Idarubicin, a new analogue of daunorubicin, was administered intravenously at a dose of 15 mg/m2 to 31 patients with previously treated patients with unfavorable non-Hodgkin's lymphoma. Clinical characteristics included median age 69 years, performance status 1, and prior chemotherapeutic regimens 1. Twenty of the patients were relapsing after prior therapy and 11 were refractory; 29 had received prior anthracycline or anthracenedione. Responses were observed in 43% of patient (3 CR and 10 PR) with a median duration of 10 + months (2-29+ months). Idarubicin was well tolerated with non-hematologic toxicities (nausea/vomiting, mucositis, and anorexia) seen in <50% of patients. Median hematologic values during the first cycle for this dosage included WBC 1300/mm3 platelets 129,000/mm3, and hemoglobin 10.9 mg/dl. With dose escalation, hematologic toxicity was dose-limiting. Symptomatic cardiac toxicity was observed in one patient who had received maximum dose doxorubicin and radiotherapy. Median values for the cardiac ejection fraction during the full course of therapy for the entire group of patients were 0.62 (initial) and 0.60 (final). Idarubicin in intravenous form is an active drug in previously treated patients with unfavorable non-Hodgkin's lymphoma. Further studies employing idarubicin in non-Hodgkin's lymphoma should be considered. Cardiac function should be followed in trials utilizing anthracycline-type chemotherapeutic agents.

Nodular lymphocyte predominant Hodgkin's lymphoma (NLPHL) is a rare and unique subtype of Hodgkin's lymphoma (HL), accounting for approximately 5% of HL. On histology, NLPHL presents with “popcorn cells” composed of lymphocytic and histiocytic cells that express CD20 and CD45, unlike the pathognomonic Reed-Sternberg cells in classic HL (cHL) that express CD15 and CD30. Such differences in histopathology may require alternative treatment approaches. We present a rare case of NLPHL with atypical features at presentation with excellent response to treatment regimen used in Non Hodgkin’s Lymphoma (NHL). A 36-year-old male presented with acute onset back pain. He also noted multiple gradually enlarging lumps in his neck, axilla, and anterior chest wall for a few months. He mentioned significant constitutional symptoms including fatigue, weight loss, and drenching night sweats. No evidence of end-organ damage was present, except significant hypercalcemia suggestive of hypercalcemia of malignancy. An excisional biopsy of his axillary lymph node confirmed the diagnosis of NLPHL with immuno-stains that were positive for CD20, CD45 and negative for CD15 and CD30. PET scan demonstrated extensive tumor burden in the skeletal system, including the sternum, and multi-stationary lymphadenopathy. Splenomegaly with lymphomatous infiltration was also present. He was assigned stage IV based on the Ann Arbor staging system. R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) was initiated with a goal of 6 cycles, differing from ABVD (adriamycin, bleomycin, vinblastine, dacarbazine) regimen that is used for cHL. Interval PET scan post 4 cycles of R-CHOP showed no evidence of residual disease. PET scan after 6 cycles demonstrated a complete response (CR), including resolution of hypermetabolic uptake in the spleen, lymph nodes and bones. NLPHL is often considered indolent in clinical courses but with a tendency for multiple late relapses compared to cHL. It still maintains a favorable prognosis. In contrast to cHL, NLPHL less frequently presents with constitutional symptoms, increased tumor burden, or at an advanced stage, which is associated with a worse prognosis. Our patient had multiple features that are unusual in NLPHL such as hypercalcemia, extensive bony involvement with hypermetabolic lytic lesions and significant constitutional symptoms. The clinical conundrum with this rare subtype is whether to treat with HL vs NHL regimens. Literature and the guidelines recommend a conservative approach for low stage NLPHL with observation vs radiation vs single agent rituximab (used in NHL!). Advanced stages require multi-agent regimens ranging from one end of the spectrum with ABVD (used in cHL) to the other end with R-CHOP and its variants (used in NHL). Our patient with a rare subtype of HL had a very unusual and aggressive presentation with CR to R-CHOP demonstrating that rituximab based regimens should be the mainstay of treatment.

