O interesse pela associação entre os hábitos alimentares e os fatores de crescimento e o câncer de mama foi recentemente elucidado. O risco e prognóstico do câncer de mama estar associado à composição corporal, fatores dietéticos, glicemia, fator de crescimento semelhante à insulina 1 e fator de crescimento vascular endotelial. Nosso objetivo foi identificar se o consumo de carnes vermelhas, leite de vaca e derivados, cereais integrais e refinados, linhaça, soja, chá verde, vegetais e frutas e os níveis séricos de glicose, IGF-1 e VEGF apresentam associação com os fatores prognósticos clínicos e patológicos do câncer de mama. Pacientes com câncer de mama submetidas à quimioterapia responderam a um questionário de freqüência alimentar semiquantitativo, e foram coletados dados antropométricos e sobre o estilo de vida. Amostras de sangue para dosagem de VEGF, IGF-1 e glicose foram coletadas antes do início da administração da quimioterapia. Os fatores prognósticos e dados da patologia foram coletados a partir dos prontuários. 61 pacientes entraram no estudo Foram analisados os dados de 59 pacientes. Houve associação entre glicemia de jejum e a circunferência da cintura (CC) (r2 = 0,16; β = 1,2; IC 95% 0,3-1,2; p = 0,002) e índice de massa corporal (r2 = 0,12; β = 1,295; IC 95% 0,4-2,1; p = 0,005), bem como entre glicemia de jejum e relação cintura-quadril(RCQ) (r2 = 0,07; β = 0,001; IC 95% 0-0,02; p = 0,04). Houve associação do maior tamanho do tumor e maior CC com a ingestão de mais de 226,1g de cereais refinados por dia (p <0,05). Houve associação do maior IMC, RCQ e CC com a ingestão de mais de 140,1 g de carne vermelha por dia (p <0,05).Nós encontramos resultados interessantes relacionados com a composição corporal e os níveis de glicemia de jejum e também com a composição corporal e ingestão de maiores quantidades de carne vermelha. Tumores de maior tamanho e maior CC foram relacionados à ingestão de cereais refinados, chamando a atenção para a necessidade de mais estudos avaliando o consumo deste grupo de alimentos em pacientes com câncer de mama. / Interest in the association of food habits, serum growth factors and breast cancer has been recently raised. Breast cancer risk and prognosis seems to be linked to body composition, dietary factors, serum glucose, insulin-like growth factor 1 and vascular endothelium growth factor. We aimed to identify whether the consumption of red meat, dairy products, whole and refined grains, fruits and vegetables and the levels of blood glucose, IGF-1 and VEGF were associated with prognostic factors in patients with breast cancer. Patients with breast cancer submitted to chemotherapy completed a semiquantitative foodfrequency questionnaire, and anthropometric and lifestyle data were collected. VEGF, IGF-1 and blood glucose were collected before chemotherapy administration. Breast cancer prognostic factors were collected from the pathology archives. 61 patients entered the study. Data were available for 59 patients. There was association between fasting glucose and waist circumference (WC) (r2=0.16; β=1.2; 95%CI 0.3-1.2; p=0.002) and body mass index (r2=0.12; β=1.295; 95%CI 0.4-2.1; p=0.005) as well as between fasting glucose and waist-to-hip ratio (r2=0.07; β=0.001; 95%CI 0-0.02; p=0.04). There was association of larger tumor size and larger WC with the ingestion of more than 226.1 g of processed refined grains per day (p<0.05). There was association of larger BMI, WHR and WC with the ingestion of more than 140.1 g of red meat per day (p<0.05). We have found interesting findings related to body composition and fasting glucose levels as well as body composition and ingestion of higher amounts of red meat. Larger tumor size and larger WC were related to the ingestion of processed refined grains, drawing attention to the need of further studies evaluating this food group in patients with breast cancer.

No description available.

