A osteonecrose dos maxilares associada aos bisfosfonatos (OMAB) é reconhecidamente uma complicação tardia dos bisfosfonatos, que são empregados para tratar desordens esqueléticas marcadas pela perda de massa óssea. Hoje, o reconhecimento da variante clínica sem exposição óssea e de outras classes de drogas associadas à osteonecrose dos maxilares (inibidores de RANK-L, VEGF, m- TOR e TNF-a) integram um novo aspecto do conceito dessa entidade patológica. Vários fatores de risco para o desenvolvimento de OMAB foram identificados, incluindo procedimentos odontológicos invasivos, má higiene oral, o uso de bisfosfonatos (particularmente, os bisfosfonatos nitrogenados como o pamidronato e o zoledronato), infusões frequentes e tempo prolongado de exposição aos bisfosfonatos. A saúde bucal é um fator significativo que afeta o risco de OMAB e, juntamente com a predisposição genética, pode explicar algumas das diferenças de incidência encontrada na literatura. Fatores genéticos parecem influenciar o risco de desenvolvimento da OMAB. Os polimorfismos de nucleotídeo único dos genes CYP2C8 e RBMS3 foram significativamente associados com um risco mais elevado. Enquanto o gene CYP2C8 está envolvido na inibição dos osteoclastos, diferenciação dos osteoblastos e regulação do tônus vascular, RBMS3 é um gene envolvido no metabolismo ósseo e foi associado à massa óssea reduzida e a fraturas osteoporóticas. Contudo, houve limitações metodológicas nesses estudos, dos quais apenas um abordou a diferença da frequência de polimorfismos associados à OMAB em grupos étnicos distintos. Até o momento faltam estudos genéticos sobre polimorfismos associados com OMAB que tenham sido replicados e validados com evidências convincentes, particularmente, envolvendo populações não caucasianas. Ainda hoje permanece um grande desafio: estratificar o risco para desenvolvimento da OMAB no contexto clínico. Assim, o objetivo do presente estudo é investigar a associação de fatores clínicos (saúde bucal) e genéticos com a ocorrência da OMAB. Realizou-se um estudo transversal com pacientes oncológicos expostos ao zoledronato e/ou pamidronato por pelo menos 7 meses, com ou sem OMAB. Submeteram-se os participantes à avaliação odontológica. Avaliou-se a condição de cárie dentária e doença periodontal através do índice de dentes cariados perdidos e obturados (CPOD) e índice periodontal comunitário. O índice gengival e o índice de higiene oral simplificado (IHOS) também constaram nessa avaliação. Para a discriminação dos genótipos dos genes CYP2C8 e RBMS3, 2 ml de saliva foram coletados e processados para a técnica de PCR quantitativa. A amostra consistiu de 80 pacientes (69 mulheres e 11 homens). O índice geral de OMAB foi 11,2% (câncer de mama: 11,3%; câncer de próstata: 22,2%). Houve forte correlação positiva entre o estadiamento clínico da OMAB e CPOD (rho=0.9189, p=0.001). Inflamação gengival moderada e cálculo dentário alcançaram, respectivamente, 72% e 50% dos indivíduos com OMAB. Bolsa periodontal de 4 mm ou mais envolveu 37,5% desse grupo. IHOS revelou aproximadamente 25% dos indivíduos desse grupo com higiene oral regular. O polimorfismo do gene CYP2C8 estava presente em 50% dos pacientes com OMAB, enquanto 12% apresentou mutação para o gene RBMS3. Em conclusão, a saúde bucal da população oncológica foi bastante precária e o polimorfismo do gene CYP2C8 pareceu se associar à OMAB em população oncológica. / Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is recognized as a late complication of bisphosphonates, which are used to treat skeletal disorders characterized by loss of bone mass. The recognition of clinical variation without bone exposure and other classes of drugs associated with osteonecrosis of the jaws (RANK-L, VEGF, m-TOR and TNF-inhibitors) are part of a new aspect of the pathological concept. Several risk factors for the development of BRONJ have been identified, including