Marek’s disease (MD) of chickens is an economically important, contagious, neoplastic disease caused by Gallid herpesvirus type 2. All chicken are susceptible to MDV infection and neoplastic transformation, but, only susceptible genotypes develop gross lymphomas. Lymphomas regress in resistant genotypes from 21 days post infection (dpi). The central aims of this study were to understand the mechanisms of non-MHC associated genetic resistance and the molecular pathways of neoplastic transformation. We hypothesized that, a) in resistant chickens at 21 dpi the tissue microenvironment is compatible with cell mediated immunity but in susceptible lines antagonistic to cell mediated immunity, b) resistant genotypes present immunogenic peptides on their MHC class I which while the peptides presented by susceptible genotypes do not induce CTL immunity resulting in tumor progression. We used inbred, MHC homozygous MD resistant (L6) and susceptible (L7) chickens and reductionist methods to test our hypotheses. Our results indicated that the tumor microenvironment is pro T-regulatory in both resistant and susceptible genotypes, and, the host immune response (pro Th-1 in resistant and pro Th-2/T-reg in susceptible) influences the tumor regression or progression. Statistical analysis of MHC class I bound peptides from resistant and susceptible genotypes confirmed that they present the same peptides and perhaps genes outside the MHC locus play an important role in determining resistance. Next, using Systems Biology tools like genomics, proteomics, Gene Ontology modeling and pathway analysis we compared the transcriptome and proteome of neoplastically transformed cells (CD30hi) and non-neoplastically transformed cells (CD30lo) which are the two components of tumor microenvironment. We demonstrated that: a) in situ, CD30lo cells are pre-neoplastic and the proteome involved in transformation and potential mechanisms that may be controlled by MDV oncogene Meq; b) Meq can drive a feed forward loop that induces CD30 transcription and overexpression, increased CD30 signaling, which then activates NFêB and, in turn, increases Meq transcription; c) Meq transcriptional repression or activation from the CD30 promoter generally correlates with a polymorphism in the CD30 promoter between MD-resistant and -susceptible chicken genotypes and so a herpesvirus has evolved to utilize NFêB as a direct transcriptional activator for its oncogene.

No description available.

Introdução: Os linfomas abrangem um grupo heterogêneo de neoplasias originadas no sistema linfático, diferentes quanto à sua histologia, prognóstico e epidemiologia, embora possa haver grande número de aspectos clínicos comuns. De acordo com sua morfologia, dividem-se dois grupos: os linfomas Hodgkin (LH) e os linfomas não-Hodgkin (LNH). Objetivo: Avaliar a tendência temporal da incidência de linfomas no período de 1997 a 2012, identificando a influência de fatores como o sexo, a idade, o período e a coorte e nascimento. Metodologia: Trata-se de um estudo ecológico. Foram obtidas, do Registro de Câncer de Base Populacional de São Paulo (RCBP-SP), informações sobre todos os casos novos de linfomas no Município de São Paulo, diagnosticados no período de 1997 a 2012. Informações sobre o número de habitantes do Município foram obtidas online através do site do Departamento de Informática do SUS. Para avaliar a tendência da incidência de linfomas no decorrer do período, segundo sexo e faixa etária, foram ajustados modelos lineares generalizados (MLG). Para avaliar a influência da idade, do período de diagnóstico e das coortes de nascimento na tendência da incidência dos linfomas, foi utilizado o modelo idade-período-coorte (IPC). Resultados e conclusões: Dos 18.037 casos analisados, 20,5% eram do tipo LH e 79,5% do tipo LNH. Entre os casos de LH, 52,6% eram homens e 70,0% tinham entre 20 e 39 anos. A taxa de incidência de LH padronizada por idade, por 100 mil habitantes, variou de 5,0 em 1997 para 4,0 em 2012, entretanto, não foi detectada nenhuma tendência significativa na incidência ao longo do tempo (p>0,05). O risco de desenvolver LH foi