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Acute myeloid leukemia (AML) with t(8;21) (q22;q22), which forms RUNX1::RUNX1T1 fusion gene, is classified as a favorable-risk group. However, the presence of mutations in KIT exon 17 results in an adverse prognosis in this group. Avapritinib, a novel tyrosine kinase inhibitor, was designed to target KIT mutation. We report a retrospective study of four pediatric patients with AML with t(8:21) and KIT exon 17 mutation who were treated with avapritinib, three of them failed to demethylate drugs and donor lymphocyte infusion targeting RUNX1::RUNX1T1-positivity after allogeneic hematopoietic stem cell transplantation (allo-HSCT). So far, all patients with RUNX1::RUNX1T1 positivity had turned negative after 1, 9, 7, 2 months of avapritinib treatment. The common adverse effect of avapritinib is neutropenia, which is well-tolerated. This case series indicates that avapritinib may be effective and safe for preemptive treatment of children with AML with t(8;21) and KIT mutation after allo-HSCT, providing a treatment option for preventing relapse after allo-HSCT.
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Most tumors are sporadic and originated from somatic mutations. Some rare germline mutations cause familial tumors, often involving multiple tissues or organs. Tumors from somatic mosaicism during embryonic development are extremely rare. We describe here a pediatric patient who developed both an ovarian germ cell tumor and systemic mastocytosis. Targeted DNA next-generation sequencing analysis revealed similar genomic changes including the same KIT D816V mutation in both tissues, suggesting a common progenitor cancer cell. The KIT mutated cells are likely from early embryonic development during germ cell migration. A literature search found additional eight similar cases. These diseases are characterized by pediatric-onset, all-female, neoplastic proliferation in both gonad and bone marrow, and a common oncogenic cause, that is, KIT mutation, constituting a clinically and genetically homogenous disease entity. Importantly, the association of germ cell tumors with hematopoietic neoplasms suggests that the primordial germ cells are the primitive hematopoietic stem cells, a much-debated and unsettled question.
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Mastocitose Sistêmica/genética , Neoplasias Embrionárias de Células Germinativas/genética , Neoplasias Ovarianas/genética , Proteínas Proto-Oncogênicas c-kit/genética , Medula Óssea/metabolismo , Medula Óssea/patologia , Pré-Escolar , Feminino , Mutação em Linhagem Germinativa , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/metabolismo , Neoplasias Hematológicas/patologia , Humanos , Mastocitose Sistêmica/metabolismo , Mastocitose Sistêmica/patologia , Neoplasias Embrionárias de Células Germinativas/metabolismo , Neoplasias Embrionárias de Células Germinativas/patologia , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Proteínas Proto-Oncogênicas c-kit/metabolismoRESUMO
BACKGROUND: Myelodysplastic syndrome (MDS) is a rare disease in children and the treatment option before the allogeneic hematopoietic stem cell transplantation (allo-HSCT) is rarely reported. Our main objective was to report our single-center experience with the DNA-hypomethylating agent, decitabine-combined minimally myelosuppressive regimen (DAC + MMR) bridged allo-HSCT in children with MDS. METHODS: Twenty-eight children with de novo MDS who underwent allo-HSCT between 2011 and 2020 were enrolled. Patients were divided into subgroups (refractory cytopenia of childhood [RCC] and advanced MDS [aMDS]) and treated by HSCT alone or pre-transplant combination treatment based on risk stratification. The patients' clinical characteristics, treatment strategies and outcomes were retrospectively evaluated. RESULTS: Twenty patients with aMDS had received pre-transplant treatment (three were treated with decitabine alone, thirteen with DAC + MMR, and four with acute myeloid leukemia type [AML-type] induction therapy). DAC + MMR was well tolerated and the most common adverse events were myelosuppression and gastrointestinal reaction. DAC + MMR had shown an improved marrow complete remission (mCR) compared with AML-type chemotherapy (13/13, 100% versus 2/4, 50%, P = 0.044). The median follow-up for total cohort was 53.0 months (range, 2.3-127.0 months) and the 4-year overall survival (OS) was 71.4 ± 8.5%. In the subgroup of aMDS, pretreatment of DAC + MMR resulted in a much better survival rate than AML-type chemotherapy (84.6 ± 10.0% versus 0.0 ± 0.0%, P < 0.001). CONCLUSIONS: The DAC + MMR bridged allo-HSCT may be recommended as a novel and effective approach.
