Head and neck cancer (HNC) accounts for 3-5% of all malignancies in the United States and is the sixth most common cancer worldwide. Over the past two decades, radiation therapy (RT) has become a frequent therapeutic strategy, however one of its side effects, dysphagia has had a huge impact on patients’ quality of life. The value of determining the true prevalence of dysphagia is remarkable, which is what prompted us to carry out a study to determine the prevalence, trends, and risk factors for dysphagia following completion of RT over one year in patients diagnosed with HNC at Boston Medical Center over a 7-year period. A retrospective cohort study was conducted that involved a chart review of the medical records of all patients who completed RT for HNC cancer from January 1, 2003 to December 31, 2009 at Boston University Medical Center. 113 eligible patients were who had comprehensive treatment and follow up data at 3, 6, 9 or 12 months post RT were analyzed. Outcome variables of interest included feeding tube status, diet status, subjective swallow status, and percent weight loss from end of RT. 113 patients were identified for this study, of which 31% (n=35) were female and 69% (n=78) were male. Average age was 58.6 years old (35 to 88). The most common cancer sites were oropharynx and nasopharynx (38.9%) as well as hypopharynx and larynx (31%). 71.7% of the cohort had chemotherapy (CT) in addition to RT, and about half the patients had some degree of surgery. Altogether, the most “clinically meaningful” indicator of dysphagia (diet level of moderate/severe diet restriction) showed that the prevalence or probability of dysphagia to be 49% at 3 months, 56% at 6 months, 45% at 9 months, and 31% at 12 months. Our results suggest that about half the patients who undergo RT may be expected to develop a significant swallowing dysfunction in the first year following RT. This is extremely useful data for a health care provider to present to a patient after diagnosis of HNC and should complement counseling provided to them at the time of creating a treatment plan. Interestingly most of the patients who developed moderate/severe dysphagia did so within the first 6 months of completion of RT. Only oral cavity as cancer site was associated with moderate/severe dysphagia in our cohort of patients.

Orientador: Regina Helena Garcia Martins / Banca: Eulália Sakano / Banca: Vilma Terezinha Anselmo-Lima / Banca: Norimar Hernandez Dias / Banca: Noeme Rocha de Souza / Banca: Regina Helena Garcia Martins / Resumo: O câncer de cabeça e pescoço corresponde a 5% de todas as neoplasias malignas do organismo, sendo os sítios mais prevalentes a cavidade oral, faringe e laringe. O principal fator de risco é o tabagismo e o carcinoma espinocelular é o tipo histológico mais frequente. Marcadores de células tumorais como o p53 e Ki-67 têm sido estudados em tumores de cabeça e pescoço pela sua imunoexpressão positiva para as células neoplásicas e em proliferação. Estudos experimentais possibilitam avaliar os efeitos nocivos do tabaco sobre as vias aéreas, sendo este o objetivo deste estudo. OBJETIVOS: Estudar, em ratos, os efeitos da exposição aguda à fumaça de cigarro sobre as mucosas da língua, faringe e laringe, por meio de análise histológica, morfométrica e imunohistoquímica da expressão das proteínas p53 e Ki-67. MATERIAL E MÉTODO: Ratos Wistar foram subdivididos em dois grupos de 20 animais cada: grupo controle (GC), ração e água ad libitum e grupo tabaco (GT) expostos à inalação de fumaça de 40 cigarro/dia por 60 dias. Os animais foram eutanaziados e realizado biópsias da língua, faringe e laringe para os estudos histopatológico, histomorfométrico e imunohistoquímico das proteínas p53 e do ki-67. RESULTADO: As análises de microscopia de luz da língua dos animais do grupo tabaco (GT) revelaram algumas alterações mais marcantes nesse grupo em cada sítio, sendo que na língua, ganharam destaque a hiperplasia epitelial (GT-90%), hiperplasia de células da camada basal (GT-95%) e displasia epitelial de grau leve a moderado (GT- 85%); na faringe, destacaram-se a hiperplasia de células da camada basal... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: INTRODUCTION: The head and neck cancer represents 5% of all malignant neoplasm of the body, with the sites most prevalent oral cavity, pharynx and larynx. The main risk factor is smoking and squamous cell carcinoma is the most frequent histological type. Tumor cell markers such as p53 and ki-67 have been studied in head and neck tumors by their positive immunostaing for proliferating and neoplastic cells. Experimental studies to assess the possible harmful effects of smoking on the airways which are the objective of this study. OBJECTIVES: To study the effects of acute exposure to cigarette smoke on the mucosa of the tongue, pharynx and larynx in rats; using histological, morphometric and immunohistochemical expression of p53 and ki- 67. MATERIALS AND METHODS: Wistar rats were divided into two groups of 20 animals each control group (CG), food and water ad libitum and tobacco group (GT) exposed to inhalation of smoke from 40 cigarettes/day for 60 days. The animals were euthanized and biopsies of the tongue; pharynx and larynx were performed for histological studies, histomorphometric and immunohistochemical study of p53 and ki- 67. RESULTS: The light of the tongue microscopy analysis showed in GT group: epithelial hyperplasia (GT-90%), hyperplasia of the basal cell layer (GT-95%) and dysplasia of mild to moderate (GT-85%); in pharynx, highlighted the hyperplasia of the basal cell layer (GT-85%), dysplasia (GT-25%) and vascular congestion (GT-95%); predominated in the larynx cell hyperplasia of the basal layer (GT-70%), epithelial hyperplasia (GT-55%), congestion (GT-100%) and inflammatory infiltration of polymorphonuclear neutrophils (GT-25%).The morphometric study identified high measures of the keratin layer in group... (Complete abstract click electronic access below) / Doutor

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.

