Purpose: The five point Deauville (D) scale is widely used to assess interim PET metabolic response to chemotherapy in Hodgkin lymphoma (HL) patients. An International Validation Study reported good concordance among reviewers in ABVD treated advanced stage HL patients for the binary discrimination between score D1,2,3 and score D4,5. Inter-reader reliability of the whole scale is not well characterised. Methods: Five international expert readers scored 100 interim PET/CT scans from paediatric HL patients. Scans were acquired in 51 European hospitals after two courses of OEPA chemotherapy (according to the EuroNet-PHL-C1 study). Images were interpreted in direct comparison with staging PET/CTs. Results: The probability that two random readers concord on the five point D score of a random case is only 42% (global kappa = 0.24). Aggregating to a three point scale D1,2 vs. D3 vs. D4,5 improves concordance to 60% (kappa = 0.34). Concordance if one of two readers assigns a given score is 70% for score D1,2 only 36% for score D3 and 64% for D4,5. Concordance for the binary decisions D1,2 vs. D3,4,5 is 67% and 86% for D1,2,3 vs D4,5 (kappa = 0.36 resp. 0.56). If one reader assigns D1,2,3 concordance probability is 92%, but only 64% if D4,5 is called. Discrepancies occur mainly in mediastinum, neck and skeleton. Conclusion: Inter-reader reliability of the five point D-scale is poor in this interobserver analysis of paediatric patients who underwent OEPA. Inter-reader variability is maximal in cases assigned to D2 or D3. The binary distinction D1,2,3 versus D4,5 is the most reliable criterion for clinical decision making.

Le syndrome néphrotique idiopathique (SNI) est une néphropathie glomérulaire définie par une protéinurie massive associée à une hypoalbuminémie, sans lésions inflammatoires rénales, ni dépôts de complexes immuns circulants. Les travaux réalisés au cours de ma thèse concernent l’étude du rôle potentiel du gène c-mip dans la physiopathologie du SNI.Dans un premier temps, nous avons étudié la physiopathologie moléculaire de l’association maladie de Hodgkin et SNI. Nous avons démontré que cette association était liée à une forte induction de c-mip à la fois dans les cellules de Reed Sternberg (dont la présence signe le lymphome hodgkinien) et les podocytes qui sont des cellules spécialisées du glomérule rénal (Audard, et al. 2010). Nous avons montré que l’induction de c-mip résultait d’un défaut quantitatif et/ou qualitatif du gène Fyn, à la fois chez les patients et dans un modèle de souris déficiente en Fyn. Nous avons trouvé que c-mip était fortement induit dans les podocytes au cours du SNI ainsi que dans la glomérulopathie extramemenbraneuse (GEM). La surexpression de c-mip par transgénèse chez la souris déclenche une protéinurie néphrotique dont le mécanisme implique une rupture, médiée par c-mip, de la voie de signalisation de la néphrine (Science Signaling, 2010 co-auteur). L’étude de la néphrite de Heyman, le modèle expérimental de la GEM humaine, a permis de montrer que l’induction de c-mip coincidait avec l’apparition de la protéinurie et était associée à l’inhibition de l’activité RhoA, à une perte de la synaptopodine, à une diminution du VEGF tandis que l’expression de la DAPK (death-associated protein kinase) est fortement augmentée (Audard et al, manuscrit soumis 1). Nous avons recherché si l’hypogammaglobulinémie au cours du SNI était associée à des anomalies fonctionnelles des lymphocytes B (LB). Nous avons trouvé que c-mip interagit avec la sous unité régulatrice de la PI3 kinase et empêche la dissociation de la sous unité catalytique, p110, nécessaire à l’activation de la PI3 kinase. Enfin, l’expression de l’IL 21, une cytokine–clé secrétée par les lymphocytes T et intervenant dans la commutation isotypique, était fortement réduite dans le SNI (Audard et al, manuscrit en préparation 2). Ces résultats donnent un éclairage nouveau sur la physiopathologie moléculaire du SNI et suggèrent un rôle crucial de c-mip dans les anomalies lymphocytaires et podocytaires observées chez les patients / Idiopathic nephrotic syndrome comprises several podocyte diseases of unknown origin, affecting the glomerular podocyte, which plays a key role in controlling the permeability of the kidney