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Transplante de Células-Tronco Hematopoéticas , Síndromes Mielodisplásicas , Criança , Decitabina/uso terapêutico , Humanos , Síndromes Mielodisplásicas/terapia , Doenças Raras , Estudos RetrospectivosRESUMO
BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) is a heterogeneous disease with major diagnostic and therapeutic difficulties. A large-scale multicenter study of pediatric HLH is still lacking in China. PROCEDURE: The Histiocytosis Study Group of the Chinese Pediatric Society conducted this retrospective study in 2014. A total of 323 patients diagnosed with HLH between 2011 and 2013 from 12 hospitals were registered. RESULTS: The median age at diagnosis was 2.2 years (range, 0-14.6 years), with a peak age of HLH onset at 0 to 3 years (63%). Mutations in HLH-related genes were found in 27.9% (24/86) patients who underwent genetic testing. PRF1, UNC13D, STXBP2 and LYST were the predominant genes involved. Sixteen patients (66.7%) presented with only monoallelic mutations in one gene. Epstein-Barr virus (EBV) infection was the major condition related to HLH, which was documented in 74.4% (201/270) of the patients who underwent EBV detection. Of 252 evaluable patients, 64.7% (163) achieved non-active disease at the eighth week and patients treated with a protocol containing etoposide presented higher remission rates (75.6% vs. 46.8%, P < 0.001). In multivariate analysis, a younger age at diagnosis (<12 months), platelet count less than 80×109 /L, central nervous system involvement, and initial treatment using a protocol without etoposide (not HLH-94/04) were independent prognostic factors indicating resistant disease. DISCUSSION: This study first multicenter assessment of HLH in China shows some different features in Chinese children with HLH compared with those in western countries, including older age, vulnerability to EBV infection, and a high proportion of patients with single monoallelic genetic mutations.
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Biomarcadores/metabolismo , Linfo-Histiocitose Hemofagocítica/patologia , Adolescente , Criança , Pré-Escolar , Quimioterapia Combinada , Feminino , Seguimentos , Humanos , Lactente , Recém-Nascido , Linfo-Histiocitose Hemofagocítica/tratamento farmacológico , Linfo-Histiocitose Hemofagocítica/genética , Masculino , Proteínas de Membrana/genética , Proteínas Munc18/genética , Mutação/genética , Perforina/genética , Prognóstico , Estudos Retrospectivos , Proteínas de Transporte Vesicular/genéticaRESUMO
Histone modification is dysregulated in various types of cancers, including hematological malignancies. However, the expression profile of histone-modifying enzymes in pediatric acute monoblastic leukemia (AML FAB M5) has not been investigated. In this study, we evaluated the mRNA expression profile of 85 genes that encode enzymes involved in histone-modification in 27 pediatric AML FAB M5 samples by using a novel real-time PCR array. We obtained a gene cluster consisting of a total of 28 genes (15 up-regulated genes and 13 down-regulated genes). This gene signature revealed up-regulated expression of putative oncogenes GCN5L2, SETD8, KDM5C, AURKA and AURKB, and downregulated putative tumor suppressor genes (TSGs) EP300, PRMT3, PRMT8 and NOTCH2. We investigated possible biological interactions between differentially expressed genes using ingenuity pathway analysis (IPA) and found 12 significant networks. Among these, gene expression, cancer, and embryonic development showed the highest number of networks with 39 focus molecules and had an associated significance score of 68. Further, Rb, CDKN2C, and E2F1 were found to be upstream regulators of histone-modifying enzymes. This study provides additional insights into the molecular pathogenesis of pediatric AML FAB M5. These genes represent interesting targets with potential for diagnostic, prognostic and therapeutic application in pediatric AML patients.
