A dissertation submitted to the Faculty of Science, University of the Witwatersrand, Johannesburg, in partial fulfilment of the requirements for the degree of Master of Science, 2017 / Aim: The aim of this study was to quantify random and systematic setup errors in a population of head and neck cancer patients for the purposes of evaluating departmental positioning and immobilization techniques, verification and treatment protocols, as well as validating the treatment margins used. Methods and Materials: All patients had more than one phase of radiation, each consisting of different megavoltage photon field arrangements. Some phases were also treated with electron fields in addition to the photon fields. Random and systematic setup errors in all three principal directions were calculated for two groups of patients, using record and verify system couch position data. For one group (20 patients) the positioning and immobilization device system was mechanically localized to the treatment couch, and for the other group (38 patients), it was visually centered on the treatment couch. Within both groups of patients, the patient position was either verified online with portal imaging or verified offline on a conventional radiotherapy simulator. Results: For the patient group treated with the base plate visually centered on the treatment table the population random and systematic setup errors calculated for the photon fields were only indicative of setup uncertainties in the anterior-posterior direction. For the patient group treated with the base plate localized to the treatment couch, the population random and systematic setup errors were found to be within the 5 mm clinical to planning target volume expansion margin used at Livingstone Hospital. Due to treatment couch position differences from fraction to fraction, setup errors made during this study could not reliably be determined for electron field treatments Conclusions: Results indicate that the base plate should be localized to the treatment couch when calculating random and systematic setup errors for photon fields using the couch position as a surrogate for patient position. For this method to be used to calculate setup errors for electron fields, shielding should always be fastened to the same position at the endface of the applicator. Offline and online verification did not significantly influence systematic setup errors. / XL2018

Human papillomavirus (HPV) is a sexually transmitted infection contributing to 70% of oropharyngeal cancers in the United States. The incidence of HPV-related oropharyngeal cancers is greater in Kentucky's population than in any other state. Research has demonstrated the cost of treating oropharyngeal cancer on a national level, but little information exists as to state-specific costs. The purpose of this quantitative study was to examine radiation therapy costs for treating HPV-related oropharyngeal cancer in Kentucky in relation to age, gender, race, and insurance. A theory by Aday and Andersen was applied to explain the relationship between the independent and dependent variables. Cluster sampling was used to randomly select 130 de-identified men and women age 40-65 years who had been diagnosed with oropharyngeal cancer. The data were collected from an existing database. The study used descriptive analysis with correlational, longitudinal data to examine the relationship of categorical and continuous variables. The mean cost for radiation therapy treatment was $123,629.14 (SD= $58,697.36). The multiple regression indicated that the null hypothesis was accepted showing that the independent variables were not statistically significant predictors of the z Score of Cost Difference [F (4,122) = 0.972, p = 0.425]. The results showed no significant independent predictor variables (p > 0.05); gender [t (127) = -0.943, p = 0.348], race [t (127) = 1.378, p = 0.171], insurance type [t (127) = -1.512, p = 0.133], and age group [t (127) = -0.230, p = 0.818]). The results may contribute to positive social change in the development of cancer prevention strategies and policies.

For radiation treatment of cancer and image-based quantitative assessment of treatment response, target structures like tumors and lymph nodes need to be segmented. In current clinical practice, this is done manually, which is time consuming and error-prone. To address this issue, a semi-automated graph-based segmentation approach was developed. It was validated with 60 real datasets, segmented by two users manually and with this new algorithm, and 44 scans of a phantom dataset. The results showed a statistically significant improvement in intra- and interoperator consistency of segmentations, a statistically significant improvement in speed of segmentation, and reasonable accuracy against consensus images and phantoms. As such, the algorithm can be applied in cases that otherwise would use manual segmentation.

No description available.