filter to proteins. It is characterized by massive proteinuria and hypoalbuminemia, with no inflammatory lesions or cell infiltration. This works focused on the potential role of c-mip in the pathogenesis of INS. We showed that occurrence of minimal change nephrotic syndrome in the course of Hodgkin lymphoma (cHL-MCNS) is closely related to the induction of c-mip in both Hodgkin-Reed Sternberg cells and podocytes (Audard, et al. 2010), which is caused by a qualitative and/or quantitative defect in Fyn in both HRS and podocytes cells. We found that c-mip is upregulated in podocytes of patients with membranous nephropathy (MN). Transgenic mice overproducing c-mip in the podocytes developed heavy proteinuria without morphological alterations, inflammatory lesions or cell infiltrations. We showed that c-mip turned off podocyte proximal signaling by preventing the interaction between Fyn and nephrin, resulting in the inhibition of nephrin signaling pathway (Science signaling, 2010 coauthor). Moreover, the induction of c-mip in passive type Heymann nephritis (the experimental model of MN) was concomitant to proteinuria occurrence and is associated with reduction of RhoA activity, downregulation of synaptopodin and VEGF expression whereas DAPK expression is significantly increased (Audard et al manuscript submitted 1).We demonstrated that hypogammaglobulinemia, a common feature in INS patients, may result from a defect in B lymphocytes. We found that c-mip interacts with p85 regulatory subunit and prevent its dissociation from p110 catalytic subunit, resulting in inactivation of PI3 kinase. Finally, the expression of IL21, a key cytokine involved in class switching recombination, is repressed in active phases of INS, which may contribute for immunoglobulin disorders commonly observed in these patients (Audard et al manuscript in progress 2).Altogether, these results suggest that c-mip is a major player of lymphocyte and podocytes dysfunction observed in patients with INS

No description available.

Células-tronco (CT) são células com um alto poder de indiferenciação, plasticidade celular e autorrenovação. Baseado na autorrenovação das CT, pesquisas recentes sugerem que uma falha durante este processo pode levar ao surgimento de um novo tipo de célula, sendo esta responsável pelo aparecimento, propagação e manutenção de diversos tipos de neoplasias. Além disso, apresenta resistência às formas de tratamento convencionais do câncer. Tais células foram denominadas de células-tronco tumorais (CTT). As CTT já foram caracterizadas em leucemias e em diversos tipos de tumores sólidos, porém, até o presente momento, não foram descritas em linfoma não- Hodgkin (LNH). Por esta razão, o presente estudo teve como objetivo investigar a presença de CTT em pacientes com LNH. Biópsias de linfonodos e medulas ósseas (MO) de pacientes com LNH foram as fontes utilizadas para isolar e cultivar as CT mesenquimais. Uma vez caracterizadas as CTT, estas foram inoculadas em camundongos imunodeprimidos para observar uma possível formação de tumor. As células isoladas de biópsias de linfonodo não apresentaram CD133 positivo, marcador de membrana presente nas CTT, bem como não expressaram os genes de indiferenciação (Nanog e Oct-4) e não formaram tumores quando inoculadas nos animais. Por outro lado, as células isoladas de MO apresentaram subpopulações de células positivas para o CD133, expressaram os genes de indiferenciação e, após inoculadas, desenvolveram tumores em camundongos imunodeprimidos. Com isto, concluise que as células isoladas dos linfonodos possam ser fibroblastos, indicando, assim, uma dificuldade de se isolar as CTT deste material. Enquanto que, como já bem descrito e estabelecido na literatura, CT foram facilmente isoladas de MO, entretanto, quando isoladas de pacientes LNH foi ainda possível caracterizar a presença de uma subpopulação de CTT / Stem cells (SC) are undifferentiated cells, with high capacity of cellular plasticity and self-renewal. Based on the self-renewal, recent research suggests that a failure during this process, it can lead to the emergence of a new type of cell, which is responsible for the development, propagation and maintenance of several types of malignancies. Moreover, it is resistant