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1.
Hematol Oncol ; 2020 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-32809224

RESUMO

Over the years, the prognosis of adolescents treated for acute lymphoblastic leukemia (ALL) has improved. However, this age group still represents a challenge with an overall survival (OS) of 60% compared to 85% in younger children. Herein, we report the outcome of adolescents treated in the European Organisation for Research and Treatment of Cancer (EORTC) 58951 clinical trial. EORTC 58951 clinical trial included patients with de novo ALL between 1998 and 2008. For this study, we analyzed data of all adolescents between 15 and under 18. Data from 97 adolescents were analyzed, 70 had B-lineage and 27 had T-lineage ALL. The 8-year event-free survival (EFS) and OS for the B-cell precursor ALL cases were 72.3% (59.4%-81.7%) and 80.8% (67.4%-89.1%), respectively. For the T-lineage, the 8-year EFS and OS were 57.4% (36.1%-74.0%) and 59.0% (36.1%-76.2%), respectively. "B-other" ALL, defined as BCP-ALL lacking any known recurrent genetic abnormalities were more frequent in our adolescent population (52.8%) than in younger children (27.1%). Outcome of adolescents in the EORTC 58951 study is supporting the findings that adolescents have better outcome in pediatric compared to adults' trials. Nevertheless, in pediatric studies, adolescents still have a worse prognosis than younger children. Despite the fact that specific unfavorable characteristics may be linked to the adolescent population, a careful study and characterization of adolescents "B-other" genetic abnormalities in ALL is critical to improve the outcome of this population.

3.
Bull Cancer ; 107(6): 629-632, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32387061

RESUMO

Since the emergence of the SARS-CoV-2 infection, many recommendations have been made. However, the very 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, even if data for this population are still scarce. They may have to evolve according to the rapid evolution of knowledge on COVID-19.


Assuntos
Infecções por Coronavirus/epidemiologia , Pneumonia Viral/epidemiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/epidemiologia , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antivirais/farmacocinética , Antivirais/uso terapêutico , Criança , Técnicas de Laboratório Clínico , Terapia Combinada , Comorbidade , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/prevenção & controle , Gerenciamento Clínico , Síndrome de Down/epidemiologia , Interações Medicamentosas , Neutropenia Febril/induzido quimicamente , Neutropenia Febril/tratamento farmacológico , Neutropenia Febril/prevenção & controle , Feminino , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Hospedeiro Imunocomprometido , Masculino , Pandemias/prevenção & controle , Pneumonia Viral/diagnóstico , Pneumonia Viral/prevenção & controle , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Recidiva , Indução de Remissão , Risco , Medição de Risco , Terapia de Salvação , Avaliação de Sintomas
4.
Eur J Clin Nutr ; 74(8): 1247-1249, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32313189

RESUMO

We report the case of a 14-year-old boy with a completely normal medical and social background (good student and handball practice). A dentist monthly followed this patient for an orthodontic treatment. Facing with symptoms associating purpura, pancytopenia, and limbs pain, the first diagnosis that came to mind to emergency pediatricians was acute leukemia and the patient was addressed to a hematology department. However, additional psychiatry investigations revealed an avoiding restrictive food intake disorder (ARFID) associated with serious vitamin deficiencies (Vitamins B9 and D) and responsible for scurvy, mimicking acute leukemia onset. Strikingly, this young patient has been undergoing a close medical follow-up since infancy because of a selective diet. Since growth, education, and development were normal, the risk of pursuing this unbalanced diet has been neglected and this child was admitted at diagnosis in a life-threatening condition.

7.
Hematol Oncol ; 37(4): 483-486, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31408541

RESUMO

In absence of red blood cells disease or immune defect, parvovirus B19 (PVB-19) is usually considered as a benign condition. Here, we report the case of a 10-year-old boy, previously healthy, presenting with a PVB-19 infection revealed by a bicytopenia and a voluminous axillary adenopathy. Pathophysiology examination showed reactional lymphoid population. Nine months later and in the absence of remission, a new biopsy of the same adenopathy revealed a Hodgkin lymphoma with area of T-cell rich aggressive large B-cell lymphoma. This case suggests PVB-19 as potential trigger of this malignant childhood hemopathy. Although no definitive conclusion can be drawn, our clinical case questions the role of PVB-19 in lymphomagenesis.


