Made available in DSpace on 2014-06-11T19:31:05Z (GMT). No. of bitstreams: 0 Previous issue date: 2008-08-13Bitstream added on 2014-06-13T21:02:08Z : No. of bitstreams: 1 behling_eb_dr_arafcf.pdf: 524574 bytes, checksum: 4282566c71831604413ca31e88390247 (MD5) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / Universidade Estadual Paulista (UNESP) / As crianças com câncer necessitam manter o crescimento linear e o ganho de peso para uma melhor evolução clínica. Assim, o tratamento da criança com câncer deve garantir não só sua sobrevivência, mas proporcionar crescimento e desenvolvimento adequados. A avaliação nutricional é utilizada para reconhecer o paciente com maior facilidade de desenvolver a má nutrição garantindo assim um planejamento nutricional adequado. O objetivo do presente estudo foi avaliar o estado nutricional de crianças antes, durante e após o tratamento quimioterápico. Foram avaliadas 14 crianças com câncer, com idade entre 5 a 15 anos, divididas em dois grupos: Grupo Tumores Sólidos e Grupo Tumores Hematológicos. Estas foram avaliadas através dos dados de ingestão alimentar, antropometria, análise por Impedância Bioelétrica (BIA) e por Diluição Isotópica. Os resultados encontrados demonstram que os pacientes apresentaram um aumento de peso, estatura, índice de massa corporal, circunferência do quadril, da cintura e do braço, da prega cutânea subescapular, assim como o aumento da massa gorda pela técnica de diluição isotópica durante o tratamento quimioterápico, no Grupo Tumores Hematológicos. No Grupo Tumores Sólidos as crianças apresentaram uma diminuição da massa magra, quando analisado pela impedância bioelétrica. Houve uma correlação positiva entre a prega cutânea tricipital e a massa gorda obtida através da BIA e pela Diluição Isotópica. A circunferência muscular do braço também se correlacionou com a massa magra estimada pela BIA e pela Diluição Isotópica. Não houve mudança na ingestão energética e de macronutrientes nos três momentos da pesquisa. Esses resultados demonstram que os pacientes com tumores hematológicos apresentaram aumento de peso, estatura e de massa gorda, fato este não ocorrido no Grupo Tumores Sólidos. / Children with cancer need to maintain growth and weight gain to a better clinic evolution. So, the treatment of children with cancer must not only guarantee the survival but also adequate growth and development. The nutritional assessment is useful to recognize the patient who is more accessible to develop malnutrition leading to an adequate nutritional plan. The aim of this study was to assess the nutritional status in children before, during and after chemotherapy treatment. In this study, 14 children with cancer were evaluated ranging from 5-15 years old devided into two groups: Hematologic Tumor Group and Solid Tumor Group. They were evaluated through dietary intake, anthropometry, bioimpedance analysis (BIA) and isotopic dilution. The results show that the patients increase weight, stature, body mass index, hip, waist and arm circumferences, subscapular skinfold thickness, as well as an increase in fat-mass with isotopic dilution technique during the chemotherapy treatment, in the Hematologic Tumors Group. In the Solid Tumor Group the children showed a reduction in fat free mass when assessed by bioelectric impedance. There was a positive correlation between triceps skinfold thickness and fat-mass with BIA and Isotopic Dilution technique. The arm muscle circumference correlated with the fatfree- mass estimated by the BIA and Isotopic Dilution. There was no change in energetic intake and macronutrients at the three moments of the research. These results demonstrate that patients with hematologic tumors had an increase in body weight, stature and fat-mass, which was not observed in Solid Tumors Group. The good correlation between anthropometry and isotopic dilution technique and BIA show its applicability in clinical practice.