invasive dental procedures, poor oral hygiene, use of bisphosphonate (particularly, nitrogen-containing bisphosphonate such as pamidronate and zoledronate), frequent infusions and prolonged exposure to bisphosphonate. Oral health is a significant factor that affects the risk of BRONJ and, along with a genetic predisposition, it might explain epidemiological differences found in literature. Genetic factors seem to impact the risk of developing BRONJ. Single nucleotide polymorphisms of the CYP2C8 and RBMS3 genes were significantly associated with a higher risk. While the CYP2C8 gene is involved in osteoclast inhibition, osteoblast differentiation and regulation of vascular tone, RBMS3 is a gene involved in bone metabolism and has been associated with reduced bone mass and osteoporotic fractures. However, methodological limitations are present in these studies, of which only one addressed the difference in the frequency of polymorphisms associated with BRONJ in different ethnic groups. So far genetic studies have been lacking on polymorphisms associated with BRONJ that have been replicated and validated with convincing evidence, particularly involving non- Caucasian populations. In clinical context, a great challenge remains: classify patients in high risk for the development of BRONJ. Thus, the present study aims to investigate an association of clinical (oral health) and genetic factors with the occurrence of BRONJ. A cross-sectional study was performed with oncologic patients exposed to zoledronate and/or pamidronate for at least 7 months, with or without BRONJ. Participants were submitted to dental evaluation. Dental caries and periodontal disease were evaluated through the index of missing and filled teeth (DMFT) and community periodontal index. The gingival index and the simplified oral hygiene index (SOHI) were also included in this evaluation. For the discrimination of genotypes of the CYP2C8 and RBMS3 genes, 2 ml of saliva were collected and processed for the quantitative PCR technique. The sample consisted of 80 patients (69 women and 11 men). The overall BRONJ index was 11.2% (breast cancer: 11.3%, prostate cancer 22.2%). There was a strong positive correlation between the clinical staging of BRONJ and DMFT (rho=0.9189, p=0.001). Moderate gingival inflammation and dental calculus comprised, respectively, 72% and 50% of individuals with OMAB. Periodontal pocket of 4 mm or more involved 37.5% of this group. SOHI revealed approximately 25% of individuals in this group with regular oral hygiene. The polymorphism of the CYP2C8 gene was present in 50% of patients with BRONJ, while 12% had a mutation for the RBMS3 gene. In conclusion, the oral health of the cancer population was very precarious and CYP2C8 gene polymorphism is apparently associated with BRONJ in cancer population.

Radiation and medical drugs are used to fight head and neck cancer, but unfortunately in some cases these treatments cause development of other diseases and injuries. Osteoradionecrosis (ORN) and medical-related osteonecrosis of the jaw (MRONJ) are dreaded late complications in jaws from radiation therapy and medical drugs and cause great suffering to those affected. The full extent of ORN and MRONJ may be difficult to diagnose due to visualizing problems in quantifying boundaries of osteonecrosis and healthy tissues. Maxillofacial surgeons now use radiology and clinical appearance to differ affected bone, which may result in unprecise estimation of the area that is affected. As a possible adjuvant diagnostic procedure, visualizing osteonecrosis by examining neutrophil elastase (NE) activity in jaws was tested in patients. A newly developed positron emission tomography (PET) tracer specific for NE was used for observation and measurement in PET/CT images. An image processing software was used for visualization, segmentation, and analysis. Areas with osteonecrosis were identified in the ORN patients, but not in their entirety and all activity could not be equated with osteonecrosis as undiagnosed areas as well absorbed the tracer. Visualization of MRONJ displayed unexpectedly low activity in the diagnosed area.    