Assuntos
Eritema Infeccioso/complicações , Doença de Hodgkin/etiologia , Linfoma de Células B/etiologia , Neoplasias Primárias Múltiplas/etiologia , Viremia/complicações , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfócitos B/patologia , Medula Óssea/patologia , Medula Óssea/virologia , Criança , Eritema Infeccioso/sangue , Eritema Infeccioso/patologia , Eritema Infeccioso/virologia , Doença de Hodgkin/patologia , Humanos , Linfoma de Células B/patologia , Masculino , Neoplasias Primárias Múltiplas/patologia , Pancitopenia/etiologia , Pseudolinfoma/etiologia , Indução de Remissão , Rituximab/administração & dosagem , Linfócitos T/patologia , Sequenciamento Completo do Exoma
8.
Antiviral Res ; 168: 114-120, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31152759

RESUMO

Genotypic diagnosis of HSV drug resistance can be performed routinely in a clinically relevant time. Nevertheless, data about HSV mutations (polymorphism or resistance) is not exhaustive which hinders the interpretation of such tests. The UL23, UL30, and UL5 genes are of greatest interest as these encode, respectively, thymidine kinase, DNA polymerase, and helicase, which, if mutated may affect the effectiveness of acyclovir, foscarnet, cidofovir, and helicase-primase inhibitors. The present study aimed to extensively characterize UL23, UL30, and UL5 genes. A total of 239 clinical HSV1 recovered from patients admitted to the hematology departments of the Lyon teaching hospitals were included in this single-center retrospective study. Drug resistance was evaluated using the neutral red dye-uptake assay, and sequencing using the Sanger method. Additional information on HSV1 natural polymorphism and resistance is now available. Twenty-two amino acid substitutions related to polymorphism were described on UL23 (E43A, L50M, L68R, Q109K, A133V, A136N, S150L, D258N, S263L, P280S, N301S, A316S, M322L, I326V, D330A, D338H, Q342H, T344I, Q349R, V352L, R370W, E371D), and 6 amino acid substitutions on UL30 (G641R, G645D, E649G, G679D, R681L, I966M). Moreover, the UL23 substitution L242P was added to ACV resistance-related mutations. There were 12 substitutions on UL23 (A37S, V70M, S74L, H151N, P154S, P155Q, L159R, E225L, Y248H, Q270R, N303Y, M372I), and 8 on UL5 (L49I, L138V, S173L, A280T, A575V, V600A, A602T, D862N) that remain of unclear significance with regards to drug resistance. The mean (±standard deviation, SD) number of natural polymorphisms in UL23 was 2.53 (±2.55), in UL30 it was 0.83 (±1.02), and in UL5 it was 5.00 (±1.59) There was no association between HSV1 phenotype and the frequency of substitutions. The results reported herein provide valuable new information concerning HSV1 mutations that will assist the interpretation of genotypic assays.


Assuntos
Herpes Simples/microbiologia , Herpesvirus Humano 1/genética , Herpesvirus Humano 1/isolamento & purificação , Proteínas Virais/genética , Antivirais/farmacologia , DNA Helicases/antagonistas & inibidores , DNA Helicases/genética , DNA Primase/antagonistas & inibidores , DNA Primase/genética , DNA Polimerase Dirigida por DNA/genética , Farmacorresistência Viral/efeitos dos fármacos , Farmacorresistência Viral/genética , Inibidores Enzimáticos/farmacologia , Exodesoxirribonucleases/antagonistas & inibidores , Exodesoxirribonucleases/genética , Feminino , Genótipo , Hematologia , Herpes Simples/tratamento farmacológico , Herpesvirus Humano 1/classificação , Humanos , Masculino , Mutação , Filogenia , Polimorfismo Genético , Estudos Retrospectivos , Timidina Quinase/antagonistas & inibidores , Timidina Quinase/genética , Proteínas Virais/antagonistas & inibidores
9.
Stem Cell Reports ; 11(5): 1075-1091, 2018 11 13.
Artigo em Inglês | MEDLINE | ID: mdl-30449320