Malgré des années de recherches sur la douleur et les incapacités chroniques, peu de conclusions claires émergent quant aux facteurs de risque les plus pertinents. La majorité des auteurs s’entendent toutefois sur un fait, les troubles musculo-squelettiques et l’adaptation à leurs nombreuses conséquences est un processus complexe, multidimensionnel et déterminé par l’interaction de facteurs biopsychosociaux. Deux articles sont présentés avec comme objectifs généraux d’identifier les déterminants importants de l’ajustement à un trouble musculo-squelettique. Le premier article consiste en une recension des écrits systématique visant à résumer tous les facteurs pronostiques biopsychosociaux de l’ajustement multidimensionnel aux troubles musculo-squelettiques et examinant leur pertinence à déterminer ces divers indicateurs d’ajustement, principalement la participation au travail, les limitations fonctionnelles, la douleur, la qualité de la vie, la détresse psychologique et la rechute. Les 105 études prospectives recensées et correspondant aux critères d’inclusion et d’exclusion ont été analysés et chaque association significative a été résumée. Par la suite, 68 études qui ont inclus des facteurs sociodémographiques, biologiques, psychologiques et sociaux ont été analysées séparément. Leur qualité méthodologique a été évaluée, un niveau d’évidence a par la suite été établi pour chaque association entre les facteurs de risque et les diverses variables de résultats. Les divergences dans ces associations entre les différentes phases de chronicité ont également été identifiées. Un niveau d’évidence élevée a été découvert concernant le rôle des attentes de rétablissement, certaines pratiques de gestion intégrées de l’incapacité, les stratégies d’adaptation (coping), la somatisation, la comorbidité, la durée de l’épisode symptomatique et un niveau modéré d’évidence a été découvert pour les comportements de douleur. Lorsque vient le temps de prédire les divers indicateurs d’ajustement de sujets souffrant de troubles musculo-squelettiques, chacun tend à être associé à des facteurs de risque différents. Peu de différences ont été relevées lorsque les phases de chronicité ont été prises en compte. Ces résultats confirment la nature biopsychosociale de l’ajustement aux troubles musculo-squelettiques bien que les facteurs psychosociaux semblent être prédominants. Le second article est une étude prospective avec un suivi de 2 et 8 mois. Elle a été menée auprès de 62 travailleurs accidentés, principalement en phase de chronicité et prestataires d’indemnités de revenu de la CSST (Commission en Santé et Sécurité du Travail du Québec). L’objectif de cette étude était d’identifier les déterminants de l’engagement actif dans un processus de retour a travail par opposition à l’incapacité chronique, tout en adoptant une approche biopsychosociale. Cet objectif a été poursuivi en faisant l’étude, d’une part, de la pertinence de facteurs de risque ayant déjà fait l’objet d’études mais pour lesquelles aucun consensus n’est atteint quant à leur utilité prédictive et d’autre part, de certains facteurs de risque négligés, voire, même omis de ce domaine de recherche. Suite à des analyses multivariées, le genre, les attentes de rétablissement en terme de capacité à retourner au travail et l’importance du travail ont été identifiés comme des déterminants de l’incapacité chronique liée au travail. Après 8 mois, l’âge, la consolidation médicale, les symptômes traumatiques, le support au travail et l’importance du travail ont été également identifiés comme des déterminants d’incapacité chronique liée au travail. Ces résultats démontrent l’importance d’aborder l’étude de l’incapacité chronique et de la réinsertion professionnelle selon une perspective multidimensionnelle. Ces résultats corroborent également les conclusions de notre recension des écrits, puisque les facteurs psychosociaux ont été identifiés comme étant des déterminants importants dans cette étude. / Despite years of research on chronic pain and disability, there is yet little consensus on a core set of risk factors. One thing that most agree on, is the fact that musculoskeletal disorders and the adjustment to its consequences is a complex, multidimensional process determined by biopsychosocial factors interacting with one another. Two articles are presented with the overall goal of identifying significant determinants of adjustment to musculoskeletal disorders. The first article is a systematic literature review that aimed at reviewing all pertinent biopsychosocial prognostic factors of adjustment to musculoskeletal disorders and assessed their relevance in predicting multidimensional outcomes, namely work participation, functional disability, pain, quality of life, psychological distress and recurrence. The 105 prospective studies identified and fitting the inclusion and exclusion criteria were analyzed and all significant associations were summarized. Then, 68 studies that included sociodemoraphic and biopsychosocial risk factors were separately analysed for their methodological quality, level of evidence (LOE) was established for each association between risk factors and outcome variables and existing differences were highlighted between phases of chronicity. Strong evidence was found for recovery expectations, coping, somatization, comorbidity, duration of episode, disability management and moderate evidence was found for pain behaviours. When it comes to predicting different outcomes reflecting the adjustment process of subjects with musculoskeletal disorders, each tends to have a different set of predictors. Few significant differences were found according to phases of chronicity. These results support the biopsychosocial nature of the adjustment to musculoskeletal disorders with a predominance of psychosocial determinants. The second article is a prospective study with follow-ups at 2 and 8 months and was conducted on a sample of 62 mostly chronic occupationally injured workers receiving compensation benefits from the CSST (Quebec Workers’ Compensation Board). The study aimed to identify determinants of active involvement in a return to work process while adopting a biopsychosocial approach. It did so by investigating the pertinence of previously studied risk factors but for which no consensus yet exists, but also by investigating the pertinence of previously neglected or even omitted risk factors. After multivariate analysis, gender, work recovery expectations and importance of work were predictive of work outcomes at 2 months. After 8 months, age, medical consolidation, trauma symptoms, work support and importance of work predicted work outcomes. The results show the importance of approaching chronic work disability from a multidimensional perspective, although corroborating our literature review’s findings that psychosocial variables appear to be more significant predictors in this study.

