RESUMO
Myelodysplastic syndromes (MDS) are a heterogeneous group of pre-leukemic hematopoietic disorders characterized by cytopenia in peripheral blood due to ineffective hematopoiesis and normo- or hypercellularity and morphologic dysplasia in bone marrow (BM). An inflammatory BM microenvironment and programmed cell death of hematopoietic stem/progenitor cells (HSPCs) are thought to be the major causes of ineffective hematopoiesis in MDS. Pyroptosis, apoptosis and necroptosis (collectively, PANoptosis) are observed in BM tissues of MDS patients, suggesting an important role of PANoptosis in MDS pathogenesis. Caspase 8 (Casp8) is a master regulator of PANoptosis, which is downregulated in HSPCs from most MDS patients and abnormally spliced in HSPCs from MDS patients with SRSF2 mutation. To study the role of PANoptosis in hematopoiesis, we generated inducible Casp8 knockout mice (Casp8-/-). Mx1-Cre-Casp8-/- mice died of BM failure within 10 days of polyI:C injections due to depletion of HSPCs. Rosa-ERT2Cre-Casp8-/- mice are healthy without significant changes in BM hematopoiesis within the first 1.5 months after Casp8 deletion. Such mice developed BM failure upon infection or low dose polyI:C/LPS injections due to the hypersensitivity of Casp8-/- HSPCs to infection or inflammation-induced necroptosis which can be prevented by Ripk3 deletion. However, impaired self-renewal capacity of Casp8-/- HSPCs cannot be rescued by Ripk3 deletion due to activation of Ripk1-Tbk1 signaling. Most importantly, mice transplanted with Casp8-/- BM cells developed MDS-like disease within 4 months of transplantation as demonstrated by anemia, thrombocytopenia and myelodysplasia. Our study suggests an essential role for a balance in Casp8, Ripk3-Mlkl and Ripk1-Tbk1 activities in the regulation of survival and self-renewal of HSPCs, the disruption of which induces inflammation and BM failure, resulting in MDS-like disease.
Assuntos
Síndromes Mielodisplásicas , Animais , Humanos , Camundongos , Transtornos da Insuficiência da Medula Óssea/complicações , Caspase 8/genética , Caspase 8/metabolismo , Inflamação/metabolismo , Camundongos Knockout , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/metabolismoRESUMO
Male infertility is defined as a failure to conceive after 12 months of unprotected intercourse owing to suspected male reproductive factors. Non-malignant red blood cell disorders are systemic conditions that have been associated with male infertility with varying severity and strength of evidence. Hereditary haemoglobinopathies and bone marrow failure syndromes have been associated with hypothalamic-pituitary-gonadal axis dysfunction, hypogonadism, and abnormal sperm parameters. Bone marrow transplantation is a potential cure for these conditions, but exposes patients to potentially gonadotoxic chemotherapy and/or radiation that could further impair fertility. Iron imbalance might also reduce male fertility. Thus, disorders of hereditary iron overload can cause iron deposition in tissues that might result in hypogonadism and impaired spermatogenesis, whereas severe iron deficiency can propagate anaemias that decrease gonadotropin release and sperm counts. Reproductive urologists should be included in the comprehensive care of patients with red blood cell disorders, especially when gonadotoxic treatments are being considered, to ensure fertility concerns are appropriately evaluated and managed.
Assuntos
Transtornos da Insuficiência da Medula Óssea , Hemoglobinopatias , Infertilidade Masculina , Humanos , Masculino , Fertilidade , Infertilidade Masculina/etiologia , Saúde Reprodutiva , Eritrócitos/patologia , Hemoglobinopatias/complicações , Transtornos da Insuficiência da Medula Óssea/complicaçõesRESUMO
Bone marrow failure syndromes are rare disorders characterized by bone marrow hypocellularity and resultant peripheral cytopenias. The most frequent form is acquired, so-called aplastic anemia or idiopathic aplastic anemia, an auto-immune disorder frequently associated with paroxysmal nocturnal hemoglobinuria, whereas inherited bone marrow failure syndromes are related to pathogenic germline variants. Among newly identified germline variants, GATA2 deficiency and SAMD9/9L syndromes have a special significance. Other germline variants impacting biological processes, such as DNA repair, telomere biology, and ribosome biogenesis, may cause major syndromes including Fanconi anemia, dyskeratosis congenita, Diamond-Blackfan anemia, and Shwachman-Diamond syndrome. Bone marrow failure syndromes are at risk of secondary progression towards myeloid neoplasms in the form of myelodysplastic neoplasms or acute myeloid leukemia. Acquired clonal cytogenetic abnormalities may be present before or at the onset of progression; some have prognostic value and/or represent somatic rescue mechanisms in inherited syndromes. On the other hand, the differential diagnosis between aplastic anemia and hypoplastic myelodysplastic neoplasm remains challenging. Here we discuss the value of cytogenetic abnormalities in bone marrow failure syndromes and propose recommendations for cytogenetic diagnosis and follow-up.
