La leucémie lymphoblastique aiguë (LLA) est responsable d’environ 25% de l’ensemble des cancers pédiatriques. Chez 85% des enfants diagnostiqués, la LLA entraîne une prolifération massive et incontrôlée de lymphocytes immatures de type précurseurs B dans la moelle osseuse (LLA pré-B). Des avancées intéressantes ont été faites au cours des trente dernières années et ont mené à une augmentation de l’efficacité des traitements thérapeutiques. Plus de 80% des enfants atteints de LLA seront guéris de cette maladie. Malheureusement, ces traitements manquent de spécificité à cause du manque de connaissances sur les mécanismes moléculaires impliqués durant l’initiation et le développement de la LLA pré-B pédiatrique. En d’autres termes, nous connaissons peu de chose sur l’étiologie de cette maladie. Plus de 25% des enfants atteints de la LLA pré-B présentent la translocation chromosomique t(12;21)(p13;q22) qui implique les gènes ETV6 et AML1. Celle-ci est formée in utero et mène à l’expression de la protéine chimère transcriptionnelle ETV6-AML1, dont la présence seule ne suffit pas au développement de la LLA pré-B. Ainsi, d’autres événements génétiques sont nécessaires au développement de cette leucémie. La délétion de l’allèle résiduel de ETV6 est un événement génétique fréquemment rencontré au moment du diagnostic de la LLA pré-B t(12;21)+. Cette délétion entraîne l’inactivation complète de ETV6 dans les lymphocytes pré-B leucémiques. ETV6 est un répresseur transcriptionnel de la famille Ets. Mon hypothèse de recherche est que ETV6 agit comme gène suppresseur de tumeur dans la LLA pré-B pédiatrique. L’inactivation de ETV6 causerait une dérégulation de l’expression de ses cibles transcriptionnelles et, par le fait même, favoriserait l’initiation et le déroulement de la leucémogenèse pédiatrique. Dans le cadre de mon projet, comme peu de cibles transcriptionnelles de ETV6 sont connues, j’ai effectué des expériences d’immunoprécipitation de la chromatine et des essais luciférases qui ont permis d’identifier six nouvelles cibles transcriptionnelles: TP53 (p53 et Δ133p53), SPHK1, IL-18, PTGER4 et LUM. J’ai démontré que la régulation transcriptionnelle médiée par ETV6 requiert la présence de ses deux domaines fonctionnels: PNT (interactions protéiques) et ETS (liaison à l’ADN). Ces domaines favorisent la reconnaissance d’un site EBS consensus dans une région située près du promoteur de base. Ce mécanisme peut dépendre du promoteur régulé par ETV6, mais également du contexte cellulaire. Des études fonctionnelles réalisées sur des lymphocytes pré-B leucémiques ont permis de mesurer l’impact de la dérégulation de l’expression des cibles transcriptionnelles de ETV6 sur trois voies biologiques: la prolifération cellulaire, l’apoptose induite par un stress génotoxique et la migration cellulaire dirigée par la voie de signalisation CXCL12/CXCR4. Ceci a permis de démontrer l’implication des gènes SPHK1, IL-18 et PTGER4 durant la leucémogenèse pédiatrique. Cette étude est une des premières à suggérer le rôle de ETV6 comme gène suppresseur de tumeur dans la LLA pré-B pédiatrique. Suite à l’inactivation du répresseur transcriptionnel ETV6, l’augmentation de l’expression de ses cibles transcriptionnelles favoriserait la prolifération et la survie des lymphocytes pré-B leucémiques dans la moelle osseuse. L’identification de nouveaux gènes impliqués dans le développement de la LLA pré-B pédiatrique ouvre la porte au développement de nouveaux traitements thérapeutiques qui pourront présenter une meilleure spécificité envers l’étiologie de la maladie. / Acute lymphoblastic leukemia (ALL) accounts for approximately 25% of all paediatric cancers. Approximately 85% of ALL cases happen in immature B precursors lymphocytes (pre-B ALL). Pre-B ALL is a sporadic cancer that leads to the massive proliferation of leukemia pre-B lymphocytes in the bone marrow. During the past 30 years, the scientific community has developed efficient therapeutic treatments against paediatric ALL, reaching more than 80% cure rate. However, these treatments lack specificity