maior no sexo masculino do que no feminino apenas na faixa etária de 0 a 14 anos (p<0,001), nas demais, o risco foi semelhante para ambos os sexos (p>0,05). O risco de desenvolver LH segundo a faixa etária apresentou um padrão etário bimodal. No sexo feminino, os maiores riscos ocorreram nas faixas de 20 a 39 e de 65 anos e mais e, no masculino, nas faixas de 15 a 19 e de 65 anos e mais. O modelo IPC apontou uma influência da coorte de nascimento na incidência de LH em mulheres: para aquelas nascidas antes de 1960, quanto mais antiga a coorte, maior o risco de LH; para as nascidas após 1960, o risco relativo permaneceu estável. Entre os casos de LNH, 51,6% eram homens e 77,4% tinham mais de 40 anos. A taxa de incidência de LNH padronizada por idade, por 100 mil habitantes, passou de 22,6 em 1997 para 17,0 em 2012. Foi detectada uma tendência de decréscimo na incidência de LNH de 1,7% ao ano em todas as faixas etárias, em ambos os sexos (p<0,001). O risco de desenvolver LNH aumentou continuamente com o avançar da idade, em ambos os sexos. O modelo IPC não detectou efeitos de período. Para os homens, as coortes mais velhas apresentam maior risco e, as mais jovens, menor risco. Para as mulheres nascidas antes de 1960 o comportamento foi semelhante ao dos homens, para as nascidas após 1960, o risco relativo permaneceu estável. / Introduction: Lymphomas comprise a heterogeneous group of neoplasias originating in the lymphatic system, different in their histology, prognosis and epidemiology, although there may be a large number of common clinical aspects. According to their morphology, two groups are divided: Hodgkin\'s lymphomas (HL) and non-Hodgkin\'s lymphomas (NHL). Objective: To evaluate the temporal trend of the incidence of lymphomas in the period from 1997 to 2012, identifying the influence of factors such as sex, age, period and cohort and birth. Methodology: This is an ecological study. Information about all new cases of lymphomas in the city of São Paulo, diagnosed in the period from 1997 to 2012, were obtained from the São Paulo Population Based Cancer Registry. Information on the number of inhabitants of the Municipality were obtained online through the website of the SUS Department of Informatics. To evaluate the trend of lymphoma incidence during the period, according to sex and age group, generalized linear models (GLM) were adjusted. The age-period-cohort (APC) model was used to evaluate the influence of age, diagnosis period and birth cohorts on the trend of lymphoma incidence. Results and conclusions: Of the 18,037 cases analyzed, 20.5% were HL type and 79.5% NHL type. Among the cases of HL, 52.6% were men and 70.0% were between 20 and 39 years old. The age-standardized incidence rate of HL per 100,000 population ranged from 5.0 in 1997 to 4.0 in 2012, however, no significant trend in incidence over time was detected (p> 0.05). The risk of developing HL was greater in males than in females only in the age group 0 to 14 years (p <0.001), in the others, the risk was similar for both sexes (p> 0.05). The risk of developing HL according to the age group presented a bimodal age pattern. In females, the highest risks occurred in the 20-39 and 65-year-olds, and in the male, in the 15-19 and 65 years and older ranges. The APC model pointed to an influence of the birth cohort on the incidence of HL in women: for those born before 1960, the older the cohort, the higher the risk of HL; for those born after 1960, the relative risk remained stable. Among the cases of NHL, 51.6% were men and 77.4% were over 40 years old. The age-standardized incidence rate of NHL per 100,000 population increased from 22.6 in 1997 to 17.0 in 2012. A trend of a decrease in the incidence of NHL of 1.7% per year was observed in all ranges in both sexes (p <0.001). The risk of developing NHL increased steadily with advancing age in both sexes. The APC model did not detect period effects. For men, older cohorts are at higher risk, and younger cohorts are at lower risk. For women born before 1960 the behavior was similar to that of men, for those born after 1960, the relative risk remained stable.