Aminoglycoside antibacterial agents, such as amikacin, continue to play an important role in the treatment of Gram-negative infections. However, although extremely effective, they are not without potential adverse events, the most important of which being nephro- and ototoxicity. Research into factors thought to influence both the efficacy and toxicity, has challenged the rationale upon which these agents have classically been dosed. Various studies in adult patients have found that a new approach to dosing (use of single daily administration) has equal or greater efficacy or safety compared to the standard multiple daily dosing of these agents. Similar studies comparing regimens in children are few, and as yet no comparative investigation has been performed using amikacin in children (as a separate and distinct group). Additionally, in evaluating the impact of altering dose regimens, it is imperative that the documented age-related aminoglycoside pharmacokinetic alterations, be taken into account. Amikacin pharmacokinetic parameters (determined using traditional methods) have been previously published for various (usually small) groups of children. However, population parameters are not currently available for South African children . This study therefore aimed to investigate optimal amikacin dosing in children by studying: a) the comparative efficacy and toxicity of two dosing regimens, and b) the population pharmacokinetic parameters derived using one of the alternative approaches capable of utilising routine, sparse serum drug concentration time data. This investigation was conducted in the paediatric surgical and burns wards of King Edward VIII Hospital , Durban. Study patients (0.6-12 years) received amikacin either once daily (15mg/kg) or twice daily (7.5 mg/kg) by slow intravenous bolus. Concomitant medication was given as prescribed. Regimen efficacy (favourable, unfavourable or indeterminate outcome) was assessed by patient temperatures, clinical improvement and white cell counts. Clinical nephrotoxicity was evaluated by changes in serum creatinine, and renal tubular damage (investigated in a small subgroup of patients) was indicated by detection of urinary low molecular weight proteins. Ototoxicity (cochleotoxicity) was assessed by pure tone audiometry. Pertinent demographic and treatment details (amikacin concentration time data) were recorded for the population pharmacokinetic analysis. The Nonlinear Mixed Effects Model (NONMEM) programme was used to derive appropriate models describing clearance (CL) and volume of distribution (V), as well as mean values of these pharmacokinetic parameters for this population. Fifty four patients were entered into the regimen assessment. Patients in the single daily regimen (n=27) had significantly greater (p<0.05) mean (SO) peak (±0.5 hour post-dose) serum amikacin levels (37.7 (6.9) mg/L) as well as cumulative dose (91.5 (26.5) mg/kg) and duration of therapy (5.7 (1 .5) days) when compared with those of the twice daily group (19.5 (3.7) mg/L, 70.1 (26.1) mg/kg and 4.6 (1 .6) days respectively). No statistically significant differences were found between the groups in terms of outcome (18/24 and 22/25 patients in the once and twice daily dosing groups had favourable outcomes; there were no unfavourable outcomes). Pure tone audiometry (evaluated post-therapy , in 20 patients from each dosing regimen) revealed no statistically significant differences between the number of patients in the two groups with possible drug-related ototoxicity. None of the patients assessed (including an additional 14 patients with burn injury) developed clinical nephrotoxicity. Urinalysis was performed in 17 amikacin treated patients (9 and 8 from the once and twice daily dosing regimens respectively) and 9 control subjects. Low molecular weight proteinuria was absent in all of the latter patients except one, in whom pre-existing renal disease was suspected. Tubular dysfunction ascribed to possible drug effect was detected in similar numbers of patients in the two treatment groups (3 and 2 patients in the once and twice daily dosing groups respectively). In the pharmacokinetic assessment (156 serum levels from 82 patients) using a one compartment model, the final models which best described the data were as follows : CL (Uhr) = 0.271 x age(yrs) + 2.46 x body surface areatrrr'), V (L) = 7.34 x body surface areatrn") Other fixed effects tested, which did not render the data more probable, included serum creatinine measurements at the start of treatment, gender, presence of burn injury and drug regimen. Interpatient variation was 15% and 18% for CL and V respectively, with intrapatient variation or residual error of 10%. The weight adjusted population parameter estimates (95% Confidence Interval) for this group were CL =0.180 (0.175 ,0.185) Uhr/kg and V =0.293 (0.286, 0.300) Ukg, which are within the range of values published previously for other children of similar ages. The findings of this investigation , consistent with those of other similar studies, indicate that daily amikacin administration (in combination with a B-lactam), to children with normal renal function, has similar efficacy to, and no greater toxicity than multiple daily dosing. However, the role, if any, of the significantly greater cumulative dose and duration of therapy in the daily dosing group is unknown. As uncertainty remains regarding the precise duration of certain post-exposure events (and hence, the ideal duration of the interdose interval), and with the rapid drug clearance in this group of patients , future in vitro and in vivo investigations may shed even further light on the optimal dosing approach in these patients. / Thesis (M.Med.)-University of Natal, Durban, 1996.

