RESUMO
OBJECTIVE: To obtain a national overview of the epidemiology and management of invasive fungal infections (IFIs) in France for severely immunocompromised children who were treated for acute leukemia or had undergone allogeneic hematopoietic stem cell transplantation (a-HSCT). STUDY DESIGN: We performed a national multicenter retrospective study to collect epidemiologic data for proven and probable IFIs in children with acute leukemia under first- line or relapse treatment or who had undergone a-HSCT. We also conducted a prospective practice survey to provide a national overview of IFI management in pediatric hematology units. RESULTS: From January 2014 to December 2017, 144 cases of IFI were diagnosed (5.3%) in 2721 patients, including 61 cases of candidiasis, 60 cases of aspergillosis, and 23 cases of infection with "emergent" fungi, including 10 cases of mucormycosis and 6 cases of fusariosis. The IFI rate was higher in patients with acute myelogenous leukemia (12.9%) (OR, 3.24; 95% CI, 2.15-4.81; P < .0001) compared with the rest of the cohort. Patients undergoing a-HSCT had an IFI rate of only 4.3%. In these patients, the use of primary antifungal prophylaxis (principally fluconazole) was associated with a lower IFI rate (OR, 0.28; 95% CI, 0.14-0.60; P = 4.90 ×10-4) compared with a-HSCT recipients who did not receive antifungal prophylaxis. The main cause of IFI in children receiving prophylaxis was emergent pathogens (41%), such as mucormycosis and fusariosis, which were resistant to the prophylactic agents. CONCLUSIONS: The emerging fungi and new antifungal resistance profiles uncovered in this study should be considered in IFI management in immunocompromised children.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Hospedeiro Imunocomprometido , Infecções Fúngicas Invasivas/epidemiologia , Leucemia Mieloide Aguda/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Adolescente , Criança , Pré-Escolar , Feminino , França , Humanos , Incidência , Lactente , Recém-Nascido , Infecções Fúngicas Invasivas/diagnóstico , Infecções Fúngicas Invasivas/terapia , Masculino , Estudos RetrospectivosRESUMO
BACKGROUND: Hepatitis-associated aplastic anemia (AA) is a rare syndrome combining acute hepatitis of variable severity and AA. Hepatitis may be severe enough to require urgent liver transplantation (LT). Herein, we describe clinical presentation and management of a cohort of pediatric patients diagnosed with AA after undergoing LT for nonviral hepatitis. METHODS: To describe this rare clinical situation, we performed a national survey and identified nine children treated for AA following LT during the last 10 years in France. RESULTS: All patients were treated first for hepatic failure with urgent LT. AA was diagnosed with a median delay of 34 days [21-200] from the diagnosis of hepatitis. Seven children were treated with antithymocyte globulin/cyclosporine, one with CSA alone and one received bone marrow transplantation. At the last visit (median follow-up: 4 years), outcomes were excellent: all patients were alive and in hematological remission (complete remission: 7; partial remission: 2). Immunosuppressive therapy was pursued in all patients due to the liver transplant. No unusual toxicities were reported. CONCLUSION: AA after LT is considered a therapeutic challenge. Nevertheless, hematological outcome is good using a standard immunosuppressive approach.
Assuntos
Anemia Aplástica , Hepatite , Terapia de Imunossupressão/efeitos adversos , Transplante de Fígado , Adolescente , Anemia Aplástica/epidemiologia , Anemia Aplástica/cirurgia , Criança , Pré-Escolar , Feminino , Seguimentos , França/epidemiologia , Hepatite/epidemiologia , Hepatite/etiologia , Hepatite/terapia , Humanos , MasculinoRESUMO
Runt-related transcription factor 1 (RUNX1) is a well-known master regulator of hematopoietic lineages but its mechanisms of action are still not fully understood. Here, we found that RUNX1 localizes on active chromatin together with Far Upstream Binding Protein 1 (FUBP1) in human B-cell precursor lymphoblasts, and that both factors interact in the same transcriptional regulatory complex. RUNX1 and FUBP1 chromatin localization identified c-KIT as a common target gene. We characterized two regulatory regions, at +700 bp and +30 kb within the first intron of c-KIT, bound by both RUNX1 and FUBP1, and that present active histone marks. Based on these regions, we proposed a novel FUBP1 FUSE-like DNA-binding sequence on the +30 kb enhancer. We demonstrated that FUBP1 and RUNX1 cooperate for the regulation of the expression of the oncogene c-KIT. Notably, upregulation of c-KIT expression by FUBP1 and RUNX1 promotes cell proliferation and renders cells more resistant to the c-KIT inhibitor imatinib mesylate, a common therapeutic drug. These results reveal a new mechanism of action of RUNX1 that implicates FUBP1, as a facilitator, to trigger transcriptional regulation of c-KIT and to regulate cell proliferation. Deregulation of this regulatory mechanism may explain some oncogenic function of RUNX1 and FUBP1.
