Introduction:Acute Lymphoid Leukemia (ALL) is the most frequent cancer in young people and, if analyzed together with Non-Hodgkin Lymphoma (NHL), we find that they are responsible for at least one third of all cases of childhood cancer. Present-day therapeutic protocols include high doses of glucocorticoids (GC), drugs associate with high potential for elevating intraocular pressure (IOP) and, consequently provoking damage to the fibers of the optic nerve fibers, a pathology classified as cortisone glaucoma. In genetically susceptible patients, ocular hypertension normally occurs some weeks into the use of a steroid but is generally reversible with the suspension of its use. However, depending on the levels of ocular pressure and the duration of ocular hypertension, it can result in optic neuropathology and, in extreme cases, blindness. Since ALL and NHL are oncological disorders with elevated potential for cure of young people with have high life expectancy, the identification of eventual long-term treatment complications could give support to a delineation still lacking in scientific literature, that is, an ophthalmological protocol for these cases. Objective: The aim of this study was to evaluate the behavior of intraocular pressure in pediatric patients treated with GC for the acute lymphoproliferative neoplasias that are most common during childhood and adolescence.Methods: A systematic review of the theme was carried out, followed by a descriptive, prospective study of children and adolescents of both sexes who were diagnosed with ALL and NHL, and who were registered for beginning chemotherapeutic treatment at the Dr. Oswaldo Leite Oncology Center of Sergipe. The inclusion criteria were: diagnosis of ALL or NHL-T confirmed by immunophenotyping of bone marrow or peripheral blood samples (ALL), or immunohistochemistry of material obtained by open biopsy (NHL); age less than 19; no previous chemotherapy; absence of previous diagnosis compatible with glaucoma or any other disorder envolving change in intraocular pressure; no systemic use of GC in the six months preceding diagnosis of ALL or NHL. Patients whose evaluation of IOP might not have been technically adequate, as well as those who expired during the follow-up period, were excluded. Intraocular pressure was measured before treatment (D0), on the eighth (D8), the fourteenth (D14) and twentieth (D28) treatment day. The IOP results above 21 mm Hg were considered to be ocular hypertension. Results: Results of the systematic review indicate the need for new studies, for the review found a total of only three published articles whose results varied between total control of ocular pressure and visual function, to irreversible blindness. The results of our field research involved 15 patients, two of them with ocular hypertension, and with a statistically significant difference of measurements of IOP between D0 vs D8 and D0 vs D14 (p=0.013). Conclusion: The possibility of silent ocular hypertension, with the consequent risk of irreversible blindness, indicates the need to assess the introduction of a protocol for verification of IOP in patients recently diagnosed with ALL and NHL, including weekly exams, at least until the complete cessation of GC use. / Introdução: Leucemia Linfóide Aguda (ALL) é o câncer mais comumente encontrado entre os jovens e, se analisada em conjunto com o Linfoma não-Hodgkin (NHL), são responsáveis por pelo menos um terço dos casos de câncer infantil. Protocolos terapêuticos atuais incluem altas doses de glicocorticóides (GC), droga associada com alto potencial para elevar a pressão intraocular (IOP) e, consequentemente, provocar danos às fibras do nervo óptico, patologia classificada como glaucoma cortisônico. A hipertensão ocular geralmente ocorre com algumas semanas de uso de GC em pacientes geneticamente susceptíveis, mas é geralmente reversível com a descontinuação do tratamento. Entretanto, dependendo dos níveis pressóricos oculares e do tempo de elevação, pode resultar em neuropatia