Assuntos
Anemia Aplástica , Doenças da Medula Óssea , Leucemia Mieloide Aguda , Síndromes Mielodisplásicas , Humanos , Anemia Aplástica/diagnóstico , Anemia Aplástica/genética , Anemia Aplástica/terapia , Doenças da Medula Óssea/diagnóstico , Doenças da Medula Óssea/genética , Doenças da Medula Óssea/terapia , Transtornos da Insuficiência da Medula Óssea/diagnóstico , Transtornos da Insuficiência da Medula Óssea/terapia , Transtornos da Insuficiência da Medula Óssea/complicações , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/terapia , Leucemia Mieloide Aguda/complicações , Aberrações Cromossômicas , Análise Citogenética , Peptídeos e Proteínas de Sinalização Intracelular/genéticaRESUMO
Despite recent advancements, treatment of cytopenia due to bone marrow failures (BMF) and myeloid neoplasms remains challenging. Androgens promote renewal and maturation of blood cells and may be beneficial in these forms. Here we report a systematic review of androgens use as single agent in hematologic conditions. Forty-six studies, mainly retrospective with various androgen types and doses, were included: 12 on acquired aplastic anemia (AA), 11 on inherited BMF, 17 on myelodysplastic syndromes (MDS), and 7 on myelofibrosis. Responses ranged from 50 to 70% in inherited BMF, 40-50% in acquired AA and MDS, while very limited evidence emerged for myelofibrosis. In acquired AA, response was associated with presence of non-severe disease; in MDS androgens were more effective on thrombocytopenia or mild to moderate anemia, whilst limited benefit was observed for transfusion dependent anemia. Toxicity profile mainly consisted of virilization and liver enzyme elevation, whilst the risk of leukemic evolution remains controversial.
Assuntos
Anemia Aplástica , Síndromes Mielodisplásicas , Transtornos Mieloproliferativos , Neoplasias , Pancitopenia , Mielofibrose Primária , Trombocitopenia , Humanos , Androgênios/uso terapêutico , Mielofibrose Primária/complicações , Estudos Retrospectivos , Neoplasias/complicações , Anemia Aplástica/tratamento farmacológico , Anemia Aplástica/etiologia , Síndromes Mielodisplásicas/terapia , Transtornos da Insuficiência da Medula Óssea/complicações , Transtornos Mieloproliferativos/etiologia , Transtornos Mieloproliferativos/complicaçõesRESUMO
The diagnostic work up and surveillance of germline disorders of bone marrow failure and predisposition to myeloid malignancy is complex and involves correlation between clinical findings, laboratory and genetic studies, and bone marrow histopathology. The rarity of these disorders and the overlap of clinical and pathologic features between primary and secondary causes of bone marrow failure, acquired aplastic anemia, and myelodysplastic syndrome may result in diagnostic uncertainty. With an emphasis on the pathologist's perspective, we review diagnostically useful features of germline disorders including Fanconi anemia, Shwachman-Diamond syndrome, telomere biology disorders, severe congenital neutropenia, GATA2 deficiency, SAMD9/SAMD9L diseases, Diamond-Blackfan anemia, and acquired aplastic anemia. We discuss the distinction between baseline morphologic and genetic findings of these disorders and features that raise concern for the development of myelodysplastic syndrome.