The conclusion drawn from the results and the analysis is that NE activity can be found in osteonecrosis patients, but the activity itself does not provide complete information to visualize and quantify the diseased area and it cannot be equated with osteonecrosis. To verify NE activity as osteonecrosis, tissue samples from the affected area need to be collected for histological examination

Malgré l’amélioration du taux de survie, les survivants de la leucémie aiguë lymphoblastique (LAL) pédiatrique souffrent toujours de séquelles de la maladie et des traitements, dont au niveau neuromusculosquelettique (NMSQ). L’objectif de ce mémoire était de décrire les déficiences, limitations d’activité et restrictions de participation que présentent les survivants de LAL pédiatrique à long terme ainsi que d’explorer la prise en charge usuelle en physiothérapie de ces séquelles NMSQ. Le premier article est un d’étude descriptive rétrospective. Les résultats de cette étude supportent les séquelles NMSQ documentées dans la littérature en plus d’apporter des précisions sur les différences entre les survivants présentant ou non une ostéonécrose de la hanche. Le niveau d’association a également été évalué entre certaines variables de déficiences et limitations d’activité. Le second article est une étude de cas unique. Cette étude a permis de constater que, bien que les physiothérapeutes d’un des centres spécialisés en hémato-oncologie pédiatrique du Québec soient expertes dans le domaine, il n’existe actuellement aucune prise en charge standardisée des séquelles NMSQ des survivants de la LAL à long terme. L’identification des barrières et facilitateurs à l’implantation d’une prise en charge perçue comme optimale par les physiothérapeutes apporte des pistes de solution pertinentes à l’amélioration des pratiques. Les projets de recherche présentés dans ce mémoire permettent de constater que les déficiences et les limitations d’activité des survivants de la LAL pédiatrique sont importantes. Les physiothérapeutes sont parmi les détenteurs d’enjeux clés dans l’optimisation de la prise en charge de cette population grandissante. / Although survival rate has improved, survivors of childhood acute lymphoblastic leukemia (cALL) still suffer from late adverse effects related to the disease and its treatment including neuromusculoskeletal (NMSK) morbidities. The aims of this research were to describe the impairments, activity limitations, and participation restrictions of long-term survivors of cALL and explore current physiotherapy clinical practice regarding these NMSK late adverse effects. The first manuscript is a retrospective descriptive study. Results of this study confirm the long-term NMSK late adverse effects documented in the literature and provide additional information about differences between survivors with and without hip osteonecrosis. Furthermore, relationships between some variables of impairments and activity limitations were identified. The second manuscript is a case study. A focus group with expert physiotherapists in pediatric hemato-oncology from a specialized centre revealed that standardized clinical practice guidelines for the management of long term NMSK late adverse effects of survivors of cALL are lacking. Identification of barriers and facilitators to the implementation of clinical practice perceived as optimal by physiotherapists provides relevant solutions to improve long-term care of this population. Findings from these studies highlight that impairments and activity limitations of survivors of cALL are important. Physiotherapists are key stakeholders in optimizing long-term care of this growing population.

