At present, there is no cure for bone metastasis. The current goals in patient care are to palliate pain, prevent pathological bone fracture and increase the strength and function of bone, so as to extend the life expectancy and maintain a good quality of life. Bisphosphonate treatment is the currently standard therapy of bone metastasis and is commonly used by physicians; it alleviates the tumour-induced hypercalcemia in 90% of patients and reduces the metastatic bone pain in 50% of patients. Moreover, it also prevents the pathological fracture of the affected bones. However, while effective, bisphosphonate injections are very costly, though its oral formulation is less expensive it is also less efficacious, and causes gastrointestinal discomfort. Furthermore, prolonged use of bisphosphonate treatment may lead to certain adverse effects, including hypocalcemia. These factors will prohibit the longterm use of such medication as it can negatively affect the treatment outcome. / Based on enormous medical potentials illustrated by the aforementioned findings, BBYNG deserves wider clinical application, large-scale clinical study on its preventive effect against bone metastasis and detailed investigation of its mode(s) of action in the body. / Based on the above-described understanding of Chinese medicine and bone metastasis, supplementing the kidney and strengthening bone could be the basic principle for the treatment of bone metastasis using Chinese medicine. In view of this theory, and in addition to the clinical observation and a thorough search of the available literature, we selected relevant kidney-tonifying Chinese herbs, namely (Fructus Ligustri Lucidi), (Rhizoma Drynariae), (Herba Epimedii), (Psoralea Corylifolia) and wide-spectrum anticancer herbs (Herba Hedyotidis Diffusae) for the preparation of a combined formula--BBYNG. / Chinese medicine has long been used to treat cancers. Its advantages reside in its holistic properties, which bring palliative, corrective and convalescing functions against damage caused by radiotherapy, chemotherapy and surgery. These features position Chinese medicines as the adjuvant to orthodox cancer treatment. During the late stage of tumour development, when standard therapy is no longer effective, Chinese medicine plays a critical role as an integrated therapy. Searching for a safe, inexpensive and effective Chinese medicine preparation suitable for prolonged use as adjunct therapy in late cancer cases is of paramount importance. / Clinical results. Both Chinese medicine and Western medicine treated patients showed no significant change in their blood parameters or liver and kidney examinations before and after drug administration; Male subjects on BBYNG, their bone mass density remained stable after 6 months treatment and the subjects on OSTAC showed slightly decreased In females, subjects on BBYNG remained stable, but subjects on OSTAC slightly increased. / Clinical study. The study was designed as a randomized, parallel-group comparison between BBYNG formula and Bisphosphonate. The patients who meet the inclusion/exclusion criteria were randomly assigned to receive either BBYNG granules, which was prepared by a GMP manufacturer, or Clodronic acid. The treatment period was 6 months (24 weeks). For both groups, various clinical parameters such as body functions, blood examinations, bone density (BMD) assessment, X-ray examinations, pain intensity and quality of life were evaluated and compared. / Conclusions. (1) As an adjuvant to patients with bone metastases, BBYNG is effective in relieving the metastatic bone pain, improving the quality of life. (2) In the animal model, BBYNG reduced the metastatic bone damage, prolonged the survival and enhanced the T lymphocyte immunity in the tumour-bearing mice. (3) In vitro study on the breast and lung cancer cell lines showed that BYYNG could induce apoptosis and prevent tumour cell invasion. It suggests that BYYNG may restrict tumour growth and development, thus reducing the occurrence of bone metastasis. / In accordance with Chinese medicine, bone metastasis can be categorized into "bone tumour" "bone erosion" "bone wilting" "bone necrosis" and "bone impediment". The main cause of bone metastasis is twofold: cancer toxicity, and in Chinese medicine theory, the kidney governs the bone marrow, if the kidney is not functioning in balance, then the bone will become weak. Cancer toxicity is the "pathogenic cause" to skeletal metastases, while kidney weakness decreases the body defence against