RESUMO
Methotrexate (MTX), one of the important pillars in the treatment of different forms of cancer, is associated with the development of hepatotoxicity. The 677C>T variant (rs1801133) in the methylenetetrahydrofolate reductase (MTHFR) gene might affect the development of hepatotoxicity. Results in literature are, however, contradictive. The aim of this study was to evaluate the role of the MTHFR 677C>T polymorphism in MTX-induced hepatotoxicity by analyzing a Dutch cohort of pediatric patients treated with high doses of MTX and subsequently performing a meta-analysis. Ninety-eight patients receiving 542 courses of high-dose MTX were genotyped for the MTHFR 677C>T variant. Hepatotoxicity was evaluated retrospectively according to common terminology criteria for adverse events-National Cancer Institute criteria. The influence of MTHFR 677C>T on hepatotoxicity was examined using a generalized estimating equation (GEE) analysis. A fixed-effect meta-analysis based on this and previous studies investigating the association between the MTHFR 677C>T polymorphism and uniformly coded hepatotoxicity was performed. The GEE analysis showed an increased risk of developing hepatotoxicity for T versus C allele (odds ratio (OR) 1.8; 95% confidence interval (CI) 1.0-3.2, P=0.04). This finding was not supported by the meta-analysis including seven studies and 1044 patients; the OR for the 677T versus C allele was 1.1 (95% CI 0.84-1.5, P=0.25). Heterogeneity between studies was observed, possibly related to differences in MTX dose and leucovorin rescue. In conclusion, in patients with cancer, the MTHFR 677T allele has only a minor role in the development of MTX-induced hepatotoxicity. Observed heterogeneity between studies warrants further study into (tailored) leucovorin rescue.
Assuntos
Doença Hepática Induzida por Substâncias e Drogas/genética , Metotrexato/efeitos adversos , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Doença Hepática Induzida por Substâncias e Drogas/patologia , Criança , Feminino , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Masculino , Metotrexato/administração & dosagem , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Several studies in adults have shown patient reported outcomes (PROs) to be effective in enhancing patient-physician communication and discussion of Health Related Quality of Life outcomes. Although less studied, positive results have been demonstrated in children. A PRO-intervention needs to be feasible in clinical practice to be successful. In the current study, 74 parents of children who successfully completed their cancer treatment and 21 pediatric oncologists (POs) evaluated a PRO-intervention and gave recommendations for future use in their practice. Most parents and POs suggested PROs to be an important part of standard care, starting during treatment, with an assessment frequency of every 3 months.
Assuntos
Oncologia , Pais/psicologia , Avaliação de Resultados da Assistência ao Paciente , Médicos/psicologia , Padrões de Prática Médica , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Lactente , Recém-Nascido , Masculino , Assistência ao Paciente , Prognóstico , Qualidade de VidaRESUMO
BACKGROUND: We report on the treatment of children and adolescents with acute lymphoblastic leukemia (ALL) in first relapse. The protocol focused on: (1) Intensive chemotherapy preceding allogeneic stem cell transplantation (SCT) in early bone marrow relapse; (2) Rotational chemotherapy in late relapse, without donor; (3) Postponement of cerebro-spinal irradiation in late isolated CNS relapse; and (4) Treatment in very late bone marrow relapse with chemotherapy only. METHODS: From January 1999 until July 2006 all 158 Dutch pediatric patients with ALL in first relapse were recorded. Ninety-nine patients were eligible; 54 patients with early and 45 with late relapse. Eighteen patients had an isolated extra-medullary relapse; 69 patients had bone marrow involvement only. RESULTS: Five-years EFS rates for early and late relapses were 12% and 35%, respectively. For early relapses 5 years EFSs were 25% for patients transplanted; 0% for non-transplanted patients. For late relapses 5 years EFS was 64% for patients treated with chemotherapy only, and 16% for transplanted patients. For very late relapses EFS was 58%. CONCLUSIONS: Our data suggest the superiority of SCT for early relapse patients. For late relapses a better outcome is achieved with chemotherapy only using the rotational chemotherapy scheme. The most important factor for survival was interval between first CR and occurrence of the first relapse.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Transplante de Células-Tronco , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Medula Óssea/terapia , Neoplasias do Sistema Nervoso Central/terapia , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Humanos , Lactente , Masculino , Análise Multivariada , Países Baixos , Leucemia-Linfoma Linfoblástico de Células Precursoras/radioterapia , Modelos de Riscos Proporcionais , Recidiva , Indução de Remissão , Análise de Sobrevida , Neoplasias Testiculares/terapiaRESUMO