because of the lack of knowledge regarding the molecular mechanisms involved in the initiation and progression of paediatric pre-B ALL. In other words, we know little about the aetiology of this disease. Approximately 25% of children affected with pre-B ALL carry the chromosomal translocation t(12;21)(p13;q22) involving the ETV6 and AML1 genes. This translocation originates in utero and leads to the expression of the transcriptional chimera ETV6-AML1, which alone is insufficient to trigger the development of pre-B ALL. Therefore, other genetic events would be required to initiate paediatric leukemogenesis. The deletion of the residual allele of ETV6 is frequently observed at the diagnosis of pre-B ALL t(12;21)+. This leads to the complete inactivation of ETV6 in leukemia pre-B lymphocytes. ETV6 is a transcriptional repressor of the Ets family. My research hypothesis is that ETV6 acts as a tumour suppressor gene in paediatric pre-B ALL. The inactivation of ETV6 would lead to the deregulated expression of its transcriptional targets and, consequently, would favour the initiation and progression of paediatric leukemogenesis. Given the fact that only very few ETV6 transcriptional targets are known, I initially performed chromatin immunoprecipitation experiments and luciferase assays that enabled the identification of six novel transcriptional targets: TP53 (p53 and Δ133p53), SPHK1, IL-18, PTGER4 and LUM. The ETV6-mediated transcriptional regulation involves both functional domains: PNT (protein interactions) and ETS (DNA-binding domain). These functional domains facilitate the recognition of consensus EBS sites located in a region close to the basal promoter, a molecular mechanism used according to the target promoter and cellular context. Functional studies using leukemia pre-B lymphocytes were useful to understand the role of the ETV6 transcriptional targets during cell proliferation, induction of apoptosis and cell migration through the CXC12/CXCR4 signalling pathway. These functional studies showed the implication of SPHK1, IL-18 and PTGER4 genes during paediatric leukemogenesis. This study is one of the first to support the role of ETV6 as a tumour suppressor gene in paediatric pre-B ALL. Once ETV6 is inactivated, the increased expression of its transcriptional targets favours the proliferation and survival of leukemia pre-B lymphocytes in the bone marrow. The identification of new genes involved in the development of paediatric pre-B ALL opens new doors to the development of therapeutic treatments with a better specificity toward the aetiology of the disease.

We report a murine model, R26-βcat, expressing a stable form of β-catenin in T cells. R26-βcat pre-leukemic mice show a developmental block in T-cell differentiation and exhibit increased resistance to apoptosis. Interestingly, the mice develop T cell lymphomas independent of the Notch pathway. Furthermore, we showed that loss of the tumour suppressor Pten and over-expression of Myc was favoured; and may constitute the secondary events contributing to this leukemogenesis. We also demonstrated that R26-βcat tumours are malignant, heterogeneous and that leukaemia stem cells (LSC) were enriched in DP cells. Furthermore, the self-renewal capapcity of R26-βcat LSCs can to be exhausted.We propose that the R26-βcat model defines a new sub-group of Notch-independent T-ALL and the β-catenin may serve as a potential therapeutic target for these tumours.

No description available.

No description available.

