Diss. (sammanfattning) Stockholm : Karol. inst., 2006. / Härtill 7 uppsatser.

Thesis (Ph. D.)--University of Washington, 2004. / Vita. Includes bibliographical references (leaves 92-105).

Thesis (doctoral)--University of Helsinki, 2005. / At head of title: Institute of Dentistry, Department of Pediatric and Preventive Dentistry, University of Helsinki, Finland; Hospital for Children and Adolescents, University of Helsinki, Finland. Includes bibliographical references. Also available on World Wide Web.

Thesis (Ph. D.)--University of Washington, 2005. / Vita. Includes bibliographical references (leaves 120-130).

Lysosomal storage disorders (LSDs) are caused by defective lysosomal degradation of macromolecules resulting in accumulation of substrates in various tissues. This gradually leads to organ dysfunction and the classical clinical presentation with multisystem involvement. Historically the management of LSDs was confined to symptomatic treatment only. More recently other therapies have become available. Treatment options include cellular therapy in the form of Haemopoietic Stem Cell Transplant (HSCT), Enzyme Replacement Therapy (ERT), Substrate Reduction Therapy (SRT), Chaperone Mediated Therapy (CMT) and gene therapy. Whilst HSCT and ERT are established strategies in clinical practice for some LSDs, others are still in the development phase. The easy accessibility of ERT in the developed world (despite a high cost burden of approximately £144,000 per patient per annum in the UK), fewer risks associated with its administration and good metabolic and clinical outcome, have made ERT the treatment of choice for a number of LSDs. In recent years immune response has been identified as a significant factor in attenuating or nullifying the response to ERT. Despite recognition of this problem, there is a lack of reliable diagnostic tools to test and evaluate the antibody responses in the centres delivering ERT and far too little attention has been focused on development, optimisation and standardization of immune assays. In this project, IgG ELISA and two different functional enzyme inhibition assays (catalytic inhibition and cellular uptake inhibition) were developed and optimized. The immune response to ERT was then studied in recipients of ERT in MPSI, MPSVI and Pome disease. Our practice of delivering ERT in recipients of allogeneic HSCT prior to transplant provided us with an opportunity to study the immune response in MPSIH patients during ERT and following HSCT. We demonstrated functionally active antibodies in long term recipients of ERT in MPSI and Pompe disease. Allo-immune response in MPSVI did not inhibit the delivered enzyme therapy. A high titre inhibitory immune response was detected in the majority of MPSIH patients after exposure to ERT. This immune response was abrogated by allogeneic HSCT rendering these patients tolerant to replaced enzyme, confirming HSCT as an effective immune tolerance induction mechanism.

O Transplante de Células-tronco hematopoiéticas (TCTH) alogênico é um procedimento com grande potencial de cura para uma variedade de doenças malignas e não malignas, tanto no grupo pediátrico como em pacientes adultos. O objetivo do trabalho foi descrever o perfil dos pacientes pediátricos submetidos ao TCTH alogênico no Hospital de Clínicas de Porto Alegre, assim como verificar a incidência das principais complicações e seus possíveis fatores de risco. Foi realizado um estudo de coorte retrospectivo de 100 pacientes entre 0 e 21 anos submetidos ao TCTH alogênico no HCPA entre 1995 e 2011. A mediana de idade do receptor foi 9,5 anos, sendo 55% do sexo masculino. As principais doenças de base foram as leucemias agudas (48%), onde 60,4% eram LLA, 37,5% LMA e 2,1% leucemia secundária. 73% dos transplantes foram de doadores aparentados e a medula óssea foi a principal fonte empregada (85,4%). A incidência de DECH aguda foi de 46% e de DECH crônica de 30,8%. Vinte pacientes recaíram da doença de base e 38 evoluíram para o óbito. A SG em 10 anos foi de 57% e a SLD para as leucemias agudas foi de 45%. Em análise multivariada, o doador não aparentado, o uso de TBI e a recaída da doença de base foram fatores de risco para a SG. Para a DECH crônica, o uso de outras profilaxias para DECH exceto CSA+MTX foi fator de risco. Nosso trabalho foi importante para descrever as características, principais desfechos e fatores de risco associados do TCTH no grupo pediátrico de nossa instituição. / Allogeneic hematopoietic stem cell transplantation (HSCT) is a potentially curative procedure for a variety of malignant and non-malignant diseases. The aim of this study was to describe the pediatric population submited to HSCT at Hospital de Clínicas de Porto Alegre and identify the incidence and risk factors of the main outcomes. We retrospectively reviewed 100 patients from 0 to 21 years old who underwent allogeneic HSCT between 1995 and 2011. The median age was 9,5 years and 55% were male. Acute leukemia was the most prevalent disease in this group (48%), from which 60,4% were ALL, 37,5% AML and 2,1% secondary leukemia. 73% of the transplants were from related donors and the bone marrow was the source in 85,4% of the procedures. The incidence of acute GVHD was 46% and of chronic GVHD was 30,8%. Twenty patients relapsed and 38 died. The OS at 10 years was 57% and the DFS for the group transplanted with acute leucemia was 45%. Unrelated donor, TBI and relapse were associated with a worse survival on multivariate analysis. Other GVHD prophylaxis than CSA+MTX was a risk factor for chronic GVHD on multivariate analysis. Our study was important to understand the characteristics, outcomes and risk factors for the HSCT in the pediatric group of a single institution in Brazil.

