Les cancers des voies aéro-digestives supérieures sont connus pour entraîner, par eux-mêmes et par leur traitement, une altération significative de la qualité de vie. Depuis le milieu des années septante, un grand nombre dauteurs ont étudié cette qualité de vie. De nombreux outils de mesure ont été fabriqués et le sujet occupe de plus en plus de place tant dans la littérature que dans les congrès scientifiques. Pourtant, jusquà présent, aucune étude importante ne sest penchée sur la perception quont les médecins de la qualité de vie de leurs malades souffrant dun cancer de la tête et du cou ainsi que sur les implications de cette « représentation» médicale. Nous proposons donc ici dessayer de pallier à ce manque et de présenter un travail sur une large population médicale. Lensemble de la population ORL belge ainsi que 3000 médecins traitants belges ont été contactés. Chacun dentre eux a reçu un questionnaire par la poste. Ce questionnaire, totalement anonyme, formulé dans la langue maternelle de chaque médecin (français ou néerlandais) avait pour but de recueillir de manière la plus précise possible des indications sur la perception des soignants. Ces questions portaient aussi bien sur la perception générale de la qualité de vie que sur les symptômes importants et sur les différents traitements habituellement utilisés en oncologie cervico-faciale. Une étude statistique sérieuse de ces réponses nous a conduits à appréhender de manière nettement plus scientifique cette problématique. Par ailleurs, nous nous sommes attachés à comparer dans la mesure du possible cette perception médicale avec ce que le patient pense vraiment de sa propre qualité de vie (sur base de la littérature scientifique existante). 245 ORL ont répondu à létude tandis que 506 généralistes faisaient de même. Lanalyse des réponses démontre que le monde médical accorde énormément dimportance à la qualité de vie. Cette attention portée à la qualité de vie paraît plus importante que chez les patients eux-mêmes. Les médecins sont très majoritairement prêts à sacrifier le pronostic en terme de survie pour maintenir une qualité de vie quils jugeraient plus acceptable. Sur base de la littérature, ceci va à lencontre de la volonté première du malade. Une moitié des médecins répondeurs reconnaissent ne pas présenter dempathie pour leur malade cancéreux. Il transparaît que les soignants perçoivent la qualité de vie liée à un cancer des voies aéro-digestives supérieures comme étant moins bonne que pour dautres localisations néoplasiques. Probablement pour cette raison, ils pensent très majoritairement quune prise en charge psychologique est indispensable pour de tels patients. Ils pensent également de manière générale que leur façon daborder le patient peut indirectement influencer sa qualité de vie. Pour les médecins, tous les symptômes nont pas la même importance en terme de qualité de vie. La douleur joue, pour eux, un rôle prépondérant. Elle est suivie dans lordre par la respiration, lalimentation, la voix et finalement lapparence physique. Des différences interculturelles ont été retrouvées notamment pour la voix et lalimentation. Les médecins perçoivent également différemment les traitements habituellement utilisés en oncologie cervico-faciale sur base de la qualité de vie quils peuvent offrir aux patients traités. La radiothérapie est clairement mieux perçue que la chirurgie. La chimiothérapie offre la moins bonne qualité de vie post-thérapeutique aux yeux de nos confrères. Ces différences ne semblent pas sappuyer sur des éléments cliniques solides quand on se place du côté des patients (sur base de la littérature). Il est important de remarquer également que bien que le médecin traitant souhaite participer à la décision thérapeutique, il se sent sous informé quant aux cancers des voies aéro-digestives et à la qualité de vie résiduelle. En conclusion, nous pouvons affirmer que le médecin considère la qualité de vie du malade comme un point essentiel dans sa prise en charge et est prêt à sacrifier partiellement la survie pour préserver la qualité de vie. Ceci doit ouvrir un débat éthique important et doit nous amener à une question fondamentale : « Sachant que notre représentation de soignant diffère autant de celle du patient tant du point de vue de la qualité de vie que du but principal du traitement, sommes-nous autorisés à imposer notre perception de la maladie et de ses effets dans le choix thérapeutique? ». Par ailleurs, sur base de nos résultats, il serait judicieux que les spécialistes cervico-faciaux puissent mieux informer leurs collègues sur le cancer de la tête et du cou ainsi que sur la qualité de vie résiduelle.

