patients with head and neck cancer, then the fragments of TP53 and ATM were amplified and subsequently sequenced to check for any polymorphism which may be responsible for the radiosensitivity of patients. Statistical analysis was performed using the SPSS 17.0 software. Results and Discussion: In univariate analysis, patients who had experienced adverse effects RT suspended acute low and high grade with RTOG skin (p = 0.012). Those who had a family history of cancer showed higher adverse acute laryngeal RTOG TGI high (p = 0.040). The exchange C> T at position 11322 of TP53 (intron 3), the ATM and TP53 polymorphisms analyzed and the frequency of acute and chronic adverse effects were not significant (p>05). Conclusions: Based on these results is of utmost importance that alternatives are created to predict the dose to be prescribed during radiotherapy, preventing adverse effects and discontinuation of treatment and also providing better tumor control. / O câncer de cabeça e pescoço, no Brasil, é o quinto mais comum, sendo o tipo histológico mais predominante de carcinoma de células escamosas. A radioterapia é uma das modalidades de tratamento com eficácia variável, podendo desempenhar um papel importante no controle do tumor. Diante essa terapêutica, o paciente está exposto a radiações ionizantes que podem causar efeitos adversos gerando a interrupção do tratamento. O objetivo foi avaliar a associação de polimorfismos dos genes TP53 e ATM em pacientes com câncer de cabeça e pescoço com efeitos adversos sobre os tecidos normais apresentados como resultado da radioterapia. Materiais: O DNA foi extraído de 54 amostras de sangue periférico de pacientes com câncer de cabeça e pescoço, em seguida os fragmentos de TP53 e ATM foram amplificados e posteriormente sequenciados a fim de verificar se os polimorfismos poderiam estar associados à radiossensibilidade dos pacientes selecionados. A análise estatística foi realizada utilizando o software SPSS 17.0. Resultados e Discussão: Por meio de análise univariada, pacientes que tiveram a RT suspensa apresentaram efeitos adversos agudo de baixo e alto grau com RTOG de pele (p=0,012). Aqueles que tinham história familiar de câncer apresentaram maiores efeitos adversos agudo de laringe com RTOG TGI alto (p=0,040). A troca C>T na posição 11322 do gene TP53 (intron 3), os polimorfismos de TP53 e ATM analisados e a frequência de efeitos adversos agudos e crônicos não foram significativos para (p>0,05). Conclusões: Diante dos resultados obtidos é de suma importância que alternativas sejam criadas para predizer a dose a ser prescrita durante a radioterapia, prevenindo os efeitos adversos e a interrupção do tratamento e ainda, promovendo melhor controle tumoral.

Neste estudo clínico verificaram-se os efeitos do laser em baixa intensidade na prevenção e tratamento da mucosite oral radio e/ou radioquimioinduzida. Foram selecionados 31 pacientes portadores de câncer em cabeça e pescoço a serem submetidos à radioterapia ou a radioterapia em associação a quimioterapia, os quais foram distribuídos aleatoriamente em três grupos: grupo 1 (controle) tratamento medicamentoso; grupo 2 tratamento medicamentoso e laserterapia diária, a partir do início da ulceração referente à mucosite grau 2 e grupo 3 tratamento medicamentoso e laserterapia diária a ser iniciada imediatamente antes do início da radioterapia. Os parâmetros de irradiação foram: comprimento de onda de 660nm, potência de 100mW, modo de operação contínuo, aplicação pontual, energia de 2J por ponto em 30 pontos pré-determinados, sendo o tempo utilizado de 20s por ponto. O grupo controle recebeu tratamento medicamentoso que consistia no uso de um conjunto de medidas preventivas e terapêuticas para abordagem dos efeitos adversos agudos radioinduzidos. Os resultados foram avaliados, quanto à ocorrência, graus e escore de dor associados à mucosite oral, perda de massa corpórea, uso de sonda nasogástrica, necessidade de internação e interrupção do tratamento oncológico decorrentes da mucosite oral. Os resultados indicam que o protocolo de aplicação do laser em sua forma preventiva é o mais efetivo na prevenção e tratamento da mucosite oral e que seu uso diário contribuiu para o alívio da sintomatologia dolorosa colaborando para melhora da qualidade de vida do paciente oncológico. / In this clinical study verified the effects of low intensity laser in the prevention and treatment of oral mucositis radio and/or chemical induced. Thirty one patients with head and neck cancer were selected before being submitted to cancer exclusive radiotherapy or radio and associated chemotherapy. The patients were distributed into three randomly groups as follows: group 1- (control) conventional medicine treatment; group 2 conventional medicine treatment and daily lasertherapy as soon as grade two oral mucositis appeared; group 3 conventional medicine treatment and daily lasertherapy to be initiated immediately before radiotherapy sessions.The irradiation parameters were: wavelength of 660nm, potency of 100mW, continuous mode, punctual application, 2J energy on thirty pre-determined 30 points, with 20s of exposure per point. The control group received medical treatment which consisted in using a set of preventive and therapeutic approach for acute radiation-induced adverse effects. Results were evaluated observing occurrence and grade of oral mucositis, score of pain, loss of body mass, use of nasogastric sound line, internment and interruption of oncologic treatment due to oral mucositis. The results showed that the preventive protocol as used was the most effective in prevention and treatment of oral mucositis and that its daily application contributed in relieving the painful symptomatology so collaborating to maintain and/or bettering the life quality of oncologic patients.

