Bakgrund: Varje år insjuknar 300 000 barn i cancer och akut lymfatisk leukemi (ALL) är den vanligaste cancersjukdomen hos barn. Sjukdomen innebär intensiva behandlingar som kommer påverka barnet men även barnets föräldrar. Kvalitén på vårdandet påverkar föräldrarnas upplevelse av vården och detta innebär att sjuksköterskor har ett stort ansvar att vårda utifrån ett livsvärldsperspektiv. Syfte: Syftet med denna studie var att belysa föräldrars upplevelser när deras barn insjuknat i akut lymfatisk leukemi. Metod: Metoden som används var en litteraturöversikt, nio kvalitativa artiklar och en kvantitativ artikel analyserades för att bidra till evidensbaserad kunskap. Resultat: Utifrån analysen framkom fyra kategorier; När sjukdomen blir ett faktum, Tillvägagångssätt för att hjälpa sitt barn, Faktorer som påverkar hanteringen av behandling samt Relationer och kommunikationens betydelse med tillhörande underkategorier. Konklusion: Föräldrar upplever starka känslor i samband med att barnet får diagnosen. Sjukdomen medför förändringar i det som tidigare ansågs som en normal vardag. Information och kunskap från vårdpersonal är betydelsefullt för föräldrarna då det kan underlätta föräldrars förståelse för sjukdomen. Genom att belysa föräldrarnas upplevelse när deras barn drabbats av ALL kan bredare förståelse för hur grundutbildade sjuksköterskor kan bemöta dessa föräldrar. / Background: Every year, 300 000 children develop cancer where Acute Lymphoblastic Leukemia (ALL) is the most common form of childhood cancer. The disease involves intensive treatment which will not only affect the child but also the parents. The quality of care affects parents’ experience of Health Care, this means that nurses have responsibility to care from a life-world-perspective. By paying attention to how illness, suffering and health are experienced and affect parents, the quality of care can be ensured. Aim: The aim of this study is to highlight parents’ experiences when their child has developed ALL. Method: The method is a literature review, ten scientific articles were selected and formed the basis of the study. Results: Based on the analysis, four categories emerged; When the disease becomes reality, Approaches to help their child, Factors affecting the management of treatment and The importance of relationships and communication with associated subcategories. Conclusion: Parents experience strong emotions related to their child’s diagnosis. The disease will lead to changes in what was previously considered a normal everyday life. Information and knowledge from healthcare providers is important as it can strengthen parents’ management of the disease. By highlighting the parents’ experience when their child has developed ALL, a broader understanding of how registered nurses encounter these meetings.

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京都大学 / 新制・課程博士 / 博士(医学) / 甲第24085号 / 医博第4861号 / 新制||医||1059(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 髙折 晃史, 教授 生田 宏一, 教授 金子 新 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 新制・論文博士 / 博士(医学) / 乙第13609号 / 論医博第2319号 / 新制||医||1073(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 村川 泰裕, 教授 竹内 理, 教授 永井 純正 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM