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.

Head and neck cancer is one of the most common cancers worldwide. The current standard of care for head and neck cancer includes surgical resection of the tumor followed by chemoradiation. This targeted head and neck radiation causes dysfunction of the salivary glands, which leads to xerostomia, mucositis, dysphagia, dental caries, and malnutrition. These side effects greatly decrease patient quality of life and increase their financial responsibility. Current therapies available to ameliorate these negative side effects are expensive, only provide short-term relief, and many of them have negative side effects of their own. Therefore, another therapy is needed to prevent salivary gland dysfunction or restore its function following targeted head and neck radiation. Autophagy is a homeostatic cellular mechanism that could be targeted as a therapeutic mechanism in the salivary glands following targeted head and neck radiation. Autophagy is a catabolic process necessary to maintain cellular homeostasis. It has been shown to play a beneficial role in a variety of disease states including diabetes mellitus, obesity, and cancer. The role of autophagy in the response of cancerous tissue to radiation has been vastly studied. However, the role autophagy plays in normal tissue response to radiation remains poorly understood and much more research in this area is needed.Atg5^(f/f);Aqp5-Cre mice have a conditional knockout of Atg5, a gene necessary for autophagy, in the salivary glands. These mice have unchanged baseline levels of apoptosis, proliferation, and stimulated salivary flow rates when compared to wild-type mice. Therefore, they are a useful model to investigate the role of autophagy in the response of the salivary glands to targeted head and neck radiation. These Atg5^(f/f);Aqp5-Cre autophagy-deficient mice display increased radiosensitivity following targeted head and neck radiation. Furthermore, post-therapy use of CCI-779, a rapalogue and inducer of autophagy, allowed for restoration of salivary gland function following targeted head and neck radiation. Taken together, these results implicate autophagy as playing a beneficial role in normal salivary function following radiation. Therefore, autophagy could be utilized by normal salivary gland tissue following targeted head and neck radiation to maintain salivary gland function.

No description available.

Anatomical changes can have significant clinical impact during head and neck radiotherapy. Adaptive radiotherapy (ART) may be applied to account for such changes. Implementation of ART to alter dose delivery requires deformable image registration (DIR) to assess 3D deformations. This study evaluates the performance and accuracy of a commercial DIR system for clinical applications. The investigations in this project were carried out using images of induced changes in two standard radiotherapy phantoms (RANDO® and CIRS®) and one in-house built phantom. CT image data before and after deformation of the phantoms were processed using Eclipse / SmartAdapt® v.10 system employing a Demons-based algorithm. A DIR protocol was designed, and algorithm performance was assessed quantitatively, using volume analysis and the Dice Similarity Index (DSI), and also evaluated qualitatively. In addition, algorithm performance was assessed for 5 head and neck cancer patients using clinical CT images. Each original planning CT image containing contours of 10 volumes of interest including treatment target volumes and organs at risk was deformed to match a second CT image acquired during the course of the treatment. The original structures were deformed, copied onto the target image and compared to reference contours drawn by 3 radiation oncologists. Phantom investigations gave varied results with average DSI scores ranging from 0.69 to 0.93, with an overall average of 0.86 ± 0.08. These quantitative results were reflected qualitatively, with generally accurate matching between reference and DIR-generated structures. Although air gaps in the phantoms compromised algorithm performance and gave rise to physically aberrant results. Clinical results were generally better with a DSI range of 0.75-0.99 and an overall average of 0.89 ± 0.05, suggesting high DIR accuracy. Qualitatively, some minor contour deformations were noted, as well as artefacts in the axial direction that were due to the CT slice resolution (3 mm) that was used to scan the patients. In addition, contour propagation between images using DIR reduced the time required by physicians to contour the images of head and neck cancer patients by ~47%. This study demonstrated that deformable image registration using a Modified Demons algorithm yields clinically acceptable results and time-saving benefits in contouring that improve clinical workflow. The study also showed that it is feasible to incorporate deformable image registration as part of an adaptive radiotherapy strategy for head and neck cancer, provided further studies are designed to carry out accurate and verifiable dose deformation.