A preservação da mobilidade mandibular é um aspecto fundamental para a manutenção da qualidade de vida de pacientes oncológicos submetidos à radioterapia. Este estudo avalia o tempo mínimo de 1 ano decorrido após a realização do tratamento radioterápico, dose e aparelho radioterápico empregados para terapêutica, utilização de sonda nasogástrica e tipo de alimentação, acompanhamento e fisioterapia miofuncional. Integraram este estudo pacientes da Fundação Oncocentro do Estado de São Paulo. Os dados clínicos foram coletados nos respectivos prontuários e as mensurações da amplitude dos movimentos mandibulares de máxima abertura, protrusão e lateralidade direita e esquerda foram registradas em sessão clínica com auxílio de um paquímetro digital. Observou-se que: os gêneros masculino e feminino respondem de modo semelhante na avaliação do comprometimento da mobilidade mandibular; a radioterapia associada à oncocirurgia é a opção terapêutica mais utilizada para o tratamento oncológico de tumores da cavidade oral; o tempo decorrido para a detecção da alteração da mobilidade mandibular é bastante longo, impondo-se medidas preventivas e mesmo interceptadoras mais precoces como o acompanhamento e tratamento com terapia miofuncional; a dose de irradiação e o tipo de aparelho radioterápico empregados no tratamento de pacientes oncológicos são determinantes da alteração da mobilidade mandibular; a utilização de sonda nasogástrica e a dieta pastosa potencializam o efeito da radioterapia no que diz respeito à mobilidade mandibular. / The preservation of mandibular mobility is a fundamental aspect for the maintenance of the quality of life of cancer patients undergoing radiotherapy. This study evaluates the minimum time of 1 year after radiotherapy, dose and radiotherapy used for therapy, use of nasogastric tube and type of feeding, monitoring and myofunctional physiotherapy. Patients at the São Paulo Oncocentro Foundation were enrolled in this study. The clinical data were collected in the respective charts and the measurements of the amplitude of the mandibular movements of maximum opening, protrusion and right and left laterality were recorded in a clinical session with the aid of a digital caliper. It was observed that: the masculine and feminine genera respond similarly in the evaluation of mandibular mobility impairment; radiotherapy associated with oncosurgery is the most used therapeutic option for the oncological treatment of tumors of the oral cavity; the elapsed time to detect the change in mandibular mobility is quite long, imposing preventive and even earlier interceptive measures such as monitoring and treatment with myofunctional therapy; the dose of irradiation and the type of radiotherapy used in the treatment of cancer patients are determinants of the mandibular mobility alteration; the use of nasogastric tube and pasty diet potentiate the effect of radiotherapy with respect to mandibular mobility.

