The goal of this thesis was to evaluate the cost-effectiveness of implantable Doppler technology (IDT) used to monitor free tissue transfer (FTT) procedures in the treatment of cancer of the upper aerodigestive tract (UADT). First, a systematic review of the literature on the effectiveness of traditional and IDT monitoring techniques was performed. Second, a utility survey using a time trade-off technique was created and administered. The results from this survey were used to establish utility values for health states common in patients undergoing FTT procedures. Third, a cost study using the microcosting data available through the Ottawa Hospital was performed. Finally, a decision analytic model was created and an economic evaluation from the payer perspective was completed. A probabilistic sensitivity analysis (PSA) and a value of information analysis (VOI) were performed. The thesis found that the currently available evidence supports IDT as a cost-effective intervention. Further research should be directed towards determining the effectiveness of both traditional and IDT monitoring.

Background In the treatment of head and neck cancers (HNCs), radiotherapy (RT) has the advantage of organ preservation compared to surgery. However, treatment toxicities associated with RT can affect important functions for everyday life, both in the acute and late stage. RT to macroscopic tumour in HNC is commonly combined with elective RT to cervical lymph nodes at risk of microscopic involvement. The resulting risk reduction of the elective treatment based on dose-volume parameters is sparsely evaluated. So is the relationship between the elective treatment and treatment toxicity. The present thesis addresses these aspects. A strategy aimed at improving the outcome of RT is accelerated fractionation (AF). AF strives to shorten total treatment time to minimise proliferation of the tumour tissue during the RT period. We have investigated the impact of AF on both disease control and toxicity. Methods In the ARTSCAN study, 750 patients with localised HNC were randomised between AF (68 Gy in 4.5 weeks) and conventional fractionation (CF) (68 Gy in 7 weeks). The elective treatment volume was prescribed 46 Gy with CF in both treatment arms. The thesis is based on four individual papers, investigating the issues above in the whole study population or in sub-populations. Results No difference in disease control or late toxicity between CF and AF was observed at five years. However, there was an increased acute toxicity with AF. Weight loss was associated with treatment volume, independent of tumour stage. The elective treatment volume was found to be an independent risk factor for late aspiration, as well as mean dose to the pharyngeal constrictor muscles, neck dissection, and age at randomisation. There was a significant risk reduction for node relapses in volumes treated to an elective dose. Only a relapse in volumes treated to >60 Gy affected the survival. Conclusion The present thesis questions the benefit of AF in definitive RT as well as extensive elective treatment of the cervical nodes.

Head and neck cancer is the sixth leading type of cancer with 90 percent of head and neck cancer arising from squamous cell lining on the epithelium of the oral and nasal cavity, pharynx, and salivary gland. Even with tremendous achievements on chemotherapeutic drugs and therapies, the long-term prognosis of patients with advanced head and neck squamous cell carcinoma (HNSCC) has shown little improvement over the last three decades. Cisplatin is one of widely used chemotherapeutic drugs for multiple cancers, including head and neck cancer, but the prolonged use of this drug is limited by its toxicity and by the development of resistance. To overcome these major roadblocks to improved prognosis requires mechanism-based therapeutic strategies to maximize the antitumor effect of drugs while limiting their toxicities. Cisplatin exerts anticancer effects via multiple mechanisms, yet its most prominent mode of action involves the generation of DNA lesions followed by the activation of the DNA damage response and the induction of BCL-2 family-dependent mitochondrial apoptosis. DNA damage activates a tumor suppressor p53 to induce apoptosis. One of its functions is to induce the expression of several pro-apoptotic proteins such as Noxa, which binds to an anti-apoptotic BCL-2 family protein, MCL-1 (myeloid leukemia cell-1) to inactivate its pro-survival function and induce apoptosis. We examined Noxa expression and apoptosis induced by cisplatin in p53-wild-type HN30 and HN31, p53-truncated and inactive HN4 and HN12, and p53-deleted HN22 and HN8 HNSCC cell lines. We found that Noxa was induced in HN30 and HN31 cells and down-regulation of Noxa by shRNA (short-hairpin RNA) decreased apoptosis, indicating Noxa contribution to cisplatin-induced apoptosis. Interestingly, cisplatin treatment induced Noxa and apoptosis even in p53-deleted HN22 and HN8 cells, suggesting the existence of the p53-independent pathways for the induction of Noxa. Based on these observations, we hypothesized that modulation of Noxa/MCL-1 axis could mimic cisplatin-induced cell death. We found that Noxa overexpression induced cell death in all cell lines tested regardless of p53 status. This finding could be applicable as a potential therapeutic strategy to treat head and neck cancer.