Submitted by Jos? Henrique Henrique (jose.neves@ufvjm.edu.br) on 2018-01-04T16:33:42Z No. of bitstreams: 2 license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) jorge_andres_rueda_ardila.pdf: 2023531 bytes, checksum: f404efb27a2e6ec9624c8477f8ce4680 (MD5) / Approved for entry into archive by Rodrigo Martins Cruz (rodrigo.cruz@ufvjm.edu.br) on 2018-01-17T18:47:58Z (GMT) No. of bitstreams: 2 license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) jorge_andres_rueda_ardila.pdf: 2023531 bytes, checksum: f404efb27a2e6ec9624c8477f8ce4680 (MD5) / Made available in DSpace on 2018-01-17T18:47:58Z (GMT). No. of bitstreams: 2 license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) jorge_andres_rueda_ardila.pdf: 2023531 bytes, checksum: f404efb27a2e6ec9624c8477f8ce4680 (MD5) Previous issue date: 2017 / A enzima L-asparaginase ? atualmente utilizada na ind?stria de alimentos e na ind?stria farmac?utica devido ? facilidade de catalisar a rea??o de hidr?lise da L-asparagina em aspartato e am?nia. Esta propriedade tem aplica??o na ind?stria dos alimentos, pois evita a produ??o de compostos carcinog?nicos como as acrilamidas. Por outro lado, na ind?stria farmac?utica, esta rea??o enzim?tica det?m o crescimento de c?lulas leuc?micas devido ? falta de L-asparagina que estas c?lulas devem afrontar. Conforme as c?lulas leuc?micas t?m pouca ou nenhuma asparagina sintetase, as rotas metab?licas dependem exclusivamente da absor??o desse amino?cido do meio fisiol?gico. V?rias pesquisas foram feitas desde que a L-asparaginase mostrou a habilidade de reduzir alguns c?nceres na d?cada de 50. Estas pesquisas incluem a triagem de micro-organismos produtores, a otimiza??o de meios de cultura para melhorar a produ??o e a procura de uma metodologia que consiga purificar a enzima a partir do estrato bruto. Tais pesquisas se intensificaram recentemente no Brasil devido a uma crise de abastecimento gerada pela interrup??o da importa??o pelo fornecedor. A L-asparaginase ? um princ?pio ativo de alta demanda para tratar a leucemia linfobl?stica aguda e por isso deve ser produzida no Brasil. Este estudo foi realizado utilizando a linhagem Penicillium sp. T8.3 e teve como objetivo aprimorar a produ??o da enzima ajustando as condi??es de cultivo, usando glicerol e L-asparagina (como fontes de carbono e nitrog?nio, respectivamente) e pH como as tr?s vari?veis de entrada. Os experimentos foram desenvolvidos aplicando ferramentas da estat?stica multivari?vel como planejamento fatorial, desenho composto central para gerar um modelo matem?tico emp?rico. Foram analisadas a concentra??o de am?nio e a atividade enzim?tica produzida nos bioprocessos. A atividade enzim?tica foi determinada em rea??o conduzida a 37 ?C e pH 7,0, condi??es semelhantes ? do meio fisiol?gico. Todos os dados estat?sticos foram gerados com o programa Statistica 7.0 ?. Foi produzida uma atividade m?xima de 12,7 U por bioprocesso estacion?rio conduzido em meio ajustado com 15,5 g.L-1 de glicerol, 5,6 g.L-1 de L-asparagina e pH 4,8. Desse modo, o ajuste das condi??es de cultivo permitiu elevar a produ??o em mais de 30 vezes e alcan?ar uma atividade enzim?tica superior ? maioria dos relatos da literatura que tratam da produ??o da enzima f?ngica. O modelo estat?stico previu a produ??o enzim?tica com 77% de acerto, mostrando sua validade experimental e o potencial da linhagem T8.3 para a produ??o de L-asparaginase eucarionte. / Disserta??o (Mestrado) ? Programa de P?s-gradua??o em Ci?ncias Farmac?uticas, Universidade Federal dos Vales do Jequitinhonha e Mucuri, 2017. / The enzyme L-asparaginase is nowadays used in both pharmaceutics and food industry because of its ability to catalyze the reaction of hydrolysis of L-asparaginase into ammonia and aspartate. This feature is useful in the food industry because it hinders the formation of carcinogenic compounds such as acrylamide. On the other hand, in the pharmaceutical industry, this enzymatic reaction prevents some leukemic cells from growing due to asparagine depletion. Since these cells have low levels or no asparagine synthase, their metabolic routes depend on amino acid absorption from physiological medium. Several researches have been carried out since L-asparaginase showed to reduce some cancers in the 50?s. These researches include the screening of producing-microorganisms, optimization of the culture media to increase enzyme production, and development of methodology to purify the enzyme from crude extracts. Such researches have recently been intensified in Brazil due to a supply crisis resulting from interruption of the importer activities. L-asparaginase is a pharmaceutical of high