RESUMO
Despite advances in our understanding of the molecular basis for particular subtypes of acute myeloid leukemia (AML), effective therapy remains a challenge for many individuals suffering from this disease. A significant proportion of both pediatric and adult AML patients cannot be cured and since the upper limits of chemotherapy intensification have been reached, there is an urgent need for novel therapeutic approaches. The transcription factor c-MYB has been shown to play a central role in the development and progression of AML driven by several different oncogenes, including mixed lineage leukemia (MLL)-fusion genes. Here, we have used a c-MYB gene expression signature from MLL-rearranged AML to probe the Connectivity Map database and identified mebendazole as a c-MYB targeting drug. Mebendazole induces c-MYB degradation via the proteasome by interfering with the heat shock protein 70 (HSP70) chaperone system. Transient exposure to mebendazole is sufficient to inhibit colony formation by AML cells, but not normal cord blood-derived cells. Furthermore, mebendazole is effective at impairing AML progression in vivo in mouse xenotransplantation experiments. In the context of widespread human use of mebendazole, our data indicate that mebendazole-induced c-MYB degradation represents a safe and novel therapeutic approach for AML.
Assuntos
Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/metabolismo , Mebendazol/farmacologia , Proteólise/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-myb/metabolismo , Animais , Criança , Feminino , Humanos , Lactente , Masculino , Camundongos , Oncogenes/efeitos dos fármacos , Complexo de Endopeptidases do Proteassoma/metabolismoAssuntos
Antibióticos Antineoplásicos/administração & dosagem , Hemangioendotelioma/tratamento farmacológico , Hemangioma/tratamento farmacológico , Síndrome de Kasabach-Merritt/tratamento farmacológico , Neoplasias de Tecido Vascular/tratamento farmacológico , Sarcoma de Kaposi/tratamento farmacológico , Sirolimo/administração & dosagem , Neoplasias Cutâneas/tratamento farmacológico , Administração Oral , Pré-Escolar , Esquema de Medicação , Feminino , Humanos , Lactente , Masculino , Resultado do TratamentoRESUMO
We report an 18-months old boy with trisomy 21 who initially presented with myelodysplastic syndrome MDS, and later transformed into acute megakaryoblastic leukaemia AML. At presentation he was found to have some unusual findings namely multiple soft tissue masses over scalp, left elbow and over the knee joints as well as hard mass felt in left hip. Biopsy of soft tissue of scalp revealed granulocytic sarcoma. Generally granulocytic sarcoma is seen with AML-M2 and its association with AML-M7, to our belief has rarely been reported previously.
Assuntos
Carcinoma de Células Escamosas/complicações , Doenças do Pé/complicações , Neutropenia/complicações , Anormalidades da Pele/complicações , Neoplasias Cutâneas/complicações , Dedos do Pé , Carcinoma de Células Escamosas/imunologia , Criança , Feminino , Doenças do Pé/imunologia , Humanos , Neutropenia/imunologia , Neutrófilos/fisiologia , Anormalidades da Pele/imunologia , Neoplasias Cutâneas/imunologiaRESUMO
AIM: To review the gastrointestinal mucosal histological features of biopsies from children with Shwachman-Diamond syndrome (SDS) examined at a single specialist centre. METHODS: Search of a clinical database was performed to identify SDS cases and their gastrointestinal biopsies were reviewed for morphological parameters such as crypt:villous ratio, crypt hyperplasia and abnormal inflammatory infiltrates. Histological sections were also immunostained with CD4, CD20 and HLA-DR to determine the nature of the inflammatory infiltrate. RESULTS: 15 SDS cases were included, 7 (47%) of which showed morphologically normal duodenal villous architecture, whereas 8 (53%) showed varying degrees of enteropathic histological features ranging from villous blunting to partial villous atrophy and duodenitis. 11/15 (73%) showed some degree of duodenal inflammation, including increased lamina propria density of plasma cells, macrophages and eosinophils. CONCLUSION: Varying degrees of duodenal inflammatory enteropathic features are present in more than 50% of symptomatic children with SDS. This suggests that, in addition to pure pancreatic exocrine failure, an enteropathic component may contribute to symptoms in some cases, and be potentially responsive to appropriate therapy.