As imagens de ressonância magnética (RM) ponderadas em Difusão são conhecidas como uma técnica funcional capaz de refletir alterações estruturais e celulares de neoplasias. No câncer de mama, a difusão e sua quantificação através dos valores do coeficiente de difusão aparente (CDA) têm sido utilizados para avaliar resposta tumoral após quimioterapia neoadjuvante (QTN). Os variados desfechos clínicos do câncer de mama, incluindo as diferentes respostas ao tratamento quimioterápico podem estar relacionados à heterogeneidade da doença. A presença das células tronco tumorais (CTT) é uma das hipóteses aceitas para explicar os diferentes comportamentos biológicos dos tumores. Este estudo buscou avaliar uma possível associação entre os valores de CDA nas neoplasias invasivas da mama e a presença de marcadores de CTT e os principais marcadores prognósticos da doença em pacientes tratadas com QTN. Foram avaliadas prospectiva e consecutivamente as imagens de RM pré-tratamento de 27 pacientes com câncer da mama que realizaram QTN seguida de cirurgia. Os valores de CDA média, p10, p25 e p50 foram obtidos através de duas mensurações, uma com único ROI e outra com múltiplos ROIs envolvendo toda extensão tumoral. Esses valores de CDA foram correlacionados: à quantificação por citometria de fluxo de CTT com fenótipos ESA+/CD44+/CD24-, células ESA+ com alta atividade ALDH1 e células ESA+/ABCG2+, à capacidade de formação de mamoesferas, e aos principais fatores prognósticos do câncer de mama, incluindo estágio clínico, doença axilar linfonodal, grau tumoral, receptores de estrógeno (RE), receptores de progesterona (RP) e superexpressão do HER2. Também foi realizada correlação dos valores de CDA com a resposta patológica completa após QTN. A presença de CTT, a capacidade de formação de mamoesferas e a resposta patológica completa não se correlacionaram aos valores de CDA. Para ambas as medidas e todos os parâmetros avaliados de CDA (x10-3mm2/s), os valores foram significantemente menores nos tumores com estágio clínico III e IV vs II (0,90±0,16; 1,02±0,18); com doença linfonodal após QTN vs axila livre (0,89±0,16; 1,01±0,17); RE+ vs RE- (0,90±0,16; 1,00±0,18); RP+ vs RP- (0,91±0,16; 0,98±0,18) e HER2+ vs HER2- (0,92±0,17;0,97±0,18). Tumores grau 1 apresentaram CDA com valores significativamente maiores em relação aos tumores grau 2 (diferença 0,18; CI: 0,03-0,33, p=0,02). Os valores de CDA dos tumores de mama pré-QTN não predizem a presença de CTT, a capacidade de formação de mamoesferas ou a resposta patológica completa, porém se correlacionam com o estágio clínico da doença, doença linfonodal axilar após QTN, grau tumoral e expressão das proteínas RE, RP e HER2, sendo um promissor marcador de agressividade tumoral / The diffusion-weighted magnetic resonance imaging (DWMRI) is a functional technique able to reflect structural and cellular changes in the tumors. In the breast cancer, the diffusion-weighted images and its numeric value known as the apparent diffusion coefficient (ADC) has been applied to evaluate pathologic response in patients treated with neoadjuvant chemotherapy (NC). The difference in the clinical results after breast cancer treatment, including different rates of responses to the NC has been associated to the heterogeneity of the disease. The presence of the breast cancer stem cells (BCSC) is an accepted hypothesis to explain the different biologic breast cancers behaviors. The aim of this study was to correlate the ADC value of invasive breast cancer with the presence of cancer stem cells markers and the major prognostic factors in patients treated with neoadjuvant chemotherapy. Prospectively, the MRI pre-treatment of twenty-seven consecutive patients with invasive breast cancer posteriorly treated with NC followed by surgery were evaluated. The ADC values mean, 10th percentile, 25th percentile, 50th percentile were obtained from two measurements, one of them with a unique ROI and the other with multiple ROIs encompassing the entire lesion. The ADC values were correlated to: presence of BCSCs (cell surface markers CD44+/CD24-, ABCG2 and ALDH1) identified by flow cytometric analysis, tumor grade, breast cancer staging, lymph nodal involvement, expression of estrogen receptors (ER), expression of progesterone receptors (PR) and expression of HER2. The assay mammospheres (Mammocult ®) were analyzed in 18 samples. Additionally, the ADC values were correlated to the pathologic complete response after QN treatment. There were no correlations between ADC values and breast cancer stem cells markers or mammospheres formation efficiency. For all parameters calculated, the ADC values (x10- 3 mm 2 /s) were lower in: breast cancer stage III and IV than stage II (0,90±0,16; 1,02±0,18), tumors with lymph node metastasis than without lymph node metastasis (0,89±0,16; 1,01±0,17), ER expression than ER negative (0,90±0,16; 1,00±0,18), PR expression than PR 10 negative (0,91±0,16; 0,98±0,18) and HER2 expression than HER2 negative (0,92±0,17; 0,97±0,18). The ADC values were significantly higher in grade-1 tumors (difference 0,18; CI: 0,03-0,33) compared to grade-2 tumors (p=0,02). The tumors values of ADC pretreatment were not correlated to the pathologic complete response after NC. The ADC values in pre-treatment invasive breast cancers are not a predictor of BCSC presence, mammospheres formation efficiency or pathologic complete response to QN. However it is correlated to the tumor grade, breast cancer staging, lymph nodal involvement, expression of ER, PR and HER2 and may represent a promising marker of tumor aggressiveness