Alterações no padrão normal de metilação do DNA têm sido caracterizadas como um importante mecanismo na gênese de neoplasias. Esta modificação do DNA é denominada de epigenética uma vez que altera o padrão de expressão das células sem alterar a seqüência do DNA. No câncer, as alterações epigenéticas observadas consistem na hipermetilação das ilhas CpG nos promotores dos genes acompanhada de uma hipometilação global dos dinucleotídeos CpG dispersos pelo genoma. Este evento mostra geralmente ser câncer-específico, ou seja, alguns genes que são metilados em um tipo de câncer, não o são na maioria dos outros tipos. O objetivo deste projeto foi identificar, através da construção de bibliotecas subtrativas de RaSH, genes silenciados por metilação nas linhagens de câncer de cabeça e pescoço FaDu, UM-SCC-14A, UM-SCC-17A e UM-SCC-38 e que possuem expressão induzida após o tratamento com o agente demetilante 5-aza-2-deoxicitidina. Uma vez que a metilação leva a diminuição gradual da expressão gênica, o método RT-PCR semi-quantitativo foi utilizado para validação da expressão diferencial dos genes candidatos PLAU, CD82, RBBP4, AOF2, TMSB10, HSPA5 e LAMC2 nas linhagens não tratadas e tratadas com o agente demetilante 5-aza-2-deoxicitidina. Para todos os genes candidatos foi observado aumento na expressão gênica após o tratamento em pelo menos uma das quatro linhagens. Na linhagem UM-SCC-14 A, os genes CD82, RBBP4, AOF2, HSPA5 e LAMC2 mostraram aumento na expressão após o tratamento com o agente demetilante, sendo que o gene LAMC2 também mostrou esse aumento de expressão na linhagem UM-SCC-17A. Na linhagem UM-SCC-38A todos os genes mostraram aumento de expressão após o tratamento. Embora novos estudos sobre a metilação da região promotora dos genes selecionados sejam necessários, aumentam as evidências de que os genes selecionados sejam regulados pelo mecanismo de metilação e que estejam metilados nas linhagens estudadas. / Abnormalities on the normal pattern of DNA methylation have been caracterized as an important mechanism on carcinogenesis. This modification is called epigenetic and can be defined as a heritable change in gene expression that is not accompanied by changes in DNA sequence. The epigenetic alterations observed on cancer include hypermethylation of selected CpG island gene promoters and simultaneous global hypomethylation. The aim of this project was to identify, by rapid subtraction hybridization, genes silenced by methylation on head and neck cancer lineages with alterations on gene expression after the treatment with 5-aza-2-deoxycytidine. The cancer lineages we used for our experiments were: FaDu, UM-SCC-14A, UM-SCC-17A e UM-SCC-387A and seven genes (PLAU, CD82, RBBP4, AOF2, TMSB10, HSPA5 and LAMC2) were analysed by semiquantitative RT-PCR and for all of them an increaseament of gene expression was observed. For the UM-SCC-14A lineage, the genes CD82, RBBP4, AOF2, HSPA5 and LAMC2 were upregulated after the treatment with demethylating agent as well as LAMC2 was uperegulated on UM-SCC-17A. For the UM-SCC-38A lineage all the genes showed increased expression after the treatmente with -aza-2-deoxycytidine. Our work is another evidence that some genes may be regulated by methylation during carcinogenesis.