Receptor Tyrosine Kinase (RTK) inhibitors, such as erlotinib/tarceva, have been introduced in the past decade as a promising therapeutic option in Head and Neck Squamous Cell Carcinoma (HNSCC), however, they lack significant efficacy as single agents. As a result, RTK inhibitors require a combination based therapeutic approach with other treatment modalities. To uncover such a combination of agents, we performed a high throughput Prestwick library screen that included 1200 compounds approved by the FDA on HNSCC cell lines and found that monensin, a coccidial antibiotic, synergistically enhanced the cytotoxicity of erlotinib. RT-PCR revealed that monensin induced the expression of Activation of Transcription Factor (ATF) 3 and its downstream target C/EBP homologous protein (CHOP) which are key regulators of apoptosis. Furthermore, RNA-Seq analysis suggests that monensin augments erlotinib cytotoxicity by disturbing lipid and sterol biosynthesis. Therefore, identifying the mechanism of action exerted by monensin may open alternative avenues of cancer treatment.

Despite improvements in treatment, the prognosis for patients with advanced head and neck squamous cell carcinomas (HNSCC) has only improved to a minor degree. To raise the success rate and minimize morbidity further developments in diagnostics are highly desired. Radioimmunodiagnosis could offer a more specific and sensitive diagnostic method. Herein, we have evaluated different radioimmunoconjugates directed against CD44v6 and epidermal growth factor receptor (EGFR) for imaging of HNSCC. The studies were performed in a murine HNSCC xenograft model. Initially, the 111In-labeled anti CD44v6 chimeric monoclonal antibody U36 (cMAb U36) was evaluated. The novel radioimmunoconjugate showed high and accumulating tumor uptake. Since small molecules might be advantageous for imaging, due mainly to their shorter circulation half-life in the bloodstream, we then investigated antibody fragments F(ab’)2 and Fab’ derived from cMAb U36. The highest tumor-to-blood ratio was achieved with the dimeric antibody fragment F(ab’)2, compared with both the intact anti-body and monomeric Fab’. Furthermore, the possibility of improving EGFR-targeted imaging was explored by pre-blocking EGFR. The liver uptake of injected labeled human epidermal growth factor (hEGF) was significantly reduced when an excess of unlabeled hEGF was injected 30 minutes in advance. However, as hEGF stimulates cell proliferation it may be inadvisable to treat cancer patients with large amounts. Alternatively, pre-blocking with an anti-EGFR Affibody molecule (ZEGFR:955)2 demonstrated similar decrease in liver uptake as unlabeled hEGF. Finally, (ZEGFR:955)2 was compared with other Affibody molecules with higher affinity to EGFR, ZEGFR:1907 and (ZEGFR:1907)2, as pre-blocking agents. In addition, a novel hEGF radioimmunoconjugate, [67Ga]Ga-NOTA-Bn-NCS-hEGF was used for EGFR targeting. The dimeric (ZEGFR:1907)2 showed greatest reduction in non-tumor uptake, and highest tumor-to-organ ratio in EGFR expressing organs, when injected in advance of the radioimmunoconjugate. To summarize, the results presented here demonstrate how different radioimmunoconjugates as well as pre-blocking EGFR can improve the radioimmunodiagnosis of head and neck squamous cell carcinomas.

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.

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.

Dissertation (Ph.D.).--University of Texas Graduate School of Biomedical Sciences at San Antonio, 2007. / Vita. Includes bibliographical references.