As imagens de ressonância magnética (RM) ponderadas em Difusão são conhecidas como uma técnica funcional capaz de refletir alterações estruturais e celulares de neoplasias. No câncer de mama, a difusão e sua quantificação através dos valores do coeficiente de difusão aparente (CDA) têm sido utilizados para avaliar resposta tumoral após quimioterapia neoadjuvante (QTN). Os variados desfechos clínicos do câncer de mama, incluindo as diferentes respostas ao tratamento quimioterápico podem estar relacionados à heterogeneidade da doença. A presença das células tronco tumorais (CTT) é uma das hipóteses aceitas para explicar os diferentes comportamentos biológicos dos tumores. Este estudo buscou avaliar uma possível associação entre os valores de CDA nas neoplasias invasivas da mama e a presença de marcadores de CTT e os principais marcadores prognósticos da doença em pacientes tratadas com QTN. Foram avaliadas prospectiva e consecutivamente as imagens de RM pré-tratamento de 27 pacientes com câncer da mama que realizaram QTN seguida de cirurgia. Os valores de CDA média, p10, p25 e p50 foram obtidos através de duas mensurações, uma com único ROI e outra com múltiplos ROIs envolvendo toda extensão tumoral. Esses valores de CDA foram correlacionados: à quantificação por citometria de fluxo de CTT com fenótipos ESA+/CD44+/CD24-, células ESA+ com alta atividade ALDH1 e células ESA+/ABCG2+, à capacidade de formação de mamoesferas, e aos principais fatores prognósticos do câncer de mama, incluindo estágio clínico, doença axilar linfonodal, grau tumoral, receptores de estrógeno (RE), receptores de progesterona (RP) e superexpressão do HER2. Também foi realizada correlação dos valores de CDA com a resposta patológica completa após QTN. A presença de CTT, a capacidade de formação de mamoesferas e a resposta patológica completa não se correlacionaram aos valores de CDA. Para ambas as medidas e todos os parâmetros avaliados de CDA (x10-3mm2/s), os valores foram significantemente menores nos tumores com estágio clínico III e IV vs II (0,90±0,16; 1,02±0,18); com doença linfonodal após QTN vs axila livre (0,89±0,16; 1,01±0,17); RE+ vs RE- (0,90±0,16; 1,00±0,18); RP+ vs RP- (0,91±0,16; 0,98±0,18) e HER2+ vs HER2- (0,92±0,17;0,97±0,18). Tumores grau 1 apresentaram CDA com valores significativamente maiores em relação aos tumores grau 2 (diferença 0,18; CI: 0,03-0,33, p=0,02). Os valores de CDA dos tumores de mama pré-QTN não predizem a presença de CTT, a capacidade de formação de mamoesferas ou a resposta patológica completa, porém se correlacionam com o estágio clínico da doença, doença linfonodal axilar após QTN, grau tumoral e expressão das proteínas RE, RP e HER2, sendo um promissor marcador de agressividade tumoral / The diffusion-weighted magnetic resonance imaging (DWMRI) is a functional technique able to reflect structural and cellular changes in the tumors. In the breast cancer, the diffusion-weighted images and its numeric value known as the apparent diffusion coefficient (ADC) has been applied to evaluate pathologic response in patients treated with neoadjuvant chemotherapy (NC). The difference in the clinical results after breast cancer treatment, including different rates of responses to the NC has been associated to the heterogeneity of the disease. The presence of the breast cancer stem cells (BCSC) is an accepted hypothesis to explain the different biologic breast cancers behaviors. The aim of this study was to correlate the ADC value of invasive breast cancer with the presence of cancer stem cells markers and the major prognostic factors in patients treated with neoadjuvant chemotherapy. Prospectively, the MRI pre-treatment of twenty-seven consecutive patients with invasive breast cancer posteriorly treated with NC followed by surgery were evaluated. The ADC values mean, 10th percentile, 25th percentile, 50th percentile were obtained from two measurements, one of them with a unique ROI and the other with multiple ROIs encompassing the entire lesion. The ADC values were correlated to: presence of BCSCs (cell surface markers CD44+/CD24-, ABCG2 and ALDH1) identified by flow cytometric analysis, tumor grade, breast