Introdução: O câncer é um processo de crescimento e disseminação celular descontrolado que pode acontecer em qualquer lugar do corpo, produzindo alterações fisiológicas e emocionais. Existem vários fatores de risco desta doença como o consumo de álcool, cigarro, alguns hábitos de alimentação, exposição crônica a fatores de risco devido a profissão e até alguns comportamentos sexuais. O tratamento depende do tipo e localização anatômica do câncer, podendo receber radioterapia, quimioterapia, extirpação cirúrgica, ou uma combinação das três terapias em fases avançadas da doença. Objetivo: Determinar a prevalência do câncer da cabeça e pescoço (CCP) dos pacientes atendidos no Serviço de Oncologia do Hospital de Especialidades \"Eugenio Espejo\", no período de 2002 a 2015. Métodos: O trabalho é um estudo descritivo, retrospectivo e transversal com a finalidade de determinar a prevalência do câncer da cabeça e pescoço nos pacientes atendidos no Serviço de Oncologia do Hospital de Especialidades \"Eugenio Espejo\" localizado em Quito - Equador, no período de 2002 a 2015. Os dados foram retirados das fichas clínicas hospitalares. O principal argumento apresentado que levou a está pesquisa é a ausência de dados deste porte no Equador. Foram estudadas variáveis relacionadas às condições demográficas, tipo e sítio anatômico, tipo de tratamento recebido e evolução. A informação foi coletada numa ficha de dados elaborada em Excel, com idade, sexo, ocupação, tipo, localização, diagnóstico e tipo de tratamento, tempo e evolução do tratamento. Os dados foram codificados e analisados no pacote estatístico STATA versão 14.0. Análise estatística descritiva foi realizada para as frequências absolutas e relativas. Os testes Qui-quadrado e de Poisson foram utilizados com nível significância de 95% e alfa de 0,05%. Resultados: Câncer de cabeça e pescoço ocorreu principalmente no sexo feminino com 50,7%, na faixa etária de 50-60 anos (20,3%), e com baixo nível de escolaridade (90,5%). O local de residência mais frequente foi Serra, com 76,7%. O pacientes apresentaram ocupações domésticas em 38,4% dos casos, a região anatômica mais prevalente foi a cavidade bucal com 36,4%, sendo que a localização mais afetada foi a língua (C01-C02). O tratamento que prevaleceu foi o tratamento cirúrgico em 38,9% dos casos. O tempo de tratamento variou entre 1 e 180 dias em 44,5%, e 31,8% finalizaram o tratamento. Não foi observada associação entre o câncer de cabeça e pescoço (CCP) e variáveis sociodemográficas ou clínicas, salvo o local de residência, para o qual se encontrou relação significativa em relação aos tipos de câncer. / Introduction: Cancer is a process of uncontrolled cell growth and dissemination that can occur anywhere in the body, producing physiological and emotional alterations. There are several etiological factors of this disease such as alcohol consumption, smoking, eating habits, chronic exposure to risk factors due to profession and even some sexual behaviors. Treatment depends on the type and anatomical location of the cancer, patients may receive radiation therapy, chemotherapy, surgical excision, or a combination of these therapies in advanced stages of the disease. Objective: To determine the prevalence of head and neck cancer (H&NC) among patients treated at the Oncology Service of \"Eugenio Espejo\" Hospital Quito-Equador, from 2002 to 2015. Methods: This is a descriptive, retrospective and cross-sectional study. Data were obtained from the medical records of patients treated with a diagnosis of CCP, at the Oncology Service of the Hospital \"Eugenio Espejo\". The variables to be considered were demographic data, etiological factors, type of cancer, anatomical location, treatment received and treatment evolution time. The information was collected in a datasheet elaborated in Excel, variables such as age, sex, occupation, etiological factors, stage, type, location, diagnosis and type of treatment, time and treatment evolution were retrieved. The data were coded and analyzed in the statistical package STATA version 14.0. An analysis of descriptive statistics was performed for absolute and relative frequencies. The Chi-square and Poisson tests were used with a confidence level of 95% and assumed alpha of 0.05%. Results: In those patients with H&NC, women predominated with 50.7%, the prevalent age group was 50-60 years with 20.3%, low level of education prevailed with 90.5%, the place of residence (Highlands) with 76.7%, domestic occupations were observed in 38.4% of the cases, the most prevalent anatomical region was the oral cavity with 36.4%, and the most affected location being the tongue (C01-C02), the treatment that prevailed was is the surgical treatment with 38.9% of the cases, treatment time ranged from 1 to 180 days with 44.55% and 31.8% of patients concluded the treatment. There has been no association between H&NC and socio-demographic or clinical variables, except the place of residence, for which a significant relation was found in relation to the types of cancer.