Η μεθυλοτρανσφεράση της θειοπουρίνης (TPMT) είναι ένα ένζυμο του κυτταροπλάσματος, που καταλύει τη μεθυλίωση των θειοπουρινικών φαρμάκων, όπως η 6-μερκαπτοπουρίνη (6-MP), η οποία έχει καθιερωθεί στη θεραπεία συντήρησης παιδιών με ΟΛΛ. Ένα πολυμορφικό στοιχείο (VNTR) στον υποκινητή του γονιδίου ΤΡΜΤ, φαίνεται να επηρεάζει τα επίπεδα δραστικότητας του ενζύμου που παράγεται. Πρόκειται για διαδοχικές επαναλήψεις τριών διαφορετικών αλληλουχιών (A, B και C), ο αριθμός των οποίων κυμαίνεται από τρεις έως εννέα. Η περιοχή VNTR είναι πλούσια σε επαναλήψεις των βάσεων GC, οι οποίες αποτελούν πιθανές θέσεις πρόσδεσης μεταγραφικών παραγόντων. Μερικοί ασθενείς, οι οποίοι ακολουθούν θεραπεία με 6-ΜΡ, δεν είναι ανθεκτικοί στην καθιερωμένη δόση του φαρμάκου και παρουσιάζουν μυελοτοξικότητα ως αποτέλεσμα της ανεπάρκειας του ενζύμου TPMT. Στην παρούσα εργασία πραγματοποιήθηκε μία εκτεταμένη μελέτη της περιοχής VNTR, με απώτερο σκοπό την αξιολόγησή της ως πιθανό φαρμακογονιδιωματικό δείκτη, που να σχετίζεται με την πρόβλεψη ανεπιθύμητων παρενεργειών σε ασθενείς με ΟΛΛ, οι οποίοι λαμβάνουν 6-ΜΡ. Αρχικά, προσδιορίστηκε η συχνότητα των διαφορετικών VNTR αλληλομόρφων στον ελληνικό πληθυσμό, σε ένα σύνολο υγιών ατόμων, με σκοπό να αντιπαραβάλλουμε τις συχνότητες αυτές με δεδομένα από άλλες πληθυσμιακές ομάδες. Τα αποτελέσματά που προέκυψαν συμφωνούν με τα αντίστοιχα στοιχεία που υπάρχουν για άλλους πληθυσμούς. Οι μέθοδοι γονοτύπησης που εφαρμόσθηκαν περιλαμβάνουν την αντίδραση της PCR και τον προσδιορισμό αλληλουχίας κατά Sanger. Στη συνέχεια μελετήθηκε η επίδραση συγκεκριμένων μοτίβων VNTR στον υποκινητή του γονιδίου υγιών ατόμων, στη μεταγραφή του γονιδίου, καθώς και στην έκφραση του ενζύμου ΤΡΜΤ. Η ικανότητα μεταγραφής εκτιμήθηκε με τη μέθοδο της ποσοτικής Real Time PCR, ενώ τα επίπεδα έκφρασης του ενζύμου προσδιορίστηκαν μέσω της αντίδρασης χημειοφωταύγειας, με χρήση κατάλληλων αντισωμάτων. Ο μικρός αριθμός δειγμάτων δεν επέτρεψε την εξαγωγή ασφαλών συμπερασμάτων για το ρόλο της VNTR περιοχής, στην μεταγραφή του γονιδίου ΤΡΜΤ. Σύμφωνα με τα αποτελέσματά μας, διακρίνεται μία τάση συσχέτισης, η οποία όμως απαιτεί περαιτέρω διερεύνηση. / Thiopurine S-methyltransferase (TPMT) is a cytosolic enzyme that catalyzes S-methylation of thiopurine drugs, such as 6-mercaptopurine (6-MP), which is typically used as maintenance therapy in pediatric acute lymphoblastic leukemia (ALL). A variable number of tandem repeat (VNTR) within the TPMT promoter has been reported to “modulate” levels of this enzyme activity. The VNTR region architecture is defined by three types of repeats (A, B and C) rang¬ing from three to nine (VNTR*3 to VNTR*9). These repeats are GC rich, and are putative binding sites of various transcription factors. Some patients do not tolerate standard doses of 6-MP and develop myelotoxicity as a consequence of inherited TPMT deficiency. In this study, we performed an extensive analysis of VNTR region, in order to evaluate it as a putative pharmacogenomic marker to predict 6-MP toxicity, in ALL patients. The frequency of TPMT alleles bearing different VNTR architectures was investigated in the Hellenic population. The results of this study were consistent with data, already existed, from other populations. The number and type of tandem repeats were determined by PCR amplification followed by direct re-sequencing. Moreover, we explored the influence of specific VNTR motifs, within the TPMT promoter of healthy individuals, on transcription and expression of TPMT gene. Quantitative Real-Time PCR was performed in order to investigate the influence of VNTR architecture on TPMT gene transcription. The expression levels of TPMT enzyme were estimated by chemiluminescence reaction, using appropriate antibodies. The role of VNTR region on TPMT gene transcription was not clarified through this study, owing to small cohort of samples included. A statistical trend of association has been observed, requiring, however, further investigation.