Assuntos
Anemia Aplástica , Doenças da Medula Óssea , Síndromes Mielodisplásicas , Transtornos Mieloproliferativos , Neoplasias , Humanos , Anemia Aplástica/genética , Anemia Aplástica/complicações , Síndrome Congênita de Insuficiência da Medula Óssea/complicações , Doenças da Medula Óssea/genética , Doenças da Medula Óssea/complicações , Doenças da Medula Óssea/diagnóstico , Patologistas , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/complicações , Transtornos da Insuficiência da Medula Óssea/complicações , Células Germinativas , Neoplasias/complicações , Peptídeos e Proteínas de Sinalização IntracelularRESUMO
Clonal evolution to secondary paroxysmal nocturnal hemoglobinuria (PNH) or myeloid neoplasia (MN) represents one of the long-term complications of patients with aplastic anemia (AA). The recent evidence in the field of immunology and the application of next-generation sequencing have shed light on the molecular underpinnings of these clonal complications, revealing clinical and molecular risk factors as well as potential immunological players. Particularly, whether MN evolution represents a failed tumor surveillance or a maladaptive recovery is still a matter of controversy in the field of bone marrow failure syndromes. However, recent studies have explored the precise dynamics of the immune-molecular forces governing such processes over time, generating knowledge useful for potential early therapeutic strategies. In this review, we will discuss the immune pathophysiology of AA and the emergence of clonal hematopoiesis with regard to the adaptive and maladaptive mechanisms at the basis of secondary evolution trajectories operating under the immune pressure.
Assuntos
Anemia Aplástica , Hemoglobinúria Paroxística , Neoplasias , Humanos , Anemia Aplástica/complicações , Hemoglobinúria Paroxística/genética , Neoplasias/complicações , Transtornos da Insuficiência da Medula Óssea/complicações , Evolução Clonal/genéticaRESUMO
Pathogenic variants in MECOM, a gene critical to the self-renewal and proliferation of hematopoietic stem cells, are known to cause a rare bone marrow failure syndrome associated with amegakaryocytic thrombocytopenia and bilateral radioulnar synostosis known as RUSAT2. However, the spectrum of disease seen with causal variants in MECOM is broad, ranging from mildly affected adults to fetal loss. We report two cases of infants born preterm who presented at birth with symptoms of bone marrow failure including severe anemia, hydrops, and petechial hemorrhages; radioulnar synostosis was not observed in either patient, and, unfortunately, neither infant survived. In both cases, genomic sequencing revealed de novo variants in MECOM considered to be responsible for their severe presentations. These cases add to the growing body of literature that describe MECOM-associated disease, particularly MECOM as a cause of fetal hydrops due to bone marrow failure in utero. Furthermore, they support the use of a broad sequencing approach for perinatal diagnosis, as MECOM is absent from available targeted gene panels for hydrops, and highlight the importance of postmortem genomic investigation.
Assuntos
Anemia , Hidropisia Fetal , Recém-Nascido , Gravidez , Lactente , Feminino , Adulto , Humanos , Hidropisia Fetal/genética , Hidropisia Fetal/diagnóstico , Fatores de Transcrição , Transtornos da Insuficiência da Medula Óssea/complicações , Proteína do Locus do Complexo MDS1 e EVI1RESUMO
BACKGROUND: Coronavirus disease 2019 (COVID-19) represents an important infectious complication associated with high mortality rates in patients with hematologic diseases. There have not been published any epidemiologic studies from Czech Republic so far. PATIENTS AND METHODS: This study is the first analysis of patients with hematologic malignancies and bone marrow failure syndromes treated at single hematology center in the Czech Republic between March 1 and December 31, 2020, in whom COVID-19 infection was confirmed. RESULTS: The sample comprised 96 patients aged 26 to 84 years (median, 66.0 years). At the time of their COVID-19 diagnosis, 75 patients (78.1%) were treated for hematologic diseases. Twenty-seven patients (28.1%) in the sample had complete remission (CR) of their hematologic disease. They were nonsignificantly more likely to have asymptomatic to moderate COVID-19 infection than those who failed to achieve CR (74.1% vs. 56.5%; P = .06). A more severe course of the infection was significantly correlated with older age (P = .047). Lung involvement was also statistically significantly associated with older age (P = .045). Over the study period, a total of 15 patients died. Age greater than 60 years was significantly associated with deaths from COVID-19 (P = .036), with failure to achieve CR having a statistically nonsignificant impact on mortality (P = .22). CONCLUSION: These results confirm the prognostic significance of age for achieving treatment response of hematologic disease as well as the severity and mortality of COVID-19 in hematology patients.