Assuntos
Duodeno/patologia , Atrofia , Biópsia , Doenças da Medula Óssea/imunologia , Doenças da Medula Óssea/patologia , Linfócitos T CD4-Positivos/imunologia , Criança , Duodenite/imunologia , Duodenite/patologia , Duodenoscopia , Duodeno/imunologia , Insuficiência Pancreática Exócrina/imunologia , Insuficiência Pancreática Exócrina/patologia , Antígenos HLA-DR/metabolismo , Humanos , Imunidade nas Mucosas , Mucosa Intestinal/imunologia , Mucosa Intestinal/patologia , Lipomatose , Síndrome de Shwachman-DiamondRESUMO
Haemophagocytic lymphohistiocytosis (HLH) is a rare and rapidly progressive disease which, untreated, invariably leads to death. Gaucher disease is a rare lysosomal storage disorder. The acute neuronopathic variant; type II, is also rapidly progressive. We report an infant with Gaucher disease type II manifesting as HLH. Immunoblot revealed a deficiency of Munc 13-4, an intracellular protein responsible for docking of secretory lysosomes. This, and other possible pathogenetic mechanisms to explain the link are discussed.
Assuntos
Doença de Gaucher/complicações , Doença de Gaucher/diagnóstico , Linfo-Histiocitose Hemofagocítica/diagnóstico , Linfo-Histiocitose Hemofagocítica/etiologia , Diagnóstico Diferencial , Evolução Fatal , Feminino , Doença de Gaucher/genética , Humanos , Lactente , Proteínas de Membrana/deficiência , Proteínas de Membrana/genéticaRESUMO
We report successful outcome in 13 children (median age 2.2 years) with high-risk AML who received SCT from an unrelated (11) or identical sibling (2) donor after a preparative regimen consisting of BU, CY and melphalan. Three children were 'poor'-risk in first CR, three in the second CR, five in PR and two had resistant disease. Immunotherapeutic strategies were employed to maximize a GVL response escalating through a reduced dose of alemtuzumab, early taper of CsA, donor lymphocyte infusion and treatment with alpha-IFN. Ten out of 13 (77%) children are alive in CR at a median of 41 months (range: 17-88) from SCT. There was no TRM, but three children relapsed and died 3, 4 and 17 months after SCT. These encouraging early results warrant further studies in children with very high-risk AML.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Transplante de Células-Tronco/métodos , Condicionamento Pré-Transplante/métodos , Alemtuzumab , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados , Anticorpos Antineoplásicos/uso terapêutico , Bussulfano/uso terapêutico , Criança , Pré-Escolar , Terapia Combinada , Ciclofosfamida/uso terapêutico , Ciclosporina/uso terapêutico , Feminino , Doença Enxerto-Hospedeiro/prevenção & controle , Humanos , Imunoterapia , Lactente , Masculino , Melfalan/uso terapêutico , Quimeras de Transplante/imunologia , Transplante HomólogoRESUMO
Glanzmann thrombasthenia (GT) is a rare autosomal recessive platelet function disorder. Stem cell transplantation (SCT) is curative, but it is only indicated in selected patients with a severe clinical phenotype or who develop anti-platelet antibodies. SCT have previously been limited to full intensity myeloablative conditioning regimens. This study details the successful outcome of SCT in five consecutive patients with GT, three of whom received reduced intensity conditioning (RIC) with stem cells from non-sibling donors. This is the first time RIC SCT has been reported in GT, and offers the possibility of curative therapy with reduced late effects.
Assuntos
Transplante de Células-Tronco/métodos , Trombastenia/terapia , Criança , Pré-Escolar , Feminino , Sobrevivência de Enxerto , Doença Enxerto-Hospedeiro , Humanos , Masculino , Quimeras de Transplante , Condicionamento Pré-Transplante/métodos , Resultado do TratamentoRESUMO
Each year at the Annual Scientific Meeting of the British Society for Haematology, there is a slide session in which microscopic slides of six patients with haematological disorders are discussed by two experts. Further data and the final diagnosis are then provided. The slide session is presented here, as it occurred at the meeting.
Assuntos
Células Sanguíneas/patologia , Células da Medula Óssea/patologia , Diagnóstico por Imagem , Adulto , Forma Celular , Eosinofilia/patologia , Eritrócitos/patologia , Feminino , Humanos , Lactente , Recém-Nascido , Leucemia/patologia , Leucócitos/patologia , Masculino , Pessoa de Meia-Idade , Osteopetrose/patologiaRESUMO
The thrombocytopenia-absent radius (TAR) syndrome is a congenital malformation syndrome characterised by bilateral absence of the radii and a thrombocytopenia. The lower limbs, gastrointestinal, cardiovascular, and other systems may also be involved. Shaw and Oliver in 1959 were the first to describe this condition, but it was Hall et al in 1969 who reported the first major series of patients. Since then most reports have been based on single or small numbers of cases. We report the results of a clinical study looking at the phenotype of 34 patients with TAR syndrome. All cases had a documented thrombocytopenia and bilateral radial aplasia, 47% had lower limb anomalies, 47% cow's milk intolerance, 23% renal anomalies, and 15% cardiac anomalies. Congenital anomalies not previously described in association with TAR syndrome included facial capillary haemangiomata, intracranial vascular malformation, sensorineural hearing loss, and scoliosis. Karyotype analysis, chromosome breakage studies including premature centromeric separation and fluorescence in situ hybridisation studies looking for a deletion of chromosome 22q11 were undertaken. Two abnormal karyotypes were identified.