RESUMO

Fanconi anemia (FA) causes bone marrow failure early during childhood, and recent studies indicate that a hematopoietic defect could begin in utero. We performed a unique kinetics study of hematopoiesis in Fancg-/- mouse embryos, between the early embryonic day 11.5 (E11.5) to E12.5 developmental window (when the highest level of hematopoietic stem cells [HSC] amplification takes place) and E14.5. This study reveals a deep HSC defect with exhaustion of proliferative and self-renewal capacities very early during development, together with severe FA clinical and biological manifestations, which are mitigated at E14.5 due to compensatory mechanisms that help to ensure survival of Fancg-/- embryos. It also reports that a deep HSC defect is also observed during human FA development, and that human FA fetal liver (FL) HSCs present a transcriptome profile similar to that of mouse E12.5 Fancg-/- FL HSCs. Altogether, our results highlight that early mouse FL could represent a good alternative model for studying Fanconi pathology.


Assuntos
Desenvolvimento Embrionário , Anemia de Fanconi/patologia , Células-Tronco Hematopoéticas/patologia , Animais , Apoptose , Ciclo Celular , Dano ao DNA , Embrião de Mamíferos/patologia , Eritrócitos/metabolismo , Proteína do Grupo de Complementação G da Anemia de Fanconi/deficiência , Proteína do Grupo de Complementação G da Anemia de Fanconi/metabolismo , Feminino , Ontologia Genética , Transplante de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas/metabolismo , Humanos , Fígado/embriologia , Fígado/metabolismo , Camundongos Endogâmicos C57BL , Fenótipo , Placenta/metabolismo , Gravidez , Transcriptoma/genética
10.
Blood ; 131(7): 717-732, 2018 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-29146883

RESUMO

Bone marrow (BM) failure (BMF) in children and young adults is often suspected to be inherited, but in many cases diagnosis remains uncertain. We studied a cohort of 179 patients (from 173 families) with BMF of suspected inherited origin but unresolved diagnosis after medical evaluation and Fanconi anemia exclusion. All patients had cytopenias, and 12.0% presented ≥5% BM blast cells. Median age at genetic evaluation was 11 years; 20.7% of patients were aged ≤2 years and 36.9% were ≥18 years. We analyzed genomic DNA from skin fibroblasts using whole-exome sequencing, and were able to assign a causal or likely causal germ line mutation in 86 patients (48.0%), involving a total of 28 genes. These included genes in familial hematopoietic disorders (GATA2, RUNX1), telomeropathies (TERC, TERT, RTEL1), ribosome disorders (SBDS, DNAJC21, RPL5), and DNA repair deficiency (LIG4). Many patients had an atypical presentation, and the mutated gene was often not clinically suspected. We also found mutations in genes seldom reported in inherited BMF (IBMF), such as SAMD9 and SAMD9L (N = 16 of the 86 patients, 18.6%), MECOM/EVI1 (N = 6, 7.0%), and ERCC6L2 (N = 7, 8.1%), each of which was associated with a distinct natural history; SAMD9 and SAMD9L patients often experienced transient aplasia and monosomy 7, whereas MECOM patients presented early-onset severe aplastic anemia, and ERCC6L2 patients, mild pancytopenia with myelodysplasia. This study broadens the molecular and clinical portrait of IBMF syndromes and sheds light on newly recognized disease entities. Using a high-throughput sequencing screen to implement precision medicine at diagnosis can improve patient management and family counseling.


Assuntos
Doenças da Medula Óssea/genética , Mutação em Linhagem Germinativa , Adolescente , Doenças da Medula Óssea/epidemiologia , Criança , Pré-Escolar , Estudos de Coortes , Análise Mutacional de DNA , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , Recém-Nascido , Masculino , Síndromes Mielodisplásicas/epidemiologia , Síndromes Mielodisplásicas/genética , Sequenciamento Completo do Exoma
11.
Eur J Med Genet ; 59(3): 173-8, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26855057