Assuntos
COVID-19 , Doenças Hematológicas , Adulto , Idoso , Idoso de 80 Anos ou mais , Transtornos da Insuficiência da Medula Óssea/complicações , Transtornos da Insuficiência da Medula Óssea/diagnóstico , Transtornos da Insuficiência da Medula Óssea/epidemiologia , Transtornos da Insuficiência da Medula Óssea/terapia , COVID-19/complicações , COVID-19/diagnóstico , COVID-19/epidemiologia , COVID-19/terapia , Teste para COVID-19/métodos , Teste para COVID-19/estatística & dados numéricos , República Tcheca/epidemiologia , Progressão da Doença , Feminino , Doenças Hematológicas/complicações , Doenças Hematológicas/diagnóstico , Doenças Hematológicas/epidemiologia , Doenças Hematológicas/terapia , Neoplasias Hematológicas/complicações , Neoplasias Hematológicas/diagnóstico , Neoplasias Hematológicas/epidemiologia , Neoplasias Hematológicas/terapia , Hospitalização/estatística & dados numéricos , Humanos , Masculino , Pessoa de Meia-Idade , Mortalidade , Prevalência , SARS-CoV-2/fisiologiaRESUMO
The landscape of aplastic anemia (AA) is changing as new therapeutic options become available and sophistic diagnostics enable us to decipher various subgroups of bone marrow failure syndromes (BMFS) such as telomeropathies and other constitutional diseases with manifestations beyond childhood.This article briefly summarizes developments of the last few years with potential clinical impact and puts it into perspective. Focus is given to the growing list of inherited BMFS and the need to e.âg. screen patients at all ages for telomeropathies before initiation of treatment as part of routine evaluation of AA. The usage of next generation sequencing (NGS) to differentiate between AA and malignancies such as myelodysplatic syndrome (MDS) and the need to watch out for potential clonal evolution during and after treatment is also briefly discussed. Recent data on combinations of immunosuppressive therapy (IST) with thrombopoietin receptor agonists (TRA) for patients with severe AA as well as newer data with TRA mono-therapy for patients with moderate AA are presented. Finally the importance of supportive measures, structures and quality of life aspects are highlighted.
Assuntos
Anemia Aplástica/diagnóstico , Anemia Aplástica/terapia , Transtornos da Insuficiência da Medula Óssea/complicações , Androgênios/uso terapêutico , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Imunossupressores/uso terapêutico , Síndromes Mielodisplásicas/complicações , Síndromes Mielodisplásicas/diagnóstico , Cuidados Paliativos , Receptores de Trombopoetina/agonistas , Transplante de Células-TroncoRESUMO
COVID-19 has now spread globally, and 10-20% of the cases are thought to proceed to a severe condition. However, information on COVID-19 in immunodeficient patients remains limited. We treated a 56-year-old man who developed COVID-19 after chemotherapy for mantle cell lymphoma. After 1 month of prolonged fever, the patient's respiratory condition deteriorated rapidly, and he died. COVID-19 in immunocompromised patients after chemotherapy, even with mild symptoms, can cause rapid immune reconstitution and respiratory deterioration. Therefore, caution is advised until negative PCR test results for SARS-CoV-2 are confirmed.
Assuntos
Transtornos da Insuficiência da Medula Óssea/induzido quimicamente , COVID-19/etiologia , Infecção Hospitalar/induzido quimicamente , Linfoma de Célula do Manto/tratamento farmacológico , SARS-CoV-2/isolamento & purificação , Transtornos da Insuficiência da Medula Óssea/complicações , COVID-19/diagnóstico por imagem , Infecção Hospitalar/complicações , Infecção Hospitalar/etiologia , Humanos , Hospedeiro Imunocomprometido , Linfoma de Célula do Manto/complicações , Linfoma de Célula do Manto/imunologia , Masculino , Pessoa de Meia-Idade , Faringe/virologia , Reação em Cadeia da Polimerase , Radiografia Torácica , SARS-CoV-2/genética , Tomografia Computadorizada por Raios X , Tratamento Farmacológico da COVID-19RESUMO
INTRODUCCIÓN: Los síndromes de falla medular (SFM) son trastornos infrecuentes, con una incidencia anual de 2-4 casos por millón. Las opciones de tratamiento incluyen terapia de inmunosupresión (TIS) y restaura ción de la hematopoyesis con trasplante de progenitores hematopoyéticas (TPH). OBJETIVO: Analizar los desenlaces de pacientes pediátricos diagnosticados con SFM tratados en una institución de alta complejidad. PACIENTES Y MÉTODO: Estudio retrospectivo de pacientes pediátricos con diagnóstico de SFM que consultaron a la Fundación Valle del Lili, Cali. Se realizo análisis estadístico descriptivo según SFM adquirida (SFMA) y SFM congénita (SFMC). Los desenlaces incluyeron: tratamiento, complicaciones, supervivencia global (SG) en los trasplantados, calculada con el método Kaplan Meier. RESULTADOS: Se incluyeron 24 pacientes con SFM, edad 6,5 ± 4 años, 50% mujeres. El 58% fue ron SFMC, 9 con anemia de Fanconi, 2 disqueratosis congénita, 2 trombocitopenia amegacariocítica congénita, uno anemia Diamond-Blackfan. Doce pacientes con TPH tuvieron SG a 5 años de 83%. SFMA correspondió al 42%, 6 recibieron TIS-TPH, 3 TIS y 1 TPH, la SG del grupo con TIS-TPH fue 86%. Seis pacientes fallecieron, 4/6 relacionadas con infección. CONCLUSIONES: En esta serie fue mayor el número de casos con SFMC. La SG de los pacientes llevados a TPH es comparable con la reportada en estudios recientes. La causa de muerte predominante fue infecciosa que también se ha reportado previamente. El tratamiento instaurado en los pacientes de esta serie mostró resultados favorables en un centro de alta complejidad en un país latinoamericano.