Os microRNAs (miRNAs, miRs) são pequenos RNAs não codificadores presentes em diferentes organismos. Esses RNAs regulam a tradução de genes alvos por meio de ligação seqüência-específica a RNAs mensageiros (mRNAs). Dependendo do grau de complementaridade, podem inibir a tradução e/ou induzir a degradação desses mRNAs. No presente estudo, foi investigado por PCR em tempo real o padrão de expressão de quatro microRNAs (miR-21, -205, -342 e let-7a ) em quatro linhagens celulares derivadas de tumores da cavidade oral e da faringe (FaDu, Hep-2, SCC9 e UM-SCC-38), em queratinócitos orais normais e em amostras de tumor e margens cirúrgicas pareadas de 34 pacientes com carcinomas epidermóides de cabeça e pescoço (CECP). Foi também investigada a correlação da expressão dos MiRs de interesse com as características clinicopatológicas de pacientes com CECP. Nas linhagens celulares, os níveis dos miRs foram similares ou mais baixos que os de queratinócitos normais, ou os miRs não se expressaram. Somente o miR-342 mostrou níveis elevados na linhagem FaDu. Em células Hep-2 tratadas com estradiol, a expressão de miR-let-7a mostrou-se reduzida. Em tumores primários, níveis baixos de miR-let-7a foram observados em carcinomas de soalho de boca e laringe. A expressão de miR-21, -205 e -342 mostrou grande variabilidade entre as amostras e foi reduzida em um dos sítios anatômicos. Não foi observada correlação entre a expressão dos miRs e as características clinicopatológicas dos pacientes com CECP. A análise de três genes alvo candidatos (LYZ, MGLL e SPRR3) mostrou, em carcinomas de soalho de boca e laringe, associação positiva entre a expressão de miR-let-7a e de seu alvo predito MGLL, uma lipase que pode favorecer o fenótipo maligno aumentando os níveis de ácidos graxos livres e sinais lipídicos oncogênicos. O significado dessa associação não pode ser deduzida dos experimentos realizados pelo presente trabalho. / MicroRNAs (miRNAs, miRs) are small, non-coding RNAs present in different organisms. They regulate the translation of target genes through sequence specific binding to mRNA. Depending on the degree of sequence complimentary, they can inhibit translation and/or degradation of target mRNAs In the present study, we used real time PCR to investigate the expression pattern of four microRNAs (miR-21, -205, -342 e let-7a ) in four cell lines derived from tumors of oral cavity and pharinx (FaDu, Hep-2, SCC9 e UM-SCC-38), in normal oral keratinocytes and in matched tumor / surgical margin samples from 34 patients with head and neck squamous cell carcinomas (HNSCC). We also aimed to correlate the miR expression with the clinicopathological features in HNSCC. In cell lines, the miR levels were similar or lower than those in normal keratinocytes, or even absent. Only miR-342 showed high levels in FaDu cell line. In Hep-2 cells treated with estradiol, miR-let-7a expression was reduced. In primary tumors, low miR-let-7a levels were observed in floor of the mouth and larynx carcinomas. The expression of miR-21, -205 and -342 showed high variability between samples and was reduced in one anatomical site. No correlation was observed between miR expression and clinopathological features of head and neck cancer patients. The analysis of three potential target genes (LYZ, MGLL e SPRR3) showed, in floor of the mouth and larynx carcinomas, a positive correlation between the expression of miR-let-7a and its predicted target gene MGLL, a lipase that may support the malignant phenotype by increasing levels of free fatty acids and oncogenic lipid signals. The meaning of such association was not clear from our data.

by Hon-wing Tsui. / Thesis (M.Ph.)--Chinese University of Hong Kong, 1988. / Bibliography: leaves 151-203.