the cancer. A vicious cycle ensues when cancer and kidney deficiency and bone weakness occurs simultaneously coincidently and worsens the conditions. / In vitro study on tumour cell lines. The anticancer effects of different concentrations of BBYNG formula and various single components against human breast cancer and lung cancer cell lines were evaluated by cell viability test (MTT assay), cell apoptosis test and invasion suppression test. / In vitro study results. BBYNG and the aqueous extracts of its component herbs at very low drug concentrations stimulated the growth of three tumour cell lines tested. When the concentrations were slightly increased, they showed an inhibitory effect on cancer cell proliferation. As the drug concentrations further increased, the extracts showed cytotoxic effects on these tumor cells. At the noncytotoxic dose, the extracts could trigger apoptosis and enhance the caspase-3 activity in all three tumour cell lines. In addition, at this "non toxic" concentration, the extracts markedly inhibited the in vitro invasive property of the 4T1 breast cancer cell lines in our Matrigel invasion model. Thus these in vitro results suggested that BBYNG possess anticancer, invasion-inhibitory and anti-metastatic activities. / In vivo animal study results. (Tumour growth was slower in the BBYNG treatment group when compared to the OSTAC and control groups, but this was not significantly difference) BBYNG significantly delayed tumour growth in tumour bearing mice, but it did not minimize the tumour size markedly. Moreover, BBNYG did minimize the mobility restriction caused by tumours, reduce the damage to bones, prolong the survival time and enhanced the T lymphocyte immunity. / In vivo animal study. A well-established animal model for breast cancer was used to evaluate and compare the pharmacological effects of BBYNG formula and Clodronic acid, as shown by different indicators such as tumour progression, animal's mobility, survival time, bone metastasis-induced fracture intensity and the immunological status of the tumour-bearing mice. / Malignant tumour is characterized by early metastasis. Among them 37 to 80 (depending on which type of cancer) patients show tendency of bone metastasis. Bone metastasis is usually accompanied by various complications, such as severe pain, pathological bone fracture, hypercalcemia, and bone marrow suppression, which can substantially affect the quality of life of the patients. Thus, the prevention and treatment of bone metastasis in cancer is an issue worth pursuing. / Malignant tumours leading to high mortality and morbidity are a serious threat to human health. It is the leading cause of death in China. In Hong Kong, there are over 20 thousand new cancer cases and more than 1100 people die due to cancers every year. / Study objectives. To elucidate the efficacy and some pharmacological aspects of BBYNG in regard to the treatment of bone metastasis through clinical observation and different laboratory experiments. This study would be of significant reference value to the disease-oriented drug formulation and application, mechanistic study and research methodology of the treatment of bone metastasis using Chinese medicines. / The clinical and laboratory experimental results are summarized as below: / The research study is composed of three parts, the clinical study, in vivo animal study and in vitro study on tumour cell lines. The research methods used are as follows: / Those on BBYNG treatment showed more a stable and satisfactory quality of life than those in the Western medicine-treated group. For the Clodronic acid treatment group, patients generally showed worsened symptoms and quality of life deteriorated. The ECOG index of the BBYNG group was statistically better than that of the Clodronic acid group. Within the 72-week clinical observational period, the mortality of Clodronic acid group is significantly higher that of the BBYNG group. The effects of BBYNG group as presented in relieving the pain-induced influence on patients' emotion, interpersonal relationship and entertainment was more pronounced than that in the Clodronic acid group. / Wu Ka. / 論文(哲學博士)--香港中文大學, 2006. / 參考文獻(p. 299-324). / Adviser: Leung Ping Chung. / Source: Dissertation Abstracts International, Volume: 68-03, Section: B, page: 1570. / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstracts in Chinese and English. / School code: 1307. / Lun wen (zhe xue bo shi)--Xianggang Zhong wen da xue, 2006. / Can kao wen xian (p. 299-324). / Wu Ka.