INTRODUCTION: Bone marrow failure (BMF) syndromes are rare disorders with an annual incidence of 2-4 cases per million. Treatment options include immunosuppressive therapy (IST) and hematopoietic stem cell transplantation (HSCT). OBJECTIVE: To analyze the outcomes of pediatric patients diagnosed with BMF treated in a tertiary care center. PATIENTS AND METHODP: Retrospective study of pediatric patients diagnosed with BMF who consulted at Fundación Valle de Lili, Cali. Descriptive statistical analysis was performed according to Acquired BMF (ABMF) and Inherited BMF (IBMF). The outcomes include treatment, complications, overall survival (OS) in transplant patients, calculated using the Kaplan Meier method. RESULTS: We included 24 patients with BMF, average age 6.5 ± 4 years, and 50% were women. 58% presented IBMF, 9 with Fanconi anemia (FA), 2 dyskeratosis congenita, 2 congenital amegakaryocytic thrombocytopenia, and 1 presented Diamond-Blackfan anemia. 12 patients treated with HSCT had a 5-year OS of 83%. ABMF represented 42%. 6 patients received IST-HSCT, 3 received IST, and 1 received HSCT. The OS of the IST-HSCT group was 86%. Six patients died, four of them related to infection. CONCLUSIONS: In this series, there was a higher number of cases with IBMF. The OS of patients treated with HSCT is similar to that reported in recent studies. The most frequent cause of death was of infectious origin which has also been previously reported. The treatment esta blished in the patients showed favorable results in a Latin American tertiary care center.
Assuntos
Humanos , Masculino , Feminino , Recém-Nascido , Lactente , Pré-Escolar , Criança , Adolescente , Transplante de Células-Tronco Hematopoéticas , Transtornos da Insuficiência da Medula Óssea/terapia , Imunossupressores/uso terapêutico , Taxa de Sobrevida , Estudos Retrospectivos , Resultado do Tratamento , Colômbia , Terapia Combinada , Estimativa de Kaplan-Meier , Centros de Atenção Terciária , Transtornos da Insuficiência da Medula Óssea/complicações , Transtornos da Insuficiência da Medula Óssea/diagnóstico , Transtornos da Insuficiência da Medula Óssea/mortalidadeRESUMO
BACKGROUND: The occurrences of hyperuricemia and acute kidney injury after antithymocyte globulin treatment are unusual in kidney transplant recipients. Here, we report a unique case of acute kidney injury with extreme hyperuricemia after antithymocyte globulin treatment in a kidney transplant recipient with underlying aplastic anemia. CASE PRESENTATION: A 40-year-old woman with aplastic anemia who received a kidney transplant 5 years 6 months before presented to our emergency department with complaints of oliguria, generalized edema, and general weakness 6 days after receiving antithymocyte globulin treatment for acute T-cell-mediated rejection. Urinalysis revealed 100 uric acid crystal particles. The blood chemistry test results showed rapid increases in serum creatinine (from 2.86 mg/dL to 5.58 mg/dL) and uric acid levels (from 10.2 mg/dL to 32.7 mg/dL), which suggested acute uric acid nephropathy. Tumor lysis syndrome was suspected to be the cause of the acute uric acid nephropathy; hence, the patient was reevaluated for aplastic anemia. Human leukocyte antigen-DR15 was positive, and flow cytometry revealed a low percentage of glycophosphatidyl inositol-deficient granulocytes (2.9%), which suggested paroxysmal nocturnal hemoglobinuria clones. These findings indicate that the previously diagnosed aplastic anemia had either originally been hypocellular myelodysplastic syndrome (MDS) or later transformed into hypocellular MDS, which is a type of bone marrow failure syndrome. CONCLUSIONS: Clinicians should consider unexpected tumor lysis syndrome to be the cause of complications after antithymocyte globulin treatment in kidney transplant recipients with underlying bone marrow failure syndrome.