The potential role of antibodies and T lymphocytes in the eradication of cancer has been demonstrated in numerous animal models and clinical trials. In the last decennia new strategies have been developed for the use of tumor-specific T cells and antibodies in cancer therapy. Effective anti-tumor immunotherapy requires the identification of suitable target antigens. The expression of tumor-specific antigens has been extensively studied for most types of adult tumors. Pediatric patients should be excellent candidates for immunotherapy since their immune system is more potent and flexible as compared to that of adults. So far, these patients do not benefit enough from the progresses in cancer immunotherapy, and one of the reasons is the paucity of tumor-specific antigens identified on pediatric tumors. In this review we discuss the current status of cancer immunotherapy in children, focusing on the identification of tumor-specific antigens on pediatric solid tumors.
Assuntos
Imunoterapia Ativa , Neoplasias/terapia , Antígenos de Neoplasias/imunologia , Criança , Ensaios Clínicos como Assunto , Humanos , Neoplasias/imunologiaRESUMO
The twitcher mouse is an animal model of galactosylceramidase deficiency, comparable to Krabbe's disease, a lysosomal storage disease in humans. As in most lysosomal storage diseases, neurological deterioration is a prominent feature of the disease in these mice. Transplantation of enzymatically normal congenic bone marrow was earlier found to result in prolonged survival and increased levels of galactosylceramidase in the visceral organs of twitcher mice. It is now reported that bone marrow transplantation results in increased galactosylceramidase levels in the central nervous system (CNS). Concomitantly, the levels of psychosine, a highly toxic lipid that progressively accumulates in the CNS of untreated twitcher mice, stabilized at much lower levels in the CNS of treated twitcher mice. Histologically, a gradual disappearance of globoid cells, the histological hallmark of Krabbe's disease, and the appearance of foamy macrophages capable of metabolizing the storage product were seen in the CNS. By immunohistochemical labeling it was demonstrated that these foamy macrophages were of donor origin. The infiltration of enzymatically competent, donor-derived macrophages was accompanied by extensive remyelination in the CNS. It is concluded that after bone marrow transplantation, donor-derived macrophages infiltrate the affected brain tissue and are capable of inducing a partial reversal of the enzyme deficiency.
Assuntos
Transplante de Medula Óssea , Encéfalo/enzimologia , Galactosidases/deficiência , Galactosilceramidase/deficiência , Macrófagos/transplante , Medula Espinal/enzimologia , Animais , Medula Óssea/enzimologia , Medula Óssea/imunologia , Encéfalo/patologia , Cerebelo/patologia , Galactosilceramidase/metabolismo , Antígenos H-2/análise , Imuno-Histoquímica , Leucodistrofia de Células Globoides/enzimologia , Leucodistrofia de Células Globoides/patologia , Leucodistrofia de Células Globoides/terapia , Macrófagos/enzimologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes Neurológicos , Microscopia Eletrônica , Bainha de Mielina/patologia , Psicosina/metabolismo , Medula Espinal/patologiaRESUMO
Gross cytogenetic anomalies are traditionally being used as diagnostic, prognostic and therapeutic markers in the clinical management of cancer, including childhood acute lymphoblastic leukemia (ALL). Recently, it has become increasingly clear that genetic lesions driving tumorigenesis frequently occur at the submicroscopic level and, consequently, escape standard cytogenetic observations. Therefore, we profiled the genomes of 40 childhood ALLs at high resolution. We detected multiple de novo genetic lesions, including gross aneuploidies and segmental gains and losses, some of which were subtle and affected single genes. Many of these lesions involved recurrent (partially) overlapping deletions and duplications, containing various established leukemia-associated genes, such as ETV6, RUNX1 and MLL. Importantly, the most frequently affected genes were those controlling G1/S cell cycle progression (e.g. CDKN2A, CDKN1B and RB1), followed by genes associated with B-cell development. The latter group includes microdeletions of the B-lineage transcription factors PAX5, EBF, E2-2 and IKZF1 (Ikaros), as well as genes with other established roles in B-cell development, that is RAG1 and RAG2, FYN, PBEF1 or CBP/PAG. The fact that we frequently encountered multiple lesions affecting genes involved in cell cycle regulation and B-cell differentiation strongly suggests that both these processes need to be targeted independently and simultaneously to trigger ALL development.