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Enzimas/genética , Histonas/metabolismo , Leucemia Monocítica Aguda/genética , RNA Mensageiro/genética , Estudos de Casos e Controles , Criança , Regulação para Baixo , Enzimas/metabolismo , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Leucemia Monocítica Aguda/enzimologia , Leucemia Monocítica Aguda/patologia , Prognóstico , Reação em Cadeia da Polimerase em Tempo Real , Regulação para CimaAssuntos
Proteínas de Fusão Oncogênica/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Proteínas Tirosina Quinases/antagonistas & inibidores , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Criança , Pré-Escolar , Inibidores Enzimáticos/uso terapêutico , Feminino , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Hibridização in Situ Fluorescente/métodos , Lactente , Recém-Nascido , Cariótipo , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Proteínas Tirosina Quinases/genética , Proteínas Tirosina Quinases/metabolismo , Indução de Remissão , Transplante Homólogo/métodos , Resultado do TratamentoRESUMO
Autoimmune hemolytic anemia (AIHA) is a rare disease in children, and its clinical severity varies. To better understand disease manifestation and treatment outcome, we analyzed 68 children diagnosed as AIHA for clinical characteristics, laboratory findings, and treatment outcomes. Data show that primary AIHA accounted for 39.7% of all patients, whereas secondary AIHA accounted for 60.3%. Among them, Evans syndrome (ES) accounted for 20 cases (29.4%). Average hemoglobin was lower in the 1-year or below age group than in the above 1-year age group, combined-antibody group than single-antibody group, and IgM-contained group than non-IgM-contained group (P<0.05 for all). The duration of therapy in the ES group was longer than that in the AIHA-only group (P<0.05). During the follow-up period, 29 cases (29/45, 64.4%) remained in continuous remission. In total, 35.6% of patients relapsed after first complete remission and 56.3% of them still showed good response to glucocorticoid after relapse. There was no difference in the duration of therapy or relapse rate between the intravenous immunoglobulin (IVIG)-treatment group and the non-IVIG-treatment group. In conclusion, the severity of anemia correlates with age and serologic types of direct antiglobulin test. Glucocorticoid is efficacious for AIHA regardless of whether it is a first attack or relapse in this cohort of young patients. ES needs longer treatment duration. IVIG does not improve the outcome of AIHA.
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Anemia Hemolítica Autoimune/diagnóstico , Anemia Hemolítica Autoimune/terapia , Adolescente , Anemia Hemolítica Autoimune/sangue , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Estudos RetrospectivosRESUMO
BACKGROUND: Wilms' tumor (WT) is one of the most common malignant neoplasms of the urinary tract in children. Anaplastic histology (unfavorable histology) accounts for about 10% of whole WTs, and it is the single most important histologic predictor of treatment response and survival in patients with WT; however, until now the molecular basis of this phenotype is not very clearly. METHODS: A real-time polymerase chain reaction (PCR) array was designed and tested. Next, the gene expression profile of pediatric anaplastic histology WT and normal adjacent tissues were analyzed. These expression data were anlyzed with Multi Experiment View (MEV) cluster software further. Datasets representing genes with altered expression profiles derived from cluster analyses were imported into the Ingenuity Pathway Analysis Tool (IPA). RESULTS: 88 real-time PCR primer pairs for quantitative gene expression analysis of key genes involved in pediatric anaplastic histology WT were designed and tested. The gene expression profile of pediatric anaplastic histology WT is significantly different from adjacent normal controls; we identified 15 genes that are up-regulated and 16 genes that are down-regulated in the former. To investigate biological interactions of these differently regulated genes, datasets representing genes with altered expression profiles were imported into the IPA for further analysis, which revealed three significant networks: Cancer, Hematological Disease, and Gene Expression, which included 27 focus molecules and a significance score of 43. The IPA analysis also grouped the differentially expressed genes into biological mechanisms related to Cell Death and Survival 1.15E(-12), Cellular Development 2.84E(-11), Cellular Growth and Proliferation 2.84E(-11), Gene Expression 4.43E(-10), and DNA Replication, Recombination, and Repair 1.39E(-07). The important upstream regulators of pediatric anaplastic histology WT were TP53 and TGFß1 signaling (P = 1.15E(-14) and 3.79E(-13), respectively). CONCLUSIONS: Our study demonstrates that the gene expression profile of pediatric anaplastic histology WT is significantly different from adjacent normal tissues with real-time PCR array. We identified some genes that are dysregulated in pediatric anaplastic histology WT for the first time, such as HDAC7, and IPA analysis showed the most important pathways for pediatric anaplastic histology WT are TP53 and TGFß1 signaling. This work may provide new clues into the molecular mechanisms behind pediatric anaplastic histology WT.