Assuntos
Subunidade alfa 2 de Fator de Ligação ao Core/genética , Proteínas de Ligação a DNA/genética , Elementos Facilitadores Genéticos , Regulação Leucêmica da Expressão Gênica , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Proteínas Proto-Oncogênicas c-kit/genética , Proteínas de Ligação a RNA/genética , Animais , Antineoplásicos/farmacologia , Sequência de Bases , Sítios de Ligação , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/metabolismo , Células da Medula Óssea/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cromatina/química , Cromatina/metabolismo , Subunidade alfa 2 de Fator de Ligação ao Core/metabolismo , Proteínas de Ligação a DNA/metabolismo , Células HEK293 , Humanos , Mesilato de Imatinib/farmacologia , Camundongos , Camundongos Endogâmicos NOD , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Células Precursoras de Linfócitos B/efeitos dos fármacos , Células Precursoras de Linfócitos B/metabolismo , Células Precursoras de Linfócitos B/patologia , Cultura Primária de Células , Ligação Proteica , Proteínas Proto-Oncogênicas c-kit/metabolismo , Proteínas de Ligação a RNA/metabolismo , Transdução de Sinais , Transcrição Gênica , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: Little is known about care management for foreign patients in pediatric oncology in European centers. We aimed to describe care given to children, adolescents, and young adults who came to France for cancer treatment, and to determine whether their geographical origin had an influence on decision making. PROCEDURE: We conducted a monocentric retrospective study on all foreign patients aged 0-25 years and hospitalized for at least one night in Institut Curie (Paris, France) from 2009 to 2013. We analyzed the potential advantages of receiving treatment in France as well as their social and familial consequences. RESULTS: A total of 93 foreign patients' files were retrieved. Most of these patients came from Africa (70%). In accord with the specific expertise of the institution, retinoblastoma was the most frequent tumor type (39%). An antitumor treatment had already been administrated in the native country in 44% of patients. We considered that 66% of patients received a significant medical advantage from care in our institution. The treatment provided in France was considered impossible in the native country in 44% of cases. The social and familial impact on the patients' families was high (59%). Almost all patients (96%) received the treatment that would have been proposed to their French counterparts. CONCLUSIONS: There were notable medical advantages for foreign patients who come to France for their oncologic treatment despite important familial consequences. Patients' geographical origin did not have an influence on medical decisions.
Assuntos
Atenção à Saúde , Emigrantes e Imigrantes , Família , Retinoblastoma/terapia , Adolescente , Adulto , Feminino , França , Humanos , Masculino , Estudos RetrospectivosAssuntos
COVID-19 , Atenção à Saúde , Neoplasias , SARS-CoV-2 , Adolescente , COVID-19/epidemiologia , COVID-19/terapia , Criança , Pré-Escolar , Feminino , França/epidemiologia , Humanos , Lactente , Masculino , Oncologia , Neoplasias/epidemiologia , Neoplasias/terapia , Pediatria , Guias de Prática Clínica como Assunto , Sociedades MédicasRESUMO
Inflammatory myofibroblastic tumors (IMT) are rare tumors in children and young adults, considered by the World Health Organization to be intermediate malignancies and rarely metastasizing, with the presence of an anaplastic lymphoma kinase rearrangement in about 50% of the cases. We report the case of a teenager who presented with a metastatic aggressive IMT that was life-threatening despite multiple treatments, and which responded repeatedly to anaplastic lymphoma kinase-targeted crizotinib therapy. Crizotinib induced drastic primary tumor regression, which was sufficient to allow surgical resection and to control distant disease. This case shows that crizotinib is a promising therapy in IMT, even in adolescents and young adults.