O objetivo deste estudo foi avaliar a efetividade de uma formulação farmacêutica experimental (solução com 1,54% de pilocarpina em spray) sobre o fluxo salivar (FS), experiência de boca seca e qualidade de vida (QV), comparado com placebo, em pacientes tratados com radioterapia (RTx) para câncer de cabeça e pescoço (CCP). Este ensaio clínico randomizado, controlado, duplo-cego e crossover foi realizado em pacientes com xerostomia (n=28). O FS foi medido pela sialometria estimulada (técnica do hálito fresco), a experiência de boca seca pelo Xerostomia Inventory (XI) e a QV pelo Oral Health Impact Profile (OHIP-14). As avaliações foram feitas antes do início da terapêutica - baseline (T0), um (T1), dois (T2) e três (T3) meses após iniciar o uso do spray, além da mensuração do FS uma hora após o baseline (T0+), seguido de período washout de 01 mês e após crossover, os mesmos períodos foram avaliados. O FS apresentou maior após uma hora (p=0,003 - teste de Wilcoxon) e dois meses (p=0,002 - teste de Friedman) de uso do spray com pilocarpina; melhoria na experiência de xerostomia, verificado pela diminuição significante (p<0,05 - teste de Friedman) dos escores em cinco itens do XI; melhoria na QV, verificado pela diminuição significante (p<0,05 - teste de Friedman) dos escores em três itens do OHIP-14, com o passar de alguns dos períodos de avaliação. A aplicação tópica da formulação de pilocarpina em spray melhoraram significantemente o FS, experiência de xerostomia e QV para os pacientes tratados com RTx para CCP. / The aim of this study was to evaluate the effectiveness of an experimental pharmaceutical formulation (1.54% pilocarpine spray solution) on salivary flow (SF), dry mouth experience and quality of life (QoL), compared to placebo, in patients treated with radiotherapy (RTx) for head and neck cancer (HNC). This randomized, controlled, double-blind, crossover clinical trial was performed in patients with xerostomia (n = 28). SF was measured by stimulated sialometry (fresh breath technique), dry mouth experience by Xerostomia Inventory (XI) and QoL by the Oral Health Impact Profile (OHIP-14). The evaluations were done before - baseline (T0), one (T1), two (T2) and three (T3) months after starting the spray, besides the measurement of FS one hour after the baseline (T0+), followed by a washout period of 1 month and after crossover, the same periods were evaluated. The SF presented higher after one hour (p=0.003 - Wilcoxon test) and two months (p=0.002 - Friedman test) of the use of the pilocarpine spray; improvement in the xerostomia experience, verified by the significant decrease (p<0.05 - Friedman test) of the scores in five items of XI; improvement in the QoL, verified by the significant decrease (p<0.05 - Friedman\'s test) of the scores on three items of the OHIP-14, with the passing of the evaluation of some periods. Topical application of the pilocarpine spray formulation significantly improved SF, xerostomia experience and QoL for patients treated with RTx for HNC.

Neste estudo clínico verificaram-se os efeitos do laser em baixa intensidade na prevenção e tratamento da mucosite oral radio e/ou radioquimioinduzida. Foram selecionados 31 pacientes portadores de câncer em cabeça e pescoço a serem submetidos à radioterapia ou a radioterapia em associação a quimioterapia, os quais foram distribuídos aleatoriamente em três grupos: grupo 1 (controle) tratamento medicamentoso; grupo 2 tratamento medicamentoso e laserterapia diária, a partir do início da ulceração referente à mucosite grau 2 e grupo 3 tratamento medicamentoso e laserterapia diária a ser iniciada imediatamente antes do início da radioterapia. Os parâmetros de irradiação foram: comprimento de onda de 660nm, potência de 100mW, modo de operação contínuo, aplicação pontual, energia de 2J por ponto em 30 pontos pré-determinados, sendo o tempo utilizado de 20s por ponto. O grupo controle recebeu tratamento medicamentoso que consistia no uso de um conjunto de medidas preventivas e terapêuticas para abordagem dos efeitos adversos agudos radioinduzidos. Os resultados foram avaliados, quanto à ocorrência, graus e escore de dor associados à mucosite oral, perda de massa corpórea, uso de sonda nasogástrica, necessidade de internação e interrupção do tratamento oncológico decorrentes da mucosite oral. Os resultados indicam que o protocolo de aplicação do laser em sua forma preventiva é o mais efetivo na prevenção e tratamento da mucosite oral e que seu uso diário contribuiu para o alívio da sintomatologia dolorosa colaborando para melhora da qualidade de vida do paciente oncológico. / In this clinical study verified the effects of low intensity laser in the prevention and treatment of oral mucositis radio and/or chemical induced. Thirty one patients with head and neck cancer were selected before being submitted to cancer exclusive radiotherapy or radio and associated chemotherapy. The patients were distributed into three randomly groups as follows: group 1- (control) conventional medicine treatment; group 2 conventional medicine treatment and daily lasertherapy as soon as grade two oral mucositis appeared; group 3 conventional medicine treatment and daily lasertherapy to be initiated immediately before radiotherapy sessions.The irradiation parameters were: wavelength of 660nm, potency of 100mW, continuous mode, punctual application, 2J energy on thirty pre-determined 30 points, with 20s of exposure per point. The control group received medical treatment which consisted in using a set of preventive and therapeutic approach for acute radiation-induced adverse effects. Results were evaluated observing occurrence and grade of oral mucositis, score of pain, loss of body mass, use of nasogastric sound line, internment and interruption of oncologic treatment due to oral mucositis. The results showed that the preventive protocol as used was the most effective in prevention and treatment of oral mucositis and that its daily application contributed in relieving the painful symptomatology so collaborating to maintain and/or bettering the life quality of oncologic patients.