Neuroblastoma (NB) is the most common solid tumor of early infancy. Despite a significant improvement in the general survival rate for children with cancer, the prognosis of high-risk NB remains low, at about 30%, despite the use of intensive chemo-radiotherapy followed by differentiation therapy with retinoic acid (RA). Relapses in this category of NB are often due to the emergence of multi-drug and RA-resistant minimal residual cancer cells. The use of natural 13-cis RA, as a single chemo-preventive agent, has improved the survival rate to 50% for high-risk NB patients. However, the prevalence of RA-resistance is high in high-risk NB, and in solid cancers, in general. RA-resistance in cancer cells is mediated by a number of factors. Loss of RA-induced expression of the putative tumor suppressor gene, retinoic acid receptor-beta (RARβ), is one of the most common factors that have been reported in RAresistant phenotypes of a wide range of cancer cells. The transcriptional regulation of RAR(β) gene and other retinoid responsive-genes is believed to be regulated by the ligand-dependent transactivation of the homo- or heterodimer complexes of the retinoic acid receptor (RAR) and retinoid X receptor (RXR) subtypes, namely alpha (α), beta (β) and gamma (γ). It is believed that the anti-cancer activities of natural all-trans RA and 13-cis RA are mediated through activation of RAR-complexes. The loss of RA-induced RAR β expression can be caused by aberrant recruitment of chromatin structure modifying enzymes, histone deacetylases (HDACs), which have major roles in the global regulation of gene transcription. However, the mechanism of RA-resistance in NB cells is unclear. This thesis set out to identify the molecular mechanism of RA-resistance and to develop a new therapeutic approach to overcome RA-resistance in NB cells. The data in this thesis demonstrated that deregulation or over-expression of proto-oncogene MYCN caused a total RA-resistance in NB cells in vitro and in vivo, despite the strong induction of RARI3 expression. The data also indicated that the activation of RAR-dependent pathways by aRA or 13RA alone is not sufficient to overcome MYCN-mediated RA-resistance in NB cells. In the light of this observation, this thesis went on to examine whether combined targeting activation of RAR and RXR subtypes with receptor specific ligands could enhance the therapeutic efficacy of the retinoid signaling pathway. NB cells were treated with a panel of receptor-specific retinoids, namely aRA, l3RA, 9RA (RAR-specific), CD 417, CD 2314 (RARβ-specific), CD 666 (RARγ-specific), CD 336 (RARα-specific), CD 3640, CD 2872 (RXR-specific), as a single agent or in combination at a low concentration of 0.1 ??M. The results showed that combined targeting activation of RARα and RXR was not only the most effective combination, but also overcame MYCN-mediated RA-resistance in NB cells in vitro.Collectively, these data demonstrated the combined targeting activation of RAR and RXRs as a new approach to enhance the efficacy of retinoid therapy and overcome RA-resistance in the treatment of high-risk NB, and other cancers. The emerging therapeutic potential of HDAC inhibitors (HDACi) as front line anti-cancer agents, or adjuvants to other agents such as RA, has suggested a new approach in the treatment of cancer. However, the molecular mechanism of the remarkably specific anticancer actions of HDACi is still largely speculation. The data presented in this study was the first to demonstrate a novel sequential order and the dosage-dependent roles of basal p21Wafl expression and G2/M arrest as protective mechanisms against HDACi-induced apoptosis. In addition, this thesis also examined and compared the therapeutic efficacy of HDACi as a single agent and in combination with other anti-cancer agents such as RA, IFNα and chemotherapeutic agents. Evaluation of the therapeutic effects of combinations of aRA, IFN and HDACi showed that combination of HDACi and IFNα exhibited the strongest synergy against NB cells in vitro. Treatment of MYCN transgenic mice, which consistently develop abdominal NB tumors that closely mirror the human disease in both physiological and biological aspects, with hydroxamic acid-based HDACi, trichostatin A (TSA), alone reduced tumor growth by nearly 50%, compared to the solvent control and IFNα alone, which had no effect on NB tumor growth. The most exciting finding was that the combination of HDACi and IFNα synergistically reduced tumor mass and angiogenesis by over 80% without any apparent systemic side-effects. The therapeutic effect of treatment with HDACi correlated with the induction of acetylation of histone 4 protein (H4) in both tumor and organ tissues, indicating a wide therapeutic index for HDACi in vivo. Collectively, the data in this study have demonstrated basal p21 Wafl expression as a potential marker of sensitivity to HDACi-based therapy, and the therapeutic efficacy of a novel combination of HDACi with IFNα in vivo. These preclinical data have provided an evidence-based rationale for a clinical trial of the combination of HDACi and IFNα in the treatment of high risk NB.