Introdução: Os linfomas abrangem um grupo heterogêneo de neoplasias originadas no sistema linfático, diferentes quanto à sua histologia, prognóstico e epidemiologia, embora possa haver grande número de aspectos clínicos comuns. De acordo com sua morfologia, dividem-se dois grupos: os linfomas Hodgkin (LH) e os linfomas não-Hodgkin (LNH). Objetivo: Avaliar a tendência temporal da incidência de linfomas no período de 1997 a 2012, identificando a influência de fatores como o sexo, a idade, o período e a coorte e nascimento. Metodologia: Trata-se de um estudo ecológico. Foram obtidas, do Registro de Câncer de Base Populacional de São Paulo (RCBP-SP), informações sobre todos os casos novos de linfomas no Município de São Paulo, diagnosticados no período de 1997 a 2012. Informações sobre o número de habitantes do Município foram obtidas online através do site do Departamento de Informática do SUS. Para avaliar a tendência da incidência de linfomas no decorrer do período, segundo sexo e faixa etária, foram ajustados modelos lineares generalizados (MLG). Para avaliar a influência da idade, do período de diagnóstico e das coortes de nascimento na tendência da incidência dos linfomas, foi utilizado o modelo idade-período-coorte (IPC). Resultados e conclusões: Dos 18.037 casos analisados, 20,5% eram do tipo LH e 79,5% do tipo LNH. Entre os casos de LH, 52,6% eram homens e 70,0% tinham entre 20 e 39 anos. A taxa de incidência de LH padronizada por idade, por 100 mil habitantes, variou de 5,0 em 1997 para 4,0 em 2012, entretanto, não foi detectada nenhuma tendência significativa na incidência ao longo do tempo (p>0,05). O risco de desenvolver LH foi maior no sexo masculino do que no feminino apenas na faixa etária de 0 a 14 anos (p<0,001), nas demais, o risco foi semelhante para ambos os sexos (p>0,05). O risco de desenvolver LH segundo a faixa etária apresentou um padrão etário bimodal. No sexo feminino, os maiores riscos ocorreram nas faixas de 20 a 39 e de 65 anos e mais e, no masculino, nas faixas de 15 a 19 e de 65 anos e mais. O modelo IPC apontou uma influência da coorte de nascimento na incidência de LH em mulheres: para aquelas nascidas antes de 1960, quanto mais antiga a coorte, maior o risco de LH; para as nascidas após 1960, o risco relativo permaneceu estável. Entre os casos de LNH, 51,6% eram homens e 77,4% tinham mais de 40 anos. A taxa de incidência de LNH padronizada por idade, por 100 mil habitantes, passou de 22,6 em 1997 para 17,0 em 2012. Foi detectada uma tendência de decréscimo na incidência de LNH de 1,7% ao ano em todas as faixas etárias, em ambos os sexos (p<0,001). O risco de desenvolver LNH aumentou continuamente com o avançar da idade, em ambos os sexos. O modelo IPC não detectou efeitos de período. Para os homens, as coortes mais velhas apresentam maior risco e, as mais jovens, menor risco. Para as mulheres nascidas antes de 1960 o comportamento foi semelhante ao dos homens, para as nascidas após 1960, o risco relativo permaneceu estável. / Introduction: Lymphomas comprise a heterogeneous group of neoplasias originating in the lymphatic system, different in their histology, prognosis and epidemiology, although there may be a large number of common clinical aspects. According to their morphology, two groups are divided: Hodgkin\'s lymphomas (HL) and non-Hodgkin\'s lymphomas (NHL). Objective: To evaluate the temporal trend of the incidence of lymphomas in the period from 1997 to 2012, identifying the influence of factors such as sex, age, period and cohort and birth. Methodology: This is an ecological study. Information about all new cases of lymphomas in the city of São Paulo, diagnosed in the period from 1997 to 2012, were obtained from the São Paulo Population Based Cancer Registry. Information on the number of inhabitants of the Municipality were obtained online through the website of the SUS Department of Informatics. To evaluate the trend of lymphoma incidence during the period, according to sex and age group, generalized linear models (GLM) were adjusted. The age-period-cohort (APC) model was used to evaluate the influence of age, diagnosis period and birth cohorts on the trend of lymphoma incidence. Results and conclusions: Of the 18,037 cases analyzed, 20.5% were HL type and 79.5% NHL type. Among the cases of HL, 52.6% were men and 70.0% were between 20 and 39 years old. The age-standardized incidence rate of HL per 100,000 population ranged from 5.0 in 1997 to 4.0 in 2012, however, no significant trend in incidence over time was detected (p> 0.05). The risk of developing HL was greater in males than in females only in the age group 0 to 14 years (p <0.001), in the others, the risk was similar for both sexes (p> 0.05). The risk of developing HL according to the age group presented a bimodal age pattern. In females, the highest risks occurred in the 20-39 and 65-year-olds, and in the male, in the 15-19 and 65 years and older ranges. The APC model pointed to an influence of the birth cohort on the incidence of HL in women: for those born before 1960, the older the cohort, the higher the risk of HL; for those born after 1960, the relative risk remained stable. Among the cases of NHL, 51.6% were men and 77.4% were over 40 years old. The age-standardized incidence rate of NHL per 100,000 population increased from 22.6 in 1997 to 17.0 in 2012. A trend of a decrease in the incidence of NHL of 1.7% per year was observed in all ranges in both sexes (p <0.001). The risk of developing NHL increased steadily with advancing age in both sexes. The APC model did not detect period effects. For men, older cohorts are at higher risk, and younger cohorts are at lower risk. For women born before 1960 the behavior was similar to that of men, for those born after 1960, the relative risk remained stable.