demand to treat acute lymphoblastic leukemia, and therefore, it must be produced by Brazil. This study was carried out with the strain Penicillium sp. T8.3, and aimed to improve enzyme production by adjusting culture conditions, and by evaluating glycerol and L-asparagine ? as carbon and nitrogen sources, respectively ? and pH as input variables. The experiments were developed by using multivariable statistic tools such as factorial planning and central composite design to generate an empirical mathematical model. It was analyzed the ammonium concentration and the enzymatic activity produced in the bioprocesses. L-asparaginase activity was determined in reactions conduced at 37 ?C and at pH 7.0, similar to the physiological conditions. All statistical data were obtained with the software Statistica 7.0 ?. A maximum activity of 12.7 U was produced by stationary bioprocess in media adjusted with 15.5 g.L-1 glycerol, 5.6 g.L-1 L-asparagine, and pH 4,8. Thus, adjustment of culture conditions allowed to increase production by 30 times, and to reach an enzyme activity higher than those reported by most of the literature that deals with production of the fungal enzyme. The statistical model predicted enzyme production with 77% of accuracy, showing its experimental validity and the potential of strain T8.3 to produce the eukaryote L-asparaginase. / La enzima L-asparaginasa es usada actualmente en la industria de alimentos y en la industria farmac?utica debido a su facilidad para catalizar la reacci?n de degradaci?n de L-asparagina en amoniaco y aspartato. Esta caracter?stica es ?til en la industria de alimentos puesto a que evita la producci?n de compuestos cancer?genos como la acrilamida. Por otro lado, en la industria farmac?utica, esta reacci?n detiene el crecimiento de c?lulas leuc?micas debido al desabastecimiento de L-asparagina al que las c?lulas se enfrentan. Ya que estas c?lulas tienen poca o ninguna asparagina sintetasa, sus rutas metab?licas dependen exclusivamente de la absorci?n de amino?cidos desde el medio fisiol?gico. Varias investigaciones se han llevado a cabo desde que la L-asparaginasa mostr? su capacidad para reducir algunos c?nceres en los a?os 50. Estas investigaciones incluyen la clasificaci?n de microorganismos como productores de esta enzima, la mejora de los medios de cultivo para optimizar la producci?n, y la b?squeda de una metodolog?a para purificarla desde el extracto celular. Estos temas de investigaci?n han ganado inter?s en Brasil debido a que el proveedor de este f?rmaco detuvo sus servicios. La L-asparaginasa presenta una alta demanda para tratar la leucemia linfobl?stica aguda y por lo tanto debe ahora producirse en Brasil. Este estudio se llev? a cabo utilizando una cepa Penicillium sp. T8.3 cuyo objetivo fue optimizar la producci?n de la enzima mediante ajustes en las condiciones de cultivo usando glicerol y L-asparagina (como fuentes de carbono y de nitr?geno, respectivamente) y pH como las tres variables de entrada. Los experimentos fueron desarrollados utilizando herramientas de estad?stica multivariable como un planeamiento factorial y un dise?o de compuesto central para obtener un modelo matem?tico emp?rico. Se analizaron la concentraci?n de amoniaco y la actividad enzim?tica en los procesos biotecnol?gicos. La actividad enzim?tica fue determinada en una reacci?n a 37 ?C y pH 7.0, condiciones similares al medio fisiol?gico. Todos los datos estad?sticos fueron obtenidos del programa Statistica 7.0 ?. Se obtuvo una actividad m?xima de 12.7 U en proceso biotecnol?gico estacionario en un medio ajustado con 15.5 g.L-1 de glicerol, 5.6 g.L-1 de L-asparagina y pH 4.8. Este ajuste de las condiciones de cultivo logr? aumentar la producci?n en m?s de 30 veces, bien como alcanzar una actividad enzim?tica superior a la mayor?a de los relatos de literatura que tratan de la producci?n de la enzima de hongos. El modelo estad?stico predijo la producci?n enzim?tica en 77% de acierto, mostrando su validez experimental y el potencial de la cepa T8.3 para la producci?n de la L-asparaginasa eucariota.