Assuntos
Injúria Renal Aguda/etiologia , Anemia Aplástica/complicações , Soro Antilinfocitário/efeitos adversos , Hiperuricemia/etiologia , Fatores Imunológicos/efeitos adversos , Transplante de Rim , Síndromes Mielodisplásicas/complicações , Síndrome de Lise Tumoral/etiologia , Injúria Renal Aguda/patologia , Adulto , Transtornos da Insuficiência da Medula Óssea/complicações , Feminino , Rejeição de Enxerto/tratamento farmacológico , HumanosRESUMO
INTRODUCTION: Bone marrow failure (BMF) syndromes are rare disorders with an annual incidence of 2-4 cases per million. Treatment options include immunosuppressive therapy (IST) and hematopoietic stem cell transplantation (HSCT). OBJECTIVE: To analyze the outcomes of pediatric patients diagnosed with BMF treated in a tertiary care center. PATIENTS AND METHOD: Retrospective study of pediatric patients diagnosed with BMF who consulted at Fundación Valle de Lili, Cali. Descriptive statistical analysis was performed according to Acquired BMF (ABMF) and Inherited BMF (IBMF). The outcomes include treatment, complications, overall survival (OS) in transplant patients, calculated using the Kaplan Meier method. RESULTS: We included 24 patients with BMF, average age 6.5 ± 4 years, and 50% were women. 58% presented IBMF, 9 with Fanconi anemia (FA), 2 dyskeratosis congenita, 2 congenital amegakaryocytic thrombocytopenia, and 1 presented Diamond-Blackfan anemia. 12 patients treated with HSCT had a 5-year OS of 83%. ABMF represented 42%. 6 patients received IST-HSCT, 3 received IST, and 1 received HSCT. The OS of the IST-HSCT group was 86%. Six patients died, four of them related to infection. CONCLUSIONS: In this series, there was a higher number of cases with IBMF. The OS of patients treated with HSCT is similar to that reported in recent studies. The most frequent cause of death was of infectious origin which has also been previously reported. The treatment esta blished in the patients showed favorable results in a Latin American tertiary care center.
Assuntos
Transtornos da Insuficiência da Medula Óssea/terapia , Transplante de Células-Tronco Hematopoéticas , Imunossupressores/uso terapêutico , Adolescente , Transtornos da Insuficiência da Medula Óssea/complicações , Transtornos da Insuficiência da Medula Óssea/diagnóstico , Transtornos da Insuficiência da Medula Óssea/mortalidade , Criança , Pré-Escolar , Colômbia , Terapia Combinada , Feminino , Humanos , Lactente , Recém-Nascido , Estimativa de Kaplan-Meier , Masculino , Estudos Retrospectivos , Taxa de Sobrevida , Centros de Atenção Terciária , Resultado do TratamentoRESUMO
Immune-mediated processes are considered important in the pathogenesis of bone marrow failure syndromes (BFS). We previously reported that natural killer group 2D (NKG2D) ligands were expressed on pathological blood cells of patients with BFS and that NKG2D immunity may be involved in bone marrow failure. In addition to membranous NKG2D ligands on the cell surface, soluble NKG2D ligands can exist in plasma. We therefore examined the relationship between soluble NKG2D ligands and blood cell counts in 86 patients with BFS, including aplastic anemia, myelodysplastic syndrome with single lineage dysplasia, and paroxysmal nocturnal hemoglobinuria. Approximately half of the BFS patients were positive for soluble NKG2D ligands in the plasma by enzyme-linked immunosorbent assay, and soluble NKG2D ligand-positive BFS patients exhibited severe cytopenia regardless of membranous NKG2D ligand expression. In vitroanalyses demonstrated that soluble ULBP1, an NKG2D ligand, down-regulated NKG2D receptors on CD2-positive cells in peripheral blood. Moreover, soluble ULBP1 attenuated the cytotoxic effects of peripheral blood mononuclear cells on K562, which express membranous ULBP1. Our results suggest that soluble NKG2D ligands can be easy-to-measure biomarkers for the prediction of activity of immune-meditated bone marrow injury in BFS and that soluble NKG2D ligands suppress redundant immune-mediated bone marrow injury.