Lymphomas are neoplasms of the human immune system and can be divided into two categories, Hodgkin’s lymphoma (HL) and non-Hodgkin lymphoma (NHL). Anaplastic large cell lymphoma (ALCL) is a form of NHL that shares a common distinctive feature with HL, the overexpression CD30. The expression of cytokine receptor CD30 is restricted to proliferating B and T lymphocytes in healthy individuals while its overexpression is associated with several lymphoproliferative diseases such as ALCL and HL. The activation of CD30 via ligand or antibodies triggers various cellular responses ranging from apoptosis to cell proliferation and it is thought that the variable cellular response to CD30 activation may be due to cell surface levels of CD30. The human CD30 gene is regulated at the transcriptional level and previous studies characterising its promoter have identified several factors that regulate the expression this gene. However none of these identified factors explain for the high levels of CD30 observed in HL and ALCL. Therefore this study focused on the identification and functional analysis of transcriptionally active regions located up or downstream of the CD30 promoter region. The first aim for this study was to identify and characterise regions within the human CD30 gene that are involved in its transcriptional regulation. Phylogenetic footprinting identified several regions downstream of the CD30 promoter that displayed high levels of sequence homology indicating potential functional significance. Validation of these regions through two in vivo approaches, DNase 1 hypersensitivity assay and chromatin accessibility studies localised potential transcriptionally active regions to intron 1 of the CD30 gene.

Les antidépresseurs de type Inhibiteur Sélectif de la Recapture de la Sérotonine (SSRI pour Selective Serotonin Reuptake Inhibitor), dont fait partie la fluoxétine (Prozac), ont été décrits comme capables de déclencher l'apoptose de cellules tumorales in vitro et in vivo, suggérant une potentielle utilisation de ces molécules pour le traitement des cancers. Cependant, leur mécanisme apoptotique n’a pas été élucidé à ce jour. Nous avons donc entrepris de déterminer les étapes de l'apoptose induite par la fluoxétine et les SSRI, en choisissant comme modèle d'étude des lignées cellulaires de lymphomes non-Hodgkiniens agressifs. Nous avons identifié plusieurs étapes de la signalisation apoptotique de la fluoxétine et des SSRI. Ainsi, via une inhibition de la chaîne respiratoire, la fluoxétine induit la production d'espèces réactives de l'oxygène conduisant à la surexpression des récepteurs de mort DR4 et DR5 ; la fluoxétine induit également l'activation de la caspase-8. DR4 et DR5 sont très probablement la cause de l'apoptose induite par la fluoxétine, de façon indépendante de leur ligand, TRAIL (TNF-Related Apoptosis-Inducing Ligand). Partant du constat que l'utilisation de TRAIL comme antitumoral pour le traitement des lymphomes présente des résultats prometteurs mais encore insuffisants, nous avons envisagé que la fluoxétine puisse augmenter l’apoptose induite par TRAIL dans ce type de tumeurs. Nous montrons en effet qu'une association de la fluoxétine avec TRAIL conduit à une augmentation de l'action apoptotique de TRAIL dans les lignées de lymphomes non-Hodgkiniens agressifs. De plus, nos résultats montrent que la fluoxétine induit la mort cellulaire d'une façon indépendante de la caspase-8. Cet effet semble trouver son origine dans une surcharge en calcium de la mitochondrie, alimentée par une stimulation maintenue de l'entrée de calcium par les canaux CRAC (Calcium Release Activated Calcium). En conclusion, les éléments de la signalisation calcique et apoptotique de la fluoxétine et des SSRI que nous avons identifiés encouragent leur utilisation en thérapie, et notamment dans le cadre d'associations avec TRAIL et d'autres molécules pour permettre une augmentation de l'apoptose des cellules tumorales, voire des cellules résistantes à l'apoptose induite par TRAIL. / Selective Serotonin Reuptake Inhibitor (SSRI) antidepressants, such as fluoxetine (Prozac), have been shown to induce apoptosis in cancer cells in vitro and in vivo, suggesting a potential use for cancer treatment. However, their apoptotic mechanism