O câncer pediátrico é raro em números absolutos, porém quando comparado às incidências em adultos vem apresentando aumento nas taxas de incidência, exigindo um preparo do sistema de saúde para acompanhamento. Este acompanhamento não pode ser igual ao do adulto, visto que crianças possuem diferenças fisiológicas nas diferentes faixas etárias pediátricas. Sendo assim, estudos de utilização de medicamentos são importantes nesta população, a fim de promover o uso racional dos mesmos, bem como, garantir seu uso seguro e uma terapêutica eficaz. O presente estudo tem por objetivo avaliar as prescrições de antineoplásicos, na unidade de oncologia pediátrica de um hospital universitário de Porto Alegre, identificando os protocolos mais utilizados, e posteriormente contextualizando-os com o preconizado no referencial teórico. Foi realizado um estudo transversal prospectivo envolvendo internações realizadas na unidade de oncologia pediátrica do Hospital de Clínicas de Porto Alegre (HCPA). Foram analisadas 274 internações, das quais 40 eram primeira internação e 234 reinternações. A maioria dos pacientes tinha idade de 0 a 10 anos, uma discreta prevalência do sexo masculino, de raça/cor branca, residentes na mesorregião metropolitana. A principal forma de financiamento das internações foi o público, e a principal causa de internação foi o tratamento, sendo o mais frequente o quimioterápico. Foram analisados os protocolos utilizados durante as internações de pacientes com diagnóstico de Leucemia Linfocítica Aguda, Retinoblastoma e Sarcoma de Ewing. Os protocolos são conjunto de regras criadas a partir de grupos cooperativos ou da indústria farmacêutica, permitindo um maior conhecimento sobre os medicamentos utilizados na pediatria. A oncologia pediátrica com sua particularidade de ser uma doença culturalmente ligada ao óbito possui maior facilidade de estudos deste porte. Porém, ainda são necessários mais estudos de utilização destes medicamentos, a fim de agregar conhecimento aos protocolos de tratamento. / Pediatric cancer is rare in absolute numbers, but when compared to the incidence in adults has shown an increase in incidence rates, requiring a prepared system health for following. Pediatrics treatment can’t be the same as that of adults, because children have different physiological differences in pediatric age groups. Studies of medication use in this population are very important in order to promote the rational use of drugs, as well as to guarantee their safe use and effective therapy. The present study aims to evaluate the anticancer prescriptions in pediatric oncology unit of a university hospital in Porto Alegre, identifying the most used protocols, and contextualizing them later with the recommendations in the theoretical framework. A prospective cross-sectional study involving hospital admissions in the pediatric oncology unit of the Hospital de Clínicas de Porto Alegre (HCPA) was performed. We analyzed 274 admissions, which 40 were first admission and 234 were readmissions. These admissions most patients were aged 0 to 10 years, white race, a slight male prevalence, residing in Metropolitan Mesoregion. The financing the hospital admissions was public, and the maining cause of hospitalization was treatment, the most frequent being the chemotherapy. We analyzed the protocols used during the admissions of patients diagnosed with Acute Lymphocytic Leukemia, Retinoblastoma and Ewing's Sarcoma. Protocols are studies that allow a greater knowledge about medicines for pediatric use. The pediatric oncology with its characteristic of being a disease has culturally linked with death ease of studies of this size. However, more studies of medication use are still needed to use these drugs in order to knowledge to the treatment protocols.

Les leucémies aiguës (LA) sont un groupe hétérogène d'hémopathies malignes dues à latransformation oncogénique clonale des cellules souches hématopoïétiques (CSH). On distingue les LA myéloblastiques etlymphoblastiques (LAL). Les LAL sont classées selon le type de précurseur lymphoïde atteint, leur degré de maturité et leurs anomalies cytogénétiques.Le traitement permettant d'obtenir 80 à 90 % de rémission complète (RC) comporte une chimiothérapie d'induction, une consolidation et une intensification(intensification retardée ou allogreffe de CSH selon la situation pronostique). Néanmoins la survie globale à long terme n'est que de 40 à 50 %, du fait de la survenue de rechutes et de la toxicité des traitements. Différents groupes pronostiques basés sur la cytogénétique et la biologie moléculaire se dégagent,pouvant bénéficier de thérapeutiques adaptées. Dans les LAL à chromosome philadelphie (LAL à Ph),antérieurement de mauvais pronostic, les inhibiteurs de tyrosine kinase (ITK) permettent d'obtenir 80% de RCavec cependant un taux de rechute non négligeable. Nous avons démontré qu'une intensification thérapeutique par autogreffe chez des patients avec une maladie résiduelle indétectable permettait une survie à long terme prolongée avec une toxicité moindre que celle de l'allogreffe. En montrant l'implication de l'autotaxine dans les mécanismes de résistance aux ITK dans les LAL à Ph, nous ouvrons la voie à l'utilisation potentielle de nouvelles thérapeutiques. Dans les LAL T, groupe considéré de bon pronostic, un tiers des patients rechute. Nous avons démontré que l'absence de mutation de Notch et/ou FBXW7 ou la présence de mutations de RAS ou PTEN était de mauvais pronostic identifiant un sous-groupe de LAL T dont le traitement devait être renforcé. Nos travaux ont ainsi contribué à l'identification des groupes pronostiques dans les LAL et à l'adaptation des