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Objetivo: Avaliar as características clínicas e laboratoriais para diferenciar leucemia linfoblástica aguda (LLA) da artrite idiopática juvenil forma sistêmica (AIJs) no início da doença. Métodos: Cinquenta e sete pacientes com LLA com envolvimento musculoesquelético, sem blastos no sangue periférico e sem terapia com glucocorticoide no início da doença e 102 pacientes com AIJs (critérios ILAR) foram retrospectivamente avaliados. Foram estudadas as seguintes características: febre, exantema reumatoide, artrite, dor em membros, hepatomegalia, esplenomegalia, pericardite, miocardite, pleurite, perda de peso, sangramento, anemia, leucopenia, neutropenia, plaquetopenia, níveis séricos elevados de velocidade de hemossedimentação (VHS) e de desidrogenase lática (DHL). Resultados: A mediana da idade de início da doença foi significativamente maior em pacientes com LLA comparada com AIJs (5,8 vs. 3,8 anos, p=0,0006). As frequências de dor em membros, hepatomegalia, perda de peso e manifestações hemorrágicas foram significativamente maiores em LLA versus AIJs (70% vs. 1%, p<0,0001; 54% vs. 32%, p=0,0075; 30% vs. 8%, p=0,0005; 98% vs. 0%, p=0,0053; respectivamente). Igualmente, as frequências de anemia, leucopenia, neutropenia, plaquetopenia e DHL elevado foram significativamente maiores em LLA versus AIJs (88% vs. 57%, p<0,0001; 39% vs. 1%, p<0,0001; 60% vs. 1%, p<0,0001; 77% vs. 1%, p<0,0001; 56% vs. 14%, p<0,0001; respectivamente). Consideravelmente, a análise multivariada mostrou que dor em membros (OR=553; 95% IC=46,48-6580,42; p<0,0001) e plaquetopenia (OR=754,13; 95% IC=64,57-8806,72; p<0,0001) permaneceram como variáveis independentes que diferenciaram pacientes com LLA de pacientes com AIJs. O R2 de Nagelkerke foi de 0,91. A curva de sobrevida de Kaplan-Meier foi similar em pacientes com LLA com e sem dor em membros (p=0,8347). Conclusão: O presente estudo enfatiza a importância de investigar pacientes com LLA que apresentam manifestações musculoesqueléticas, particularmente dor em membros com plaquetopenia / Objective: To assess clinical and laboratorial features which differentiate acute lymphoblastic leukemia (ALL) from systemic onset juvenile idiopathic arthritis (SoJIA) at disease onset. Methods: Fifty seven ALL patients with musculoskeletal involvement, without blasts on peripheral blood and glucocorticoid therapy at onset of disease and 102 SoJIA patients (ILAR criteria) were retrospectively evaluated. The following features were studied: fever, rheumatoid rash, arthritis, limb pain, hepatomegaly, splenomegaly, pericarditis, myocarditis, pleuritis, weight loss, bleeding, anemia, leukopenia, neutropenia, thrombocytopenia, high erythrocyte sedimentation rate and high lactic dehydrogenase (LDH) levels. Results: The median age at disease onset was significantly higher in ALL compared to SoJIA patients (5.8 vs. 3.8years, p=0.0006). The frequencies of limb pain, hepatomegaly, weight loss and hemorrhagic manifestations were significantly higher in ALL versus SoJIA patients (70% vs. 1%, p<0.0001; 54% vs. 32%, p=0.0075; 30% vs. 8%, p=0.0005; 98% vs. 0%, p=0.0053; respectively). Likewise, the frequencies of anemia, leukopenia, neutropenia, thrombocytopenia and high LDH levels were significantly higher in ALL versus SoJIA patients (88% vs. 57%, p<0.0001; 39% vs. 1%, p<0.0001; 60% vs. 1%, p<0.0001; 77% vs. 1%, p<0.0001; 56% vs. 14%, p<0.0001; respectively). Remarkably, multivariate analysis showed that limb pain (OR=553; 95% CI=46.48-6580.42; p<0.0001) and thrombocytopenia (OR=754.13; 95% CI=64.57-8806.72; p<0.0001) remained as independent variables that differentiate ALL from SoJIA patients. The R2 of Nagelkerke was 0.91. The Kaplan-Meier survival curves were similar in ALL patients with and without limb pain (p=0.8347). Conclusion: The present study emphasizes the importance to investigate ALL patients who have musculoskeletal manifestations, particularly limb pain associated with thrombocytopenia