Introduction: Research suggests that patients with head and neck cancer from poorer backgrounds are more likely to have recurrences or die earlier than similar patients from affluent backgrounds. Survival is influenced by tumour characteristics on presentation and a range of individual factors such as socioeconomic status and comorbidity. Deprived patients of more advanced age have a higher likelihood of having comorbidity; this may be due to high-risk lifestyle behaviours such as smoking and drinking. Therefore, it seems reasonable to assume that survival will be lower in these deprived patients which can be attributed to comorbidity compared to index diseases such as the head and neck cancer itself. Survival rates for head and neck cancer patients are approximately 50% in the first five years in Scotland. This is dependent on a range of individual and tumour-related factors such as head and neck cancer sub-type and stage at diagnosis. The risk of head and neck cancer developing in deprived patients has been likened to that of developing head and neck cancer in heavy smokers. While the relationship between deprivation and comorbidity in head and neck cancer has been established, how both factors affect survival is yet to be explored. Reviewing these two factors individually has demonstrated the need to assess how both interact with each other in determining clinical presentation and survival. Aim: The aims of this thesis are:- 1. To investigate the roles and interrelationship between comorbidity and deprivation on the survival of HNC patients. 2. To investigate whether there are differences in HNC presentation based on comorbidity and deprivation. 3. To ascertain whether patients from deprived backgrounds with comorbidity present with more advanced cancers. Methods: In order to answer the research questions, this project began by describing the index disease, HNC and how comorbidity and deprivation are placed within the epidemiology of this disease using systematic review methods. The rationale for embarking upon this study was highlighted. Data linkage of administrative datasets We used anonymised patient data that was accessed through an encrypted repository held by the Health Informatics Centre. The data that was used in the retrospective cohort analysis was obtained from a prospective dataset collected by the Fife Head and Neck cancer Specialist Nurse (Fife data) and a retrospective case note review from the Tayside oncology records held by the Ear Nose and Throat Department and the Oral and Maxillofacial Surgery team. Thereafter we matched the patient data with that from routine medical datasets such the Scottish Morbidity Records, SMR01- inpatient discharges and SMR06 – Cancer Registry data. We conducted survival analysis methods with the intent of assessing the impact of both comorbidity and deprivation in determining survival. Results: The systematic review found that worsening levels of comorbidity were linked to reduced survival whereas patients with low incomes and poor educational attainment also had poor survival outcomes. Being young and having severe comorbidity appeared to also be associated with poorer survival. In the retrospective cohort analysis, the level of association between risk of death with comorbidity and deprivation could not be clearly ascertained in the patients from Fife. The Tayside data to a larger extent supported the systematic review findings particularly for the comorbidity measures with clearly defined measures of association for the Scottish Index of Multiple Deprivation income and education domains. Conclusions: This thesis was able to use evidence triangulation by way of a systematic review of the literature followed by a retrospective cohort analysis to investigate what influence on prognosis both comorbidity and deprivation posed in patients with head and neck cancer. There was substantiation of both factors interacting with head and neck cancer to cause a significantly reduced impact on survival. The inherent difficulties of measuring socioeconomic status and comorbidity encountered in this thesis may go some way towards illustrating the complexity and multifaceted nature of both comorbidity and socioeconomic status; particularly the quite complex interplay between socioeconomic status, comorbidity, stage at diagnosis, and access to care in head and neck cancer, and these factors’ ultimate impact on survival. We found that socioeconomic status i.e. deprivation, comorbidity, stage at diagnosis, access to care, and survival are all potentially causally related. Future work directed at using administrative data linked to medical records would not be sufficient; there is need for epidemiological and clinical studies to unravel the survival disadvantage. To this end clinical cohorts could be nested within larger registry based studies which would allow for uniform interventions based on clinical practice guidelines, uniform SES measurement and ascertainment of comorbidity using a head and neck cancer comorbidity index, i.e. the Washington University Head and Neck Cancer Index.