traitements afin d'améliorer les chances de survie. / Acute leukemias are a heterogeneous groups of malignant hematological diseases due to the clonaloncogenic transformation of hematopoietic stem cells(HSTs). We distinguish acute myeloblastic leukaemiafrom acute lymphoblastic leukemia (ALL). ALLs are classified according to the type of lymphoid precursoraffected, its degree of maturity, and with associated cytogenetic abnormalities.Treatment incorporating induction therapy,consolidation, and intensification – delayedintensification or allogeneic stem cell transplantation(SCT) according to prognostic factors – enable 80 to 90% of complete remission (CR). Nevertheless, long-termoverall survival is only 40 to 50% because of relapseand treatment-related toxicity. Different prognosticgroups based on cytogenetic abnormalities andmolecular biology are emerging and patients from eachprognostic group can benefit from adapted therapies.In chromosome Philadelphia-positive ALL (Ph+ ALL) which used to be of particular bad prognosis, tyrosinekinase inhibitors (TKIs) enables 80% of CR but with ahigh-relapse risk. We demonstrated that high-dosetherapy followed by autologous SCT enables prolongedlong-term survival with less drug-related toxicity ascompared to allogeneic SCT in patients with undetectable minimal residual disease. By showing the implication of autotaxine in the resistance to TKIs inPh+ LAL, we enable the use of novel therapeutics inclinical practice.T-cell ALL is considered of poor prognosis as one thirdof patients relapse. In this group of patients we showedthat the absence of a Notch and/or a FBXW7 mutation or the presence of mutations in RAS or PTEN identified a subgroup of patients in whom the treatmentmust be intensified. Our research has contributed to the identification of prognostic groups in ALL and to theadjustment of treatment according to potential survival.

O câncer pediátrico é raro em números absolutos, porém quando comparado às incidências em adultos vem apresentando aumento nas taxas de incidência, exigindo um preparo do sistema de saúde para acompanhamento. Este acompanhamento não pode ser igual ao do adulto, visto que crianças possuem diferenças fisiológicas nas diferentes faixas etárias pediátricas. Sendo assim, estudos de utilização de medicamentos são importantes nesta população, a fim de promover o uso racional dos mesmos, bem como, garantir seu uso seguro e uma terapêutica eficaz. O presente estudo tem por objetivo avaliar as prescrições de antineoplásicos, na unidade de oncologia pediátrica de um hospital universitário de Porto Alegre, identificando os protocolos mais utilizados, e posteriormente contextualizando-os com o preconizado no referencial teórico. Foi realizado um estudo transversal prospectivo envolvendo internações realizadas na unidade de oncologia pediátrica do Hospital de Clínicas de Porto Alegre (HCPA). Foram analisadas 274 internações, das quais 40 eram primeira internação e 234 reinternações. A maioria dos pacientes tinha idade de 0 a 10 anos, uma discreta prevalência do sexo masculino, de raça/cor branca, residentes na mesorregião metropolitana. A principal forma de financiamento das internações foi o público, e a principal causa de internação foi o tratamento, sendo o mais frequente o quimioterápico. Foram analisados os protocolos utilizados durante as internações de pacientes com diagnóstico de Leucemia Linfocítica Aguda, Retinoblastoma e Sarcoma de Ewing. Os protocolos são conjunto de regras criadas a partir de grupos cooperativos ou da indústria farmacêutica, permitindo um maior conhecimento sobre os medicamentos utilizados na pediatria. A oncologia pediátrica com sua particularidade de ser uma doença culturalmente ligada ao óbito possui maior facilidade de estudos deste porte. Porém, ainda são necessários mais estudos de utilização destes medicamentos, a fim de agregar conhecimento aos protocolos de tratamento. / Pediatric cancer is rare in absolute numbers, but when compared to the incidence in adults has shown an increase in incidence rates, requiring a prepared system health for following. Pediatrics treatment can’t be the same as that of adults, because children have different physiological differences in pediatric age groups. Studies of medication use in this population are very important in order to promote the rational use of drugs, as well as to guarantee their safe use and effective therapy. The present study aims to evaluate the anticancer prescriptions in pediatric oncology unit of a university hospital in Porto Alegre, identifying the most used protocols, and contextualizing them later with the recommendations in the theoretical framework. A prospective cross-sectional study involving hospital admissions in the pediatric oncology unit of the Hospital de Clínicas de Porto Alegre (HCPA) was performed. We analyzed 274 admissions, which 40 were first admission and 234 were readmissions. These admissions most patients were aged 0 to 10 years, white race, a slight male prevalence, residing in Metropolitan Mesoregion. The financing the hospital admissions was public, and the maining cause of hospitalization was treatment, the most frequent being the chemotherapy. We analyzed the protocols used during the admissions of patients diagnosed with Acute Lymphocytic Leukemia, Retinoblastoma and Ewing's Sarcoma. Protocols are studies that allow a greater knowledge about medicines for pediatric use. The pediatric oncology with its characteristic of being a disease has culturally linked with death ease of studies of this size. However, more studies of medication use are still needed to use these drugs in order to knowledge to the treatment protocols.