RESUMO

Noonan syndrome is associated with a range of malignancies including acute lymphoblastic leukemia (ALL). However, little information is available regarding the frequency, natural history, characteristics and prognosis of ALL in Noonan syndrome or RASopathies in general. Cross-referencing data from a large prospective cohort of 1176 patients having a molecularly confirmed RASopathy with data from the French childhood cancer registry allowed us to identify ALL in 6 (0.5%) patients including 4/778 (0.5%) with a germline PTPN11 mutation and 2/94 (2.1%) with a germline SOS1 mutation. None of the patients of our series with CFC syndrome (with germline BRAF or MAP2K1/MAP2K2 mutation - n = 121) or Costello syndrome (with HRAS mutation - n = 35) had an ALL. A total of 19 Noonan-ALL were gathered by adding our patients to those of the International Berlin-Munster-Frankfurt (I-BFM) study group and previously reported patients. Strikingly, all Noonan-associated ALL were B-cell precursor ALL, and high hyperdiploidy with more than 50 chromosomes was found in the leukemia cells of 13/17 (76%) patients with available genetics data. Our data suggest that children with Noonan syndrome are at higher risk to develop ALL. Like what is observed for somatic PTPN11 mutations, NS is preferentially associated with the development of hyperdiploid ALL that will usually respond well to chemotherapy. However, Noonan syndrome patients seem to have a propensity to develop post therapy myelodysplasia that can eventually be fatal. Hence, one should be particularly cautious when treating these patients.


Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras/epidemiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/etiologia , Proteínas ras/genética , Adolescente , Criança , Pré-Escolar , Feminino , Genótipo , Humanos , Lactente , Recém-Nascido , Masculino , Mutação , Segunda Neoplasia Primária/etiologia , Síndrome de Noonan/complicações , Síndrome de Noonan/genética , Síndrome de Noonan/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Prevalência , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Proteína SOS1/genética , Proteínas ras/metabolismo
12.
Eur J Haematol ; 97(1): 70-7, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26380877

RESUMO

BACKGROUND: Allogeneic hematopoietic stem cell transplantation (alloHSCT) is a procedure with a high infection risk. Strict isolation of patients is the rule to prevent such condition. OBJECTIVE: We compared the occurrence of severe infections (bacteremia and invasive fungal infection, IFI) in children undergoing alloHSCT before and after the move to a new protected unit with decreases in isolation methods. METHODS: The study was conducted over a 10-year period. Unit 1 (2002-2007) consisted of laminar airflow rooms where caregivers were required to wear a sterile outfit (gown, gloves, hat, and mask). Unit 2 (2008-2012) included spacious positive air pressure rooms with HEPA filters where only a clean gown and mask were required to be worn. RESULTS: Two hundred eighty-six alloHSCTs were performed (144 in Unit 1 and 142 in Unit 2). We reported a total incidence of 4.78 infections/1000 hospital-days including 4.4 episodes of bacteremia and 0.38 episodes of IFI. There was no statistical difference in the incidence of infections: n = 4.98/1000 hospital-days in Unit 1 vs. n = 4.6/1000 in Unit 2 (P = 0.63). CONCLUSION: The lack of difference in the occurrence of severe infection supports our decision to decrease unnecessary high protection in alloHSCT units to improve children's daily life.


Assuntos
Infecções Bacterianas/epidemiologia , Infecções Bacterianas/etiologia , Ambiente Controlado , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Micoses/epidemiologia , Micoses/etiologia , Adolescente , Antibioticoprofilaxia , Bacteriemia/etiologia , Infecções Bacterianas/prevenção & controle , Infecções Bacterianas/terapia , Criança , Pré-Escolar , Feminino , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Lactente , Recém-Nascido , Masculino , Micoses/prevenção & controle , Micoses/terapia , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Análise de Sobrevida , Transplante Homólogo , Adulto Jovem
13.
J Pediatr Hematol Oncol ; 37(7): 560-5, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26165404

RESUMO

BACKGROUND: Invasive aspergillosis (IA) is associated with a high mortality rate despite the introduction of new antifungal agents. Several therapeutic strategies have been proposed to improve mortality rates in IA, including combination of drugs. METHODS: Here, we report the outcome of treatments based on a combination of antifungal agents on IA, including voriconazole and liposomal amphotericin B, in a pediatric population from 2001 to 2010. Our population included children with diverse hematological diseases or with bone marrow transplantation. RESULTS: Over a 10-year period, we diagnosed 19 cases (2,8%) of invasive pulmonary aspergillosis with an overall survival rate of 58%. CONCLUSION: Compared with the previous study conducted from 1986 to 2000, the overall survival rate (bone marrow transplantation excluded) greatly improved (12.5% to 58%), especially for patients treated for acute leukemia.


