RESUMO
Individuals with Fanconi anemia (FA) have a high risk of developing myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), yet the secondary somatic mutations lending to these malignancies remain to be further elucidated. We employed a next-generation sequencing myeloid neoplasia gene panel to determine the mutational spectrum of FA-related MDS/AML. Ten of 16 patients showed missense, nonsense, insertion or duplication mutations in 13 genes. In contrast to findings in MDS in the general population, mutations in genes involved in RNA splicing were rarely affected. Mutations in RUNX1 and genes of the RAS pathway appeared more instrumental in the pathogenesis of FA myeloid malignancies. RUNX1 mutations were associated with more advanced disease. Interestingly, one patient with refractory anemia with ring sideroblasts harbored the SF3B1 p.K700E mutation highlighting the mutation's causative role in MDS with ring sideroblasts even in the context of FA. On the whole, our findings implicate a different genetic architecture of FA MDS/AML from adult sporadic MDS. Notably, the genetic events resemble those described in pediatric MDS.
Assuntos
Anemia Sideroblástica/genética , Anemia de Fanconi/genética , Leucemia Mieloide Aguda/genética , Síndromes Mielodisplásicas/genética , Fatores de Processamento de RNA/genética , Adulto , Anemia Sideroblástica/patologia , Criança , Anemia de Fanconi/patologia , Humanos , Leucemia Mieloide Aguda/patologia , Mutação , Síndromes Mielodisplásicas/patologia , Fosfoproteínas , Fatores de Processamento de RNA/metabolismoRESUMO
In planning a clinical trial for demonstrating the efficacy of pioglitazone to resolve leukoplakia and erythroplakia in Fanconi anemia patients we had to discuss the need for a randomized controlled trial particularly under sample-size restrictions as very promising results were available from a single-arm clinical trial. Unfortunately, at a later stage, we had to suffer from the fact that single-arm clinical trials may sometimes mislead. When revisiting our planning at a later stage of a grant application, results of a randomized controlled trial had become available which were less impressive, but may still be of clinical interest. However, these results were perceived as disappointing in the light of previously raised hopes based on the results of the single-arm trial. We highlight some major problems when research is based on single-arm trials compared to randomized controlled trials. After debunking common arguments for the conduct of single-arm trials in rare disease we conclude that particularly in rare disease research should be based on randomized building blocks simply because more robust evidence is generated. The plea for single-arm trials should be substituted by a plea for cooperation of all stakeholders to provide best evidence for decision making under sample-size restrictions.
Assuntos
Medicina Baseada em Evidências/métodos , Anemia de Fanconi/tratamento farmacológico , Leucoplasia/tratamento farmacológico , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Tiazolidinedionas/uso terapêutico , Tomada de Decisão Clínica/métodos , Anemia de Fanconi/diagnóstico , Humanos , Hipoglicemiantes/uso terapêutico , Leucoplasia/diagnóstico , Pioglitazona , Tamanho da AmostraAssuntos
Evolução Clonal/genética , DNA (Citosina-5-)-Metiltransferases/genética , Leucemia Mieloide Aguda/genética , Mutação , Síndromes Mielodisplásicas/genética , Lesões Pré-Cancerosas/genética , Adolescente , Alelos , Biomarcadores , Medula Óssea/patologia , Metilação de DNA , DNA Metiltransferase 3A , Análise Mutacional de DNA , Feminino , Humanos , Leucemia Mieloide Aguda/diagnóstico , Contagem de Leucócitos , Síndromes Mielodisplásicas/diagnósticoRESUMO
A substantial number of individuals with Fanconi anemia (FA) develop bone marrow failure and are treated with androgen therapy in order to increase blood counts. The authors retrospectively identified 70 patients who received androgen therapy any time between July 1976 and September 2014. Among these patients, 37 had medical records for analysis. Twenty-five of the 37 (68%) patients had response in hemoglobin level (n = 25), platelet count (n = 21), and/or absolute neutrophil count (n = 13). The median rise in hemoglobin was 6.5 mg/dL, platelet count 70,000/mm(3), and absolute neutrophil count (ANC) 1530/µL. The majority of patients (n = 22) had a response in 2 or more blood parameters. Reasons for discontinuation of therapy included development of cytogenetic aberrations (n = 9), lack of response (n = 7), hepatic adenoma (n = 6), progression to myelodysplastic syndrome/acute myeloid leukemia (n = 3), stabilization of blood parameters (n = 3), resolution of cytopenia secondary to mosaicism (n = 1), virilization (n = 1), development of anogenital carcinoma (n = 1), inaccessibility of medication (n = 1), and unknown (n = 1). Four patients at last follow-up remain on androgen therapy. These results highlight that androgen therapy can significantly improve blood counts for many FA patients, but progression of underlying bone marrow disease and development of liver adenomas requires careful monitoring.