The PI3K-Akt signalling pathway is a well-established driver of cancer progression. One key process promoted by Akt phosphorylation is tumour cell motility; however the mechanism of VEGF-induced Akt phosphorylation leading to motility remains poorly understood. Previously, it has been shown that Akt phosphorylation, induced by different factors, causes both stimulation and inhibition of motility in different cell types. However, differential phosphorylation of Akt at T308 and S473 residues by VEGF and its role in head and neck cancer cell motility and progression is unknown. The cell lines investigated in this study exhibited a change in phosphorylation of Akt in response to VEGF. However, in terms of motility, VEGF stimulated oral cancer and its associated cell lines, but not normal keratinocytes or oral mucosal fibroblasts. The addition of a PI3 kinase and mTOR inhibitor, inhibited the phosphorylation of Akt and also effectively blocked VEGF-induced oral cancer cell motility, whereas only the PI3 kinase inhibitor blocked oral cancer associated fibroblast cell motility. This study therefore discloses that two different mechanisms of Akt phosphorylation control the motility potential of different cell lines. Akt phosphorylated at both residues controls oral cancer cell motility. Tobacco, alcohol and HPV infection are associated with increased risk of HNSCC. However, little is known about the underlying signalling events influencing risk. It was also aimed to investigate the relationship between these risk factors and Akt phosphorylation, to determine prognostic value. VEGF-positive HNSCC biopsies, with known HPV status, were analysed by immunohistochemistry (IHC) for Akt, phosphorylated at residues S473 and T308. Comparisons between the tissues were carried out using a Mann-Whitney U test. Associations between the variables and continuous immunohistochemical parameters were evaluated with general linear models. Patient characteristics and pAkt IHC score were analysed for possible association with overall survival by Cox proportional hazard models. Immunohistochemistry revealed that cancer patients had significantly higher levels of pAkt T308 than S473 (P < 0.001). Smoking and alcohol were found to be independent risk factors for Akt phosphorylation at T308 (P = 0.022 and 0.027, respectively). Patients with tumours positive for HPV or pAkt S473 had a poorer prognosis (P = 0.005, and 0.004, respectively). Patients who were heavy drinkers were more likely to die than non-drinkers (P = 0.003). Patients with low pAkt T308 were more likely to be HPV positive (P = 0.028). Non-drinkers were also found to have lower levels of pAkt T308 and were more likely to have tumours positive for HPV than heavy drinkers (P = 0.044 and 0.007, respectively). This study suggests different mechanisms of carcinogenesis are initiated by smoking, alcohol and HPV. The resultant data propose higher phosphorylation of Akt at T308 as a reliable biomarker for smoking and alcohol induced HNSCC progression and higher phosphorylation of Akt at S473 as a prognostic factor for HNSCC.