óptica e, em situações extremas, em cegueira. Por serem a ALL e o NHL doenças oncológicas com potencial elevado de cura, em indivíduos jovens com elevada expectativa de vida, a identificação de eventuais complicações de longo prazo decorrentes do tratamento poderá subsidiar o delineamento de um protocolo oftalmológico para esses casos, ainda inexistente na literatura científica. Objetivo: O objetivo deste estudo foi avaliar o comportamento da pressão intraocular em pacientes pediátricos portadores das mais frequentes neoplasias linfoproliferativas agudas da infância e adolescência, e que são tratados com GC. Métodos: Foi feita uma revisão sistemática sobre o tema estudado, seguida por um estudo descritivo, prospectivo, em crianças e adolescentes de ambos os sexos, com diagnóstico de ALL e NHL, matriculados para início de tratamento quimioterápico no Centro de Oncologia de Sergipe Dr. Oswaldo Leite. Os critérios de inclusão foram: diagnóstico de ALL ou NHL-T, confirmada por imunofenotipagem de amostra de medula óssea ou sangue periférico (ALL) ou imuno-histoquímica de material obtido por biópsia aberta (NHL); idade menor de 19 anos; sem quimioterapia anterior; ausência de diagnóstico prévio compatível com glaucoma ou doença anterior relacionada a qualquer mudança na pressão intra-ocular; não uso sistêmico de GC nos seis meses anteriores ao diagnóstico da ALL ou NHL. Pacientes cuja avaliação da pressão intraocular (PIO) pode não ter sido tecnicamente adequada e os que faleceram durante o período de seguimento foram excluídos. Realizaram-se medidas de pressão intraocular antes do tratamento (D0), no oitavo (D8), décimo quarto (D14) e vigésimo (D28) dias de tratamento. Os resultados da PIO acima de 21 mm de Hg foram considerados como hipertensão ocular Resultados: Os resultados da revisão sistemática apontaram para necessidade de novos estudos, limitando-se a um total de três publicações de relatos de casos envolvendo sete pacientes, com resultados variando de total controle da pressão ocular e conservação da função visual, até cegueira irreversível. Os resultados da pesquisa de campo envolveram 15 pacientes, com dois casos de hipertensão ocular e com diferença estatisticamente significativa entre as médias de PIO entre D0 vs D8 e D0 vs D14 (p = 0,013). Conclusão: A possibilidade de hipertensão ocular silenciosa, com o consequente risco de cegueira irreversível, indica a necessidade de se avaliar a introdução de um protocolo para verificação da IOP em pacientes jovens recentemente diagnosticados com ALL e NHL, incluindo exames semanais, pelo menos até a retirada completa do GC.

Dans ces travaux de thèse, nous nous sommes intéressés à l'influence du bruit synaptique sur la plasticité synaptique dans un réseau de neurones biophysiquement réalistes. Le simulateur utilisé est un système électronique neuromorphique. Nous avons implanté un modèle de neurones à conductances basé sur le formalisme de Hodgkin et Huxley, et un modèle biophysique de plasticité. Ces travaux ont inclus la configuration du système, le développement d'outils pour l'exploiter, son utilisation ainsi que la mise en place d'une plateforme le rendant accessible à la communauté scientifique via Internet et l'utilisation de scripts PyNN (langage de description de simulations en neurosciences computationnelles). / In this work, we have investigated the effect of input noise patterns on synaptic plasticity applied to a neural network. The study was realised using a neuromorphic hardware simulation system. We have implemented a neural conductance model based on Hodgkin and Huxley formalism, and a biophysical model for plasticity. The tasks performed during this thesis project included the configuration of the system, the development of software tools, the analysis tools to explore experimental results, and the development of the software modules for the remote access to the system via Internet using PyNN scripts (PyNN is a neural network description language commonly used in computational neurosciences).