Assuntos
Inflamação , Metástase Neoplásica , Neoplasias de Tecido Muscular/tratamento farmacológico , Adolescente , Quinase do Linfoma Anaplásico , Crizotinibe , Feminino , Rearranjo Gênico , Humanos , Neoplasias de Tecido Muscular/patologia , Neoplasias de Tecido Muscular/cirurgia , Inibidores de Proteínas Quinases/uso terapêutico , Pirazóis/administração & dosagem , Pirazóis/uso terapêutico , Piridinas/administração & dosagem , Piridinas/uso terapêutico , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Receptores Proteína Tirosina Quinases/genéticaAssuntos
Anemia Falciforme/complicações , Infecções por Coronavirus/epidemiologia , Leucemia de Células B/complicações , Pneumonia Viral/epidemiologia , Adolescente , Anemia Falciforme/terapia , Betacoronavirus , COVID-19 , Criança , Pré-Escolar , Feminino , França , Hematologia , Transplante de Células-Tronco Hematopoéticas , Humanos , Hospedeiro Imunocomprometido , Unidades de Terapia Intensiva , Leucemia de Células B/tratamento farmacológico , Leucemia de Células B/virologia , Masculino , Oncologia , Pandemias , Pediatria , Fatores de Risco , SARS-CoV-2 , Adulto JovemRESUMO
Acute lymphoblastic leukemias (ALL) are the most frequent cancer in children and derive most often from B-cell precursors. Current survival rates roughly reach 90% at 10 years from diagnosis. However, 15-20% of children still relapse with a significant risk of death. Our previous work showed that the transmembrane protein CD9 plays a major role in lymphoblasts migration into sanctuary sites, especially in testis, through the activation of RAC1 signaling upon blasts stimulation with C-X-C chemokine ligand 12 (CXCL12). Here, we identified common factors shared by the bone marrow and extramedullary niches which could upregulate CD9 expression and function. We found that low oxygen levels enhance CD9 expression both at mRNA and protein levels. We further determined that Hypoxia Inducible Factor 1α (HIF1α), the master transcription factor involved in hypoxia response, binds directly CD9 promoter and induce CD9 transcription. We also showed that CD9 protein is crucial for leukemic cell adhesion and migration at low oxygen levels, possibly through its action on RAC1 signaling. Mouse xenograft experiments indicate that HIF1α signaling pathway promotes ALL cells engraftment in a CD9-dependent manner. The present work increments our understanding of CD9 implication in ALL pathogenesis.
Assuntos
Hipóxia , Transdução de Sinais , Masculino , Humanos , Camundongos , Animais , Tetraspanina 29/genética , Tetraspanina 29/metabolismo , Adesão Celular , OxigênioRESUMO
Since the emergence of the SARS-CoV-2 infection, many recommendations have been made. However, the very specific nature of acute lymphoblastic leukemias and their treatment in children and adolescents led the Leukemia Committee of the French Society for the fight against Cancers and leukemias in children and adolescents (SFCE) to propose more specific recommendations. Here is the second version of these recommendations updated according to the evolution of knowledge on COVID19.
Assuntos
COVID-19/epidemiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/uso terapêutico , Adolescente , Corticosteroides/uso terapêutico , Alanina/análogos & derivados , Alanina/uso terapêutico , Antivirais/uso terapêutico , COVID-19/diagnóstico , Teste de Ácido Nucleico para COVID-19 , Vacinas contra COVID-19/uso terapêutico , Institutos de Câncer , Criança , Quimioterapia de Consolidação , Interações Medicamentosas , França/epidemiologia , Humanos , Quimioterapia de Indução/métodos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Quimioterapia de Manutenção/métodos , Recidiva , Medição de Risco , Sociedades Médicas , Tratamento Farmacológico da COVID-19RESUMO
BACKGROUND: B Cell Precursor Acute Lymphoblastic Leukemia (BCP-ALL) is the most common pediatric cancer. Identifying key players involved in proliferation of BCP-ALL cells is crucial to propose new therapeutic targets. Runt Related Transcription Factor 1 (RUNX1) and Core-Binding Factor Runt Domain Alpha Subunit 2 Translocated To 3 (CBFA2T3, ETO2, MTG16) are master regulators of hematopoiesis and are implicated in leukemia. METHODS: We worked with BCP-ALL mononuclear bone marrow patients' cells and BCP-ALL cell lines, and performed Chromatin Immunoprecipitations followed by Sequencing (ChIP-Seq), co-immunoprecipitations (co-IP), proximity ligation assays (PLA), luciferase reporter assays and mouse xenograft models. RESULTS: We demonstrated that CBFA2T3 transcript levels correlate with RUNX1 expression in the pediatric t(12;21) ETV6-RUNX1 BCP-ALL. By ChIP-Seq in BCP-ALL patients' cells and cell lines, we found that RUNX1 is recruited on its promoter and on an enhancer of CBFA2T3 located - 2 kb upstream CBFA2T3 promoter and that, subsequently, the transcription factor RUNX1 drives both RUNX1 and CBFA2T3 expression. We demonstrated that, mechanistically, RUNX1 and CBFA2T3 can be part of the same complex allowing CBFA2T3 to strongly potentiate the activity of the transcription factor RUNX1. Finally, we characterized a CBFA2T3-mimicking peptide that inhibits the interaction between RUNX1 and CBFA2T3, abrogating the activity of this transcription complex and reducing BCP-ALL lymphoblast proliferation. CONCLUSIONS: Altogether, our findings reveal a novel and important activation loop between the transcription regulator CBFA2T3 and the transcription factor RUNX1 that promotes BCP-ALL proliferation, supporting the development of an innovative therapeutic approach based on the NHR2 subdomain of CBFA2T3 protein.