to the conventional treatment of cancer. These cells are denominated as cancer stem cells (CSC). CSC were already characterized in leukemia and in several types of solid tumors. However, until the present moment nothing was described in non- Hodgkin lymphoma (NHL). For this reason, the present study aimed to investigate the presence of CSC in patients with NHL. Biopsies of lymph nodes and bone marrow (BM) from patients with NHL were used for isolate and cultivate MSC. The techniques used to characterize these cells were flow cytometry and PCR. Once CSC were characterized, these cells were inoculated into immunodeficient animals to observe a possible tumor formation. Cells isolated from lymph node biopsies did not show the presence of CD133, a membrane marker present in the CSC, as well as did not express differentiation genes (Nanog and Oct-4) and no ability to form tumors in immunodeficient mice. In another hands, cells isolated from BM showed a subpopulation of CD133 positive, expressed undifferentiated genes and also after the inoculation was possible to observe the tumor formation in immunodeficient mice. In conclusion, isolated cells from lymph nodes could be fibroblasts, indicating a difficulty to isolate CSC from this material. Whereas, as already describe and establish in the literature, SC were easily isolate from MO. However, when isolated from NHL patients was possible to characterize the presence of CSC subpopulation

Submitted by Rosivalda Pereira (mrs.pereira@ufma.br) on 2017-10-04T19:49:22Z No. of bitstreams: 1 MarianyOliveira.pdf: 2011433 bytes, checksum: 0c698b1c9b1cd49abde1a5c6be92d253 (MD5) / Made available in DSpace on 2017-10-04T19:49:22Z (GMT). No. of bitstreams: 1 MarianyOliveira.pdf: 2011433 bytes, checksum: 0c698b1c9b1cd49abde1a5c6be92d253 (MD5) Previous issue date: 2017-04-11 / Introduction: The growing number of non-Hodgkin lymphoma (NHL) survivors and the lower quality of life (QoL) survivors have been accompanied by the clustering of difficult symptoms. Also, the categorization of survivors from similar characteristics, has been presented as a strategy in the care of this population. Objective: To analyze QoL and clustering of symptoms in NHL survivors. Methods: Cross-sectional study with a non-probabilistic, 79 patients / survivors followed up at a specialized oncohematology outpatient clinic. The EORTC-QLQC30 (QoL), the Revised Piper Fatigue Scale-RPFS (fatigue), the Distress Thermometer-DT (distress), the Mini-Sleep Questionnaire-MSQ (sleep disorders) and the Visual Analog ScaleVAS (pain), as well as socioeconomic, demographic and clinical data were used. Results: Survivors averaged 57,24 (SD = 5.10) years of age, 70.88% were 50 years old or older, 53,16% were males, and 65,82% had a good level of Karnofsky Performance Status Scale (KPS). The mean time since diagnosis was 3,29 years (SD = 3,67), 36,70% were in acute survival, followed by extended survival (24,05%) and long-term survival (19,00%). The overall mean QoL was high (73,12, SD=18,93). Few reported fatigue (18,31%). More than half reported some sleep disturbance and presence of pain, 56,05% and 56,96%, respectively. The prevalence of distress was quite high (81,69%). 62,02% of the sample reported some clustering of symptoms, the most prevalent: distress-pain-sleep disorder (20,25%), distress-pain (11,39%) e distress-pains-sleep disorder-fatigue (11,39%). Survival categories with active disease had worse overall QoL (p = 0.0073) and worse role performance (p = 0.0005). There was significant association between QoL and survival categories (p = 0.0397), with higher means among the categories in remission. Overall QoL scores were higher in the groups with distress (p = 0.0129) and pain (p = 0.0331). No significant association was found between the selected clusters of symptoms and global QoL. Conclusion: The means of QoL were high. The most prevalent survival categories were acute, followed by extended and long term. Association significant between QoL and survival categories was observed, and the categories in remission presented better overall QoL levels. Differences were found between the means of QoL in the distress and pain groups. Clusters of symptoms were present in more than half of the survivors. Distress-pain-sleep