Nas últimas décadas, verificou-se diferenças nas classificações da World Health Organization (WHO) de 2001 e da European Organization for Research and Treatment of Cancer (EORTC) de 1997 para os linfomas cutâneos primários. Em 2005, representantes dessas classificações se reuniram e em consenso estabeleceram a classificação WHO-EORTC que foi adotada pela última classificação da WHO de 2008. O presente estudo visa a avaliar a aplicabilidade dessa nova classificação em casuística retrospectiva de um único centro de referência no diagnóstico e tratamento de linfomas cutâneos. Assim, todos os casos de linfoma cutâneo de células T, excluindo-se micose fungóide (MF) e síndrome de Sézary (SS), no período de 1986 a 2009, foram analisados em relação aos aspectos clínicos, histopatológicos e imunofenotípicos, incluindo-se a realização de novas reações imunoistoquímicas. Os casos foram, então, classificados de acordo com critérios estabelecidos na classificação WHO de 2008. Houve, assim, 33 casos de linfomas cutâneos de células T não-MF e não-SS, sendo 08 (24,2%) de linfoma cutâneo de grandes células anaplásicas, 05 (15,2%) de papulose linfomatóide, 06 (18,1%) de linfoma extranodal de células NK/T tipo nasal, 05 (15,2%) de neoplasia de células dendríticas plasmocitóides blásticas, 05 (15,2%) de linfoma/leucemia de células T do adulto e 04 (12,1%) de linfoma de células T periféricas, sem outra especificação. Portanto, a classificação WHO de 2008 é aplicável à maioria dos casos de linfoma cutâneo de células T não-MF e não-SS. Entretanto, permanecem casos não classificáveis, alguns dos quais com curso clínico agressivo / Recent years have witnessed differences between the World Health Organization (WHO) 2001 and the European Organization for Research and Treatment of Cancer (EORTC) 1997 classification systems of primary cutaneous lymphomas (PCLs). In 2005, a joint WHO-EORTC classification system for PCLs has been reached and was adopted by last WHO 2008 classification. This study was performed to assess the applicability of this new classification to a single referral center. All cutaneous T-cell lymphoma (CTCL) cases, excluding mycosis fungoides (MF) and Sezary syndrome (SS), who were referred from 1986 to 2009 were included. The clinical features, histological and immunohistochemical stainings were reviewed, and additional stains were performed as needed. The cases were then reclassified according to the WHO 2008 classification. There were 33 cases of non-MF and non-SS CTCL, included 08 (24.2%) CD30+ anaplastic large-cell lymphomas, 05 (15.2%) cases of lymphomatoid papulosis, 06 (18.1%) extranodal NK/T-cell lymphoma nasal type, 05 (15.2%) blastic plasmacytoid dendritic cell neoplasm, 05 (15.2%) adult T-cell lymphoma/leukemia and 04 (12.1%) peripheral T-cell lymphomas, unspecified. The new WHO 2008 classification is applicable to most nonMF and non-SS CTCL cases. However, there is still a substantial subset of T-cell PCLs which cannot be classified beyond the unspecified peripheral T-cell category, some of which may have an aggressive course

Die Zellen des Hodgkin-Lymphoms sind, neben einer permanenten Aktivierung des NF-kB Signalweges, durch eine konstitutive AP-1 Aktivität gekennzeichnet. Die vorliegende Arbeit beschäftigte sich mit der Analyse der aberranten AP-1 Aktivität in Zellen des Hodgkin-Lymphoms. Von besonderem Interesse ist in diesem Zusammenhang der JUN Promotor, da c-Jun unter anderem die Fähigkeit besitzt seinen eigenen Promotor positiv zu regulieren (Autoregulation). Im Rahmen dieser Arbeit wurden Faktoren, die mit dem JUN Promotor in Zellen des Hodgkin-Lymphoms assoziiert sind, über verschiedene chromatographische Reinigungsschritte angereichert, mittels Massenspektrometrie identifiziert und hinsichtlich ihres Einflusses auf die c-Jun Expression analysiert. Dabei wurden die zwei Faktoren ATF-3, aus der Familie der AP-1 Proteine, und p52, aus der NF-kB Familie, hinsichtlich ihres Einflusses auf die Überexpression von c-Jun in Hodgkinzellen genauer untersucht. Die hier aufgeführten Ergebnisse tragen zu einem besseren Verständnis der Regulation der konstitutiven AP-1 Aktivität in den Hodgkinzellen bei. Im Rahmen dieser Arbeit konnten zwei Faktoren identifiziert werden, die maßgeblich an der Regulation der Expression von c-Jun in Hodgkinzellen beteiligt sind. Eine besondere Rolle kommt dabei dem Transkriptionsfaktor p52 zu, da dieser unter anderem auch die Expression anderer Mitglieder der AP-1 Familie reguliert. Ein weiterer Befund dieser Arbeit, dass p50 und p52 die zentralen Komponenten der konstitutiven NF-kB Aktivität sind, rückt