The thesis “Ancillary Ligand Effects on the Anticancer Activity of Ruthenium (II) Piano Stool Complexes” is an effort to design better antitumor metallodrugs based on ruthenium(II) complexes with various H-bond donor/acceptor ligands and to understand their mechanism of action. Chapter 1 presents a brief review of metallodrugs and their mechanism of action. Different classes of metallodrugs are discussed. A short discussion on ruthenium based anticancer drugs and their established mechanism of action is also included in this chapter. Chapter 2 deals with the synthesis, characterization and anticancer activity of Ru(II) complexes with P(III) and P(V) ligands. The effect of a strong hydrogen bond acceptor on the cytotoxicity of the complexes has been investigated which allows comparison of complexes with ligands possessing a strong hydrogen bond donor or hydrogen bond acceptor. Partial oxidation of the tertiary phosphine ligands leads to a decrease in cytotoxicity of the ligand, while coordination to ruthenium resulted in a significant increase in the cytotoxicity. A molecular mechanism of action for these complexes was suggested on the basis of various biophysical studies. These complexes bind DNA through non-intercalative interactions which lead to the destabilization of the double helix of the DNA and also unwinding of the negatively supercoiled DNA. Results show that the presence of a hydrogen bond acceptor on the ligand is not capable of enhancing interactions with DNA in comparison with hydrogen bond donor groups. Cellular studies of these complexes showed that inhibition of DNA synthesis and apoptosis occur on treatment with these complexes. Interestingly, these complexes are found to be not only cytotoxic but also antimetastatic. Chapter 3 deals with the synthesis, characterization and anticancer activity of Ru(II) complexes with biologically active S containing heterocyclic ligands and their mechanistic study. Complexation of ruthenium with mercaptobenzothiazole (MBT) gave the most cytotoxic complex (H3) in the series. Heterocyclic Ru(II) complexes behave differently as evidenced by cellular and biophysical studies. Unlike phosphine complexes, H3 shows biphasic melting of DNA at higher concentrations which suggests two different types of interaction with DNA. Chapter 4 deals with synthesis and characterization of water soluble multiruthenated hydrophilic ruthenium(II) complexes with urotropine. An increase in cytotoxicity and binding affinity has been observed with increase in the number of ruthenium atoms per molecule. The complex with three ruthenium atoms showed the best activity. However cytotoxicity of the complexes decreases with decrease in the lipophilicity of the complexes. Chapter 5 describes studies on the interaction of Ru complexes with water, ss-DNA, AMP, GMP and GSH by various spectroscopic techniques. Hydrolysis of Ru-Cl bond in the complexes correlates with the cytotoxicity. Chapter 6 reports the summary of the observations of the thesis and the future prospects of metallodrugs.

Cancer is one of the leading causes of death worldwide, and affects roughly 1.5 million new people in the United States every year. One of the leading tools in the detection and treatment of cancer is radiation. Tumors can be detected and identified using CT or PET scans, and can then be treated with external beam radiotherapy or brachytherapy. By taking advantage of the physical properties of gold and the biological properties of nanoparticles, gold nanoparticles (GNPs) can be used to improve both cancer radiotherapy and imaging. By infusing a tumor with GNPs, either using passive extravasation of nanoparticles by the tumor vasculature or active targeting of an antibody-conjugated nanoparticle to a specific tumor marker, the higher photon cross-section of gold will cause more radiation dose to be deposited in the tumor during photon-based radiotherapy. In principle, this would allow escalation of dose to the tumor while not increasing the dose to normal healthy tissue. Additionally, if a tumor infused with GNPs was irradiated by an external kilo-voltage source, the fluorescence emitted by the gold atoms would allow one to localize and quantify the GNP concentration. This work has two main aims: to quantify the GNP-mediated dose enhancement during GNRT on a nanometer scale, and to develop a refined imaging modality capable of quantifying GNP location and concentration within a small-animal-sized object. In order to quantify the GNP-mediated dose enhancement on a nanometer scale, a computational model was developed. This model combines both large-scale and small-scale calculations in order to accurately determine the heterogeneous dose distribution of GNPs. The secondary electron spectra were calculated using condensed history Monte Carlo, which is able to accurately take into account changes in beam quality throughout the tumor and calculate the average energy spectrum of the secondary charged particles created. Then, the dose distributions of these electron spectra were calculated on a nanometer scale using event-by-event Monte Carlo. The second aim is to develop an imaging system capable of reconstructing a tomographic image of GNP location and concentration in a small animal-sized object by capturing gold fluorescence photons emitted during irradiation of the object by an external beam. This would not only allow for localization of GNPs during gold nanoparticle-aided radiation therapy (GNRT), but also facilitate the use of GNPs as imaging agents for drug-delivery or other similar studies. The purpose of this study is to develop a cone-beam implementation of XFCT that meets realistic constrains on image resolution, detection limit, scan time, and dose. A Monte Carlo model of this imaging geometry was developed and used to test the methods of data acquisition and image reconstruction. The results of this study were then used to drive the production of a functioning benchtop, polychromatic cone-beam XFCT system.