A L- asparaginase é uma enzima aplicada no tratamento de Leucemia Linfoide Aguda, que atua na hidrólise da L- asparagina, privando a célula tumoral de um aminoácido essencial para o seu crescimento. A L- asparaginase, como outros biofármacos, deve ser estável, manter sua atividade específica e formar poucos agregados. A fim de manter a integridade do biofármaco, são utilizados adjuvantes nas formulações farmacêuticas, e dentre os mais importantes estão os osmólitos. Essas moléculas protegem a estrutura nativa da proteína, sendo capazes de interferir na formação de agregados e garantir a estabilidade proteica. O presente trabalho teve o objetivo de estudar o efeito dos osmólitos sacarose, sorbitol, arginina e glicina na atividade específica, estabilidade, cinética e caracterização de agregados na solução de L- asparaginase II de Erwinia chrysanthemi. Os resultados mostraram que a maioria dos osmólitos testados aumentou a atividade específica e a estabilidade da enzima, o que pode estar relacionado com o aumento da velocidade máxima e do kcat observados no ensaio cinético realizado com sacarose e sorbitol. Um perfil diferente de agregados foi encontrado para cada tipo de osmólito. A presença de sacarose ou sorbitol resultou na menor quantidade de agregados na faixa de, respectivamente, 100 a 200 e 200 a 300 nm em relação a enzima sem osmólito. Por outro lado, aumento no número total de agregados e presença de moléculas de alto peso molecular (300 a 500 nm) foram observados nas soluções enzimáticas contendo, respectivamente, glicina e arginina. Dessa forma, os resultados obtidos neste trabalho poderão auxiliar na produção e escolha da formulação de biofármacos, e, consequentemente, melhorar o tratamento medicamentoso de pacientes. / L L-Asparaginase is an enzyme applied in the treatment of Acute Lymphoblastic Leukemia, which acts on the hydrolysis of L- asparagine, depriving the tumor cell of an essential amino acid for its growth. L-asparaginase, as other biopharmaceuticals, must be stable, maintain its specific activity and form few aggregates. In order to maintain the integrity of the biopharmaceutical, adjuvants are used in the pharmaceutical formulations, and among the most importants adjuvants are the osmolytes. These molecules protect the native structure of the protein, being able of interfering in the formation of aggregates and guarantee protein stability. The present work had the objective of studying the effect of the osmolytes sucrose, sorbitol, arginine and glycine in the specific activity, stability, kinetic and aggregates characterization, in L- asparaginase II solution of Erwinia chrysanthemi. The results showed that the majority of the tested osmolytes increased the specific activity of the enzyme and its stability, which may be related to the augment of maximum velocity and kcat observed in the kinetic assay performed with sucrose and sorbitol. A different profile of aggregates was found for each type of osmolyte. The presence of sucrose or sorbitol resulted in the least amount of aggregates in the range of, respectively, 100-200 and 200-300nm in relation to the enzyme without osmolyte. On the other hand, increase in the total number of aggregates and the presence of high molecular weight molecules (300 to 500 nm) were observed in the enzymatic solutions containing, respectively, glycine and arginine. Thus, the results obtained in this work may help in the production and choice of the formulation of biopharmaceuticals and, consequently, improve the drug treatment of patients.

Introdução: o tratamento para leucemia aumentou a sobrevida de pacientes com leucemia aguda linfóide (LLA), mas a redução da força, a fadiga crônica e a qualidade de vida ainda são fatores de preocupação nessa população. Objetivo: comparar força isocinética em pacientes com LLA versus controles saudáveis. Além disso, investigar os efeitos de um programa de treinamento de força de alta intensidade combinado com exercício aeróbio de moderada intensidade em pacientes com LLA. Método: No intuito de responder aos objetivos distintos dessa dissertação, dois estudos sequênciais foram realizados. O primeiro deles trata-se de uma investigação transversal da força isocinética em pacientes com LLA versus controles saudáveis. Já o segundo teve como foco testar um programa de treinamento físico composto por exercícios intensos de força e aeróbios moderados por meio de um desenho prospectivo e longitudinal. No estudo 1, foram recrutados dez pacientes (grupo LLA) durante a fase de manutenção do tratamento de alto risco de LLA. Um grupo de dez crianças saudáveis, pareadas por idade, gênero, estatura e IMC foram selecionadas para o grupo controle (grupo CTRL). Para avaliar a força isocinética de membros inferiores e superiores, foram mensuradas a flexão e extensão concêntrica de joelho e cotovelo utilizando-se um dinamômetro isocinético. No estudo 2, os pacientes foram submetidos a 12 semanas de programa de treinamento intra-hospitalar envolvendo exercício de força de alta intensidade e exercício aeróbio a 70% do VO2 pico. Inicialmente e após 12 semanas, foram avaliados força submáxima (10 repetições máximas), qualidade de vida e os possíveis efeitos adversos. Resultados: No estudo 1, as crianças com LLA apresentaram menor torque máximo de extensão de joelho direito (-29,08%) e esquerdo (-30,8%), menor trabalho total de extensão de joelho direito (- 25,1%) e esquerdo (-23,9%), menor torque máximo normalizado de joelho direito (-24,3%) e esquerdo (-21,1%) e menor trabalho total de extensão de cotovelo (-9,5 e -9,4% para os membros direito e esquerdo, respectivamente) quando comparadas as crianças saudáveis. Além disso, o tempo de torque máximo de flexão concêntrica de joelho e cotovelo foi significantemente maior para o grupo LLA quando comparado ao grupo CTRL. No estudo 2, foi observada melhora significativa na força submáxima no supino (71%), puxada frontal (50%), leg press (73%), extensão do joelho (64%) como resultado do treinamento (p<0,01). Na avaliação dos pais sobre a qualidade de vida das crianças revelou melhora na fadiga e qualidade de vida, porém na autoavaliação das crianças, a qualidade de vida permaneceu inalterada. Não ocorreu nenhum efeito adverso. Conclusão: Crianças em manutenção do tratamento de LLA apresentam diminuição nas medidas de força isocinética quando comparadas às crianças saudáveis. Além disso, demonstramos que um programa de treinamento físico, composto por exercícios de força de alta intensidade e aeróbio de moderada intensidade, foi seguro e eficaz em melhorar a força em pacientes com LLA na fase de manutenção do tratamento. Interessantemente, a qualidade de vida dos pacientes foi melhor após a intervenção, somente na avaliação dos pais / Introduction: the treatment for acute lymphoblastic leukemia (ALL) has increased the survival rate, but reduced strength, chronic fatigue and quality of life are still concerns in this population. Objective: to compare isokinetic strength in patients with ALL versus healthy controls. Additionally, to examine the effects of an exercise program combining high-intensity resistance exercises and moderate-intensity aerobic exercises in patients who are undergoing treatment for ALL. Methods: In order to achieve the aforementioned objectives, two studies were performed. The first study is a cross-sectional study aimed to assess isokinetic muscle strenght in ALL patients versus healthy controls. The second study aimed to examine the effects of na exercise training program comprising high-intensity resistance exercises and moderate-intensity aerobic exercise by using a prospective longitudinal design. In study 1, ten patients with ALL (ALL group) during the maintenance therapy against high-risk were recruited. A group of ten age-, gender-, and BMI-matched healthy children were recruited by advertisement and served as a control (CTRL).To assess lower- and upper-limb isokinetic strength, we assessed concentric knee and elbow flexion and extension strength by using a isokinetic dynamometer. In the study 2, the patients (n = 6; 5-16 years of age) were submitted to a 12-week intra-hospital training program involving high-intensity strength exercises and aerobic exercise at 70% of the VO2 peak. At baseline and after 12 weeks, we assessed submaximal strength (10 repetition-maximum), quality of life and possible adverse. Results: In the study 1, patients with acute lymphoblastic leukemia presented lower knee extension peak torque (-29.8 and -30.8%, for the right and left limbs, respectively), knee extension total work (-25.1% and -23.9 for the right and left limbs, respectively), normalized knee peak torque (-24.3% and -21.1% for the right and left limbs, respectively), and elbow extensor total work (-9.5 and -9.4% for the right and left limbs, respectively) than controls. Additionally, concentric knee and elbow flexion time-to-peak torque was significantly higher for the patients with acute lymphoblastic leukemia group when compared to controls. In the study 2, a significant improvement was observed in the submaximal strength for bench press (71%), lat pull down (50%), leg press (73%) and leg extension (64%) as a result of the training (p n - reported quality of life was not changed. No adverse effects occurred. Conclusions: We demonstrated that patients receiving maintenance treatment against ALL present lower isokinetic strength when compared with their healthy counterparts. We demonstrate that a 12-week in-hospital training program that includes high-intensity resistance exercises and moderate-intensity aerobic exercise promotes marked strength improvements in patients during the maintenance phase of the treatment for ALL without side-effects. Interestingly, the parents\' evaluations of their children revealed an improvement in the quality of life