disorder was the most frequent. There was no association between the main clusters of symptoms and QoL. / Introdução: O aumento progressivo de sobreviventes de Linfoma não Hodgkin (LNH) e os níveis inferiores de qualidade de vida (QV) vêm sendo acompanhados da ocorrência agrupada de sintomas difíceis. Também, a categorização de sobreviventes, a partir de características semelhantes, vem sendo apresentada como estratégia no seu cuidado. Objetivo: Analisar QV e agrupamento de sintomas em sobreviventes de LNH. Materiais e Métodos: Estudo transversal, com amostra não-probabilística, de 79 pacientes/sobreviventes acompanhados em ambulatórios especializados de oncohematologia. Foram utilizados as escalas EORTCQLQC30 (QV), a Escala de Fadiga de Piper Revisada-EFPR (fadiga), o Termômetro de Distress – TD (distress), o Questionário Mini-Sleep-QMS (distúrbio do sono) e a Escala Visual Analógica-EVA (dor), além de dados socioeconômicos, comportamentais e clínicos. Resultados: Os sobreviventes tinham em média 57,24 anos (dp=5,10), 70,88% tinha 50 anos ou mais, 53,16% eram do sexo masculino, e 65,82% tinham bom nível na Escala de Funcionalidade de Karnofsky (KPS). O tempo médio de diagnóstico foi de 3,29 anos (dp=3,67), 36,70% estavam em sobrevivência aguda, seguidos de sobrevivência estendida (24,05%) e de longo prazo (19,00%). A média global de QV foi elevada (73,12±18,93). Poucos relataram fadiga (18,31%). Mais da metade tinha alguma alteração do sono e presença de dor, 56,05% e 56,96%, respectivamente. A prevalência de distress foi bastante elevada (81,69%). 62,02% da amostra apresentava algum agrupamento de sintomas, sendo os mais prevalentes: distress-dordistúrbio do sono (20,25%), distress-dor (11,39%) e distress-dor-distúrbio do sono-fadiga (11,39%). Categorias de sobrevivência com doença ativa tiveram pior medida global de QV (p=0,0073) e pior desempenho de papeis (p=0,0005). Houve associação significante entre QV e categorias de sobrevivência (p=0,0397), com médias maiores entre as categorias em remissão. Os escores globais da QV foram mais elevados nos grupos com distress (p=0,0129) e com dor (p=0,0331), com diferenças significantes. Não foi encontrada associação significante entre grupos de sintomas selcionados e QV global. Conclusão: A média de QV global foi elevada. As categorias de sobrevivência mais prevalentes foram a aguda, seguida da estendida e da de longo prazo. Foi observada associação entre QV e categorias de sobrevivência, tendo as categorias em remissão apresentado melhores níveis de QV global. Foram encontradas diferenças entre as médias de QV nos grupos com distress e com dor. Os agrupamentos de sintomas estiveram presentes em mais da metade dos sobreviventes, sendo distress-dordistúrbio do sono o mais frequente. Não houve associação entre os principais agrupamentos de sintomas e a QV.

<p>Hodgkin lymphoma (HL) is characterised histologically by a minority of malignant Hodgkin and Reed-Sternberg (HRS) cells surrounded by benign cells, and clinically by a relatively good prognosis. The treatment, however, leads to a risk of serious side effects. Knowledge about the biology of the disease, particularly the interaction between the HRS cells and the surrounding cells, is essential in order to improve diagnosis and treatment. </p><p>HL patients with abundant eosinophils in the tumours have a poor prognosis, therefore the eosinophil derived protein eosinophil cationic protein (ECP) was studied. Serum-ECP (S-ECP) was elevated in most HL patients. It correlated to number of tumour eosinophils, nodular sclerosis (NS) histology, and the negative prognostic factors high erythrocyte sedimentation rate (ESR) and blood leukocyte count (WBC). A polymorphism in the ECP gene (434(G>C)) was identified and the 434GG genotype correlated to NS histology and high ESR.