Le cancer du poumon a une incidence et une létalité parmi les plus hautes de tous les cancers diagnostiqués au Canada. En considérant la gravité du pronostic et des symptômes de la maladie, l’accès au traitement dans les plus brefs de délais est essentiel. Malgré l’engagement du gouvernement fédéral et les gouvernements provinciaux de réduire les délais de temps d’attente, des balises pour les temps d’attente pour le traitement d’un cancer ne sont toujours pas établis. En outre, le compte-rendu des indicateurs des temps d’attente n’est pas uniforme à travers les provinces. Une des solutions proposées pour la réduction des temps d’attente pour le traitement du cancer est les équipes interdisciplinaires. J’ai complété un audit du programme interdisciplinaire traitant le cancer du poumon à l’Hôpital général juif (l’HGJ) de 2004 à 2007. Les objectifs primaires de l’étude étaient : (1) de faire un audit de la performance de l’équipe interdisciplinaire à l’HGJ en ce qui concerne les temps d’attente pour les intervalles critiques et les sous-groupes de patients ; (2) de comparer les temps d’attente dans la trajectoire clinique des patients traités à l’HGJ avec les balises qui existent ; (3) de déterminer les facteurs associés aux délais plus longs dans cette population. Un objectif secondaire de l’étude était de suggérer des mesures visant à réduire les temps d’attente. Le service clinique à l’HGJ a été évalué selon les balises proposées par le British Thoracic Society, Cancer Care Ontario, et la balise pan-canadienne pour la radiothérapie. Les patients de l’HGJ ont subi un délai médian de 9 jours pour l’intervalle «Ready to treat to first treatment», et un délai médian de 30 jours pour l’intervalle entre le premier contact avec l’hôpital et le premier traitement. Les patients âgés de plus de 65 ans, les patients avec une capacité physique diminuée, et les patients avec un stade de tumeur limité étaient plus à risque d’échouer les balises pour les temps d’attente. / Lung cancer is among the most lethal and the most diagnosed cancers in Canada. Given the poor prognosis and symptom burden of the disease, timely access to treatment and quality care are essential. In spite of government commitments to reduce waiting times in cancer care, national clinical benchmarks for cancer care have yet to be established, and waiting time reporting by provinces is inconsistent. One of the proposed strategies for reducing waiting times in cancer care is the use of interdisciplinary teams. I undertook an audit of the interdisciplinary pulmonary oncology program at the Jewish General Hospital from 2004 to 2007. The primary objectives of this study were: (1) to audit the performance of the interdisciplinary pulmonary oncology service at the Jewish General Hospital with respect to waiting times for key intervals and subgroups of patients; (2) to compare waiting times in the clinical trajectory of lung cancer patients seen at the Jewish General Hospital with existing waiting time guidelines; (3) to determine those factors associated with longer waiting times in this population. A secondary objective was to suggest measures to be considered in order to reduce waiting times. The JGH’s lung cancer service was compared against benchmarks developed by the British Thoracic Society, Cancer Care Ontario, and the pan-Canadian waiting time benchmarks for radiation oncology. Patients waited a median of 9 days from the time they were ready to treat until their first treatment, and a median of 30 days from their first contact with the pulmonary service until their first treatment. Patients over age 65, those with early-stage disease and those with good performance status were less likely to meet the recommended guidelines.

Thesis (MMed) -- Stellenbosch University, 2010. / Bibliography / Objectives: To describe the establishment of a colposcopy service in a district hospital in a rural sub-district and to assess its impact on the uptake of colposcopy. Design: A retrospective double group cohort study using a laboratory database of cervical cytology results, clinical records and colposcopy clinic registers. Setting: The Overstrand sub-district in the Western Cape: 80 000 people served by 7 clinics and a district hospital in Hermanus, 120 km from its referral hospitals in Cape Town and Worcester. A colposcopy service was established at Hermanus Hospital in 2008. Subjects: All women in the Overstrand sub-district who required colposcopy on the basis of cervical smears done in 2007 and 2009. Outcome measures: The number of women booked for colposcopy at distant referral hospitals in 2007 and at the district hospital is 2009, the proportion of those women who attended colposcopy, the time from cervical smear to colposcopy, comparison between the two years. Results: The uptake of colposcopy booked for distant referral hospitals was 67% in 2007. The uptake improved by 18% to 79% for the local district hospital colposcopy service in 2009 (p=0.06). When analysed excluding patients from an area with no transport to the district hospital, the improvement was more marked at 22% (p=0.02). The delay from cervical smear to colposcopy improved significantly from 170 to 141 days (p=0.02). Conclusion: The establishment of a colposcopy service in a rural sub-district increased the uptake of colposcopy and decreased the delay from cervical smear to colposcopy. This district hospital colposcopy service removed 202 booked patients in one year from the colposcopy load of its referral hospitals.