Although unintentional weight loss (UWL) and depressive symptoms are critical outcomes following diagnosis and treatment for head and neck cancer (HNC), there is a limited understanding of how they influence one another over time. As part of a large, prospective study on HNC outcomes, growth curve modeling was used to evaluate 564 patients’ trajectories of depressive symptoms and percentage UWL and analyze longitudinal associations between these variables across the first year following HNC diagnosis. The hypothesized temporal precedence model was not supported—pretreatment depressive symptoms predicted neither total percentage weight loss at 6 months (t(561) = -1.50, p = .13), nor rates of curvilinear change in percentage weight loss over time (t(561) = 1.38, p = .17). The opposite temporal precedence model also lacked support—early weight loss predicted neither level of depressive symptoms at 6 months (t (432) = 0.24, p = .81), nor rates of linear change in depressive symptoms over time (t (432) = 1.31, p = .19). Instead, a pattern of concurrent covariation emerged—changes in depressive symptoms over time were associated with concurrent changes in UWL (t (1148) = 2.05, p = .041) and changes in UWL over time were associated with concurrent changes in depressive symptoms (t (556) = 2.43, p = .015). That is, to the extent that depressive symptoms increased on a monthly basis, patients lost incrementally more weight than was lost due to the passage of time, and to the extent that weight loss increased on a monthly basis, depressive symptoms also increased. Together, these bidirectional results depicted an ongoing transactional interplay between depressive symptoms and UWL across time, such that changes in either variable resulted in deviations from the average trajectory of the other variable. Patient-reported pain and eating abilities emerged as potential mechanisms through which these variables influence one another. The results have important clinical implications, indicating that ongoing screening and treatment for depression and weight loss throughout the first year after HNC could benefit patients’ psychological and nutritional outcomes alike.

Cancer cells are believed to exist in a condition of metabolic oxidative stress compared to normal cells because of inherent mitochondrial dysfunction. Cancer cells up regulate antioxidant defense mechanisms to combat the toxic effect of reactive oxygen species (ROS). Many anticancer agents block ROS detoxification mechanisms and utilize oxidative stress to cause cytotoxicity to cancer cells. However, ROS also up-regulate many pro-survival signaling pathways that may mediate resistance to chemotherapy. I hypothesize that ROS induces both cytotoxicity and pro-survival mechanisms in cells treated with chemotherapeutic agents such as the EGFR inhibitor erlotinib. This thesis explores how oxidative stress may induce both pro-survival and pro-death mechanisms in HNSCC cells and how this can be exploited to increase the cytotoxicity of erlotinib. The combined use of buthionine-[S,R]-sulfoximine, an inhibitor of glutathione and auranofin, an inhibitor of thioredoxin metabolism enhanced human head and neck cancer cell killing by a mechanism involving oxidative stress both in vitro and in vivo and sensitized cells to erlotinib in vitro. However, in other studies erlotinib as a single agent induced oxidative stress and this was mediated by NADPH oxidase 4 (NOX4). NOX4 mediated oxidative stress activated a process called autophagy which protected cancer cells from cytotoxic effect of erlotinib and inhibition of autophagy sensitized cells to erlotinib in vitro. These studies show that oxidative stress may have a dual role in cancer chemotherapy. ROS generated from various drug treatments can cause oxidative damage of cells culminating in cell death. However, it may also activate autophagy protecting cells against the stress and leading to decreased efficacy of the treatment. Hence inhibiting autophagy and hydroperoxide metabolism can be effective treatment modalities to enhance the cytotoxicity of erlotinib and achieve maximum therapeutic efficacy.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第22038号 / 医博第4523号 / 新制||医||1038(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 大森 孝一, 教授 松村 由美, 教授 富樫 かおり / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

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Yes / Epidemiological studies have shown that head and neck cancer (HNC) is a complex multistage process that in part involves exposure to a combination of carcinogens and the capacity of certain drug-metabolising enzymes including cytochrome P450 (CYP) to detoxify or activate such carcinogens. In this study, CYP1A1, CYP1B1 and CYP2W1 expression in HNC was correlated with potential as target for duocarmycin prodrug activation and selective therapy. In the HNC cell lines, elevated expression was shown at the gene level for CYP1A1 and CYP1B1 whereas CYP2W1 was hardly detected. However, CYP2W1 was expressed in FaDu and Detroit-562 xenografts and in a cohort of human HNC samples. Functional activity was measured in Fadu and Detroit-562 cells using P450-Glo™ assay. Antiproliferative results of duocarmycin prodrugs ICT2700 and ICT2706 revealed FaDu and Detroit-562 as the most sensitive HNC cell lines. Administration of ICT2700 in vivo using a single dose of ICT2700 (150 mg/kg) showed preferential inhibition of small tumour growth (mean size of 60 mm3) in mice bearing FaDu xenografts. Significantly, our findings suggest a potential targeted therapeutic approach to manage HNCs by exploiting intratumoural CYP expression for metabolic activation of duocarmycin-based prodrugs such as ICT2700. / The authors would like to thank Bradford Institute for Health Research for funding a PhD studentship to DP through a competitive scheme and Yorkshire Cancer Research programme Grant (B381PA) for supporting our cytochrome P450-focused drug discovery research.

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