Orientador: Jacqueline Pontes Monteiro / Banca: Daniela Saes Sartorelli / Banca: Carlos Alberto Scrideli / Banca: Maria Rita Marques de Oliveira / Banca: Maria Jacira Silva Simães / Resumo: As crianças com câncer necessitam manter o crescimento linear e o ganho de peso para uma melhor evolução clínica. Assim, o tratamento da criança com câncer deve garantir não só sua sobrevivência, mas proporcionar crescimento e desenvolvimento adequados. A avaliação nutricional é utilizada para reconhecer o paciente com maior facilidade de desenvolver a má nutrição garantindo assim um planejamento nutricional adequado. O objetivo do presente estudo foi avaliar o estado nutricional de crianças antes, durante e após o tratamento quimioterápico. Foram avaliadas 14 crianças com câncer, com idade entre 5 a 15 anos, divididas em dois grupos: Grupo Tumores Sólidos e Grupo Tumores Hematológicos. Estas foram avaliadas através dos dados de ingestão alimentar, antropometria, análise por Impedância Bioelétrica (BIA) e por Diluição Isotópica. Os resultados encontrados demonstram que os pacientes apresentaram um aumento de peso, estatura, índice de massa corporal, circunferência do quadril, da cintura e do braço, da prega cutânea subescapular, assim como o aumento da massa gorda pela técnica de diluição isotópica durante o tratamento quimioterápico, no Grupo Tumores Hematológicos. No Grupo Tumores Sólidos as crianças apresentaram uma diminuição da massa magra, quando analisado pela impedância bioelétrica. Houve uma correlação positiva entre a prega cutânea tricipital e a massa gorda obtida através da BIA e pela Diluição Isotópica. A circunferência muscular do braço também se correlacionou com a massa magra estimada pela BIA e pela Diluição Isotópica. Não houve mudança na ingestão energética e de macronutrientes nos três momentos da pesquisa. Esses resultados demonstram que os pacientes com tumores hematológicos apresentaram aumento de peso, estatura e de massa gorda, fato este não ocorrido no Grupo Tumores Sólidos. / Abstract: Children with cancer need to maintain growth and weight gain to a better clinic evolution. So, the treatment of children with cancer must not only guarantee the survival but also adequate growth and development. The nutritional assessment is useful to recognize the patient who is more accessible to develop malnutrition leading to an adequate nutritional plan. The aim of this study was to assess the nutritional status in children before, during and after chemotherapy treatment. In this study, 14 children with cancer were evaluated ranging from 5-15 years old devided into two groups: Hematologic Tumor Group and Solid Tumor Group. They were evaluated through dietary intake, anthropometry, bioimpedance analysis (BIA) and isotopic dilution. The results show that the patients increase weight, stature, body mass index, hip, waist and arm circumferences, subscapular skinfold thickness, as well as an increase in fat-mass with isotopic dilution technique during the chemotherapy treatment, in the Hematologic Tumors Group. In the Solid Tumor Group the children showed a reduction in fat free mass when assessed by bioelectric impedance. There was a positive correlation between triceps skinfold thickness and fat-mass with BIA and Isotopic Dilution technique. The arm muscle circumference correlated with the fatfree- mass estimated by the BIA and Isotopic Dilution. There was no change in energetic intake and macronutrients at the three moments of the research. These results demonstrate that patients with hematologic tumors had an increase in body weight, stature and fat-mass, which was not observed in Solid Tumors Group. The good correlation between anthropometry and isotopic dilution technique and BIA show its applicability in clinical practice. / Doutor

Acute lymphocytic leukemia (ALL) is one of the most common types of pediatric cancers. Improvements in treatment within the last 20 years have resulted in reduced mortality and a greater focus upon quality of life. Several researchers have documented neuropsychological impairments in children following treatment for ALL; however, there have not been any comparative studies documenting differences in neuropsychological functioning based upon treatment modality despite the documented effects of radiation therapy and combined radiation/chemotherapy upon the developing brain. In addition, past studies have focused on unitary measures, ignoring the hierarchical relationship between basic cognitive functions and more abstract skills. This study examined the neuropsychological functioning of 81 children who were treated for ALL at a metropolitan children's hospital. All children were tested a minimum of two years after the final treatment session and were administered the NEPSY. Results do not support any interactions or main effects with the exception of the age of the child at diagnosis. Children diagnosed prior to the age of 5 showed greater impairments on tasks measuring attention, memory, and visuospatial reasoning in comparison to peers diagnosed after age 6.

Thesis (Ph. D.)--University of North Texas, Aug., 2007. / Title from title page display. Includes bibliographical references.