</p><p>The poor prognosis in patients with abundant eosinophils in the tumours has been proposed to depend on HRS cell stimulation by the eosinophils via a CD30 ligand (CD30L)-CD30 interaction. However, CD30L mRNA and protein were detected in mast cells and the predominant CD30L expressing cell in HL is the mast cell. Mast cells were shown to stimulate HRS cell lines via CD30L-CD30 interaction. The number of mast cells in HL tumours correlated to worse relapse-free survival, NS histology, high WBC, and low blood haemoglobin. </p><p>Survival in patients with early and intermediate stage HL, diagnosed between 1985 and 1992, was generally favourable and comparatively limited treatment was sufficient to produce acceptable results for most stages. The majority of relapses could be salvaged. Patients treated with a short course of chemotherapy and radiotherapy had an excellent outcome.</p><p>In conclusion prognosis is favourable in early and intermediate stages and there are possibilities for further improvements based on the fact that mast cells and eosinophils affect the biology and prognosis of HL.</p>

Hodgkin lymphoma (HL) is characterised histologically by a minority of malignant Hodgkin and Reed-Sternberg (HRS) cells surrounded by benign cells, and clinically by a relatively good prognosis. The treatment, however, leads to a risk of serious side effects. Knowledge about the biology of the disease, particularly the interaction between the HRS cells and the surrounding cells, is essential in order to improve diagnosis and treatment. HL patients with abundant eosinophils in the tumours have a poor prognosis, therefore the eosinophil derived protein eosinophil cationic protein (ECP) was studied. Serum-ECP (S-ECP) was elevated in most HL patients. It correlated to number of tumour eosinophils, nodular sclerosis (NS) histology, and the negative prognostic factors high erythrocyte sedimentation rate (ESR) and blood leukocyte count (WBC). A polymorphism in the ECP gene (434(G&gt;C)) was identified and the 434GG genotype correlated to NS histology and high ESR. The poor prognosis in patients with abundant eosinophils in the tumours has been proposed to depend on HRS cell stimulation by the eosinophils via a CD30 ligand (CD30L)-CD30 interaction. However, CD30L mRNA and protein were detected in mast cells and the predominant CD30L expressing cell in HL is the mast cell. Mast cells were shown to stimulate HRS cell lines via CD30L-CD30 interaction. The number of mast cells in HL tumours correlated to worse relapse-free survival, NS histology, high WBC, and low blood haemoglobin. Survival in patients with early and intermediate stage HL, diagnosed between 1985 and 1992, was generally favourable and comparatively limited treatment was sufficient to produce acceptable results for most stages. The majority of relapses could be salvaged. Patients treated with a short course of chemotherapy and radiotherapy had an excellent outcome. In conclusion prognosis is favourable in early and intermediate stages and there are possibilities for further improvements based on the fact that mast cells and eosinophils affect the biology and prognosis of HL.

No description available.

No description available.

Made available in DSpace on 2015-07-22T20:49:30Z (GMT). No. of bitstreams: 0 Previous issue date: 2010-02-24. Added 1 bitstream(s) on 2015-08-11T03:26:30Z : No. of bitstreams: 1 Publico-429a.pdf: 1596515 bytes, checksum: 2107c026687c3e2ecc62f0a5fffa1409 (MD5). Added 1 bitstream(s) on 2015-08-11T03:26:30Z : No. of bitstreams: 2 Publico-429a.pdf: 1596515 bytes, checksum: 2107c026687c3e2ecc62f0a5fffa1409 (MD5) Publico-429b.pdf: 1614171 bytes, checksum: d98715f7a666adc5ceb185cce978000e (MD5). Added 1 bitstream(s) on 2015-08-11T03:26:30Z : No. of bitstreams: 3 Publico-429a.pdf: 1596515 bytes, checksum: 2107c026687c3e2ecc62f0a5fffa1409 (MD5) Publico-429b.pdf: 1614171 bytes, checksum: d98715f7a666adc5ceb185cce978000e (MD5) Publico-429c.pdf: 1500700 bytes, checksum: 77791620b06c9404d28496c4f4ca3dc3 (MD5). Added 1 bitstream(s) on 2015-08-11T03:26:30Z : No. of bitstreams: 4 Publico-429a.pdf: 1596515 bytes, checksum: 2107c026687c3e2ecc62f0a5fffa1409 (MD5) Publico-429b.pdf: 1614171 bytes, checksum: d98715f7a666adc5ceb185cce978000e (MD5) Publico-429c.pdf: 1500700 bytes, checksum: 77791620b06c9404d28496c4f4ca3dc3 (MD5) Publico-429d.pdf: 1826591 bytes, checksum: 70c3dc706cb97372e3f26a7452c01208 (MD5) / O Linfoma de Hodgkin clássico (LHC) é caracterizado pela presença de uma pequena população de células grandes mono ou multinucleadas, denominadas células de Hodgkin-Reed-Sternberg (HRS), circundadas por uma grande massa inflamatória de células não neoplásicas. O