The syndrome commonly referred to as whiplash injury" resulting from motor vehicle accidents is complex and remains a challenge to clinicians, as is evidenced by the recent report of the Quebec task force on the "whiplash syndrome". The main objective of this prospective randomised study was to evaluate two conservative treatment regimens (early immobilisation-experimental group-1, early active mobilisation experimental group-2) which are based on accepted physiological rationale and then to compare their effectiveness with existing treatment regimens that are commonly practiced (control group) in the management of "whiplash" type of injuries. To this stage, the current study is the only prospective randomised clinical trial of its type conducted with a sufficiently large sample size and over a long study period. The results of the current study clearly demonstrated that the subjects in the immobilised group recovered from their pain-related symptoms and returned to their normal duties sooner than those in the other two treatment groups. In addition to this, those subjects who received the immobilisation regimen did not show adverse effects on either the range of motion or the strength of the neck muscles. Thus, the immobilisation regimen was clearly shown to be the preferred option when compared to the other two treatment methodologies investigated in the current study.Although the primary interest of the current study was to compare the efficacy of three different treatment regimens, a series of statistical analyses were performed to establish the prognostic significance of several factors associated with "whiplash" injury. This showed that factors such as gender, age, speed of the vehicles involved, paraesthesia, intensity of pain at the time of the initial examination, interscapular pain, blurred vision and difficulty in focusing, all had prognostic value. ++ / Similarly, the type of collision, seating position, presence of headache within 24 hours post injury, pre-existing degenerative changes in the cervical spine, loss of lordosis and litigation factors had no prognostic significance. Another major emphasis of the current study has been to concentrate on the pain related symptoms of the neck which are of major concern to "whiplash" subjects and to those clinicians treating them. A paucity of such information is considered to be one of the most notable causes of difficulties encountered in the management of "whiplash" injuries.As an adjunct to the main study, the morphology of the deep pre- and post vertebral muscles of the neck region using embalmed cadavers and fresh post-mortem specimens was investigated, as the literature is deficient in--this regard. Similarly, a longitudinal study of 45 subjects was also performed using Magnetic Resonance Imaging (MRI) technology. The longitudinal nature of the M.R.I. study provided for the first time an account of the details associated with the progressive pathological changes that occurred in some disc lesions, at defined points in time following a MVA. The observations made from the adjunct studies help develop a better understanding of the pathoanatomy associated with the deep muscles of the neck region and the pathological changes that occur following a traumatic disc lesion as evidenced within 2 weeks, after 3 months and 12 months post- injury. On the basis of the observations made in the current study, a classification of the "whiplash" injury has been proposed for the consideration of clinicians. Similarly, the questionnaire used for data collection in the current study, can be readily modified and utilised in a clinical situation for establishing documentation, planning treatment strategies and for evaluation of the treatment outcomes of "whiplash" type of injuries.

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.