Within the field of radiotherapy treatments of tumour diseases, the hunt for more accurate and effective treatment methods is a continuous process. For some years ion-beam based radiotherapy, especially the proton-beam based applications, has increased in popularity and availability. The main reason behind this is the fact that ion-beam based applications make it possible to modulate the dose after the planning target volume (PTV) defined by the radiation oncologist. This means that it becomes possible to spare tissue in another way, which might result in more effective treatments, especially in the vicinity of radio sensitive organs. Ion-beam based treatments are however more sensitive to uncertainties in PTV position and beam range as ion-beams have a fixed range depending on target media and initial energy, as opposed to the conventional x-ray beams that do not really have a defined range. Instead their intensity decreases exponentially at a rate dependent of the initial energy and target media. Therefore density heterogeneities result in uncertainties in the planned treatments. As the plans normally are created using a CT-images, for which metallic implants can yield increased heterogeneities both from the implants themselves and so called metal artifacts (distortions in the images caused by different processes as the X-rays used in image acquisition goes through metals). Metallic implants affects the accuracy of a treatment, and therefore also the related risks, so it is important to have an idea of the magnitude of the impact. Therefore the aim of this study is to estimate the impact on a proton-beam based treatment plan for six cranial implants. These were one Ti-mesh implant, one temporal plate implant, one burr-hole cover implant and three craniofix implants of different sizes, which all are commonly seen at the Skandion clinic. Also the ability of the treatment planning system (TPS), used at the clinic, to simulate the effects on the plans caused by the implants is to be studied. From this result it should be estimated if the margins and practices in place at the clinic, for when it is required to aim the beam through the implant, are sufficient or if they should be changed. This study consisted of one test on the range shift effects and one test on the lateral dose distribution changes, with one preparational test in the form of a calibration of Gafchromic EBT3 films. The range shift test was performed on three of the implants, excluding the three craniofix implants using a water phantom and a treatment plan created to represent a standard treatment in the cranial area. The lateral dose distribution change test was performed as a solid phantom study using radiochromic film, for two treatment plans (one where the PTV was located \SI{2}{\centi\metre} below surface, for all implants, and one where it was located at the surface, only for the Ti-mesh and the temporal plate). The results of both tests were compared to simulations performed in the Eclipse treatment planing system (TPS) available at Skandion. The result of the range shift test showed a maximum range shift of \SI{-1.03 +- 0.01}{\milli\metre}, for the burr-hole cover implant, and as the related Eclipse simulations showed a maximal shift of \SI{-0.17 +- 0.01}{\milli\metre} there was a clear problem with the simulation. However, this might not be because of the TPS but due to errors in the CT-image reconstruction, such as, for example, geometrical errors in the representation of the implants. As the margin applied for a similar situation at the Skandion clinic (in order to correct for several uncertainty factors) is \SI{4.2}{\milli\metre} there might be a need to increase this margin depending on the situation. For the lateral distribution effects no definite results were found as the change varied in magnitude, even if it tended to manifest as a decreasing dose for the first plan and a increasing dose for the second. It was therefore concluded that further studies are needed before anything clear can be said.