has remained undetermined until now. Therefore, we have undertaken the determination of fluoxetine- and SSRIs-induced apoptotic signalling, our study model being aggressive Non-Hodgkin's Lymphoma (NHL) cell lines. We have identified several steps of the apoptotic signalling of fluoxetine and the SSRIs. Thus, via an inhibition of the respiratory chain, fluoxetine induces a reactive oxygen species production leading to the overexpression of the death receptors DR4 and DR5; fluoxetine also induces caspase-8 activation. DR4 and DR5 are probably the cause of fluoxetine-induced apoptosis, independently of their ligand TRAIL (TNF-Related Apoptosis-Inducing Ligand). Knowing that TRAIL as an antitumoral agent for lymphoma treatment has shown promising but insufficient results, we have hypothesized that fluoxetine could increase TRAIL-induced apoptosis in these tumors. Indeed, we show that fluoxetine in association with TRAIL leads to an increase in TRAIL-induced apoptosis in aggressive NHL cell lines. Furthermore, our results show that fluoxetine induces cell death in a caspase-8–independent manner. This effect seems to originate from a mitochondrial calcium overload fueled by a sustained calcium entry from the CRAC (Calcium Release Activated Calcium) channels. In conclusion, the calcium pathway and the apoptotic steps of the fluoxetine's and the SSRIs' signalling that we have delineated encourage their use in therapy, especially in association with TRAIL and other molecules in order to enable an increase in cancer cells' apoptosis, or even in cancer cells which are resistant to TRAIL-induced apoptosis.

Thesis advisor: Thomas C. Chiles / Normal B lymphocytes require extrinsic factors to grow and proliferate. Surface receptors (e.g., B-cell antigen receptor, BCR) function, in part, to link growth factors to signal transduction/metabolic pathways and the cell cycle machinery. Accumulating evidence indicates that signal transduction-dependent changes in both glucose energy metabolism and de novo transcription of the D-type cyclin-cdk4/6 pathway are necessary for quiescent B-lymphocytes to enter G1-phase of the cell cycle and grow. B cell growth represents a critical checkpoint for subsequent proliferation and clonal expansion of antigen-specific lymphocytes. On the former, we have shown earlier that acquisition of extracellular glucose and metabolism via the glycolytic pathway is required for conventional splenic B-2 lymphocytes to grow (i.e., increase cell size and mass) in response to antigen challenge; however, the metabolic fate and biological significance of glucose-derived carbons are unknown. Here, we show that in response to BCR ligation, glucose carbon flow is directed into a de novo lipogenic pathway that is regulated, in part, via phosphoinositide-3 kinase (PI-3K)-dependent activation of ATP citrate lyase (ACL), a key rate-limiting enzyme in de novo lipogenesis. Inhibition of ACL results in a loss of B-cell growth and cell viability. Regarding the latter point, the B-1a lymphocyte subset expresses cyclins D2 and D3 that are transiently expressed in a non-overlapping manner, notably cyclin D3 expression immediately precedes the G1/S phase transition, suggesting distinct functions for these D-type cyclins in B-1a lymphocyte G0-to-S phase progression. We show herein that murine B-1a cells deficient in cyclin D3 proliferate normally in response to extracellular stimuli, in part, due to a compensatory sustained up-regulation of cyclin D2. In keeping with this, human diffuse large B-cell lymphoma (DLBCL) represents a malignant clonal expansion of B cells characterized by several subsets, including germinal center (GC) and activated B-cell (ABC) types. Here, we show that the GC-type LY18 human DLBCL exhibits constitutive expression of cyclin D3, but not cyclins D1 and D2. Targeting of cyclin D3-holoenzyme complexes with cell permeable chemical- and peptide-based cdk4 inhibitors results in G1-phase arrest and apoptosis via a pathway that involves inhibition of pRb phosphorylation. By contrast, endogenous knock down of cyclin D3 with siRNA did not induce growth arrest or apoptosis, in part, due to redundancy with cyclin E. / Thesis (PhD) — Boston College, 2009. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Biology.