Assuntos
Ciclo Celular/genética , Diferenciação Celular/genética , Genes Neoplásicos , Linfócitos/citologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Linfócitos B/citologia , Aberrações Cromossômicas , Feminino , Dosagem de Genes , Perfilação da Expressão Gênica/métodos , Genômica/métodos , Humanos , Masculino , Hibridização de Ácido Nucleico , Leucemia-Linfoma Linfoblástico de Células Precursoras/etiologia , Fatores de TranscriçãoRESUMO
The effect of allogeneic bone marrow transplantation (BMT) was investigated in the neurologically affected twitcher mouse, a model for human Krabbe's disease. Twitcher mice have a hereditary deficiency of the lysosomal enzyme galactosylceramidase, which causes growth delay, tremor, and paralysis of the hind legs. Death occurs at 30-40 d of age. After BMT galactosylceramidase activity increased to donor levels in hemopoietic organs. In lung, heart, and liver, galactosylceramidase activity rose to levels intermediate between those of twitcher and normal mice. Increased galactosylceramidase activity in liver parenchymal cells indicated uptake of the donor enzyme by recipient cells of nonhemopoietic origin. Enzyme activity also increased in kidney tissue. BMT resulted in a gradual increase in galactosylceramidase activity in the central nervous system to 15% of normal donor levels. A 5-6-fold increase in galactosylceramidase activity was found in the peripheral nervous system. This increase in enzyme activity was accompanied by a partial alleviation of neurological symptoms. In particular, paralysis of the hind legs was prevented by BMT. BMT led to a modest restoration of growth and prolonged survival. In several cases, the mice survived for more than 100 d, but eventually all animals died with severe neurological disease.
Assuntos
Transplante de Medula Óssea , Galactosidases/deficiência , Galactosilceramidase/deficiência , Leucodistrofia de Células Globoides/enzimologia , Animais , Medula Óssea/enzimologia , Sistema Nervoso Central/enzimologia , Modelos Animais de Doenças , Feminino , Galactosilceramidase/biossíntese , Rim/enzimologia , Leucodistrofia de Células Globoides/terapia , Fígado/enzimologia , Pulmão/enzimologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes Neurológicos , Miocárdio/enzimologia , Baço/enzimologiaRESUMO
The contribution of genetic predisposing factors to the development of pediatric acute lymphoblastic leukemia (ALL), the most frequently diagnosed cancer in childhood, has not been fully elucidated. Children presenting with multiple de novo leukemias are more likely to suffer from genetic predisposition. Here, we selected five of these patients and analyzed the mutational spectrum of normal and malignant tissues. In two patients, we identified germline mutations in TYK2, a member of the JAK tyrosine kinase family. These mutations were located in two adjacent codons of the pseudokinase domain (p.Pro760Leu and p.Gly761Val). In silico modeling revealed that both mutations affect the conformation of this autoregulatory domain. Consistent with this notion, both germline mutations promote TYK2 autophosphorylation and activate downstream STAT family members, which could be blocked with the JAK kinase inhibitor I. These data indicate that germline activating TYK2 mutations predispose to the development of ALL.