cancer staging, lymph nodal involvement, expression of estrogen receptors (ER), expression of progesterone receptors (PR) and expression of HER2. The assay mammospheres (Mammocult ®) were analyzed in 18 samples. Additionally, the ADC values were correlated to the pathologic complete response after QN treatment. There were no correlations between ADC values and breast cancer stem cells markers or mammospheres formation efficiency. For all parameters calculated, the ADC values (x10- 3 mm 2 /s) were lower in: breast cancer stage III and IV than stage II (0,90±0,16; 1,02±0,18), tumors with lymph node metastasis than without lymph node metastasis (0,89±0,16; 1,01±0,17), ER expression than ER negative (0,90±0,16; 1,00±0,18), PR expression than PR 10 negative (0,91±0,16; 0,98±0,18) and HER2 expression than HER2 negative (0,92±0,17; 0,97±0,18). The ADC values were significantly higher in grade-1 tumors (difference 0,18; CI: 0,03-0,33) compared to grade-2 tumors (p=0,02). The tumors values of ADC pretreatment were not correlated to the pathologic complete response after NC. The ADC values in pre-treatment invasive breast cancers are not a predictor of BCSC presence, mammospheres formation efficiency or pathologic complete response to QN. However it is correlated to the tumor grade, breast cancer staging, lymph nodal involvement, expression of ER, PR and HER2 and may represent a promising marker of tumor aggressiveness

Le cancer du sein est le cancer le plus fréquent chez la femme et malgré une baisse de la mortalité ces dernières années, attribuable à une détection précoce et une meilleure prise en charge, il reste la première cause de mortalité par cancer et demeure donc un problème majeur de santé publique. La mortalité par cancer du sein s’avère être plus élevée dans le cas des cancers dits agressifs ou de mauvais pronostic tels que le cancer du sein de la femme jeune et le cancer du sein triple négatif (CSTN). Mes travaux de thèse portent sur ces deux types de cancer du sein avec comme objectifs l’étude des conséquences de la ménopause chimio-induite (MCI) chez les femmes jeunes atteintes d’un cancer du sein non métastatique d’une part et l’analyse des facteurs pronostiques de la rechute du cancer du sein triple négatif d’autre part. Le premier axe de ma thèse concerne l’étude clinique MENOCOR dont le but est d’évaluer chez les femmes jeunes atteintes d’un cancer du sein non métastatique l’impact de la MCI sur la qualité de vie (QdV). L’incidence de la MCI et l’étude des variations hormonales font également partie des objectifs secondaires. Dans le cadre de cette thèse, l’analyse intermédiaire, prévue dans le protocole, a été réalisée sur 59 patientes avec un recul de 18 mois post-chimiothérapie. Ces premiers résultats ont tendance à montrer une altération de la QdV évaluée par le QLQ-BR23 chez les patientes ménopausées vs les non ménopausées (p=0.17). A ce stade de l’essai, le QLQ-BR23 semble donc être plus adapté que le QLQ-C30 pour évaluer la QdV dans le contexte de cette étude. Nous avons également observé une prédiction possible de la MCI par le dosage de l’AMH initial et l’âge des patientes. Ainsi, ces résultats doivent être comparés à ceux de l’analyse finale et nous supposons qu’avec une puissance plus importante (effectif total prévu de 240 patientes et suivi de 30 mois post-traitement) les résultats concernant la QdV pourraient être significatifs.Le deuxième axe de ma thèse a consisté à la création d’une base de données sur le CSTN. Cette étude rétrospective s’inscrit dans la continuité des travaux réalisés au Centre Jean PERRIN et a pour but d’évaluer la dynamique et les facteurs prédictifs de la rechute du CSTN. Les analyses ont montré que l’atteinte ganglionnaire, la présence d’emboles et la taille tumorale sont les principaux facteurs pronostiques de la rechute. Les résultats présentés dans cette thèse confirment également l’hétérogénéité des CSTN avec l’existence d’une disparité des réponses à la CTNA (allant de la réponse complète à la chimiorésistance) et d’une diversité des rechutes (précoces (< 1 an), standards (1 à 5 ans) et tardives (> 5 ans)) soulignant la nécessité de poursuivre la recherche de nouveaux biomarqueurs pouvant prédire la réponse ou encore permettant de prévenir les rechutes afin d’améliorer la prise en charge des patientes. En conclusion, ces résultats permettent d’ouvrir de nombreuses perspectives de recherches. Nous prévoyons de comparer les résultats finaux de l’étude MENOCOR à ceux de l’analyse intermédiaire présentés dans cette thèse. A l’issu de l’essai, nous espérons avoir une meilleure compréhension de la MCI, de son impact sur la QdV et du rôle de l’AMH dans la prédiction de la ménopause. Concernant le CSTN, il est prévu de mener une autre étude rétrospective sur une cohorte plus large, avec cette fois-ci, l’analyse des paramètres hématologiques. En fonction des