No Brasil, o Sistema de Saúde é Universalista, com o tratamento integral gratuito ao paciente com câncer, cujo direito é assegurado por Lei e regulamentado pelo Ministério da Saúde / Instituto Nacional de Câncer José Alencar Gomes da Silva (INCA), por meio de Decreto Presidencial e Portarias. A habilitação e credenciamento de Hospitais em Unidades ou Centros de Alta Complexidade em Oncologia segue critérios rígidos, que determina como sendo obrigatória a presença do Cirurgião-Dentista na equipe multiprofissional e multidisciplinar na oncoterapia. O tratamento odontológico é compulsório e imprescindível na terapia antineoplásica, para prevenir e tratar as complicações orais: hemorragia, infecção, mucosite oral, xerostomia, cárie de radiação, trismo, alterações periodontais, osteonecrose avascular, osteorradionecrose; que podem levar à interrupção da oncoterapia, acarretando um aumento considerável nos custos da terapia implementada, a piora da qualidade de vida, e em alguns casos, podendo levar o paciente a óbito. O protocolo de cuidados orais na oncoterapia é normatizado e padronizado pelo INCA. Desta forma, foi realizado estudo do tratamento odontológico em pacientes com diagnóstico de câncer atendidos no Serviço de Odontologia Oncológica do UNACON do Hospital Geral de Palmas/Tocantins, no período de abril de 2011 a dezembro de 2016. Os dados foram obtidos de forma individualizada e estruturados segundo Variáveis Demográficas (VD), Procedimento Odontológico (PO), Procedimento Odontológico por Dente (POD) e Outras Variáveis de Interesse (OVI). O impacto financeiro de PO e POD foi avaliado pela comparação entre a tabela SIGTAP do Sistema Único de Saúde (SUS) e a tabela VRPO/SOESP (Valores Referenciais para Procedimentos Odontológicos/Sindicato dos Odontologistas do Estado de São Paulo). A maior incidência de pacientes foi observada na 5ª década de vida, com tendência à proporção homem/mulher de 1:1. Foram realizados 910 procedimentos preventivos/profilaxia/atividade educativa; 1826 raspagens supra e subgengival e aplicação tópica de flúor por hemiarcada; 932 restaurações de uma e duas faces com resina fotopolimerizável; 909 exodontias; 2746 sessões de laserterapia de baixa potência. O impacto financeiro mostrou uma defasagem significativa da Tabela SIGTAP/SUS. O estudo realizado revela a importância de uma base de dados estruturada para o registro do tratamento odontológico realizado em pacientes com diagnóstico de câncer atendidos no Sistema Único de Saúde; para que com isso seja possível fomentar, nos Sistemas de Saúde no Mundo, a elaboração e padronização de protocolo de cuidados orais na terapia antineoplásica, e o planejamento dos recursos humanos e financeiros destinados ao tratamento odontológico nos pacientes oncológicos. / In Brazil, the Health System is Universalist, with free comprehensive treatment for the cancer patient, whose right is guaranteed by Law and regulated by the Ministry of Health / National Cancer Institute José Alencar Gomes da Silva (INCA), through a Presidential Decree and Ordinances. The accreditation of Hospitals in Units or Centers of High Complexity in Oncology follows rigid criteria, which determines as mandatory the presence of the Dentist in the multiprofessional and multidisciplinary team in oncotherapy. Dental treatment is compulsory and essential in antineoplastic therapy to prevent and treat oral complications: hemorrhage, infection, oral mucositis, xerostomia, radiation caries, trismus, periodontal changes, avascular osteonecrosis, osteorradionecrosis; which can lead to interruption of oncotherapy, leading to a considerable increase in the costs of the therapy implemented, worsening of quality of life, and in some cases, leading to death. The protocol of oral care in oncotherapy is standardized by INCA. In this way, a study of the dental treatment was carried out in patients diagnosed with cancer attended at the UNACON Oncological Dentistry Service of the General Hospital of Palmas / Tocantins, from april 2011 to december 2016. Data were obtained individually and structured according to Demographics Variables (VD), Dental Procedure (PO), Dental Procedure by Tooth (POD) and Other Variables of Interest (OVI). The financial impact of PO and POD was evaluated by comparing the SIGTAP table of the Unified Health System (SUS) and the VRPO / SOESP table (Reference Values for Dental Procedures / Union of Dental Practitioners of the State of São Paulo). The highest incidence of patients was observed in the 5th decade of life, with a tendency to male to female ratios of 1: 1. Nine hundred and ten (910) preventive procedures / prophylaxis / educational activity were carried out; 1826 supra and subgingival scaling and topical application of fluoride by hemiarcate; 932 single and double sided restorations with photopolymerizable resin; 909 exodontia; 2746 sessions of low power laser therapy. The financial impact showed a significant lag in the SIGTAP / SUS Table. The study reveals the importance of a structured database for the registry of dental treatment performed in patients diagnosed with cancer treated in the Unified Health System; so that it is possible to promote, in the World Health Systems, the elaboration and standardization of oral care protocol in antineoplastic therapy, and the planning of human and financial resources for dental treatment in cancer patients.