by Shik Yuen Lo. / Thesis (M.Phil.)--Chinese University of Hong Kong, 1995. / Includes bibliographical references (leaves 102-124). / Abstract / List of Illustrations / List of Tables / Acknowledgements / Chapter 1. --- Introduction --- p.1 / Chapter 2. --- Literature Review / Chapter 2.1 --- Anatomy of the Human Nasopharynx --- p.4 / Chapter 2.2 --- Histology of the Human Nasopharynx --- p.6 / Chapter 2.3 --- Intra-epithelial Lesions of the Nasopharyngeal Epithelium --- p.10 / Chapter A. --- Hyperplasia / Chapter B. --- Metaplasia / Chapter C. --- Koilocytes / Chapter D. --- Nasopharyngeal intra-epithelial neoplasia / Chapter 2.4 --- Nasopharyngeal Carcinoma --- p.19 / Chapter A. --- Histopathological classification of NPG / Chapter B. --- Epidemiology / Chapter C. --- Etiological factors / Chapter 2.5 --- Epstein-Barr Virus and Nasopharyngeal Carcinoma --- p.27 / Chapter A. --- Serological / Chapter B. --- EBV genome in NPC / Chapter C. --- EBV encoded latent gene products / Chapter 2.6 --- Cancer Genes in Nasopharyngeal Carcinoma --- p.28 / Chapter A. --- "Tumours suppressor Gene, p53" / Chapter B. --- "Oncogenes, c-myc, ras and bcl-2" / Chapter 2.7 --- Immunohistochemical methods --- p.33 / Chapter A. --- Avidin-Biotin Complex method (ABC) / Chapter B. --- Alkaline phosphotase Anti-alkaline phosphotase method (APAAP) / Chapter C. --- Unmasking of antigens / Chapter 2.8 --- Techniques in ISH --- p.40 / Chapter 3. --- Material and Methods --- p.42 / Chapter 3.1 --- Tissue Samples --- p.42 / Chapter A. --- "Samples for ras, c-myc and p53 studies" / Chapter B. --- Samples for LMP-1 study / Chapter C. --- Samples for bcl-2 study / Chapter D. --- Samples for EBER-RNAs study / Chapter 3.2 --- Monoclonal Antibodies --- p.47 / Chapter 3.3 --- Tissue Processing --- p.49 / Chapter A. --- Tissue processing for formalin fixed tissue / Chapter B. --- Tissue processing for frozen section / Chapter 3.4 --- IHC Techniques --- p.50 / Chapter A. --- Pretreatment of Laboratory Wares / Chapter B. --- Determination of optimum dilution and incubation time for p53antibody / Chapter C. --- Determination of optimum dilution and incubation time for bcl-2 and LMP-1 antibodies / Chapter D. --- Determination of optimum dilution and incubation time for c-myc and ras / Chapter E. --- "Detection of p53, c-myc and ras by ABC method" / Chapter F. --- Detection of bcl-2 and LMP-1 by APAAP method / Chapter 3.6 --- ISH --- p.57 / Chapter A. --- Pretreatment of laboratory wares / Chapter B. --- FITC conjugated EBER oligonucleotide probe / Chapter C. --- Determination of PK dilution for paraffin section / Chapter D. --- Determination of PK dilution for frozen section / Chapter E. --- Determination of the choice of fixative for frozen section / Chapter F. --- Detection of EBER-RNAs by ISH method / Chapter 3.7 --- Statistical analysis --- p.62 / Chapter A. --- p53 / Chapter B. --- c-myc and ras / Chapter 4. --- Results --- p.63 / Chapter A. --- ras / Chapter B. --- c-myc / Chapter C. --- p53 / Chapter D. --- LMP-1 / Chapter E. --- Bcl-2 / Chapter F. --- EBER-RNAs / Chapter 5. --- Discussion --- p.86 / Chapter 6. --- Conclusion and Summary --- p.97 / Appendix --- p.99 / Reference --- p.102

No description available.

Head and neck cancers account for 3% of all newly diagnosed cancers, of which 90% are squamous cell carcinomas (SCC). Improvements in surgery, radiotherapy and chemotherapy have done little to improve the mortality of this disease over the past 20 years while current clinicopathological predictors of disease outcome are sub-optimal. Identifying molecular targets of prognostic and therapeutic significance in head and neck squamous cell carcinomas (HNSCC) may help direct novel therapies to patients whom it is most likely to benefit. Accrued knowledge of the biology of HNSCC has highlighted specific aberrations in pRb and p53 pathways which warrant further study. An immunohistochemical analysis (IHC) in a cohort of 145 patients with SCC of the anterior tongue was performed. Protein expression of the pRb and p53 pathways and related molecules that directly or indirectly influence cell cycle progression at the G1/S phase checkpoint was assessed. We determined that over-expression of E2F-1 occurred in &gt35% of these cancers and associated with improved overall survival on univariate analysis. The strongest multivariate model included: regional lymph node status, tumour grade, p16INK4A, cyclin D1 and p14ARF. This is the first study to determine that p14ARF is an independent marker of both improved diseasefree survival and overall survival in a cohort of SCC of the anterior tongue. Unrecognized molecular heterogeneity is thought to account for the unpredictable clinical response to ZD1839, an EGFR tyrosine kinase inhibitor. We explored the anti-proliferative effects following ZD1839 treatment alone or in combination with radiotherapy in cyclin D1 and E2F-1 over-expressing SCC9 HNSCC cells. SCC9 cells over-expressing cyclin D1 or E2F-1 were highly resistant to ZD1839 treatment, while E2F-1 clones were also radioresistant. Combined therapy in SCC9 controls had a greater anti-proliferative effect than each individual treatment. These data showed that cyclin D1 and E2F-1 may have utility as markers of ZD1839 resistance. The data in this thesis contribute to our knowledge of the clinical behaviour and molecular pathology of HNSCC. Specifically the molecular data identifies novel markers of outcome in SCC of the anterior tongue such as p14ARF, and therapeutic response to ZD1839 such as cyclin D1 and E2F-1. This study addresses in part, the current issues and limitations of management in HNSCC and has the potential to contribute to strategies that may be developed to improve the outcome for patients who develop HNSCC in the future.