résultats, une étude prospective pourra être mise en place afin d’étudier le rôle du microenvironnement tumoral ainsi que des paramètres hématologiques et génétiques dans la rechute des CSTN. / Breast cancer is the most common cancer among women and despite a decline in mortality in recent years, due to early detection and better treatment management, it remains a major public health issue. Breast cancer mortality has been found to be higher in the case of aggressive or poor prognostic cancers such as breast cancer in young women and the triple negative subtype of breast cancer (TNBC).This PhD focuses on these two types of breast cancer and aims to study the consequences of chemotherapy-induced menopause (CIM) in young women with non metastatic breast cancer and evaluate the prognostic factors of TNBC relapse. One of the aspect of my PhD is based on the clinical study MENOCOR. The main objective of this study is to evaluate the impact of CIM on the quality of life (QoL) of young women with non metastatic breast cancer. The incidence of CIM and the study of hormonal variations are also a part of the secondary objectives. As a part of this PhD work, the interim analysis planned in the study protocol was conducted on 59 patients with a follow-up of 18 months post-chemotherapy. These first results tend to show a QoL decrease, evaluted by the QLQ-BR23, in menopausal women vs non menopausal women (p=0.17). At this stage of the trial, the QLQ-BR23 seems to be more appropriate than the QLQ-C30 to evaluate QoL. We also underline the possible prediction of CIM by the inital AMH level and age. Thus, these results should be compared to the final analysis and we expect that with a greater power (240 patients and a follow-up of 30 months post-chemotherapy) the QoL results will reach significance.The second axis consists of a database on TNBC. This retrospective study follows the work carried out in Jean PERRIN Cancer Center and aims to evaluate dynamics and pronostic factors of TNBC relapse. The analysis showed that the main pronostic factors are the node metastasis, the presence of emboli and the tumor size. The variability of response to chemotherapy (pCR to chemoresistance) and the diversity of relapses (early relapse (<1 year), standard relapse (1 to 5 years) and late relpase (> 5 years)) confirmed the heterogeneity of TNBC highlighting the need to continue the research of new biomarkers. In conclusion, these results open up many research perspectives. We plan to compare the final results of the MENOCOR study with those of the interim analysis presented in this PhD work. At the end of the study, we expect to have a better knowledge of CIM, its impact on QoL and the role of AMH in predicting menopause. Regarding the TNBC, it is planned to conduct another larger retrospective study focused in hematologic parameters evaluating the role of hematologic and genetic parameters. Depending on the results, a prospective study could be promoted in order to evaluate the role of tumoral micro-environment, and hematologic and genetic parameters in TNBC relapse.

Patients and methods: Malignant supratentorial glioma (anaplastic astrocytoma, oligoastrocytoma, oligodendroglioma and glioblastoma incl. gliosarcoma), age 16-70y, KPS 50-100. Postoperative randomization to chemotherapy with either BCNU (B) (80 mg/m2 x 3 every 6 weeks) alone or additional VM 26 (V) (50 mg/m2 x 3 every 6 weeks) starting concomitant with radiotherapy. Central histopathological review was required. Primary endpoints were survival time (ST) and progression free survival (PFS) . In addition confirmative analysis of prognostic factors and their interaction with therapy was performed. Results: Eligible: 501 of 522 randomized pts: 82% WHO grade IV gliomas, 18% grade III gliomas. 57% male, mean KPS 74, mean age 50.9 years. The high incidence of lung toxicity – with a cumulative risk of 19% during the first year - was alarming. Survival was not significantly different ( median 50.3 (B) versus 52.4 (V) (weeks), but an increase in long term survivors was observed (18 months: 29% B, 34% V, 5 years 5% B, 12% V) and PFS showed a significant difference with a median of 31.4 (B) versus 34.3 (V) weeks. Qualitative interaction between KPS and therapy (p < 0.01) was demonstrated: pts with a KPS ≥ 70 benefited from additional VM26, those with reduced KPS < 70 did better with BCNU-monotherapy. Conclusion: Adding VM26 to BCNU is effective in the chemotherapy of malignant gliomas. Because of the demonstrated interaction with therapy performance status, not tumor grade is the crucial factor to determine application and aggressiveness of chemotherapy. With risk adapted therapy a significant proportion of patients even with glioblastoma survive for years in good general condition. BCNU should be replaced by an equipotent alkylans to avoid the unacceptable high rate of lung toxicity.