O tratamento do câncer de cabeça e pescoço acarreta consequências ao sistema estomatognático, à alimentação e à condição nutricional, porém pouco se sabe sobre a evolução dos pacientes em relação a tais aspectos após o término do tratamento antineoplásico. O presente estudo teve como objetivo verificar a relação entre a função de deglutição, o estado nutricional e o fluxo salivar em indivíduos após o tratamento do câncer de cabeça e pescoço. Foram incluídos no estudo 17 pacientes (14 homens e 03 mulheres) com média de 53 anos. A deglutição foi avaliada por meio dos exames de videofluoroscopia e eletromiografia de superfície (EMGs) dos músculos masseteres, orbicular da boca e supra-hioideos, o estado nutricional através da antropometria (IMC, CMB e %GC), a avaliação dietética com o recordatório alimentar de 24 horas e o fluxo salivar foi avaliado com estímulo mecânico. A análise dos exames demonstrou que 66,7% dos pacientes apresentaram deglutição com limitações funcionais, na escala de resíduos 58,3%, 66,7% e 58,3% com média de uma linha bário na estrutura para as consistências pudim, mel e liquida, respectivamente, enquanto a penetração laríngea esteve presente para 8,3% durante a deglutição de líquido. Na EMGs o tempo de atividade muscular durante a deglutição de pudim foi acima dos valores de normalidade, os valores da amplitude da atividade elétrica foram muito semelhantes para os músculos estudados, o que não é esperado em indivíduos sem alterações funcionais na deglutição. A avaliação antropométrica indicou que 41,2% estavam em eutrofia, segundo o IMC. As avaliações do tecido muscular e adiposo indicaram eutrofia em 52,9% e 41,2%, respectivamente. Na avaliação dietética foi verificado que 64,7% tinham seu consumo de energia acima do ideal, mas com ingestão de carboidratos, proteínas e lipídeos dentro da normalidade, sendo que 53,4% dos pacientes consumiam micronutrientes abaixo de suas necessidades. O exame de Fluxo Salivar com estímulo mecânico mostrou que 82,3% estavam com produção de saliva muito abaixo do adequado. Houve correlação significante entre a reserva de tecido muscular e o tempo da atividade muscular durante a deglutição, bem como entre o consumo de Sódio e Cálcio com a amplitude da atividade elétrica muscular para os músculos masseteres e orbicular da boca, nas consistências líquida e mel, respectivamente. Não foi encontrada correlação entre os dados das avaliações de deglutição e do fluxo salivar. Portanto, para os participantes da presente pesquisa foi verificada relação entre a deglutição e o estado nutricional, mostrando que a ingestão adequada de proteínas e dos micronutrientes sódio e cálcio influencia a atividade muscular durante a deglutição nos sobreviventes do câncer de cabeça e pescoço. / The treatment of head and neck cancer leads to consequences in the stomatognatic system, nourishment and nutritional condition. However, little is known concerning these factors in relation to the evolution of patients after the antineoplastic treatment is finished. The current study aimed to verify the connection among deglutition function, nutritional status and salivary flow in patients after treatment for head and neck cancer. The study has included 17 patients (14 men and 03 women), 53 years old average. The deglutition was evaluated through videofluoroscopy tests and surface electromyography on masseter muscles, orbicularis of the mouth and supra hyoids. The nutritional status was assessed through anthropometry (ICM, CMB and %GC) and diet evaluation by using a 24-hour food inventory, and the salivary flow was evaluated through mechanical stimuli. The analyses indicated that 66.7% of patients presented deglutition with functional limitations, with a waste scale of 58.3%, 66.7% and 58.3% with average of barium line in the structure to pudding, honey and liquid consistency, respectively, while laryngeal penetration reached 8.3% during liquid deglutition. For the surface electromyography, during flan deglutition, the time of muscle activity was above normal values. The values obtained from the electrical activity ampleness were similar to the studied muscles, which is not prospective in patients who do not have functional changes in deglutition. The anthropometric evaluation showed 41.2% of patients had eutrophy, according to ICM. The evaluation of muscle and adipose tissue showed eutrophy in 52.9% and 41.2%, respectively. The diet evaluation indicated that 64.7% had their energy consumption above the levels considered ideal, however, carbohydrates, proteins and lipids ingestion were normal, considering that 53.4% of patients ingested fewer micronutrients than necessary. The salivary flow test using mechanical stimulus showed that 82.3% had saliva production far below adequate. There was a significant correlation between muscle tissue reserve and time of muscle activity during deglutition, as well as Sodium and Calcium consumption with amplitude of muscular electrical activity for masseter muscles and orbicularis of the mouth, for liquid and honey consistency, respectively. No correlation between data of deglutition evaluations and salivary flow was found. Therefore, the relation between deglutition and nutritional status was established in the study, pointing that the adequate ingestion of proteins, sodium and calcium micronutrients affects muscle activities during deglutition in patients who survived head and neck cancer.