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BACKGROUND: Acute myeloid leukemia (AML) is the second-most common form of leukemia in children. Aberrant DNA methylation patterns are a characteristic feature of AML. GATA4 has been suggested to be a tumor suppressor gene regulated by promoter hypermethylation in various types of human cancers although the expression and promoter methylation of GATA4 in pediatric AML is still unclear. METHODS: Transcriptional expression levels of GATA4 were evaluated by semi-quantitative and real-time PCR. Methylation status was investigated by methylation-specific PCR (MSP) and bisulfate genomic sequencing (BGS). The prognostic significance of GATA4 expression and promoter methylation was assessed in 105 cases of Chinese pediatric acute myeloid leukemia patients with clinical follow-up records. RESULTS: MSP and BGS analysis showed that the GATA4 gene promoter is hypermethylated in AML cells, such as the HL-60 and MV4-11 human myeloid leukemia cell lines. 5-Aza treatment significantly upregulated GATA4 expression in HL-60 and MV4-11 cells. Aberrant methylation of GATA4 was observed in 15.0 % (3/20) of the normal bone marrow control samples compared to 56.2 % (59/105) of the pediatric AML samples. GATA4 transcript levels were significantly decreased in AML patients (33.06 ± 70.94; P = 0.011) compared to normal bone marrow/idiopathic thrombocytopenic purpura controls (116.76 ± 105.39). GATA4 promoter methylation was correlated with patient leukocyte counts (WBC, white blood cells) (P = 0.035) and minimal residual disease MRD (P = 0.031). Kaplan-Meier survival analysis revealed significantly shorter overall survival time in patients with GATA4 promoter methylation (P = 0.014). CONCLUSIONS: Epigenetic inactivation of GATA4 by promoter hypermethylation was observed in both AML cell lines and pediatric AML samples; our study implicates GATA4 as a putative tumor suppressor gene in pediatric AML. In addition, our findings imply that GATA4 promoter methylation is correlated with WBC and MRD. Kaplan-Meier survival analysis revealed significantly shorter overall survival in pediatric AML with GATA4 promoter methylation but multivariate analysis shows that it is not an independent factor. However, further research focusing on the mechanism of GATA4 in pediatric leukemia is required.
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Metilação de DNA/genética , Fator de Transcrição GATA4/genética , Leucemia Mieloide Aguda/genética , Prognóstico , Adolescente , Criança , Pré-Escolar , Ilhas de CpG/genética , Feminino , Fator de Transcrição GATA4/biossíntese , Regulação Leucêmica da Expressão Gênica , Células HL-60 , Humanos , Estimativa de Kaplan-Meier , Leucemia Mieloide Aguda/patologia , Masculino , Regiões Promotoras GenéticasRESUMO
Polo-like kinase 1 (PLK1) is highly expressed in many cancers and therefore a biomarker of transformation and potential target for the development of cancer-specific small molecule drugs. RO3280 was recently identified as a novel PLK1 inhibitor; however its therapeutic effects in leukemia treatment are still unknown. We found that the PLK1 protein was highly expressed in leukemia cell lines as well as 73.3% (11/15) of pediatric acute myeloid leukemia (AML) samples. PLK1 mRNA expression was significantly higher in AML samples compared with control samples (82.95 ± 110.28 vs. 6.36 ± 6.35; p < 0.001). Kaplan-Meier survival analysis revealed that shorter survival time correlated with high tumor PLK1 expression (p = 0.002). The 50% inhibitory concentration (IC50) of RO3280 for acute leukemia cells was between 74 and 797 nM. The IC50 of RO3280 in primary acute lymphocytic leukemia (ALL) and AML cells was between 35.49 and 110.76 nM and 52.80 and 147.50 nM, respectively. RO3280 induced apoptosis and cell cycle disorder in leukemia cells. RO3280 treatment regulated several apoptosis-associated genes. The regulation of DCC, CDKN1A, BTK, and SOCS2 was verified by western blot. These results provide insights into the potential use of RO3280 for AML therapy; however, the underlying mechanisms remain to be determined.