Ziel der vorliegenden Arbeit ist die retrospektive Beurteilung der Sicherheit und Effektivität der Leberteilresektion bei der Behandlung von Lebermetastasen des kolorektalen Karzinoms sowie der Re-Resektion bei Patienten mit Rezidivlebermetastasen. Weiterhin soll das operative Vorgehen bei synchronen Lebermetastasen hinsichtlich simultaner Resektionsverfahren und zweizeitigen Vorgehens untersucht werden. Insgesamt wurden die Ergebnisse von 660 Patienten ausgewertet, die zwischen 1988 und 2004 mit 685 Leberteilresektionen behandelt wurden. Unter diesen waren 75 Patienten, die eine Re-Resektion erhielten sowie 202 Patienten, bei denen die Lebermetastasen synchron auftraten. Neben der Analyse der postoperativen Letalität und postoperativen Komplikationen sollen prognostische Faktoren für das Langzeitüberleben und das Auftreten von Tumorrezidiven nach Leberteilresektion identifiziert werden. Da sich die Studienpopulation aus einem Zeitraum von über 15 Jahren rekrutiert, sollen außerdem verschiedene Zeitabschnitte vergleichend analysiert werden. Die Leberteilresektion ist derzeit die einzige potentiell kurative Therapie bei kolorektalen Lebermetastasen. Als prognostisch günstige Parameter in der multivariaten Analyse zeigten sich die Radikalität des Eingriffes, die Anzahl der Metastasen, vorhandene ligamentäre Lymph-knotenmetastasen sowie das Jahr der Resektion. Auch bei Rezidiven kolorektaler Lebermetastasen ist das chirurgische Vorgehen derzeit die einzige kurative Intervention. Re-Resektionen weisen ein vergleichbares operatives Risiko und vergleichbare Langzeitüberlebensraten auf wie Erstresektionen. Als einziger prognostischer Parameter für das Langzeitüberleben erwies sich in der multivariaten Analyse die Radikalität des Eingriffes. Bei synchronen Lebermetastasen sind die wichtigsten Kriterien, um eine simultane Resektion durchzuführen, die Berücksichtigung des Alters sowie des Resektionsausmaßes. Simultane Resektionen sind bei synchronen kolorektalen Lebermetastasen dann so sicher und effizient durchführbar wie Resektionen im zweizeitigen Vorgehen.

Malgré des années de recherches sur la douleur et les incapacités chroniques, peu de conclusions claires émergent quant aux facteurs de risque les plus pertinents. La majorité des auteurs s’entendent toutefois sur un fait, les troubles musculo-squelettiques et l’adaptation à leurs nombreuses conséquences est un processus complexe, multidimensionnel et déterminé par l’interaction de facteurs biopsychosociaux. Deux articles sont présentés avec comme objectifs généraux d’identifier les déterminants importants de l’ajustement à un trouble musculo-squelettique. Le premier article consiste en une recension des écrits systématique visant à résumer tous les facteurs pronostiques biopsychosociaux de l’ajustement multidimensionnel aux troubles musculo-squelettiques et examinant leur pertinence à déterminer ces divers indicateurs d’ajustement, principalement la participation au travail, les limitations fonctionnelles, la douleur, la qualité de la vie, la détresse psychologique et la rechute. Les 105 études prospectives recensées et correspondant aux critères d’inclusion et d’exclusion ont été analysés et chaque association significative a été résumée. Par la suite, 68 études qui ont inclus des facteurs sociodémographiques, biologiques, psychologiques et sociaux ont été analysées séparément. Leur qualité méthodologique a été évaluée, un niveau d’évidence a par la suite été établi pour chaque association entre les facteurs de risque et les diverses variables de résultats. Les divergences dans ces associations entre les différentes phases de chronicité ont également été identifiées. Un niveau d’évidence élevée a été découvert concernant le rôle des attentes de rétablissement, certaines pratiques de gestion intégrées de l’incapacité, les stratégies d’adaptation (coping), la somatisation, la comorbidité, la durée de l’épisode symptomatique et un niveau modéré d’évidence a été découvert pour les comportements de douleur. Lorsque vient le temps de prédire les divers indicateurs d’ajustement de sujets souffrant de troubles musculo-squelettiques, chacun tend à être associé à des facteurs de risque différents. Peu de différences ont été relevées lorsque les phases de chronicité ont été prises en compte. Ces résultats confirment la nature biopsychosociale de l’ajustement aux troubles musculo-squelettiques bien que les facteurs psychosociaux semblent être prédominants. Le second article est une étude prospective avec un suivi de 2 et 8 mois. Elle a été menée auprès de 62 travailleurs accidentés, principalement en phase de chronicité et prestataires d’indemnités de revenu de la CSST (Commission en Santé et Sécurité du Travail du Québec). L’objectif de cette étude était d’identifier les déterminants de l’engagement actif dans un processus de retour a travail par opposition à l’incapacité chronique, tout en adoptant une approche biopsychosociale. Cet objectif a été poursuivi en faisant l’étude, d’une part, de la pertinence de facteurs de risque ayant déjà fait l’objet d’études mais pour lesquelles aucun consensus n’est atteint quant à leur utilité prédictive et d’autre part, de certains facteurs de risque négligés, voire, même omis de ce domaine de