O câncer pediátrico é raro em números absolutos, porém quando comparado às incidências em adultos vem apresentando aumento nas taxas de incidência, exigindo um preparo do sistema de saúde para acompanhamento. Este acompanhamento não pode ser igual ao do adulto, visto que crianças possuem diferenças fisiológicas nas diferentes faixas etárias pediátricas. Sendo assim, estudos de utilização de medicamentos são importantes nesta população, a fim de promover o uso racional dos mesmos, bem como, garantir seu uso seguro e uma terapêutica eficaz. O presente estudo tem por objetivo avaliar as prescrições de antineoplásicos, na unidade de oncologia pediátrica de um hospital universitário de Porto Alegre, identificando os protocolos mais utilizados, e posteriormente contextualizando-os com o preconizado no referencial teórico. Foi realizado um estudo transversal prospectivo envolvendo internações realizadas na unidade de oncologia pediátrica do Hospital de Clínicas de Porto Alegre (HCPA). Foram analisadas 274 internações, das quais 40 eram primeira internação e 234 reinternações. A maioria dos pacientes tinha idade de 0 a 10 anos, uma discreta prevalência do sexo masculino, de raça/cor branca, residentes na mesorregião metropolitana. A principal forma de financiamento das internações foi o público, e a principal causa de internação foi o tratamento, sendo o mais frequente o quimioterápico. Foram analisados os protocolos utilizados durante as internações de pacientes com diagnóstico de Leucemia Linfocítica Aguda, Retinoblastoma e Sarcoma de Ewing. Os protocolos são conjunto de regras criadas a partir de grupos cooperativos ou da indústria farmacêutica, permitindo um maior conhecimento sobre os medicamentos utilizados na pediatria. A oncologia pediátrica com sua particularidade de ser uma doença culturalmente ligada ao óbito possui maior facilidade de estudos deste porte. Porém, ainda são necessários mais estudos de utilização destes medicamentos, a fim de agregar conhecimento aos protocolos de tratamento. / Pediatric cancer is rare in absolute numbers, but when compared to the incidence in adults has shown an increase in incidence rates, requiring a prepared system health for following. Pediatrics treatment can’t be the same as that of adults, because children have different physiological differences in pediatric age groups. Studies of medication use in this population are very important in order to promote the rational use of drugs, as well as to guarantee their safe use and effective therapy. The present study aims to evaluate the anticancer prescriptions in pediatric oncology unit of a university hospital in Porto Alegre, identifying the most used protocols, and contextualizing them later with the recommendations in the theoretical framework. A prospective cross-sectional study involving hospital admissions in the pediatric oncology unit of the Hospital de Clínicas de Porto Alegre (HCPA) was performed. We analyzed 274 admissions, which 40 were first admission and 234 were readmissions. These admissions most patients were aged 0 to 10 years, white race, a slight male prevalence, residing in Metropolitan Mesoregion. The financing the hospital admissions was public, and the maining cause of hospitalization was treatment, the most frequent being the chemotherapy. We analyzed the protocols used during the admissions of patients diagnosed with Acute Lymphocytic Leukemia, Retinoblastoma and Ewing's Sarcoma. Protocols are studies that allow a greater knowledge about medicines for pediatric use. The pediatric oncology with its characteristic of being a disease has culturally linked with death ease of studies of this size. However, more studies of medication use are still needed to use these drugs in order to knowledge to the treatment protocols.