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Apoptose/efeitos dos fármacos , Azepinas/toxicidade , Proteínas de Ciclo Celular/antagonistas & inibidores , Leucemia Mieloide Aguda/patologia , Inibidores de Proteínas Quinases/toxicidade , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Pirimidinas/toxicidade , Azepinas/química , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proteínas de Ciclo Celular/metabolismo , Criança , Pré-Escolar , Análise por Conglomerados , Fragmentação do DNA/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Feminino , Células HL-60 , Humanos , Células K562 , Estimativa de Kaplan-Meier , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/mortalidade , Masculino , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Pirimidinas/química , Células Tumorais Cultivadas , Regulação para Cima/efeitos dos fármacos , Quinase 1 Polo-LikeRESUMO
BACKGROUND: Acute myeloid leukemia (AML) is the second most common form of leukemia in children. Aberrant DNA methylation patterns are a characteristic feature in various tumors, including AML. Metallothionein III (MT3) is a tumor suppresser reported to show promoter hypermethylated in various cancers. However, the expression and molecular function of MT3 in pediatric AML is unclear. METHODS: Eleven human leukemia cell lines and 41 pediatric AML samples and 20 NBM/ITP (Norma bone marrow/Idiopathic thrombocytopenic purpura) control samples were analyzed. Transcription levels of MT3 were evaluated by semi-quantitative and real-time PCR. MT3 methylation status was determined by methylation specific PCR (MSP) and bisulfite genomic sequencing (BSG). The molecular mechanism of MT3 was investigated by apoptosis assays and PCR array analysis. RESULTS: The MT3 promoter was hypermethylated in leukemia cell lines. More CpG's methylated of MT3 was observed 39.0% pediatric AML samples compared to 10.0% NBM controls. Transcription of MT3 was also significantly decreased in AML samples compared to NBM/ITP controls (P < 0.001); patients with methylated MT3 exhibited lower levels of MT3 expression compared to those with unmethylated MT3 (P = 0.049). After transfection with MT3 lentivirus, proliferation was significantly inhibited in AML cells in a dose-dependent manner (P < 0.05). Annexin V assay showed that apoptosis was significantly upregulated MT3-overexpressing AML cells compared to controls. Real-time PCR array analysis revealed 34 dysregulated genes that may be implicated in MT3 overexpression and apoptosis in AML, including FOXO1. CONCLUSION: MT3 may be a putative tumor suppressor gene in pediatric AML. Epigenetic inactivation of MT3 via promoter hypermethylation was observed in both AML cell lines and pediatric AML samples. Overexpression of MT3 may inhibit proliferation and induce apoptosis in AML cells. FOXO1 was dysregulated in MT3-overexpressing cells, offering an insight into the mechanism of MT3-induced apoptosis. However, further research is required to determine the underlying molecular details.
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Metilação de DNA , Genes Supressores de Tumor , Leucemia Mieloide Aguda/genética , Proteínas do Tecido Nervoso/genética , Regiões Promotoras Genéticas , Adolescente , Sequência de Bases , Linhagem Celular Tumoral , Criança , Pré-Escolar , Primers do DNA , Feminino , Humanos , Lactente , Leucemia Mieloide Aguda/patologia , Masculino , Metalotioneína 3 , Reação em Cadeia da PolimeraseRESUMO
OBJECTIVE: To explore the clinical characteristics, molecular characteristics, treatment and prognosis of pediatric Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) with a therapeutic target. METHODS: A total of 27 patients of Ph-like ALL with targeted drug target were initially diagnosed in Children's Hospital of Soochow University from December 2017 to June 2021. The data of age, gender, white blood cell (WBC) count at initial diagnosis, genetic characteristics, molecular biological changes, chemotherapy regimen, different targeted drugs were given, and minimal residual disease (MRD) on day 19, MRD on day 46, whether hematopoietic stem cell transplantation (HSCT) were retrospective analyed, and the clinical characteristics and treatment effect were summarized. Survival analysis was performed by Kaplan-Meier method. RESULTS: The intensity of chemotherapy was adjusted according to the MRD level during induced remission therapy in 27 patients, 10 patients were treated with targeted drugs during treatment, and 3 patients were bridged with HSCT, 1 patient died and 2 patients survived. Among the 24 patients who did not receive HSCT, 1 patient developed relapse, and achieved complete remission (CR) after treatment with chimeric antigen receptors T cells (CAR-T). The 3-year overall survival, 3-year relapse-free survival and 3-year event-free survival rate of 27 patients were (95.5±4.4)%, (95.0±4.9)% and (90.7±6.3)% respectively. CONCLUSION: Risk stratification chemotherapy based on MRD monitoring can improve the prognosis of Ph-like ALL in children, combined with targeted drugs can achieve complete remission as soon as possible in children whose chemotherapy response is poor, and sequential CAR-T and HSCT can significantly improve the therapeutic effect of Ph-like ALL in children whose MRD is continuously positive during induced remission therapy.