Introduction : Grâce aux progrès des traitements et au diagnostic précoce, les cancers sont de mieux en mieux pris en charge et guéris. Toutefois durant la maladie et ses traitements, les patients ressentent souvent de la fatigue et celle-ci peut avoir un impact sur l'évolution de la maladie et la survie. La prévalence des cancers est d'autant plus élevée que la personne est âgée, personnes qui sont davantage touchées par la fatigue. Cette fatigue est accentuée par la fragilité des patients qui se caractérise par une faiblesse, une lenteur de marche ou encore une perte de poids involontaire. Des facteurs médicaux et psycho-sociaux sont associés à la fatigue et il est important de les évaluer pour mieux les prendre en compte lors de la prise en charge des patients. L'objectif de ce travail de thèse est d'étudier le rôle de certains facteurs psycho-sociaux (coping, soutien social, dépression et routinisation) associés à la fatigue chez des patients âgés et fragiles atteints d'un lymphome non-Hodgkinien.Méthode : Cette recherche, intitulée Psyfrail, est une étude ancillaire à un essai randomisé nommé Frail. Les patients inclus (n=50), âgés en moyenne de 82 ans, ont été évalués au niveau de la fatigue, de la dépression, du coping, du soutien social et de la routinisation lors d'un rendez-vous avec un psychologue avant le début des traitements (T1), au milieu (T2) et à la fin (T3). Des analyses transversales et longitudinales ont été effectuées pour mettre en évidence les facteurs associés à la fatigue aux différents temps de mesure et à son évolution.Résultats : L'utilisation de stratégies de coping centrées sur le problème à T1 est associée à une diminution des scores de fatigue générale et de réduction des activités à T1 et une diminution de la réduction de la motivation à T2. La routinisation augmente les scores de fatigue mentale et de réduction de la motivation à T2. La disponibilité du soutien social permet une moindre augmentation du score de réduction de la motivation au cours du temps. La diminution de la fatigue générale est moindre chez les patients ayant des niveaux élevés de coping centré sur l'émotion. La dépression est associée à une fatigue plus importante à T1 et T2.Conclusion : La promotion de stratégies adaptées pour aider les patients à faire face à la maladie et la prise en charge de la dépression pourrait avoir un impact positif sur la réduction de la fatigue. / Introduction: Thanks to the progress of treatments and early diagnosis, cancers are better cured. However, during the disease and its treatments, patients often experience fatigue which could have an impact on disease progression and survival. Medical and psycho-social factors are associated with fatigue, which makes them important to evaluate in order to consider them properly when taking care of patients. Cancer prevalence is higher in the elderly, who are more affected by fatigue. This fatigue increases with frailty, characterized by a state of weakness, slow walking speed or unintentional weight loss. This is why we chose to focus on this specific populationThe objective of this thesis is to study the role of several psychosocial factors (coping, social support, depression and routinization) associated with fatigue in frail elderly patients with non-Hodgkin lymphoma.Method: This research, entitled Psyfrail, is an ancillary study to a randomized trial named Frail. The 50 patients included, with a mean age of 82 years old, were evaluated in terms of fatigue, depression, coping, social support and routinization during a meeting with a psychologist before the start of treatment (T1), in the middle (T2) and at the end (T3). Cross-sectional and longitudinal analyzes were conducted to highlight the factors associated with fatigue at different measurement times and with its evolution.Results: The use of problem-focused coping at T1 is associated with a decrease in general fatigue and reduced activity scores at T1 and a decrease in the reduced motivation score at T2. Routinization increases mental fatigue and reduced motivation scores at T2. Social support availability is associated with a smaller increase in the reduced motivation score over time. The decrease in general fatigue is reduced in patients with high level of emotion focused coping. Depression is associated with a higher fatigue at T1 and T2.Conclusion: The promotion of appropriate strategies to help patients cope with the disease and the treatment of depression could have a positive impact on reducing fatigue.