recherche. Suite à des analyses multivariées, le genre, les attentes de rétablissement en terme de capacité à retourner au travail et l’importance du travail ont été identifiés comme des déterminants de l’incapacité chronique liée au travail. Après 8 mois, l’âge, la consolidation médicale, les symptômes traumatiques, le support au travail et l’importance du travail ont été également identifiés comme des déterminants d’incapacité chronique liée au travail. Ces résultats démontrent l’importance d’aborder l’étude de l’incapacité chronique et de la réinsertion professionnelle selon une perspective multidimensionnelle. Ces résultats corroborent également les conclusions de notre recension des écrits, puisque les facteurs psychosociaux ont été identifiés comme étant des déterminants importants dans cette étude. / Despite years of research on chronic pain and disability, there is yet little consensus on a core set of risk factors. One thing that most agree on, is the fact that musculoskeletal disorders and the adjustment to its consequences is a complex, multidimensional process determined by biopsychosocial factors interacting with one another. Two articles are presented with the overall goal of identifying significant determinants of adjustment to musculoskeletal disorders. The first article is a systematic literature review that aimed at reviewing all pertinent biopsychosocial prognostic factors of adjustment to musculoskeletal disorders and assessed their relevance in predicting multidimensional outcomes, namely work participation, functional disability, pain, quality of life, psychological distress and recurrence. The 105 prospective studies identified and fitting the inclusion and exclusion criteria were analyzed and all significant associations were summarized. Then, 68 studies that included sociodemoraphic and biopsychosocial risk factors were separately analysed for their methodological quality, level of evidence (LOE) was established for each association between risk factors and outcome variables and existing differences were highlighted between phases of chronicity. Strong evidence was found for recovery expectations, coping, somatization, comorbidity, duration of episode, disability management and moderate evidence was found for pain behaviours. When it comes to predicting different outcomes reflecting the adjustment process of subjects with musculoskeletal disorders, each tends to have a different set of predictors. Few significant differences were found according to phases of chronicity. These results support the biopsychosocial nature of the adjustment to musculoskeletal disorders with a predominance of psychosocial determinants. The second article is a prospective study with follow-ups at 2 and 8 months and was conducted on a sample of 62 mostly chronic occupationally injured workers receiving compensation benefits from the CSST (Quebec Workers’ Compensation Board). The study aimed to identify determinants of active involvement in a return to work process while adopting a biopsychosocial approach. It did so by investigating the pertinence of previously studied risk factors but for which no consensus yet exists, but also by investigating the pertinence of previously neglected or even omitted risk factors. After multivariate analysis, gender, work recovery expectations and importance of work were predictive of work outcomes at 2 months. After 8 months, age, medical consolidation, trauma symptoms, work support and importance of work predicted work outcomes. The results show the importance of approaching chronic work disability from a multidimensional perspective, although corroborating our literature review’s findings that psychosocial variables appear to be more significant predictors in this study.

Background: Factors predicting survival in men with lymph node-positive prostate cancer are still poorly defined. Patients and Methods: 193 prostate cancer patients with histopathologically proven lymph node involvement with a median follow-up of 7.3 years were studied. 94% of patients received immediate hormonal therapy. Kaplan-Meier curves were calculated to evaluate overall survival rates and compared with the log-rank test. Cumulative disease-specific and competing mortality rates were calculated by competing risk analysis and compared with the Pepe-Mori test. Cox proportional hazard models were used to determine the independent significance of predictors of all-cause mortality. Results: Age (70 years or older vs. younger), Gleason score (8–10 vs. 7 or lower) and the number of involved nodes (3 or more vs. 1–2) were identified as independent predictors of all-cause mortality. When patients with 0–1 of these risk factors were compared with those with 2–3 risk factors, all-cause (rates after 10 years 21% vs. 71%, p < 0.0001), disease-specific (12 vs. 37%, p = 0.009) and competing mortality (9 vs. 33%, p = 0.02) differed significantly. Conclusions: Some of the excess mortality in patients with poor-risk lymph node-positive prostate cancer may be attributed to increased competing mortality, possibly caused by an interaction between comorbid diseases and hormonally treated persistent or progressive prostate cancer. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.