Assuntos
Mutação em Linhagem Germinativa , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , TYK2 Quinase/genética , Alelos , Substituição de Aminoácidos , Exoma , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Modelos Moleculares , Fosforilação , Polimorfismo de Nucleotídeo Único , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Ligação Proteica , Conformação Proteica , Domínios e Motivos de Interação entre Proteínas , Fatores de Transcrição STAT/metabolismo , TYK2 Quinase/química , TYK2 Quinase/metabolismoRESUMO
Deletions in IKZF1 are found in ~15% of children with B-cell precursor acute lymphoblastic leukemia (BCP-ALL). There is strong evidence for the poor prognosis of IKZF1 deletions affecting exons 4-7 and exons 1-8, but evidence for the remaining 33% of cases harboring other variants of IKZF1 deletions is lacking. In an international multicenter study we analyzed the prognostic value of these rare variants in a case-control design. Each IKZF1-deleted case was matched to three IKZF1 wild-type controls based on cytogenetic subtype, treatment protocol, risk stratification arm, white blood cell count and age. Hazard ratios for the prognostic impact of rare IKZF1 deletions on event-free survival were calculated by matched pair Cox regression. Matched pair analysis for all 134 cases with rare IKZF1 deletions together revealed a poor prognosis (P<0.001) that was evident in each risk stratification arm. Rare variant types with the most unfavorable event-free survival were DEL 2-7 (P=0.03), DEL 2-8 (P=0.002) and DEL-Other (P<0.001). The prognosis of each type of rare variant was equal or worse compared with the well-known major DEL 4-7 and DEL 1-8 IKZF1 deletion variants. We therefore conclude that all variants of rare IKZF1 deletions are associated with an unfavorable prognosis in pediatric BCP-ALL.
Assuntos
Deleção de Genes , Fator de Transcrição Ikaros/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Adolescente , Adulto , Criança , Pré-Escolar , Subunidade alfa 2 de Fator de Ligação ao Core/análise , Humanos , Lactente , Cooperação Internacional , Proteínas de Fusão Oncogênica/análise , Leucemia-Linfoma Linfoblástico de Células Precursoras B/mortalidade , Prognóstico , Modelos de Riscos ProporcionaisRESUMO
Many patients do not reach haematopoietic stem cell transplantation. Shortage of unrelated donors (UDs) is still seen as the main cause. However, with a worldwide UD pool containing more than 8 million donors, it is possible that other impediments are becoming more important. We analysed 549 UD searches for Dutch patients, performed between 1987 and 2000, in order to find the reasons for failure or success to reach transplantation. Between 1996 and 2000, 59% of the patients of Northwest European origin received a graft from an UD with a median time span of 4.4 months from the start of the search. In all, 11% of the patients lacked a compatible donor, while 30% became medically unfit for transplantation. This is in contrast to the patients of non-Northwest European origin for whom UD shortage is still the most important impediment; only 32% were transplanted while 50% lacked a compatible donor. We conclude that the shortage of donors is no longer the biggest constraint in unrelated stem cell transplantation for patients of Northwest European origin. It may be more effective to optimize the chance on transplantation by making the search process more efficient.
Assuntos
Transplante de Células-Tronco Hematopoéticas/estatística & dados numéricos , Sistema de Registros , Doadores de Tecidos/provisão & distribuição , Coleta de Dados , Histocompatibilidade , Humanos , Países Baixos , Fatores de TempoRESUMO
A 13-year-old girl with acute lymphoblastic leukemia (ALL) developed extremely high plasma triglyceride (TG) concentrations of 103 mmol/l (reference value <1.8 mmol/l) during combination treatment with corticosteroids and asparaginase. Corticosteroids are known to induce the production of TG-rich particles. On the other hand, corticosteroids increase the activity of lipoprotein lipase (LPL), a key enzyme in the removal of TG from plasma. Generally, the increased LPL activity prevents an extreme rise in TG levels upon therapy with corticosteroids. In our patient, we found that the corticosteroid-induced LPL activity dramatically declined after therapy with L-asparaginase. This suggests that the extensive hypertriglyceridemia in our patient was due to an L-asparaginase-induced decrease in LPL activity. This hypothesis was further supported by the finding that hypertriglyceridemia was less severe when corticosteroids and asparaginase were given separately.