Assuntos
Antineoplásicos/farmacologia , Subunidade alfa 2 de Fator de Ligação ao Core/antagonistas & inibidores , Peptídeos/farmacologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Mapas de Interação de Proteínas/efeitos dos fármacos , Proteínas Repressoras/metabolismo , Antineoplásicos/química , Linhagem Celular Tumoral , Criança , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Subunidade alfa 2 de Fator de Ligação ao Core/metabolismo , Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Humanos , Peptídeos/química , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/metabolismo , Domínios e Motivos de Interação entre Proteínas/efeitos dos fármacos , Proteínas Repressoras/química , Proteínas Repressoras/genética , Ativação Transcricional/efeitos dos fármacosRESUMO
Data regarding coronavirus disease 2019 (COVID-19) description are still limited in pediatric oncology. The French society of pediatric oncology (SFCE) initiated a study to better describe COVID-19 in patients followed in French pediatric oncology and hematology wards. All patients diagnosed with COVID-19 and followed in a SFCE center were enrolled. Data from medical records were analyzed for all patients enrolled up to the end of May 2020. Data were available for 37 patients. Thirty-one were children under 18 years of age. Nineteen patients were female. Seventeen patients had a solid tumor, 16 had a hematological malignancy and four recently underwent hematopoietic stem cell transplantation (HSCT) for non-oncological conditions. Twenty-eight patients presented symptoms, most often with fever, cough, rhinorrhea and asthenia. Ground-glass opacities were the most frequent radiological finding with abnormalities mostly bilateral and peripherally distributed. Twenty-four patients received chemotherapy a month prior to COVID-19 diagnosis. Most patients did not require hospitalization. Three patients required oxygen at the time of diagnosis. In total, five patients were admitted in an intensive care unit because of COVID-19 and one died from the disease. Children and young adults treated for a cancer and/or with a HSCT may be at risk for severe COVID-19 and should be closely monitored.
RESUMO
Long-term survival rates in childhood acute lymphoblastic leukemia (ALL) are currently above 85% due to huge improvements in treatment. However, 15-20% of children still experience relapses. Relapses can either occur in the bone marrow or at extramedullary sites, such as gonads or the central nervous system (CNS), formerly referred to as ALL-blast sanctuaries. The reason why ALL cells migrate to and stay in these sites is still unclear. In this review, we have attempted to assemble the evidence concerning the microenvironmental factors that could explain why ALL cells reside in such sites. We present criteria that make extramedullary leukemia niches and solid tumor metastatic niches comparable. Indeed, considering extramedullary leukemias as metastases could be a useful approach for proposing more effective treatments. In this context, we conclude with several examples of potential niche-based therapies which could be successfully added to current treatments of ALL.
Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Criança , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologiaAssuntos
Transformação Celular Neoplásica/patologia , Subunidade alfa 2 de Fator de Ligação ao Core/metabolismo , Regulação Leucêmica da Expressão Gênica , Proteínas de Homeodomínio/metabolismo , Proteínas de Fusão Oncogênica/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Proteínas de Homeodomínio/genética , Humanos , Proteínas de Fusão Oncogênica/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Células Tumorais CultivadasRESUMO
Tumoral plasma cells has retained stemness features and in particular, a polycomb-silenced gene expression signature. Therefore, epigenetic therapy could be a mean to fight for multiple myeloma (MM), still an incurable pathology. Deazaneplanocin A (DZNep), a S-adenosyl-L-homocysteine hydrolase inhibitor, targets enhancer of zest homolog 2 (EZH2), a component of polycomb repressive complex 2 (PRC2) and is capable to induce the death of cancer cells. We show here that, in some MM cell lines, DZNep induced both caspase-dependent and -independent apoptosis. However, the induction of cell death was not mediated through its effect on EZH2 and the trimethylation on lysine 27 of histone H3 (H3K27me3). DZNep likely acted through non-epigenetic mechanisms in myeloma cells. In vivo, in xenograft models, and in vitro DZNep showed potent antimyeloma activity alone or in combination with bortezomib. These preclinical data let us to envisage new therapeutic strategies for myeloma.