vírus Epstein-Barr (EBV) está associado ao Linfoma de Hodgkin em cerca de 50% dos casos. O diagnóstico do LH EBV relacionado é possível por meio da identificação de proteínas virais nas células HRS. Os métodos considerados ideais para essa identificação são as reações de imuno-histoquímica utilizando anticorpos antiproteína latente de membrana (LMP1) e hibridação in situ com uma sonda para o RNA viral (EBER). A LMP-1 é considerada um oncogene clássico. Foi demonstrado que a LMP-1 pode controlar a expressão do gene da metaloproteinase 9 (MMP-9), em linhagem de células C33A. A MMP-9 é um membro da família das endopeptidases que facilita a invasão tumoral e metástases pela degradação do estroma extracelular. Objetivos: avaliar se a expressão da MMP-9 está relacionada ao status do EBV no tumor e se houve impacto na sobrevida livre de eventos (SLE) e sobrevida global (SG) em pacientes com LHC. Casuística e Métodos: foram examinados 97 pacientes com LHC. Todos os pacientes foram submetidos a protocolos de tratamentos equivalentes (MOPPABV ou ABVD). O diagnóstico histopatológico foi revisto e o subtipo classificado de acordo com a OMS. Reações de imuno-histoquímica para LMP-1 e MMP-9 e hibridação in situ para EBER foram realizadas. Resultados: A presença do EBV foi identificada em 52,5% dos casos. Houve uma maior prevalência do subtipo histológico celularidade mista em pacientes EBV positivos (P = 0,005). Não houve diferença na positividade do EBV em relação à faixa etária, sexo, estádio da doença ou pela presença de sintomas B. A presença do EBV no LHC não influenciou a SLE (P = 0,38) ou a SG (P = 0,80) com uma mediana de acompanhamento de 71 meses. A expressão da MMP-9 ocorreu em 87,6% dos casos estudados. Não houve diferença de casos positivos e negativos em relação ao status do EBV (P = 0,59). Quando avaliada a intensidade da expressão da MMP-9 nos casos positivos também não observamos correlação com a presença do EBV (P = 0,62). Não houve diferença entre o resultado da MMP-9 e os parâmetros: subtipo histológico, estádio, presença de sintomas B, idade e sexo. Não houve influência da MMP-9 na SLE (P = 0,98) e SG (P = 0,60). Conclusões: Demonstramos que a prevalência do LH relacionado ao EBV na população estudada é de 52,5%, e que a presença do vírus não altera a evolução clínica, SLE e SG de pacientes tratados uniformemente. Concluímos ainda que a MMP-9 é fortemente expressa nas células HRS. Não há correlação entre a expressão de MMP-9 e o status do EBV. Nem a SG nem a SLE foram influenciadas pela expressão dessa enzima. / Clinical and histological features of classical Hodgkin lymphoma (cHL) are primarily due to the effects of cytokines, enzymes and chemokines produced by Hodgkin-Reed-Sternberg (HRS) cells and their surrounding inflammatory cells in response to signals triggered by etiological factors such as Epstein-Barr virus (EBV). Matrix metalloproteinase-9 (MMP-9) has been associated with poorer survival in patients with aggressive non-Hodgkin lymphomas. In EBV-related cancers the expression of viral latent membrane protein 1 (LMP1) correlates with an increased MMP-9 expression. In this study, we evaluated the prognostic relevance of MMP-9 expression and EBV status in HRS cells in patients with cHL in Brazil. Material and Methods: We selected 97 patients with cHL. Patients were included if they had: 1) > 18 years, 2) Undergone similar chemotherapy protocols, 3) Paraffin blocks available for review and for EBV and MMP-9 detection and 4) Clinical, epidemiological and laboratorial parameters available. Results: EBV was detected in 52.5% of all cases. MMP-9 expression positivity was found in 87.6% of all cases. There was no correlation between MMP-9 expression and EBV status. Response to treatment and relapse rate were independent of MMP-9 expression and EBV status. When stratified according to chemotherapy protocol used or disease stage, we still did not find any difference. MMP-9 positivity did not influence overall survival and event free survival. Conclusion: MMP-9 are expressed in the majority of HRS cells and did not correlated with EBV status or survival. The consistent MMP-9 expression in HRS cells makes this enzyme a potential target for therapy. / TEDE / BV UNIFESP: Teses e dissertações