L’ostéonécrose (ON) et les fractures (FR) sont des complications qui prennent de plus en plus place dans le traitement pédiatrique de la leucémie aiguë lymphoblastique (LAL). L’ON peut être causée par différents facteurs, dont principalement l’utilisation de glucocorticoïdes. Les glucocorticoïdes sont administrés lors du traitement de la leucémie dans le but d’initier l’apoptose des cellules malignes tout en ayant un effet anti-inflammatoire. Cependant, l’utilisation de ces corticostéroïdes comprend des effets secondaires sérieux, notamment le développement d’ostéonécrose. Des variantes génétiques peuvent mettre certains patients plus à risque que d’autres. Plusieurs gènes ont déjà été signalés comme régulés par les actions glucocorticoïdes (GC). Les variations génétiques présentes dans les régions régulatrices de ces gènes peuvent affecter leur fonctionnement normal et, en fin de compte, de déterminer un risque accru de développer l’ON associé au traitement contre la leucémie. Pour cette raison, plusieurs polymorphismes ont été identifiés et étudiés dans la cohorte QcALL de Ste-Justine, concernant les gènes suivants : ABCB1, ACP1, BCL2L11, NFKB1, PARP1, et SHMT1. Ces gènes jouent majoritairement un rôle dans les mécanismes d’action des glucocorticoïdes, mais quelques-uns ont plutôt un effet direct sur le développement d’ostéonécrose. Nos recherches ont démontré une corrélation entre ces polymorphismes et l’apparition d’ostéonécrose chez les patients de la cohorte QcALL, traités aux glucocorticoïdes. L'incidence cumulative de l'ostéonécrose a été évaluée rétrospectivement chez 305 enfants atteints de la leucémie qui ont subi un traitement à l’hôpital Ste-Justine selon les protocoles DFCI de Boston (87-01, 91-01, 95-01 et 2000-01). Parmi les huit polymorphismes de BCL2L11 étudiés, les 891T> G (rs2241843) et 29201C> T (rs724710) ont été significativement associés à ON (p = 0.01 et p = 0.03, respectivement). L'association du polymorphisme 891T> G a été modulée par le type de corticostéroïde (CS), l’âge, le sexe et le groupe à risque (p ≤ 0,05). Le polymorphisme 29201C> T était particulièrement apparent chez les patients à haut risque (p = 0,003). La même étude était conduite en parallèle sur des patients de la cohorte DFCI de Boston (N = 192), et montrait des résultats significatifs pour les polymorphismes étudiés. En conclusion, les résultats de cette étude permettront de confirmer l’association de ces polymorphismes au développement d’ON chez les patients de LLA traités aux GC. / Osteonecrosis (ON) and fractures (FR) are complications that take place in the treatment of children acute lymphoblastic leukemia (cALL). They can be caused by various factors, mainly using glucocorticoids. The corticosteroids, dexamethasone (DXM) and prednisone (PDN) are administered during the treatment of leukemia to initiate apoptosis of malignant cells; while having an anti-inflammatory effect. However, the use of these corticosteroids has severe side effects, including the development of osteonecrosis. Moreover, some patients develop resistance to treatment, and are at risk of developing side effects. The genetic variants predispose some patients at higher risk than others. Several genes have been previously reported as up- or down regulated by the GCs actions. The genetic variations present in gene coding or regulatory regions can affect their function and ultimately determine an increased risk of developing ON associated to ALL therapy. Therefore, we investigated the association between several single nucleotide polymorphisms (SNPs) in six candidate genes: BCL2L11, NFKB1, PARP1, ABCB1, ACP1, and SHMT1. These genes play a role in the mechanisms of action of glucocorticoids, but some have more of a direct effect on the development of osteonecrosis. Our research has shown a correlation between these polymorphisms and the occurrence of osteonecrosis in patients in the QCALL cohort, treated with glucocorticoids. Cumulative incidence of osteonecrosis was assessed retrospectively in 305 children with ALL who underwent treatment with DFCI protocols (87-01, 91-01, 95-01 and 2000-01) in childhood ALL cohort from Quebec (QcALL). Among the eight tag BCL2L11 polymorphisms studied the 891T>G (rs2241843) and 29201C>T (rs724710) were significantly associated with ON (p = 0.01 and p = 0.03, respectively). Association of 891T>G polymorphism was modulated by type of corticosteroid (CS), age, sex and risk group (p ≤ 0.05 and that of 29201C>T was particularly apparent among high risk (p = 0.003) patients. These polymorphisms have shown significant ON association in several QcALL risk groups, mainly in corticosteroid groups, age < 10 years, and high risk (HR) group. Furthermore, the same study was conducted in parallel with patients in the replication (DFCI) cohort (N = 192), and we showed significant genetic association results for all studied polymorphisms. In conclusion, this study identifies that some ALL children have a high incidence of ON during the treatment that is highly associated with polymorphisms in different genes regulated by corticosteroids and ALL prognostic factors.