Assuntos
Androgênios , Adenoma/sangue , Adenoma/mortalidade , Adolescente , Adulto , Androgênios/efeitos adversos , Androgênios/uso terapêutico , Criança , Pré-Escolar , Anemia de Fanconi/sangue , Anemia de Fanconi/tratamento farmacológico , Anemia de Fanconi/mortalidade , Feminino , Alemanha/epidemiologia , Hemoglobinas/metabolismo , Humanos , Contagem de Leucócitos , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/mortalidade , Masculino , Segunda Neoplasia Primária/sangue , Segunda Neoplasia Primária/mortalidade , Estudos RetrospectivosRESUMO
Neonatal thrombocytopenia is a common clinical problem and may be a result of maternal and/or fetal conditions. We present a young patient with thrombocytopenia as a result of neonatal lupus, a passively acquired autoimmune disease. The diagnosis was suspected on the basis of the presence of a facial rash. This case highlights the characteristic eruption of neonatal lupus and an underappreciated cause of neonatal thrombocytopenia for the pediatric hematologist. We also review the hematological complications of neonatal lupus.
Assuntos
Doenças do Recém-Nascido/diagnóstico , Lúpus Eritematoso Sistêmico/congênito , Trombocitopenia/etiologia , Feminino , Humanos , Recém-Nascido , Doenças do Recém-Nascido/fisiopatologia , Lúpus Eritematoso Sistêmico/diagnóstico , Lúpus Eritematoso Sistêmico/fisiopatologia , Gravidez , Complicações na Gravidez , Síndrome de SjogrenRESUMO
Anaplastic ependymoma is a malignant glial tumor thought to arise from radial glial cells of the ventricular zone. Because ependymoma is frequently encountered within ventricular spaces, they are prone to leptomeningeal dissemination. Metastatic extracranial ependymoma has been reported, but in the context of progressive intracranial disease. We report on a boy who developed isolated extracranial recurrence of his anaplastic ependymoma, initially at the scalp and later metastases to cervical lymph nodes. The location of tumor recurrence proximate to the surgical site suggested surgical seeding. This case demonstrates an unusual site of recurrence of anaplastic ependymoma and highlights a previously underappreciated surgical complication.
Assuntos
Neoplasias Encefálicas/patologia , Ependimoma/secundário , Metástase Linfática/patologia , Neoplasias Cutâneas/secundário , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Encefálicas/terapia , Criança , Terapia Combinada , Ependimoma/terapia , Evolução Fatal , Humanos , Masculino , Procedimentos Neurocirúrgicos , Radioterapia , Couro Cabeludo/patologiaRESUMO
Börjeson-Forssman-Lehmann syndrome (BFLS) is a rare X-linked mental retardation syndrome that is caused by germline mutations in PHF6. We describe a 9-year-old male with BFLS, who developed T-cell acute lymphoblastic leukemia (T-ALL). The PHF6 gene is located on the X chromosome and encodes a protein with two PHD-type zinc finger domains and four nuclear localization sequences. Previously, overexpression of Phf6 was observed in murine T-cell lymphomas. Our observation indicates that BFLS may represent a cancer predisposition syndrome and that mutations of PHF6 contribute to T-ALL.
Assuntos
Proteínas de Transporte/genética , Deficiência Intelectual Ligada ao Cromossomo X/genética , Mutação , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Criança , Humanos , Masculino , Proteínas RepressorasAssuntos
Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Imunoterapia Adotiva/efeitos adversos , Síndromes Mielodisplásicas/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Criança , Pré-Escolar , Doença Enxerto-Hospedeiro , Humanos , Masculino , Síndromes Mielodisplásicas/etiologia , Síndromes Mielodisplásicas/patologia , Recidiva , Transplante HomólogoRESUMO
Immune-mediated hemolytic anemia is a well-recognized complication of hematopoietic stem cell transplantation. We report on a 6-year-old boy with X-linked adrenoleukodystrophy who developed severe delayed alloimmune hemolytic anemia associated with immune-mediated neutropenia and thrombocytopenia following major ABO incompatible unrelated cord blood transplantation. The patient's cytopenias were refractory to treatment with corticosteroids, cyclosporine, intravenous immune globulin, rituximab, and pentostatin. After one course of Campath-1H his hematologic parameters normalized, suggesting that the compound may be an effective therapy for complex immunohematologic disorders complicating hematopoietic stem cell transplantation. The case also emphasizes the importance of T-cells in transplant associated immune cytopenias.