p52 in das Zentrum zukünftiger Forschung. Die Befunde dieser Arbeit belegen, dass die aberrante Aktivierung von AP-1 im Hodgkin-Lymphom nicht auf ein einzelnes Ereignis in der Zelle zurückzuführen ist, sondern das Ergebnis eines komplexen Zusammenspiels vieler Faktoren ist. / The cells of Hodgkin''s lymphoma are characterized by a permanent activation of the NF-kB signaling pathway and a constitutive AP-1 activation. The present study focused on the analysis of aberrant AP-1 activity in cells of Hodgkin''s lymphoma. Of particular interest in this context is the JUN promoter, since c-Jun has the ability to regulate its own promoter (autoregulation). In this work different JUN promoter associated factors were enriched through various chromatographic purification steps, identified by Mass spectrometry and analyzed in terms of its influence on the expression of c-Jun. The focus was on specific factors in cells of Hodgkin''s lymphoma. The two factors ATF-3 and p52, were analyzed in terms of their influence on the overexpression of c-Jun in cells of Hodgkin''s lymphoma. Another interesting finding of this study is, p50 and p52 are central components of the constitutive NF-kB activity. This puts p52 in the center of future research. The results presented here contribute to a better understanding of the regulation of the constitutive AP-1 activity in the Hodgkin cells. In this work two Factors (ATF3 and p52) could be identified, which are are involved in the regulation of the expression of c-Jun in Hodgkin cells. A special role is played by the transcription factor p52, which also regulates the expression of other members of the AP-1 family. The findings of this study also show that the aberrant activation of AP-1 in Hodgkin''s lymphoma is not due to a single event in the cell. It is rather a result of a complex interplay of many factors.

Wachstumsfaktor bedingte Aktivierung des PI3K/Akt/mTOR Signalweg wirkt positiv auf Vermehrung und Überleben. Konstitutive Aktivierung des Signalweges in NHL ist jedoch an Tumorprogression und Therapieresistenz beteiligt. Am Zelllinienmodell wurden zwei mögliche Therapiestrategien der PI3K/Akt/mTOR Inhibition erprobt, PI3K Inhibition mit BKM120 und horizontale Kombination von Zytostatika mit PI3K/Akt/mTOR Inhibitoren Erstens, BKM120 hat Antitumoraktivität in NHL und induziert Zelltod. Auf molekularer Ebene führt BKM120 vermittelte Dephosphorylierung von CDK1 an Y15 zur Aktivierung des M-Phase Komplex CDK1/Zyklin B und Eintritt in die Mitose. Parallel erlaubt die Degradation von Zyklin A und Hochregulation von Zyklin B Progression bis zur Metaphase, hemmt jedoch die Transition in die Anaphase. Anhaltender Metaphasearrest bewirkt programmierten Zelltod über den intrinsischen Signalweg der Apoptose durch Hochregulation der BH3-onlys Puma und Hrk, Aktivierung von Bax/Bak und proteolytische Spaltung von Caspase 9. Verlust von Bax/Bak oder Caspase Inhibition schützt vor BKM120 vermitteltem Zelltod. Bax/Bak defiziente Zellen, welche zusätzlich p53 Mutationen aufweisen, werden polyploid. Die Polyploidie ist ATM-MEK1/2 abhängig und kann mit Caffeine oder U0126blockiert werden. Zur Vermeidung von Polyploidie bedingter Tumorprogression, sollte BKM120 nur in Verbindung mit MAPK/ATM Inhibitoren verwendet werden. Zweitens. Horizontale Kombination PI3K/Akt/mTOR Inhibitoren mit cytotoxischen Substanzen schützt vor Apoptose. Der Schutzeffekt tritt auschließlich bei niedrigen Konzentration auf und ist unabhängig von der Art des Inhibitors bzw. Ebene der Inhibition. Das Onkogen und NFkB Target Pim-2 ist möglicherweise am Schutzmechanismus beteiligt. Durch die PI3K/Akt/mTOR vermittelte Pim-2 Regulation ergibt sich eine neue Rückkopplungsschleife. Im Fazit erschwert die Komplexizität des PI3K/Akt/mTOR Signalweges die Etablierung von Therapien. / Growth factor mediated activation of the PI3K/Akt/mTOR pathway positively regulates proliferation and survival. Constitutive activation in NHL, however, is correlated with tumor progression and therapeutic resistance. Therefore, two possible strategies were tested in a cell line model system, Inhibition of PI3K with BKM120 and PI3K/Akt/mTOR Inhibition in addition to cytostatic drug administration. First, it is demonstrated that the pan PI3K inhibitor BKM120 has antitumor activity in NHL and induces cell death. On molecular level, BKM120 mediated dephosphorylation of CDK1 on Y15 causes activation of the M-phase complex CDK1/Cyclin B and entry into mitosis. In parallel, degradation of Cyclin A and Upregulation of Cyclin B enables progression into metaphase but inhibits transition into