BACKGROUND : Radiation oncology was these 20 last years revolutionized by the 3-dimensional conformal radiotherapy (3D-CRT) and its technical evolution, the intensity modulated radiotherapy (IMRT). Thanks to steep dose gradient dose distribution, these techniques allow to conform the prescribed dose to the Planning Target Volume (PTV) while significantly decreasing the dose delivered to the Organs at Risk (OAR). One critical step remains the accurate definition of the Gross Tumor Volume (GTV). If the GTV is underestimated, there is a risk of missing part of the target. If the GTV is overestimated, the risk is to overirradiate normal tissues. Today's gold standard for GTV definition is the Computed Tomography (CT) scanner. We though know that its poor soft tissues contrast is a factor of variability for target definition purpose. AIMS : It can be hypothesized that, for Head and Neck Squamous Cell Carcinomas located in the oropharynx or the laryngo-hypopharynx, the use of other anatomical (like Magnetic Resonance Imaging – MRI) or functional (like positron emission tomography with either 11C-methionine – MET-PET- or 18F-fluorol-deoxy-glucose – FDG-PET) imaging modalities could complement CT for GTV delineation, and have an impact on subsequent CTV and PTV delineation and dose distribution to the non target tissues outside the PTV. RESULTS : We could demonstrate that, providing an adequate and controlled methodology concerning image coregistration and tumor volume delineation on functional images, differences were observed for the delineation of primary tumor volume or GTV according to the modality used. Moreover, the trends were the same for both locations studied (oropharyngeal and laryngo-hypopharyngeal) : CT, MRI and MET-PET volumes were not significantly different in absolute volumes, but there was no total overlap, each imaging modality having the tendency to visualize different types and relatively specific pathways of tumor extension (e.g. : cartilages in MRI). What was very interesting was the significantly smaller FDG-PET volume which could have a real impact on radiation oncology practice by (1) allowing to reduce dose distribution and (2) providing fast and reproducible GTV delineation based on its functional characteristic. Furthermore, we could demonstrate on the subset of operated patients that these smaller FDG-PET volumes were not the fact of a volume underestimating delineation algorithm but well the reflection of true tumor extension. But one must keep in mind that because of spatial resolution limitations, there was still a significant overestimate of this true GTV. Also, none of the imaging modalities was able to visualize very small tumor extensions. This last fact put in the light the need for strict guidelines for CTV prediction based on GTV extension. This is what was done with the help of both anatomical and histo-pathological literature data. These guidelines were used to delineate CTVs on our images, allowing to perform comparative planning on primary tumor. It could be concluded that differences in GTV had not only an impact on CTV and subsequent PTV, but also on dose distribution, either on total irradiated volume or -perhaps more important- on mean dose to parotid glands. No significant effect could be observed on maximal dose to spinal cord. Compared to planning performed on macroscopy-based volumes, no significant difference could be found with what was done on PET-derived planning. CONCLUSION : This research paves the way for the use of FDG-PET for GTV delineation in planning the patients with oropharyngeal and laryngo-hypopharyngeal squamous cell carcinomas. / INTRODUCTION : La radiothérapie moderne a terriblement évolué ces 20 dernières années grâce au développement de la radiothérapie conformationnelle tridimensionnelle (3D-CRT) et de son évolution technique, la radiothérapie par modulation d'intensité (IMRT). Grâce à la création de gradients de dose très raides, ces techniques permettent de conformer au mieux la distribution de la dose au “Planning Target Volume” (PTV) tout en diminuant de manière significative la dose délivrée aux Organes à Risque (OAR). La précision de la définition du “Gross Tumor Volume” (GTV) ou volume tumoral macroscopique reste une étape cruciale dans le sens où une sous-estimation du volume augmente le risque de sous-doser la dose délivrée à la tumeur. Dans l'autre sens, la surestimation du volume tumoral conduit immanquablement à une surirradiation des tissus sains. La tomographie computée par scanner (CT) est l'imagerie de référence pour la définition du GTV. Cependant, le manque de constraste entre tissus mous – à fortiori entre la tumeur et les tissus environnants- constitue un facteur de variabilité reconnu quant à la précision de délimitation du GTV. BUTS : Pour les cancers de la sphère cervico-maxillo-faciale, en particulier pour les tumeurs épithéliales oropharyngées et laryngo-hypopharyngées, démontrer que l'usage complémentaire d'une autre imagerie anatomique comme la résonance magnétique (IRM) ou fonctionnelle comme la tomographie par émission de positrons utilisant soit la méthionine marquée au carbone 11 (MET-TEP), soit le fluoro-déoxy-glucose marqué au fluor 18 (FDG-TEP) peut améliorer la précision de la délimitation GTV. Dans ce cas, démontrer également que cela a un impact sur la délimitation des CTV et PTV sous-jacents et, in fine, sur la distribution de la dose aux tissus sains extérieurs au PTV. RESULTATS : Moyennant l'utilisation adéquate et contrôlée de méthodes de corégistration des images et de délimitation automatique des volumes en imagerie fonctionnelle, nous avons pu démontrer des différences en terme de GTV délimité selon les différentes modalités d'imagerie, avec une tendance identique que l'on se situe au niveau oropharyngé ou laryngo-hypopharyngé. Les GTV délimités sur CT, IRM et MET-TEP n'étaient pas significativement différents en valeurs absolues, mais chaque modalité avait tendance, au-delà d'une zone de congruence s'élevant en moyenne à 50% du volume total, à visualiser des extensions vers des zones anatomiques lui étant propre (ex. : les cartilages en IRM). Les volumes délimités en FDG-TEP étaient significativement plus petits que ceux délimités sur les autres modalités d'imagerie. Nous pûmes de plus démontrer sur un ensemble de patients opérés par laryngectomie totale que le FDG-TEP était aussi la plus précise des modalités d'imagerie. Cependant, par manque de résolution spatiale, aucune des modalités d'imagerie ne fut en mesure de couvrir totalement le GTV. Ce fait met en lumière le besoin de recommendations claires pour la prédiction du CTV sur base de l'extension du GTV. Ce travail fut réalisé sur base des données de la littérature anatomique (normale et pathologique). Ces recommendations furent utilisées pour délimiter les CTV sur les images CT, FDG-TEP et du spécimen chirurgical (les imageries IRM et MET-TEP ne furent pas analysées puisque n'apportant rien en regard du CT). Les PTV furent ensuite générés et une planification tridimensionnelle réalisée. Tant les CTV que les PTV délimités sur le FDG-TEP restaient significativement plus petits que leurs homologues délimités sur CT. Cette réduction permettait une réduction de la dose délivrée aux glandes parotides en particulier, aux tissus hors PTV de manière plus générale. CONCLUSION : Cette recherche ouvre la voie à l'utilisation du FDG-TEP pour la délimitation du GTV chez les patients atteints de tumeurs épithéliales des sphères oropharyngée et laryngo-hypopharyngée.