Assuntos
Antifúngicos/uso terapêutico , Aspergilose Pulmonar Invasiva/tratamento farmacológico , Aspergilose Pulmonar Invasiva/mortalidade , Adolescente , Antineoplásicos/efeitos adversos , Criança , Pré-Escolar , Feminino , Hematologia/estatística & dados numéricos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Hospedeiro Imunocomprometido , Lactente , Aspergilose Pulmonar Invasiva/imunologia , Leucemia/complicações , Leucemia/tratamento farmacológico , Masculino , Pediatria/estatística & dados numéricos , Estudos Retrospectivos
14.
Haematologica ; 99(7): 1220-7, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24727815

RESUMO

Dexamethasone could be more effective than prednisolone at similar anti-inflammatory doses in the treatment of childhood acute lymphoblastic leukemia. In order to check if this "superiority" of dexamethasone might be dose-dependent, we conducted a randomized phase III trial comparing dexamethasone (6 mg/m(2)/day) to prednisolone (60 mg/m(2)/day) in induction therapy. All newly diagnosed children and adolescents with acute lymphoblastic leukemia in the 58951 EORTC trial were randomized on prephase day 1 or day 8. The main endpoint was event-free survival; secondary endpoints were overall survival and toxicity. A total of 1947 patients with acute lymphoblastic leukemia were randomized. At a median follow-up of 6.9 years, the 8-year event-free survival rate was 81.5% in the dexamethasone arm and 81.2% in the prednisolone arm; the 8-year overall survival rates were 87.2% and 89.0% respectively. The 8-year incidences of isolated or combined central nervous system relapse were 2.9% and 4.5% in the dexamethasone and prednisolone arms, respectively. The incidence of grade 3-4 toxicities during induction and the frequency of osteonecrosis were similar in the two arms. In conclusion, dexamethasone and prednisolone, used respectively at the doses of 6 and 60 mg/m(2)/day during induction, were equally effective and had a similar toxicity profile. Dexamethasone decreased the 8-year central nervous system relapse incidence by 1.6%. This trial was registered at www.clinicaltrials.gov as #NCT00003728.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Criança , Pré-Escolar , Dexametasona/administração & dosagem , Feminino , Humanos , Imunofenotipagem , Quimioterapia de Indução , Lactente , Recém-Nascido , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Prednisolona/administração & dosagem , Fatores de Risco , Resultado do Tratamento
15.
J Pediatr Hematol Oncol ; 33(7): 570-2, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21941152

RESUMO

Cryptosporidium is recognized as a cause of diarrhea associated with a high mortality in immunocompromised patients. We report on 2 pediatric cases of cryptosporidiosis during maintenance chemotherapy of acute lymphoblastic leukemia. The patients presented severe diarrheas, 1 of them was complicated by a cholangitis. Withdrawal of immunosuppressive treatments and adjunction of an adequate antiparasitic treatment cured the Cryptosporidium infection in both cases.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Criptosporidiose/complicações , Quimioterapia de Manutenção , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Antiparasitários/uso terapêutico , Pré-Escolar , Criptosporidiose/diagnóstico , Criptosporidiose/tratamento farmacológico , Humanos , Quimioterapia de Manutenção/efeitos adversos , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Resultado do Tratamento
16.
Bull Cancer ; 98(8): 901-13, 2011 Aug.
Artigo em Francês | MEDLINE | ID: mdl-21865110