Assuntos
Adrenoleucodistrofia/terapia , Anemia Hemolítica Autoimune/tratamento farmacológico , Anticorpos Monoclonais/uso terapêutico , Anticorpos Antineoplásicos/uso terapêutico , Antineoplásicos/uso terapêutico , Incompatibilidade de Grupos Sanguíneos , Transplante de Células-Tronco de Sangue do Cordão Umbilical/efeitos adversos , Alemtuzumab , Anemia Hemolítica Autoimune/etiologia , Anemia Hemolítica Autoimune/fisiopatologia , Anti-Inflamatórios/uso terapêutico , Anticorpos Monoclonais Humanizados , Criança , Sangue Fetal/transplante , Humanos , Masculino , Metilprednisolona/uso terapêutico , Neutropenia/tratamento farmacológico , Neutropenia/etiologia , Neutropenia/fisiopatologia , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Púrpura Trombocitopênica Idiopática/etiologia , Púrpura Trombocitopênica Idiopática/fisiopatologiaRESUMO
We report a 3-year-old boy with a malignant triton tumor (MTT) involving the left masticator space with local invasion and regional lymph node metastasis. Family history and detection of a novel germline TP53 mutation confirmed his diagnosis of Li Fraumeni syndrome (LFS). MTT has not been previously described in association with LFS. This case along with a comprehensive review of the literature, illustrate the importance of both somatic and germline TP53 mutations in the pathogenesis MTT. The tumor could not be resected and he was successfully treated with intensive induction chemotherapy, irradiation, and high-dose chemotherapy with autologous stem cell transplantation.
Assuntos
Mutação em Linhagem Germinativa , Síndrome de Li-Fraumeni/genética , Neoplasias de Bainha Neural/genética , Neoplasias Nasais/genética , Proteína Supressora de Tumor p53/genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Pré-Escolar , Terapia Combinada , Seguimentos , Transplante de Células-Tronco Hematopoéticas , Humanos , Síndrome de Li-Fraumeni/diagnóstico , Síndrome de Li-Fraumeni/terapia , Masculino , Neoplasias de Bainha Neural/diagnóstico , Neoplasias de Bainha Neural/terapia , Neoplasias Nasais/diagnóstico , Neoplasias Nasais/terapia , Linhagem , Tomografia Computadorizada por Raios X , Transplante Autólogo , Resultado do TratamentoRESUMO
BACKGROUND: Pediatric patients with high-risk surgically resected melanoma are at risk for relapse, yet little is known about these young patients and how they tolerate high-dose interferon therapy. PROCEDURE: We reviewed medical records of patients (< or =18 years) with high-risk melanoma referred to the University of Michigan Pediatric Hematology-Oncology service between January 1989 and July 2003. RESULTS: Fourteen patients were identified with high-risk resected melanoma. The median age at diagnosis was 8.5 years. The median time to establish diagnosis was 9 months. Primary lesions were diagnosed as unequivocal melanoma, atypical epithelioid melanocytic proliferations, or atypical Spitz tumor with indeterminate malignant potential. Twelve patients had a positive sentinel lymph node (SLN) biopsy or a palpable regional lymph node and underwent regional lymph node dissection (LND). Two patients with unequivocal melanoma with Breslow depth >4 mm had negative SLN biopsies. Twelve patients received adjuvant high-dose interferon. The following toxicities were observed: constitutional symptoms, gastrointestinal symptoms, depression or neuropsychiatric symptoms, myelosuppression, elevated AST or ALT, hypothyroidism, and hypertension. Grade 3 or 4 toxicities were uncommon with exception of neutropenia, resulting in modification of therapy in one patient. All patients are alive and free of disease at follow-up (median 24.5 months). CONCLUSIONS: Invasive melanoma can occur in very young children. Despite early signs of malignancy, there is often a delay in diagnosis. Histologically, diagnosis may be difficult because of overlap with Spitz nevi. Pediatric patients tolerated adjuvant high-dose interferon well and may be less likely than adults to require therapy modification secondary to toxicities.