O Transplante de Células-tronco hematopoiéticas (TCTH) alogênico é um procedimento com grande potencial de cura para uma variedade de doenças malignas e não malignas, tanto no grupo pediátrico como em pacientes adultos. O objetivo do trabalho foi descrever o perfil dos pacientes pediátricos submetidos ao TCTH alogênico no Hospital de Clínicas de Porto Alegre, assim como verificar a incidência das principais complicações e seus possíveis fatores de risco. Foi realizado um estudo de coorte retrospectivo de 100 pacientes entre 0 e 21 anos submetidos ao TCTH alogênico no HCPA entre 1995 e 2011. A mediana de idade do receptor foi 9,5 anos, sendo 55% do sexo masculino. As principais doenças de base foram as leucemias agudas (48%), onde 60,4% eram LLA, 37,5% LMA e 2,1% leucemia secundária. 73% dos transplantes foram de doadores aparentados e a medula óssea foi a principal fonte empregada (85,4%). A incidência de DECH aguda foi de 46% e de DECH crônica de 30,8%. Vinte pacientes recaíram da doença de base e 38 evoluíram para o óbito. A SG em 10 anos foi de 57% e a SLD para as leucemias agudas foi de 45%. Em análise multivariada, o doador não aparentado, o uso de TBI e a recaída da doença de base foram fatores de risco para a SG. Para a DECH crônica, o uso de outras profilaxias para DECH exceto CSA+MTX foi fator de risco. Nosso trabalho foi importante para descrever as características, principais desfechos e fatores de risco associados do TCTH no grupo pediátrico de nossa instituição. / Allogeneic hematopoietic stem cell transplantation (HSCT) is a potentially curative procedure for a variety of malignant and non-malignant diseases. The aim of this study was to describe the pediatric population submited to HSCT at Hospital de Clínicas de Porto Alegre and identify the incidence and risk factors of the main outcomes. We retrospectively reviewed 100 patients from 0 to 21 years old who underwent allogeneic HSCT between 1995 and 2011. The median age was 9,5 years and 55% were male. Acute leukemia was the most prevalent disease in this group (48%), from which 60,4% were ALL, 37,5% AML and 2,1% secondary leukemia. 73% of the transplants were from related donors and the bone marrow was the source in 85,4% of the procedures. The incidence of acute GVHD was 46% and of chronic GVHD was 30,8%. Twenty patients relapsed and 38 died. The OS at 10 years was 57% and the DFS for the group transplanted with acute leucemia was 45%. Unrelated donor, TBI and relapse were associated with a worse survival on multivariate analysis. Other GVHD prophylaxis than CSA+MTX was a risk factor for chronic GVHD on multivariate analysis. Our study was important to understand the characteristics, outcomes and risk factors for the HSCT in the pediatric group of a single institution in Brazil.