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Transplante de Células-Tronco Hematopoéticas , Leucemia-Linfoma Linfoblástico de Células Precursoras , Receptores de Antígenos Quiméricos , Criança , Humanos , Cromossomo Filadélfia , Estudos Retrospectivos , Prognóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Neoplasia Residual , Resposta Patológica Completa , RecidivaRESUMO
Chimeric antigen receptor T-cell (CAR-T) therapy is effective in the treatment of relapsed/refractory acute B-lymphoblastic leukemia (R/R B-ALL); however, patients who receive CAR-T therapy are predisposed to infections, with considerable detrimental effects on long-term survival rates and the quality of life of patients. This study retrospectively analyzed infectious complications in 79 pediatric patients with R/R B-ALL treated with CAR-T cells at our institution. Overall, 53 patients developed 88 infections. Nine patients experienced nine infections during lymphodepletion chemotherapy, 35 experienced 41 infections during the early phase (days 0-+ 30 after infusion), and 29 experienced 38 infections during the late phase (day + 31-+ 90 after infusion). Pathogens were identified in 31 infections, including 23 bacteria, seven viruses, and one fungus. Four patients were admitted to the intensive care unit for infection and one died. In a univariate analysis, there were ten factors associated with infection, including tumor load, lymphodepleting chemotherapy, neutrophil deficiency and lymphocyte reduction, cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), etc. In a multivariate analysis, CRS ≥ grade 3 was identified as a risk factor for infection (hazard ratio = 2.41, 95% confidence interval: 1.08-5.36, P = 0.031). Therefore, actively reducing the CRS grade may decrease the risk of infection and improve the long-term quality of life of these patients.
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Imunoterapia Adotiva , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Antígenos CD19/imunologia , Imunoterapia Adotiva/efeitos adversos , Infecções/etiologia , Infecções/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Receptores de Antígenos Quiméricos/imunologia , Estudos RetrospectivosRESUMO
Congenital dyserythropoietic anemia type II (CDA II) refers to a group of extremely rare heterozygous disorders characterized by ineffective erythropoiesis and morphological abnormalities of erythrocytes and bone marrow erythroblasts. Six types of CDA with differing heterogenous genetic mutations have been identified to date. Due to the genetic and clinical heterogeneity of CDA, accurate diagnosis can be very challenging, especially with the clinical overlap observed between CDA and other dyserythropoietic diseases. A 1-month-old infant girl, born to a non-consanguineous family, presented with severe normocytic anemia that required transfusions every 2 to 3 weeks since birth, as well as jaundice. Whole exome sequencing revealed a novel compound heterozygosity in the SEC23B gene, thus establishing the diagnosis of CDA II. Analysis by multiple bioinformatics tools predicted that the mutant proteins were deleterious. Here, we report a novel variation in SEC23B that extends the mutation spectrum of SEC23B in the diagnosis of CDA II.
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Anemia Diseritropoética Congênita , Lactente , Recém-Nascido , Feminino , Humanos , Anemia Diseritropoética Congênita/diagnóstico , Anemia Diseritropoética Congênita/genética , Mutação , Heterozigoto , Eritroblastos/metabolismo , Proteínas de Transporte Vesicular/genéticaRESUMO
The outcomes of children with acute lymphoblastic leukemia (ALL) have been incrementally improved with risk-directed chemotherapy but therapy responses remain heterogeneous. Parameters with added prognostic values are warranted to refine the current risk stratification system and inform appropriate therapies. CD9, implicated by our prior single-center study, holds promise as one such parameter. To determine its precise prognostic significance, we analyzed a nationwide, multicenter, uniformly treated cohort of childhood ALL cases, where CD9 status was defined by flow cytometry on diagnostic samples of 3781 subjects. CD9 was expressed in 88.5% of B-ALL and 27.9% of T-ALL cases. It conferred a lower 5-year EFS and a higher CIR in B-ALL but not in T-ALL patients. The prognostic impact of CD9 was most pronounced in the intermediate/high-risk arms and those with minimal residual diseases, particularly at day 19 of remission induction. The adverse impact of CD9 was confined to specific cytogenetics, notably BCR::ABL1+ rather than KMT2A-rearranged leukemia. Multivariate analyses confirmed CD9 as an independent predictor of both events and relapse. The measurement of CD9 offers insights into patients necessitating intervention, warranting its seamless integration into the diagnostic marker panel to inform risk level and timely introduction of therapeutic intervention for childhood ALL.