RESUMO

Cytogenetic, molecular and phenotyping features of malignant hematologic diseases succeeded in improving their management by a more accurate stratification of patients according to several groups of risk and by providing a rational for targeted therapy. Three major types of treatment (excluding cellular therapy) are currently available in onco-hematology: conventional chemotherapy, small molecules for targeted therapy and monoclonal antibodies. Conventional chemotherapy with optimization of doses and multidrug-based regimens allowed to substantially improve survival of patients and keeps a place of choice in treatment of these diseases. Targeted treatments came from the cytogenetic and molecular characterization of hemopathies. Thus, the kinase Bcr-Abl, as a result of the translocation t(9;22)(q34;q11), has been successfully targeted by tyrosine kinase inhibitors (TKI) in chronic myeloid leukemia and Ph+ acute lymphoblastic leukemia. Molecular abnormalities like internal-tandem duplication/point activating mutations in FLT3 in some acute myeloblastic leukemia or epigenetic dysregulations in some blood malignancies can also be targeted by small molecules. Hematopoietic malignant cells are phenotypically characterized by expression of cluster of differentiation (CD) on their surface. These CD are detected by flow cytometry using specific antibodies. Monoclonal antibodies targeting different CD have been developed for treatment. Rituximab, an anti-CD20 antibody, was the first monoclonal antibody successfully developed for treatment of malignant hematologic diseases. Since rituximab, many other monoclonal antibodies are being developed. Trends in malignant hematologic diseases presented here will include treatments, which have at least entered phase I/II clinical trials in adult or childhood leukemia. They include some novel drugs of conventional chemotherapy like second-generation nucleoside analogues. We will give an overview of the small molecules targeting the different cellular pathways and we will highlight those appearing as the most promising like novel TKIs. The large field of monoclonal antibodies will be also approached focusing on antibodies developed in leukemias.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Neoplasias Hematológicas/tratamento farmacológico , Terapia de Alvo Molecular/métodos , Nucleotídeos de Adenina/uso terapêutico , Antineoplásicos/química , Arabinonucleosídeos/uso terapêutico , Química Farmacêutica , Clofarabina , Humanos , Nucleosídeos de Purina/uso terapêutico , Pirimidinonas/uso terapêutico
17.
Br J Haematol ; 153(1): 58-65, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21332712

RESUMO

l-asparaginase encapsulated within erythrocytes (GRASPA(®) ) should allow serum asparagine depletion over a longer period than the native form of the enzyme, using lower doses and allowing better tolerance. The GRASPALL 2005-01 study, a multicentre randomized controlled trial, investigated three doses of GRASPA(®) for the duration of asparagine depletion in a phase I/II study in adults and children with acute lymphoblastic leukaemia (ALL) in first relapse. Between February 2006 and April 2008, 18 patients received GRASPA(®) (50 iu/kg: n = 6,100 iu/kg: n = 6, 150 iu/kg: n = 6) after randomization, and six patients were assigned to the Escherichia coli native l-asparaginase (E. colil-ASNase) control group. GRASPA(®) was effective at depleting l-asparagine. One single injection of 150 iu/kg of GRASPA(®) provided similar results to 8 × 10,000 iu/m(2) intravenous injections of E. colil-ASNase. The safety profile of GRASPA(®) showed a reduction in the number and severity of allergic reactions and a trend towards less coagulation disorders. Other expected adverse events were comparable to those observed with E. colil-ASNase and there was also no difference between the three doses of GRASPA(®) .


Assuntos
Antineoplásicos/administração & dosagem , Asparaginase/administração & dosagem , Portadores de Fármacos , Eritrócitos/enzimologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Adolescente , Adulto , Antineoplásicos/efeitos adversos , Antineoplásicos/sangue , Antineoplásicos/uso terapêutico , Asparaginase/efeitos adversos , Asparaginase/sangue , Asparaginase/uso terapêutico , Reatores Biológicos , Criança , Pré-Escolar , Relação Dose-Resposta a Droga , Esquema de Medicação , Sistemas de Liberação de Medicamentos , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangue , Adulto Jovem
18.
Cell Cycle ; 9(16): 3286-96, 2010 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-20703084