Le cancer représente l'un des problèmes majeurs en santé publique. Jusqu'à présent, en parallèle de l'intervention chirurgical, plusieurs traitements ont été mis au point et largement utilisés en thérapie clinique telles que les chimiothérapies. Cependant, leur efficacité est parfois limitée et couplée à des effets secondaires très néfastes, laissant les patients dans une impasse thérapeutique. Par conséquent, de nouvelles approches thérapeutiques doivent être développées sur de nouvelles cibles avérées en oncologie afin d'apporter des soins personnalisés aux patients. La première partie de mon travail de thèse a été dédiée à la compréhension des mécanismes moléculaires de la nucléotidase cytosolique de type II (cN-II), une enzyme du métabolisme des purines dont l'implication dans des phénomènes de résistance à des traitements anticancéreux a pu être démontrée. Aussi, une étude sur la cinétique enzymatique à l'état pré-stationnaire et stationnaire a été entreprise sur la forme sauvage et une forme mutée de l'enzyme lui conférant une activité accrue fortement impliquée dans les cas de résistance. Par cette approche, il a été possible de décortiquer le mécanisme cinétique, de définir l'étape cinétiquement limitant afin d'identifier les intermédiaires prépondérants de la réaction pouvant être ciblés pour le développement de nouveaux inhibiteurs. Cette étude cinétique est présentée dans ce premier volet de la thèse. En second lieu, mon travail s'est focalisée sur un second membre de cette famille d'enzyme qui est l'ecto-5'-nucléotidase (CD73). Cette enzyme exprimée sous forme dimérique à la surface extracellulaire régule la concentration en adénosine extracellulaire (par hydrolyse de l'adénosine monophosphate), ce dernier étant un puissant immunosuppresseur de la réponse immune anticancéreuse. L'objectif de mon travail de thèse a été de développer de nouveaux inhibiteurs de type allostérique en utilisant une approche basée sur la structure tridimensionnelle et la dynamique moléculaire. Une des étapes clés a été tout d'abord de mettre au point un système expression hétérologue afin d'obtenir l'enzyme recombinante en quantité suffisante pour les études enzymatiques ultérieures. Différents systèmes d'expression ont été testés et seul le système en cellules d'insecte infectées par le baculovirus a permis d'obtenir l'enzyme active en grande quantité. En parallèle, une étude in silico a permis de reproduire la dynamique fonctionnelle de l'enzyme requise pour sa fonction. A partir de ses données, un criblage virtuel d'une chimiothèque de 324 000 molécules a été réalisé sur le site de dimérisation et a permis d'identifier 33 composés chefs de files. Parmi, ces composés, dix molécules se sont avérés être de puissants inhibiteurs de CD73 (Ki < 1 µM) avec un mécanisme d'inhibition de type allostérique ou non-compétitif. La cytotoxicité des composés a été évaluée sur des lignées cellulaires transformées ou tumorales montrant un effet uniquement à des concentrations très élevées (supérieures à 100 µM). L'étude des relations structure-fonction devrait permettre à présent de proposer de voies d'optimisation afin d'améliorer l'efficacité des composés les plus actifs afin d'aboutir à de nouveaux candidats médicaments. / Cancer burden still remains a major worldwide health problem. To date, several types of conventional anticancer treatments are widely used in clinical. However, the alternative effects of these treatments often leave patients impaired. Therefore, it is required to understand the unique medical needs of individual patients and to conduct effective, high–quality research focusing on the not yet identified oncotargets.The first part of my thesis is dedicated to decipher molecular basis of cN-II reaction. This study characterizes the steady state and transient state kinetics of cN-II wild type and hyperactive mutant which involved in cancer treatment resistance. Furthermore, the characterization of the rate-limiting step and reaction intermediates gave insights into the binding mechanisms and the development of small molecules inhibitors of cN-II.In the second part of this work, we aimed to investigate allosteric inhibitors of CD73 using structure-based drug design approach. In this study the suitable protein expression system was established for the production of sufficient quantities of fully active CD73. This work followed by in silico studies, including molecular dynamics, virtual screening, and hits identification and in vitro hits validations and kinetics characterizations. The cytotoxicity of the most powerful inhibitors exhibited on different cell types was determined. SAR studies gave insights into the binding mode of best compounds and function.

No description available.