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Leucemia-Linfoma Linfoblástico de Células Precursoras B , Leucemia-Linfoma Linfoblástico de Células Precursoras , Leucemia-Linfoma Linfoblástico de Células T Precursoras , Criança , Humanos , Prognóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Neoplasia Residual/diagnóstico , China , Tetraspanina 29RESUMO
Objective: To evaluate the clinical efficacy and safety of a short course of blinatumomab in children with refractory or relapsed precursor B-cell acute lymphoblastic leukemia (R/R-BCP-ALL). Methods: The clinical data of 33 R/R BCP-ALL children aged 0-18 years who underwent a short course of blinatumomab (14 days) between August 2021 and November 2022 were retrospectively collected and analyzed. Results: Among 33 patients with BCP-ALL, 26 achieved complete remission (CR), with a total remission rate of 78.8% (26/33). The duration of remission was approximately 14 days. Of the 7 children without CR, 5 were still in remission at 28 days. In 11 patients with refractory disease and 22 with recurrence, the remission rates were 90.9% (10/11) and 72.7% (16/22), respectively. The overall survival (OS) rates of the 26 patients with CR and seven patients without CR were 96.1% and 57.1% (p = 0.002), respectively, and the disease-free survival (DFS) rates were 96.1% and 42.9% (p < 0.001), respectively. Among the 26 patients with CR, 15 underwent bridging hematopoietic stem cell transplantation (HSCT) and 11 did not receive HSCT; with OS rates of 93.3% and 100% (p = 0.40) and DFS rates of 93.3% and 100% (p = 0.400), respectively. The OS for all patients was 87.9% (29/33) and the DFS was 84.8% (28/33). There were 18 cases (54.5%) of cytokine release syndrome (CRS), 2 cases (6.1%) of severe CRS (all grade 3), 1 case (3.0%) of immune effector cell-associated neurotoxicity syndrome (ICANS), 0 cases (0%) of ICANS ≥ grade 3, and no deaths caused by treatment. Conclusions: Short-term follow-up revealed a high R/R BCP-ALL remission rate in children treated with a short course of blinatumomab. The toxicity was low and controllable. No significant short-term survival benefits were observed after bridging HSCT with blinatumomab. In developing countries, a short course of blinatumomab can achieve satisfactory outcomes, while reducing household costs and saving medical resources.
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The synuclein family, consisting of α-, ß-, and γ-synuclein, is primarily expressed in neurons. Mutations of α- and ß-synuclein have been linked to Parkinson's disease and dementia with Lewy bodies, respectively. Recent studies have shown that synucleins are upregulated in various tumors, including breast, ovarian, meningioma, and melanoma, and high synuclein expression is associated with poor prognosis and drug resistance. We report a novel rearrangement of ß-synuclein in a pediatric T-cell acute lymphoblastic leukemia (T-ALL) case, where ß-synuclein (SNCB) is fused in-frame with ETS variant transcription factor 6 (ETV6), a gene frequently rearranged in acute leukemia including acute myeloid leukemia (AML), B-cell acute lymphoblastic leukemia (B-ALL), and T-ALL. An additional case of ß-synuclein rearrangement was identified in a squamous cell carcinoma of the lung through analysis of the public TCGA database. Both rearrangements involve the C-terminal of ß-synuclein. Since ß-synuclein shares extensive amino acid similarities with α-synuclein and α-synuclein binds to 14-3-3, an important regulator of apoptosis, the rearranged ß-synuclein may contribute to tumorigenesis by deregulating apoptosis. In addition, overexpression of synucleins has been shown to increase cell proliferation, suggesting that the rearranged ß-synuclein may also deregulate the cell cycle.