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.

Injuries to the neck, or cervical region, are very importantsince there is a potential risk of damage to the spinal cord.Any neck injury can have devastating if not life threateningconsequences. High-speed transportation as well as leisure-timeadventures have increased the number of serious neck injuriesand made us increasingly aware of its consequences.Surveillance systems and epidemiological studies are importantprerequisites in defining the scope of the problem. Thedevelopment of mechanical and clinical tools is important forprimary prevention of neck injuries. Thus, the main objectives of the present doctoral thesisare:- To illustrate the dimension of cervical injuries inSweden,- To develop a Finite Element (FE) model of the uppercervical spine, and- To study spinal stability for cervical injuries. The incidence studies were undertaken with data from theinjury surveillance program at the Swedish National Board ofHealth and Welfare. All in-patient data from Swedish hospitals,ranging over thirteen years from 1987 to 1999, were analyzed.During this period 14,310 nonfatal and 782 fatal cervicalinjuries occurred. The lower cervical spine is the mostfrequent location for spinal trauma, although, this changeswith age so that the upper cervical spine is the most frequentlocation for the population over 65 years of age. The incidencefor cervical fractures for the Swedish population decreased forall age groups, except for those older than 65 years of age.The male population, in all age groups, has a higher incidencefor neck fractures than females. Transportation relatedcervical fractures have dropped since 1991, leaving fallaccidents as the sole largest cause of cervical trauma. An anatomically detailed FE model of the human uppercervical spine was developed. The model was validated to ensurerealistic motions of the joints, with significant correlationfor flexion, extension, lateral bending, axial rotation, andtension. It was shown that an FE-model could simulate thecomplex anatomy and mechanism of the upper cervical spine withgood correlation to experimental data. Three studies wereconducted with the FE model. Firstly, the model of the uppercervical spine was combined with an FE model of the lowercervical spine and a head model. The complete model was used toinvestigate a new car roof structure. Secondly, the FE modelwas used for a parameter study of the ligament materialcharacteristics. The kinematics of the upper cervical spine iscontrolled by the ligamentous structures. The ligaments have tomaintain spinal stability while enabling for large rotations ofthe joints. Thirdly, the FE-model was used to study spinalinjuries and their effect on cervical spinal stability inflexion, extension, and lateral bending. To do this, the intactupper cervical spine FE model was modified to implementruptures of the various spinal ligaments. Transection of theposterior atlantooccipital membrane, the ligametum flavum andthe capsular ligament had the most impact on flexion, while theanterior longitudinal ligament and the apical ligamentinfluenced extension. It is concluded that neck injuries in Sweden is a problemthat needs to be address with new preventive strategies. It isespecially important that results from the research on fallaccidents among the elderly are implemented in preventiveprograms. Secondly, it is concluded that an FE model of thecervical region is a powerful tool for development andevaluation of preventive systems. Such models will be importantin defining preventive strategies for the future. Lastly, it isconcluded that the FE model of the cervical spine can increasethe biomechanical understanding of the spine and contribute inanalyses of spinal stability.

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.