Assuntos
Asparaginase/efeitos adversos , Hiperlipidemias/induzido quimicamente , Lipase Lipoproteica/sangue , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Adolescente , Asparaginase/uso terapêutico , Feminino , Humanos , Lipase Lipoproteica/antagonistas & inibidores , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Triglicerídeos/metabolismoRESUMO
The biological properties of a transplantable lymphocytic leukemia, L4415 in the WAG/Rij rat, are described. The radiation-induced L4415 leukemia is characterized as a relatively slowly growing, non-immunogenic, immature T-cell leukemia which shows a reproducible growth pattern upon intravenous (i.v.) transfer. Survival time following i.v. inoculation is inversely related to the number of leukemic cells in the inoculum, which allows a quantitative estimate in terms of log leukemic cell kill of the effect of treatment. The first signs of leukemic growth are found in the bone marrow, the spleen, and the liver. Leukemic cells can be detected in the peripheral blood 13 days after inoculation. Due to replacement of normal hemopoietic tissue by leukemic cells and their number increasing exponentially thereafter, normal hemopoiesis is inhibited in the later stages of the disease as indicated by severe thrombocytopenia and anemia. Death is caused by a combination of splenic rupture, gastrointestinal and pulmonary hemorrhage, and impaired functions of heavily infiltrated organs. Hepatosplenomegaly and lymphadenopathy are prominent features at autopsy. Cyclophosphamide- and radiosensitivity of the clonogenic leukemic cells have been determined, a 2.9 log cell kill could be induced by single dose cyclophosphamide inoculation and a dosage giving a surviving fraction of 0.37 (D0) of 0.99 Gy with an extrapolation number (N) of 8.5 were calculated. Based on these data, the L4415 rat leukemia may be regarded as a relevant model for human acute lymphocytic leukemia and may thus serve to explore new treatment strategies.
Assuntos
Modelos Animais de Doenças , Leucemia-Linfoma Linfoblástico de Células Precursoras/fisiopatologia , Animais , Antígenos CD/análise , Antígenos de Superfície/análise , Fígado/patologia , Tamanho do Órgão , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Ratos , Ratos Endogâmicos , Baço/patologia , Análise de SobrevidaRESUMO
Transfer of a herpes simplex virus-derived thymidine kinase (HSV-tk) gene into brain tumor cells and subsequent ganciclovir (GCV) treatment has been shown by others to be an effective treatment in rats with intracerebrally inoculated 9L gliosarcomas. Mechanism of action and reproducibility are, however, still a matter of debate. We have used the same model to test the therapeutic effects of both retrovirus- and adenovirus-mediated transfer of the HSV-tk gene followed by GCV treatment. Survival time of rats with intracerebral 9L tumors was significantly prolonged after a single administration of adenovirus carrying a HSV-tk gene as compared to controls. Retrovirus-mediated gene transfer also resulted in significantly prolonged survival time when recombinant retrovirus-producing cells were transplanted. Direct injection of the recombinant retrovirus, HSV-tk-expressing cells, virus-producing cells without GCV administration and recombinant retrovirus-lacZ or interleukin-2 (IL-2)-producing cells did not result in tumor cell kill. In the present study, no significant difference in survival of 9L brain tumor carrying rats was found after treatment with adenovirus as compared to retrovirus-mediated HSV-tk-mediated gene transfer and subsequent GCV treatment.