anaphase. Prolonged metaphase arrest induces programmed cell death via the intrinsic apoptosis pathway by upregulation of the BH3-onlys Puma and Hrk, activation of Bax/Bak and proteolytic cleavage of caspase-9. Loss of Bax/Bak or caspase inhibition protects from BKM120 induced apoptosis. Bax/Bak deficient cells with additional p53 mutation become polyploid. This polyploidy is ATM-MEK1/2 dependent and can be blocked with Caffeine or U0126. To prevent polyploidy related tumor progression, BKM120 should administered only in combination with ATM or MEK inhibitors. Second, combination of PI3K/Akt/mTOR inhibitors with cytotoxic agents protects from apoptosis. The protective effect is only detectable with low PI3K/Akt/mTOR inhibitor concentrations and independent of inhibitor type or cascade level. The oncogene and NFkB target is possibly involved in apoptosis protection and inhibition of NFkB neutralizes the protective effect. PI3K/Akt/mTOR mediated Pim-2 regulation reveals a new feedback loop within the pathway. In conclusion, the complexity of the PI3K/Akt/mTOR pathway impedes therapeutic targeting.

Die aberrante Aktivierung des NOTCH Signalweges trägt entscheidend zu verschiedensten malignen Erkrankungen im Menschen bei. Basierend auf der Analyse von hochdimensionalen Microarray-Datensätzen von klassischen Hodgkin Lymphoma Fällen und nicht-Hodgkin Fällen, haben wir eine Hodgkin Lymphoma-spezifische NOTCH Signatur identifiziert. Diese wird von dem essentiellen NOTCH-Koaktivator Mastermindlike 2 (MAML2) signifikant dominiert. Auf der Grundlage dieses Resultates haben wir die Rolle von MAML2 im Kontext des Hodgkin Lymphoma-spezifischen, aberrant regulierten NOTCH Signalweges weiter untersucht. Die signifikante Überexpression von MAML2 im Hodgkin Lymphom konnte in verschiedenen Hodgkin Lymphom Zelllinien und auch durch die immunhistochemische Analyse von primären Hodgkin Lymphom Fällen verifiziert werden. Mit Hilfe des Knockdowns von MAML2 bzw. der Inhibition des NOTCH Signalweges durch die Verwendung einer kompetitiv, dominant-negativ wirkenden, trunkierten Variante von MAML1 konnte daraufhin gezeigt werden, dass die Überexpression von MAML2 der limitierende Faktor für die Hodgkin Lymphomaspezifische, pathologische Deregulation des NOTCH Signalweges ist. Die MAML2- vermittelte Überaktivierung des NOTCH Signalweges ist darüber hinaus essentiell für die Proliferation von Hodgkin Lymphom Zelllinien und die aberrante Expression der NOTCH Zielgene HES7 und HEY1. Das konstitutive Vorhandensein von aktiviertem, intrazellulären NOTCH1 in Hodgkin Lymphom Zelllinien impliziert darüber hinaus,dass der Signalweg im Hodgkin Lymphom zellautonom aktiviert ist. In dieser Arbeit wird damit ein neuer, pathologisch hochwirksamer Mechanismus der NOTCH Signalweg-Deregulation aufgedeckt. / Inappropriate activation of the NOTCH signaling pathway, e.g. by activating mutations, contributes to the pathogenesis of various human malignancies. Using a bottom up approach based on the acquisition of high–dimensional microarray data of classical Hodgkin lymphoma (cHL) and non-Hodgkin B cell lymphomas as control, we identify a cHL specific NOTCH gene-expression signature dominated by the NOTCH co-activator Mastermind-like 2 (MAML2). This set the basis for demonstrating that aberrant expression of the essential NOTCH co-activator MAML2 provides an alternative mechanism to activate NOTCH signaling in human lymphoma cells. Using immunohistochemistry we detected high-level MAML2 expression in several B cell-derived lymphoma types, including cHL cells, whereas in normal B cells no staining for MAML2 was detectable. Inhibition of MAML protein activity by a dominant negative form of MAML or by shRNAs targeting MAML2 in cHL cells resulted in down-regulation of the NOTCH target genes HES7 and HEY1, which we identified as overexpressed in cHL cells, and in reduced proliferation. In order to target the NOTCH transcriptional complex directly we developed short peptide constructs that competitively inhibit NOTCH dependent transcriptional activity as demonstrated by NOTCH reporter assays and EMSA analyses. We conclude that NOTCH signaling is aberrantly activated in a cell autonomous manner in cHL. This is mediated by high-level expression of the essential NOTCH coactivator MAML2, a protein that is only weakly expressed in B cells from healthy donors. Using short peptide constructs we moreover show, that this approach is promising in regard to the development of NOTCH pathway inhibitors that will also work in NOTCH associated malignancies that are resistant to -secretase inhibition.