Breast cancer is a global public health problem since it is the most frequently diagnosed cancer in women in Western countries. Clinical guidelines for breast cancer prognosis/diagnosis are currently based on tumour size, histological type and grade, lymph node status as well as the expression of various cellular receptors. Yet, current predictions remain unsatisfactory to identify the best treatment for the individual patient. The search for identifying new predictive and prognostic factors is ongoing. Furthermore, compelling evidences have solidified the notion that the evolving epithelial cells, founders of the breast disease, are helped in their malignant course by the tumour microenvironment. Better characterizing the dual effect of the immune regulation but also the epithelial-stromal cross-talk on both tumour-promotion and -suppression is essential for understanding patient uniqueness and their implication in disease outcome. Because of its potential to probe tissues and cells at the molecular level without requirement for extrinsic contrast agents, infrared spectroscopy was seen as an attractive tool for clinical and diagnostic analysis in order to complement the existing methods. <p>In a first step, recording and processing methodology had to be defined in order to optimally compare IR spectra. The methodology developed and the analysis tools tested on carcinoma cell lines, demonstrated that spectra could be distinguished based on the cell line phenotypic nature. <p>The potential of IR imaging for breast tissular structure differentiation was highlighted in this thesis, demonstrating that spectral signature can be correlated with the major histological cell types observed in breast disease tissues. In order to develop a robust algorithm translating spectral data into helpful histopathological information, a spectral database of histologically well-defined breast tissues was built and used for the development of a cell type classifier. This latter one was extensively validated on independent clinical cases. Firstly, the IR-based histopathological classifier correctly assigned spectra acquired on eleven breast disease samples based on their histological nature. Secondly, lymphocyte and Collagen & Fibroblasts spectral signatures were demonstrated to be independent from tissue type and organ since, although trained on reference spectra recorded into breast disease samples, the cell type classifier correctly assigned spectra acquired on lymph nodes/tonsils and scar tissues respectively. Thirdly, we concluded that spectroscopically, breast carcinoma cell lines in culture are well-suited tumour models since spectra acquired on these carcinoma cell lines were correctly recognized as epithelium by the IR-based histological classifier. <p>By spectral characterizing lymphocytes from lymph nodes and tonsils, we demonstrated that the spectra acquired contained enough information to statistically discriminate them according to their lymphocyte activation states. Although considered as activated, the breast disease lymphoid infiltrates were found to present distinct spectral signature from lymphocytes acquired on activated lymph nodes and tonsils. Furthermore, tumour microenvironment, characterized by IR-imaging was demonstrated to exhibit a distinct spectral signature from wound healing tissues. These studies proved the uniqueness of the signature of both lymphoid infiltrate and tumour microenvironment in breast disease context. Correlating these specific spectral signatures to patient outcome and therapeutics response could help better consider the uniqueness of the patient. In a last step, considering the epithelial signature of carcinomas of both low and high grades, we demonstrated that the biochemical information reflected in the IR micro-spectra was clinically relevant for grading purpose.<p><p> <p><p>Le cancer du sein est le cancer le plus fréquemment diagnostiqué chez les femmes dans les pays occidentaux. Jusqu’à peu, les cellules épithéliales tumorales étaient vues comme les seuls acteurs de la carcinogenèse ;processus se déroulant dans un milieu extracellulaire considéré au pire comme passif ou permissif à l’évolution tumorale des cellules épithéliales adjacentes. Cependant, de nombreuses études ont montré que ce microenvironnement tumoral pouvait soit promouvoir le processus de carcinogenèse soit le combattre empêchant par la même, l’occurrence de la maladie. <p>Ce projet de thèse s’inscrit dans une problématique actuelle, à savoir une meilleure compréhension de la maladie mais également une prise en charge plus individualisée des patientes. Nous abordons ici une voie de recherche novatrice basée sur la signature globale des molécules cellulaires via leur spectre infrarouge. La technologie utilisée, à savoir la spectroscopie infrarouge, nous fournit une observation quantitative et qualitative de milliers de vibrations moléculaires. L’adaptation de réseaux de plusieurs milliers de détecteurs indépendants aux microscopes infrarouges permet, grâce aux méthodes statistiques multivariées, d’investiguer l’architecture macromoléculaire des cellules au sein d’une coupe tissulaire et de corréler les informations spectrales ainsi obtenues à l’histopathologie des tissus. Par cette technologie, nous visons à mettre au point un outil diagnostique et pronostique pour le cancer du sein basé sur l’imagerie IR. <p>Durant ce projet, nous avons montré que les différents types cellulaires observés dans les carcinomes mammaires pouvaient être distingués par le biais de leur spectre IR, qu’un modèle de reconnaissance histologique pouvait être construit, validé et surtout automatisé et que ce modèle pouvait être transposé à l’étude d’autres tissus (ganglions, amygdales et cicatrices) et d’autres types d’échantillons (cellules épithéliales en culture). Nous avons également montré que les spectres de cellules épithéliales pouvaient être corrélés au grade histopathologique de la tumeur. Les spectres acquis de ganglions/amygdales ont montré que les profils spectraux pouvaient être corrélés à l’état d’activation lymphocytaire. De plus, l’étude de l’état d’activation lymphocytaire et fibroblastique a permis de mettre en avant un profil spectral propre et bien distinct des infiltrats lymphocytaires d’une part et de la matrice extracellulaire aux abords des tumeurs invasives d’autre part. <p> / Doctorat en Sciences agronomiques et ingénierie biologique / info:eu-repo/semantics/nonPublished