Assuntos
Neoplasias Encefálicas/terapia , Técnicas de Transferência de Genes , Terapia Genética/métodos , Gliossarcoma/terapia , Timidina Quinase/genética , Adenovírus Humanos/genética , Animais , Antivirais/uso terapêutico , Sequência de Bases , Ganciclovir/uso terapêutico , Vetores Genéticos/genética , Glioma , Humanos , Interleucina-2/biossíntese , Interleucina-2/genética , Dados de Sequência Molecular , Ratos , Ratos Wistar , Proteínas Recombinantes de Fusão/biossíntese , Retroviridae/genética , Simplexvirus/enzimologia , Células Tumorais Cultivadas/transplante , beta-Galactosidase/biossíntese , beta-Galactosidase/genéticaRESUMO
Apolipoprotein E (apoE), a high affinity ligand for lipoprotein receptors, is synthesized by the liver and extrahepatic tissues, including cells of the monocyte/macrophage cell lineage. The role of monocyte/macrophage-derived apoE in atherogenesis was assessed by transplantation of apoE-deficient (apoE-/-) bone marrow into normolipidemic C57Bl/6 mice. No significant effect could be demonstrated on serum apoE levels in C57Bl/6 mice, transplanted with apoE-deficient bone marrow compared with control transplanted mice. Furthermore, no consistent effect on serum cholesteryl esters and triglyceride concentrations could be demonstrated on either a standard chow diet or a high cholesterol diet. Quantitative analysis of atherosclerosis in mice transplanted with apoE-deficient bone marrow, after two months on a high cholesterol diet, revealed a 4-fold increase in the atherosclerotic lesion area as compared to animals transplanted with apoE+/+ bone marrow. Analysis of the ability of apoE-deficient macrophages to release cholesterol after loading with acetylated LDL revealed that the release of cholesterol from apoE-deficient macrophages was impaired as compared to wild-type macrophages in the absence and the presence of specific cholesterol acceptors. In conclusion, apoE production by macrophages retards the formation of atherosclerotic plaques, possibly by mediating cholesterol efflux. We anticipate that pharmacological approaches to increase apoE synthesis and/or secretion by macrophages might be beneficial for the treatment of atherosclerosis.
Assuntos
Apolipoproteínas E/deficiência , Arteriosclerose/metabolismo , Transplante de Medula Óssea , Macrófagos/metabolismo , Animais , Aorta/metabolismo , Aorta/patologia , Apolipoproteínas E/metabolismo , Arteriosclerose/etiologia , Arteriosclerose/patologia , Colesterol/sangue , Ésteres do Colesterol/sangue , Colesterol na Dieta/administração & dosagem , Feminino , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Quimeras de Transplante , Triglicerídeos/sangueRESUMO
The correction of lysosomal enzyme deficiency was investigated for various organs of beta-glucuronidase-deficient C3H/Rij mice after allogeneic bone marrow transplantation from an enzymatically normal donor strain (C57BL/Rij). In the hemopoietic organs, the enzyme level increased to levels found in donor mice. In lung, kidney, liver, and peripheral nervous tissue, a significant increase in enzyme activity was seen to levels intermediate between those of donor and recipient. Increased enzyme activity was maintained throughout the observation period of 150 days. In skeletal muscle tissue, enzyme levels tended to be higher in recipient mice, but this increase was not significant for all data points. Bone marrow transplantation failed to significantly affect enzyme activity in central nervous system tissue. These data suggest that beneficial effects expected from bone marrow transplantation for lysosomal enzyme deficiencies depend on the type of tissue involved in the disease. In diseases severely affecting the central nervous system, cure may not be expected from bone marrow transplantation alone, whereas in diseases with only minimal central nervous system involvement, alleviation or prevention of clinical symptoms may occur.
Assuntos
Transplante de Medula Óssea , Glucuronidase/deficiência , Lisossomos/enzimologia , Animais , Feminino , Erros Inatos do Metabolismo/enzimologia , Camundongos , Camundongos Endogâmicos , Distribuição Tecidual , Transplante Homólogo , beta-Galactosidase/metabolismo , beta-N-Acetil-Hexosaminidases/metabolismoRESUMO
With respect to human leukemia, scarce data exist suggesting a difference in the leptomeningeal infiltration pattern between acute myelocytic leukemia (AML) and acute lymphocytic leukemia (ALL). In the present paper, the growth pattern of intrathecally inoculated AML and ALL in rat models is studied. It was observed that the leptomeningeal infiltration in ALL is more pronounced than in AML. In AML, no infiltration of the pia mater, ventricles or Virchow-Robin spaces were seen, in contrast to ALL, where these structures were infiltrated frequently. Both models were mimicking the pattern of leptomeningeal infiltration observed in the respective human leukemias. These animal models provide reproducible systems in which the determinants of metastatic capacity and their therapeutic implications for ALL and AML can be studied.