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Driver genomic alterations in pediatric immature T-cell acute lymphoblastic leukemia are not fully known. We report two cases of novel EVX fusions involved in the transcriptional activation of HOX family genes, ETV6::EVX2 and MSI2::EVX1/HOXA13, which activate HOXD and HOXA cluster genes transcription through enhancer hijacking. HOXA and HOXD were the only key transcription factors activated in these cases, which indicates their important roles in leukemogenesis. Our findings elucidate potential drivers for development of T-cell lymphoblastic leukemia, and are valuable for diagnosis and risk stratification of pediatric T-ALL in the era of precision medicine.
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Leucemia de Células T , Leucemia-Linfoma Linfoblástico de Células T Precursoras , Humanos , Criança , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Transcriptoma , Ativação Transcricional , Genes Homeobox , Linfócitos T , Proteínas de Ligação a RNARESUMO
We aimed to determine the relationship between lymphocyte subsets on day 30 (D30) and prognosis after allogeneic hematopoietic stem cell transplantation (allo-HSCT) in children. We retrospectively examined the clinical outcomes and lymphocyte subsets on D30 after allo-HSCT in 115 pediatric patients at the Children's Hospital of Soochow University between January 2016 and June 2019. Measurements were performed using flow cytometry on D30. Lymphocyte subsets were compared among the umbilical cord blood (UCB) (n = 22), HLA-matched sibling donor (MSD) (n = 14), haploidentical donor transplantation (HID) (n = 57), and unrelated donor transplantation (UD) (n = 22) groups. The relationships between the frequencies and counts of lymphocyte subsets and clinical outcomes were analyzed. T and B cell counts were the highest in the MSD group compared to the other groups, and natural killer cell counts were the highest in the UCB group. Lymphocyte subsets on D30 after allo-HSCT were correlated with the occurrence of acute (aGVHD) and chronic graft versus host disease (cGVHD). A high frequency of B cells (≥4.65%) was associated with the development of severe aGVHD. High frequencies of CD4+T (≥10.25%) were correlated with extensive cGVHD. Moreover, a high frequency of CD4+T cells (≥9.80%) was correlated with GVHD-free and failure-free survival (GFFS) after allo-HSCT. However, on D30, there were no statistically significant correlations between viral infections and lymphocyte subsets. The frequencies of lymphocyte subsets on D30 after allo-HSCT are good indicators of prognosis after allo-HSCT in children.
Assuntos
Síndrome de Bronquiolite Obliterante , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Humanos , Criança , Estudos Retrospectivos , Doadores não Relacionados , Subpopulações de LinfócitosRESUMO
Background: Methotrexate (MTX), utilized as a graft-versus-host disease (GvHD) prophylactic agent in allogeneic hematopoietic stem cell transplantation (allo-HSCT), has been proven to effectively decrease the occurrence of the peri-engraftment syndrome (Peri-ES) and acute GvHD (aGvHD). Changes in the pharmacodynamics of MTX are closely associated with gene polymorphisms in genes encoding drug-metabolizing enzymes and transporters. Nevertheless, the current studies mainly concentrate on leukemia or autoimmune diseases, and limited studies on allo-HSCT were reported. Methods: Here, we retrospectively assessed the relationship between MTX-related transporter and metabolizing enzyme gene polymorphisms, clinical characteristics, and outcomes in 57 pediatric patients who received haploid HSCT (haplo-HSCT) with malignant tumors at a single center. Results: We discovered all gene polymorphisms were in the Hardy-Weinberg equilibrium in our cohort. We discovered a significant correlation between platelet recovery time and ABCB1 (1236C>T) (p = 0.042). Compared with patients with SLCO1B1 (1865+4846T>C) TT, patients with SLCO1B1 (1865+4846T>C) TC/CC had an increased incidence of Peri-ES (p = 0.030). Based on the multivariate Cox analysis, we discovered that SLCO1B1 (1865+4846T>C) TT genotype was an independent protective factor for Peri-ES morbidity (hazard ratio (HR) = 0.464, p = 0.031), and the dose of mononuclear cells reinfused was significantly correlated with II-IV aGvHD (HR = 2.604, p = 0.039). Conclusion: In summary, our findings prove that the host's genotypes might modify the risk of developing Peri-ES, contribute to a better understanding of the inter-individual difference in efficacy, and facilitate the development of individualized approaches to GvHD prophylaxis.