Abstract Leukemia treatment has been implicated to be responsible for a diversity of long-term adverse effects (Pui 2008), which can occur even years after diagnosis and can seriously impair survivors’ performance status and quality of life (Campbell et al. 2007, Zeltzer et al. 2008). The aim of the present work was to assess health-related quality of life in long-term survivors of acute lymphoblastic leukemia (ALL), and to find out whether vocational rehabilitation can promote the coping at work of young people who take part in a training intervention or help them find employment. Neuropsychological testing was performed on 64 survivors. Cranial irradiation had been administered to 44 of the survivors, while 20 survivors had been treated solely with chemotherapy. A control group consisted of 45 healthy young adults. We found that young adult survivors of childhood ALL treated with cranial irradiation had clear progressive deficits in their neurocognitive functioning at a mean of 20 years after diagnosis compared with healthy controls. Non-irradiated ALL survivors performed significantly better, but even they had statistically significant impairments in some of the neuropsychological test scores compared with the controls. Rand-36-Item health Survey (RAND-36) was used to assess subjective HRQoL, depressive symptoms were assessed with Beck Depression Inventory (BDI-21), and mental distress with General Health Questionnaire (GHQ-12) in 74 survivors of ALL. The control group consisted of 146 healthy young adults selected from local population registry. ALL survivors showed good HRQoL scores in comparison to the control group. Patients who had been treated for an ALL relapse and had received the most intensive chemo- and radiotherapy had significantly higher scores on mental health and vitality than the controls. Survivors of ALL report fewer depressive symptoms and equal mental well-being compared to healthy controls. Nine out of 63 survivors were selected for rehabilitation based on their occupation and psychosocial difficulties. The occupational rehabilitation course improved physical fitness and decreased overweight in long-term survivors of ALL, but impaired their HRQoL. Our findings support the idea that ALL survivors’ subjective experience of well-being is possibly affected by a repressive adaptive style. / Tiivistelmä Leukemiahoidoilla on todettu olevan pitkäaikaisvaikutuksia (Pui 2008), jotka voivat ilmetä jopa vuosia diagnoosin jälkeen heikentäen sairaudesta selvinneiden toimintakykyä ja elämänlaatua (Campbell et al. 2007, Zeltzer et al. 2008). Tämän tutkimuksen tavoitteena oli arvioida akuutista lymfaattisesta (ALL) leukemiasta selvinneiden terveyteen liittyvää elämänlaatua pitkällä aikavälillä sekä selvittää, voidaanko ammatillisen kuntoutuksen avulla edistää interventioon osallistuneiden työssä selviytymistä tai työllistymistä. Neuropsykologiseen tutkimukseen osallistui 64 ALL pitkäaikaisselviytyjää. Heistä 44 oli saanut pään alueen sädehoitoa ja 20 pelkästään solunsalpaajahoitoa. Verrokkiryhmässä oli 45 tervettä nuorta aikuista. Havaitsimme, että lapsuudessa pään alueen sädehoitoa saaneilla ALL-selviytyjillä oli verrokkeihin verrattuna selkeitä progressiivisia muutoksia neurokognitiivisessa toimintakyvyssä keskimäärin 20 vuotta diagnoosista. Ne, jotka eivät olleet saaneet sädehoitoa suoriutuivat huomattavasti paremmin, mutta heilläkin havaittiin tilastollisesti merkittäviä puutoksia joillakin neuropsykologisten testien osa-alueilla verrokkeihin verrattuna. 74 entisen ALL-potilaan terveyteen liittyvää elämänlaatua (HRQoL) mitattiin Rand-36 -mittarilla, masennusoireita Beckin masennustestillä (BDI-21) ja henkistä hyvinvointia General Health Questionnaire -mittarilla (GHQ-12). Verrokkiryhmäksi valittiin väestörekisteristä 146 tervettä nuorta aikuista. ALL-ryhmässä tutkittavien terveyteen liittyvää elämänlaatua mittaavat pisteet olivat hyvät verrokkiryhmään verrattuna. Ne potilaat, joita oli hoidettu leukemian uusiutumisen takia ja jotka olivat saaneet intensiivisintä solunsalpaaja- ja sädehoitoa saivat huomattavasti paremmat pisteet psyykkisen hyvinvoinnin ja vitaalisuuden osa-alueilla kuin verrokit. ALL -selviytyjät raportoivat vähemmän masennusoireita, ja he arvioivat psyykkinen hyvinvointinsa yhtä hyväksi kuin verrokit. Yhdeksän ALL pitkäaikaisselviytyjää osallistui heille suunnattuun ammatilliseen kuntoutusinterventioon. Ammatillinen kuntoutuskurssi paransi ALL -selviytyjien fyysistä suorituskykyä ja vähensi ylipainoa, mutta heikensi terveyteen liittyvää elämänlaatua. Tutkimustulokset tukevat ajatusta, että repressiivinen adaptaatio voi vaikuttaa lapsuusiän leukemiasta selvinneiden subjektiiviseen hyvinvoinnin kokemukseen.