Assuntos
Sistema Nervoso Central/patologia , Leucemia Linfoide/patologia , Leucemia Mieloide Aguda/patologia , Meninges/patologia , Animais , Modelos Animais de Doenças , Feminino , Humanos , Invasividade Neoplásica , Metástase Neoplásica , Ratos , Ratos Endogâmicos BNRESUMO
Allogeneic bone marrow transplantation with marrow from HLA-identical donors has been used with increasing frequency to treat patients with lysosomal storage diseases. The effects of bone marrow transplantation largely depend on the type and stage of the disease. Generally, 'visceral symptoms' can be largely improved by transplantation, but skeletal lesions are relatively unaffected by transplantation. The effect on neurological symptoms varies.
Assuntos
Transplante de Medula Óssea , Terapia Genética , Doenças por Armazenamento dos Lisossomos/terapia , HumanosRESUMO
We report a very rapid engraftment after reinfusion of bone marrow cells derived from 'G-CSF-primed bone marrow' in a small child. As the hemopoietic recovery was equal to that seen after PBSCT, we suggest that the use of 'mobilized bone marrow' is a good alternative for PBSCT in children if contraindications to the collection of PBSCT are present.
Assuntos
Transplante de Medula Óssea , Fibrossarcoma/terapia , Doenças do Pé/patologia , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Neoplasias de Tecidos Moles/terapia , Fibrossarcoma/patologia , Mobilização de Células-Tronco Hematopoéticas , Humanos , Lactente , Masculino , Metástase Neoplásica , Neoplasias de Tecidos Moles/patologia , Transplante AutólogoRESUMO
In a retrospective study, the results of maintenance chemotherapy and allogeneic bone marrow transplantation (BMT) for children who reached a second complete remission (CR2) of their acute lymphoblastic leukemia (ALL) were compared. Case-control analysis was performed comparing 25 allogeneic transplant patients (cases) with 97 patients treated with maintenance chemotherapy (controls), who were matched for site of relapse, duration of CR1 and leukemia-free interval from onset of CR2. Until the first relapse, the children were treated according to standard protocols. The majority of patients suffered from a bone marrow relapse, mostly occurring more than 24 months after the onset of CR1. Remission reinduction treatment was heterogeneous. Patients treated with allogeneic BMT received high-dose chemotherapy and total body irradiation prior to BMT. Maintenance chemotherapy in controls was given for approximately 2 years. Following BMT, relapse rate was lower but the treatment-related mortality was higher compared with maintenance chemotherapy, resulting in leukemia-free survival rates at 4 years of 44% and 24%, respectively (not significant, NS). Case-control analysis of leukemia-free survival showed a hazard ratio of 0.756 in favor of BMT compared with chemotherapy (NS). If bone marrow relapses and central nervous system relapses were analyzed separately, a tendency to better leukemia-free survival was present after BMT compared with maintenance chemotherapy for patients with a relapse in the central nervous system, but for an isolated bone marrow relapse, no differences in leukemia-free survival were seen between the two groups of patients.
Assuntos
Antineoplásicos/uso terapêutico , Transplante de Medula Óssea , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/cirurgia , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Recidiva , Análise de Sobrevida , Transplante HomólogoRESUMO
Severe combined immune deficiency disease due to a deficiency of the enzyme adenosine deaminase is a rare disease. However, it has been used as a prototype disease for the development of a variety of treatment modalities that are currently applied in more frequent diseases. For example, allogeneic bone marrow transplantation and stem cell gene therapy have been used for adenosine deaminase deficiency before being applied in other more frequent diseases. In the present paper, the development of bone marrow transplantation and stem cell gene therapy, as well as treatment with purified enzyme, for adenosine deaminase deficiency are discussed.