INTRODUÇÃO. Os genes da família paraoxonase (PON1, PON2 e PON3) apresentam grande homologia estrutural. PON1 está associada à molécula de HDL e possui funções fisiológicas, sendo a principal a de lactonase. PON1 também pode proteger as moléculas de LDL de modificações oxidativas. Embora o papel biológico mais conhecido das paraoxonases seja a prevenção da aterosclerose, elas também atuam sobre o estresse oxidativo envolvido na patogênese de outras condições como doenças inflamatórias, infecções e neoplasias. Toda a família PON parece estar implicada no desenvolvimento de linfomas. O polimorfismo L55M de PON1 foi relacionado a um maior risco para linfomas em indivíduos da população geral, enquanto PON3 e PON2 foram relacionadas à sobrevida de células tumorais. A Imunodeficiencia comum variável (ICV) é uma doença heterogênea caracterizada pela redução dos niveis de IgG, IgA e/ou IgM e da função de anticorpo. As manifestações clínicas incluem a presença de infecções recorrentes ou crônicas, doenças inflamatórias/autoimunes e incidência aumentada de malignidades como linfomas não-Hodgkin (LNH) e câncer gástrico. OBJETIVO: estudar os polimorfismos de PON1 e PON2 bem como a atividade arilesterase de PON1 e sua relação com o perfil lipídico, morbidade, mortalidade e presença de fatores de risco para linfoma LNH em pacientes com ICV. MÉTODOS/RESULTADOS: Foram avaliadas as frequências alélicas dos polimorfismos de PON1 e PON2, o perfil lipídico e a atividade arilesterase da PON1 em 63 pacientes com ICV e 130 controles saudáveis. No grupo de pacientes foi analisada a presença de fatores de risco para LNH e parâmetros de morbidade e gravidade da doença. O polimorfismo Q192R da PON1 e os polimorfismos de PON2 (S311C e A148G) não diferiram entre os grupos e não apresentaram relação com os parâmetros analisados. O genótipo 55MM e o alelo 55M foram mais frequentes no grupo ICV em relação ao grupo controle. A atividade arilesterase foi similar em pacientes e controles apresentando correlação positiva com os níveis de HDL. Pacientes com o genótipo 55MM apresentaram menor atividade de PON1 associada a maior morbidade da doença representada pela maior frequência de infecções de vias aéreas e maior taxa de internações. O genótipo 55MM também apresentou relação com a presença de fatores de risco para LNH como hiperplasia nodular linfoide (HNL) e linfonodomegalias. Por outro lado, a análise dos alelos demonstrou que a menor morbidade da doença foi associada à presença do alelo 55L, que apresentou relação com menor frequência de HNL e linfonodomegalia e menor ocorrência de óbitos. O alelo 55M apresentou relação com história familiar de imunodeficiências e neoplasias hematológicas. CONCLUSÃO: Este constitui o primeiro relato demonstrando maior frequência do genótipo 55MM e do alelo 55M em pacientes com ICV. Nossos resultados são sugestivos de que a presença do alelo 55L possa estar associado a um melhor prognóstico da doença. Inversamente, sugerem que pacientes com o genótipo 55MM apresentem maior morbidade e, possivelmente, maior risco para LNH / INTRO: The paraoxonase gene family (PON1, PON2 and PON3) has great structural homology. PON1 is associated with the HDL molecule and possess many physiological roles, the major one being of a lactonase. PON1 also protects LDL molecules against oxidative modifications. Although the best known biological role of PONs is the prevention of atherosclerosis, they also act on the oxidative stress involved in the pathogenesis of different conditions such as inflammatory diseases, infections and malignancies. The whole PON family appears to be implicated in the development of lymphomas. The L55M polymorphism of PON1 was related with a higher risk for lymphoma in the general population while PON3 and PON2 were related to survival of tumor cells. The Common Variable Immunodeficiency (ICV) is a heterogeneous disease characterized by reduced levels of IgG, IgA and/or IgM and antibody function. Clinical manifestations include the presence of chronic or recurrent infections, inflammatory/autoimmune diseases and increased incidence of malignancies such as non-Hodgkin lymphoma (NHL) and gastric cancer. OBJECTIVE: to study the PON1 and PON2 polymorphisms and the arylesterase activity