Assuntos
Biomarcadores/sangue , Transtornos da Insuficiência da Medula Óssea/diagnóstico , Peptídeos e Proteínas de Sinalização Intracelular/sangue , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anemia Aplástica/diagnóstico , Contagem de Células Sanguíneas , Transtornos da Insuficiência da Medula Óssea/complicações , Antígenos CD2/metabolismo , Regulação para Baixo , Proteínas Ligadas por GPI/sangue , Doenças Hematológicas/complicações , Doenças Hematológicas/diagnóstico , Hemoglobinúria Paroxística/diagnóstico , Humanos , Leucócitos Mononucleares/citologia , Leucócitos Mononucleares/metabolismo , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/diagnóstico , Subfamília K de Receptores Semelhantes a Lectina de Células NK/metabolismo , Adulto JovemRESUMO
PURPOSE: The aim of this study was to evaluate seizure outcome in children with hematological malignancies and PRES and to identify prognostic factors that could help manage the syndrome. METHOD: We retrospectively reviewed the report data of 21 patients diagnosed with hematological malignancy or aplastic anemia and PRES between 2008 and 2018. Basic demographic data, oncology treatment, presymptomatic hypertension before PRES manifestation, neurological status, seizure type, and EEG and MRI findings at PRES onset and at the one-year follow-up visit were studied. Patients who developed remote symptomatic seizures or epilepsy were identified. RESULTS: We included 21 children (11 females and 10 males) in the study. Sixteen patients (76.2%) were diagnosed with ALL and the rest individually with AML, CML, T-lymphoma, Burkitt lymphoma, and severe aplastic anemia. Presymptomatic hypertension (PSH) was evaluated in 19 patients and was present in 18 (94.7%). The duration was 9 h and more in 16 patients (88.8%); the severity was grade II in 12 patients (66.7%). Seizures as the initial symptom of PRES were present in 17 patients (80.9%). Four patients (19.0%) were assessed with remote symptomatic seizures. Two of them (9.5%) had ongoing seizures at the one-year follow-up visit and were diagnosed with epilepsy. The presence of gliosis on follow-up MRI indicated worse outcome with development of epilepsy (without statistical significance). CONCLUSIONS: PRES syndrome has an overall good prognosis and the evolution to epilepsy is rare. The severity and duration of PSH or seizure severity and EEG findings at PRES onsetwere not associated with worse neurological outcomes in this study.
Assuntos
Transtornos da Insuficiência da Medula Óssea/diagnóstico por imagem , Neoplasias Hematológicas/diagnóstico por imagem , Síndrome da Leucoencefalopatia Posterior/diagnóstico por imagem , Convulsões/diagnóstico por imagem , Adolescente , Transtornos da Insuficiência da Medula Óssea/complicações , Transtornos da Insuficiência da Medula Óssea/fisiopatologia , Criança , Pré-Escolar , Estudos de Coortes , Eletroencefalografia/métodos , Feminino , Seguimentos , Neoplasias Hematológicas/complicações , Neoplasias Hematológicas/fisiopatologia , Humanos , Masculino , Síndrome da Leucoencefalopatia Posterior/complicações , Síndrome da Leucoencefalopatia Posterior/fisiopatologia , Prognóstico , Estudos Retrospectivos , Convulsões/complicações , Convulsões/fisiopatologiaRESUMO
Fanconi anemia (FA) is a life-threatening syndrome characterized by bone marrow failure and cancer predispositions. The past two decades have seen an explosion of data in the FA field, both in humans and other organisms, following the cloning of 22 FA genes. A common but notably understudied clinical feature of the disease is the reduced fertility of individuals with FA. This review focuses on the known causes of reduced fertility in FA, and integrates them with the emerging role of the FA pathway in double-strand break (DSB) repair at meiosis in a variety of organisms, as well as providing future directions for research and diagnostics.