O Transplante de Células-tronco hematopoiéticas (TCTH) alogênico é um procedimento com grande potencial de cura para uma variedade de doenças malignas e não malignas, tanto no grupo pediátrico como em pacientes adultos. O objetivo do trabalho foi descrever o perfil dos pacientes pediátricos submetidos ao TCTH alogênico no Hospital de Clínicas de Porto Alegre, assim como verificar a incidência das principais complicações e seus possíveis fatores de risco. Foi realizado um estudo de coorte retrospectivo de 100 pacientes entre 0 e 21 anos submetidos ao TCTH alogênico no HCPA entre 1995 e 2011. A mediana de idade do receptor foi 9,5 anos, sendo 55% do sexo masculino. As principais doenças de base foram as leucemias agudas (48%), onde 60,4% eram LLA, 37,5% LMA e 2,1% leucemia secundária. 73% dos transplantes foram de doadores aparentados e a medula óssea foi a principal fonte empregada (85,4%). A incidência de DECH aguda foi de 46% e de DECH crônica de 30,8%. Vinte pacientes recaíram da doença de base e 38 evoluíram para o óbito. A SG em 10 anos foi de 57% e a SLD para as leucemias agudas foi de 45%. Em análise multivariada, o doador não aparentado, o uso de TBI e a recaída da doença de base foram fatores de risco para a SG. Para a DECH crônica, o uso de outras profilaxias para DECH exceto CSA+MTX foi fator de risco. Nosso trabalho foi importante para descrever as características, principais desfechos e fatores de risco associados do TCTH no grupo pediátrico de nossa instituição. / Allogeneic hematopoietic stem cell transplantation (HSCT) is a potentially curative procedure for a variety of malignant and non-malignant diseases. The aim of this study was to describe the pediatric population submited to HSCT at Hospital de Clínicas de Porto Alegre and identify the incidence and risk factors of the main outcomes. We retrospectively reviewed 100 patients from 0 to 21 years old who underwent allogeneic HSCT between 1995 and 2011. The median age was 9,5 years and 55% were male. Acute leukemia was the most prevalent disease in this group (48%), from which 60,4% were ALL, 37,5% AML and 2,1% secondary leukemia. 73% of the transplants were from related donors and the bone marrow was the source in 85,4% of the procedures. The incidence of acute GVHD was 46% and of chronic GVHD was 30,8%. Twenty patients relapsed and 38 died. The OS at 10 years was 57% and the DFS for the group transplanted with acute leucemia was 45%. Unrelated donor, TBI and relapse were associated with a worse survival on multivariate analysis. Other GVHD prophylaxis than CSA+MTX was a risk factor for chronic GVHD on multivariate analysis. Our study was important to understand the characteristics, outcomes and risk factors for the HSCT in the pediatric group of a single institution in Brazil.

Class of 2014 Abstract / Specific Aims: Busulfan is a chemotherapy used in conditioning regimens for hematopoeitic stem cell transplant (HSCT) that requires therapeutic drug monitoring (TDM) to reduce ther risk of adverse effects. Variable oral absorption and several studies demonstrating decreased toxicity with the intravenous formulation have led to IV preference despite the lower acquisition cost of oral busulfan. However, these studies failed to consider therapeutic drug monitoring and their results may therefore be flawed. The objective of this retrospective chart review was to determine the adverse effect, outcome profile, and cost-effectiveness of IV versus PO busulfan at a single medical center under TDM. Methods: This quality improvement project was a retrospective cohort analysis using patient data from a single large academic medical center from January 2007 to April 2013. Patients were included if they were 18 years or older and had undergone HSCT using either IV or PO busulfan using standard dosing regimens. This data was then used to design a cost-effectiveness model in order to determine if IV or PO busulfan is cost effective. Main Results: There were 68 subjects receiving autologous transplants and 37 subjects receiving allogeneic transplants that received busulfan as part of their pretreatment therapy and were included in this study. Allogeneic and autologous transplant populations were analyzed separately. In both populations there was no difference in occurrence of pulmonary toxicity, HVOD, or mucositis between the IV or PO groups. IV busulfan was significantly associated with an increased need for patient controlled analgesia in both autologous and allogeneic populations (p=0.038 and 0.028 respectively). Total cost of PO therapy was $30,081 and $30,047 less than IV for autologous and allogeneic transplants, respectively. PO therapy also represented a cost savings of $41 and $57 dollars for autologous and allogeneic transplants, respectively. This was confirmed through bootstrapping technique, which found PO to be dominant to IV busulfan. Conclusion: In conclusion, this study finds PO busulfan to be a therapeutically equivalent and cost saving option as part of a pretreatment regimen for both autologous and allogeneic hematopoietic stem cell transplants when therapeutic drug monitoring is performed.

Background: Fanconi anaemia (FA) is a rare genetic disorder associated with bone marrow failure (BMF), congenital anomalies and cancer susceptibility. Stem cell transplantation (SCT) offers a potential cure for BMF or leukaemia, but incurs substantial risks. Little is known about factors influencing SCT decision making. Objective: The study objective was to explore factors influencing patients' with FA and family members' decision making about SCT. Design: Using a mixed-methods exploratory design, we surveyed US and Canadian patients with FA and family members who were offered SCT. Main variables studied: Closed-ended survey items measured respondents' beliefs about the necessity, risks and concerns regarding SCT; multivariable logistic regression was used to examine the association between these factors and the decision to undergo SCT. Open-ended survey items measured respondents' perceptions of factors important to the SCT decision; qualitative analysis was used to identify emergent themes. Results: The decision to undergo SCT was significantly associated with greater perceived necessity (OR = 2.81, P = 0.004) and lower concern about harms of SCT (OR = 0.31, P = 0.03). Qualitative analysis revealed a perceived lack of choice among respondents regarding the use of SCT, which was related to physician influence and respondent concerns about patients' quality of life. Conclusions: Overall, study results emphasize the importance of the delicate interplay between provider recommendation of a medical procedure and patient/parental perceptions and decision making. Findings can help providers understand the need to acknowledge family members' perceptions of SCT decision making and offer a comprehensive discussion of the necessity, risks, benefits and potential outcomes.