of PON1 and its correlation with the lipid profile, morbidity, mortality and the presence of risk factors for NHL in CVID patients. METHODS/RESULTS: We evaluated the allele frequencies of polymorphisms of PON1 and PON2, lipid profile and arylesterase activity of PON1 in 63 patients with CVID and 130 healthy controls. In the group of patients we analyzed the presence of risk factors for NHL and parameters of morbidity and disease severity. The Q192R polymorphism of the PON1 and PON2 polymorphisms (A148G and S311C) did not differ between groups and did not correlate with the parameters analyzed. The 55MM genotype and the 55M allele were more frequent in the CVID group than in control group. The arylesterase activity was similar in patients and controls showing a positive correlation with HDL levels. Patients with genotype 55MM had lower PON1 activity, associated with increased morbidity of the disease represented by the higher frequency of respiratory infections and a higher rate of hospitalization. The 55MM genotype also was correlated with the presence of risk factors for NHL, such as lymphoid nodular hyperplasia (HNL) and lymphadenopathy. Moreover, analysis of the alleles showed that less morbidity of the disease was associated with the presence of the allele 55L, which was correlated with a lower frequency of HNL and lymphadenopathies and fewer deaths. The 55M allele was correlated with a family history of immunodeficiency and hematological malignancies. CONCLUSION: This is the first report showing a greater frequency of 55MM genotype and 55M allele in patients with CVID. Our results suggest that the presence of 55L allele may be associated with a better prognosis. Conversely, these results suggest that patients with the 55MM genotype show higher morbidity and, possibly, higher risk for NHL

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.

Evidence that radiation-related cardiovascular disease and second primary cancers can occur in cancer survivors following radiation therapy (RT) has emerged from several independent sources. Cardiotoxicity and second cancers are of particular concern for patients with good prognosis, such as those with Hodgkin lymphoma (HL). HL patients are among the youngest to receive RT, which means that those who are cured of their cancer have decades-long natural life-expectancies during which treatment-related long-term toxicities may cause years of excess morbidity or premature mortality. A considerable amount of research has been conducted to investigate the risk of radiation-related cardiotoxicity and second cancers. However, there are still substantial gaps in knowledge. It is therefore important to improve our understanding regarding these risks and develop treatment approaches and survivorship care to minimise their impact on patients' quality of life. In this thesis, I have investigated the risk of congestive heart failure (CHF) in a cohort of 2619 HL survivors and presented, for the first time, dose-response relationships for risk of CHF versus cardiac radiation doses. I also validated the radiation dosimetry method used to estimate the cardiac doses in this study as well as for other reconstruction methods, versus a gold standard based on the patients' own computed tomography scans. Additionally, I investigated what effect the dose reconstruction errors had on the dose-response relationships. I then focused on modern RT methods and specifically on proton RT. Based on published dose-response relationships (including that developed in this thesis) I predicted cardiovascular and second cancer risks for patients treated with advanced RT. This thesis has provided new knowledge in the study of late effects in HL patients who were treated decades ago as well as for patients treated more recently with advanced RT methods. The results here can be used to facilitate progress towards personalised RT in terms of choosing the appropriate RT method by integrating individualised risk prediction in advanced RT treatment planning. The research here provides the basis for further work towards evidence-based case selection for HL patients for the first NHS proton therapy centres in the UK, opening in 2018-2021.

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.