Assuntos
Anormalidades Múltiplas/genética , Anormalidades Múltiplas/fisiopatologia , Braço/anormalidades , Rádio (Anatomia)/anormalidades , Trombocitopenia/genética , Trombocitopenia/fisiopatologia , Criança , Aberrações Cromossômicas , Cromossomos Humanos Par 22/genética , Anormalidades do Sistema Digestório , Feminino , Humanos , Hibridização in Situ Fluorescente , Recém-Nascido , Cariotipagem , Perna (Membro)/anormalidades , Masculino , Síndrome , Anormalidades Urogenitais/genéticaRESUMO
Severe congenital neutropenia (SCN) was originally described as an autosomal recessive disorder. Subsequently, autosomal dominant and sporadic forms of the disease have been recognized. All forms are manifest by persistent severe neutropenia and recurrent bacterial infection. In contrast, cyclical hematopoiesis is characterized by periodic neutropenia inter-spaced with (near) normal neutrophil counts. Recently, linkage analysis on 13 affected pedigrees identified chromosome 19p13.3 as the likely position for mutations in cyclical hematopoiesis. Heterozygous mutations in the ELA2 gene encoding neutrophil elastase were detected in all families studied. Further work also demonstrated mutations in ELA2 in sporadic and autosomal dominant SCN. However, all mutations described to date are heterozygous and thus appear to act in a dominant fashion, which is inconsistent with an autosomal recessive disease. Therefore, the current study investigated whether mutations in ELA2 could account for the disease phenotype in classical autosomal recessive SCN and in the sporadic and autosomal dominant types. All 5 exons of ELA2 and their flanking introns were studied in 18 patients (3 autosomal recessive, 5 autosomal dominant [from 3 kindreds], and 10 sporadic) using direct automated sequencing. No mutations were found in the autosomal recessive families. A point mutation was identified in 1 of 3 autosomal dominant families, and a base substitution was identified in 8 of 10 patients with the sporadic form, though 1 was subsequently shown to be a low-frequency polymorphism. These results suggest that mutations in ELA2 are not responsible for classical autosomal recessive Kostmann syndrome but provide further evidence for the role of ELA2 in SCN.
Assuntos
Elastase de Leucócito/genética , Mutação , Neutropenia/genética , Adulto , Estudos de Casos e Controles , Criança , Cromossomos Humanos Par 19 , Análise Mutacional de DNA , Saúde da Família , Feminino , Genes Dominantes , Genes Recessivos , Ligação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Neutropenia/congênito , Neutropenia/enzimologia , LinhagemRESUMO
The level of 20x10(9)/L for prophylactic platelet transfusion has rightly been challenged over the last few years, with some units recommending a level as low as 5x10(9)/L. The higher levels are usually based on retrospective data from the 1950s. We examined the more recent data and came to the conclusion that a threshold of 10x10(9)/L is safe in the stable patient; higher levels are recommended for specific clinical circumstances. This threshold will reduce donor exposure, costs and possibly donor alloimmunization. The dearth of prospective controlled clinical trials in the literature also presents an opportunity for both in-house and national audit.
Assuntos
Transfusão de Plaquetas , História do Século XX , Humanos , Transfusão de Plaquetas/história , Transfusão de Plaquetas/normas , Transfusão de Plaquetas/tendênciasRESUMO
We describe a case of a 38-year-old female who presented with diarrhoea and abdominal pain 27 days after a second 'top-up' allogeneic marrow infusion for acute myeloid leukaemia (AML) in first remission. A clinical diagnosis of gut graft-versus-host disease (GVHD) was made. Technetium (99mTc)-labelled white cell scanning and intestinal permeability studies using 51Cr-EDTA and 14C-mannitol were undertaken to confirm the diagnosis. The 99mTc white cell scan showed extensive uptake in the small bowel and the urinary excretion of 51Cr-EDTA was increased, the results being consistent with intestinal inflammation and gut GVHD. 99mTc white cell scanning and intestinal permeability studies may assist in the diagnosis of gut GVHD and in assessing its extent and response to treatment.