RESUMO

The p16(INK4a) protein is considered to regulate the cell cycle progression mainly by inhibiting cyclin-dependent kinases (CDKs) 4 and 6 activity and leading to an arrest in G(0)/G(1). Here, we report that ectopic expression of p16(INK4a) in three p16-/pRb(Wt)/p53(Wt) human cancer cell lines MCF7, U2OS and U87 induces S-phase lengthening along with G(1) accumulation. S-phase lengthening is suggested by the discrepancy between the unchanged or even increased percentage of cells in S phase found by flow cytometry DNA content analysis and the drop of BrdU labelling, and demonstrated by IdU/BrdU double labelling. p16(INK4a) induces a profound decrease in the CDK4/6-mediated pRb phosphorylation on Ser-807/811, a downregulation of CDK2 and CDK1 protein expression independently of G(1) accumulation, and a decrease in Thr/Pro phosphorylation in part carried out by CDKs. In MCF7 cells, overexpression of the p16 G101W mutant, which is unable to inhibit CDK4/6 kinase activity and shows a modified subcellular localization, does not provoke the S-phase lengthening and the inhibition of Ser807/811-pRB and of Thr/Pro phosphorylation as wild-type p16(INK4a) does. Our results demonstrate that p16(INK4a) induces a S-phase lengthening independently of cellular origin. The CDK4/6 kinase activity inhibition together with the reduced expression of CDK2 and CDK1 acting downstream of G(1) phase may prevent cells from any possible kinasic compensatory mechanisms, and thus lead to a cell cycle progression inhibition.


Assuntos
Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Proteína do Retinoblastoma/metabolismo , Fase S , Proteína Supressora de Tumor p53/metabolismo , Substituição de Aminoácidos , Linhagem Celular Tumoral , Quinase 2 Dependente de Ciclina/metabolismo , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 4 Dependente de Ciclina/metabolismo , Quinase 6 Dependente de Ciclina/metabolismo , Inibidor p16 de Quinase Dependente de Ciclina/genética , Fase G1 , Humanos , Mutagênese Sítio-Dirigida , Fosforilação
19.
Leuk Lymphoma ; 50(12): 2049-60, 2009 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19860623

RESUMO

Indirubin-3'-monoxime (IO) is a derivative of indirubin, an active compound of a traditional Chinese medicinal recipe used to treat various inflammatory and malignant diseases. The main in vitro targets of IO (i.e. cyclin dependent kinases, glycogen synthase kinase-3beta, Stat 3 and Aryl hydrocarbon receptor) are regulators of lymphocyte activation. We investigated the interest of IO and its derivative 6-bromo-indirubin-3'oxime (6BIO) for inhibiting the growth of malignant lymphoid cells. IO (1-20 microM) induced cell cycle inhibition and cell death in malignant B- (IM9, Reh6) and T- (Jurkat, CEM-T) lymphoid cell lines depending to cell type, doses, and duration of treatment. IO and 6BIO (10 microM) treatment for 24 and 48 h were compared: 6BIO treatment resulted in a stronger cytotoxicity and more profound inhibition of cell proliferation. Taken together, these results showed that IO and, moreover, its derivative 6BIO may be potent antiproliferative agents in malignant lymphoid cells.


Assuntos
Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Indóis/farmacologia , Linfócitos/efeitos dos fármacos , Oximas/farmacologia , Antibióticos Antineoplásicos/farmacologia , Autofagia/efeitos dos fármacos , Western Blotting , Ciclo Celular/efeitos dos fármacos , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Ciclina E/metabolismo , Quinase 6 Dependente de Ciclina/metabolismo , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Inibidor de Quinase Dependente de Ciclina p27 , Relação Dose-Resposta a Droga , Citometria de Fluxo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Células Jurkat , Linfócitos/metabolismo , Linfócitos/patologia , Fatores de Tempo
20.
Eur J Cancer ; 44(16): 2461-9, 2008 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-18804997

RESUMO

We report on the efficiency of treatment of first isolated extramedullary relapse of B-cell precursor acute lymphoblastic leukaemia. Sixty-eight children and adolescents were included in the trial COPRALL-97. Stratification criteria were time to relapse: first complete remission duration of less than 24 months for group G3A (n=35), relapse beyond 24 months for group G3B (n=33). Treatment consisted of risk-adapted alternating short course multiagent systemic and intrathecal chemotherapy and irradiation (18Gy). Event free survival (EFS) and overall survival (OS) for all registered patients at 6 years were 43% and 55%, respectively. EFS at 4 years for patients of group G3A and G3B were, respectively, 31% and 61% (p=0.0071) while OS at 4 years were, respectively, 40% and 76% (p=0.065). Our analyses highlighted two independent risks factors predictive of decreased EFS: early relapse and age at the initial diagnosis above 6 years. Early central nervous system relapses have a bad prognosis, and new therapeutic strategies are needed.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Transplante de Células-Tronco/métodos , Adolescente , Idade de Início , Neoplasias do Sistema Nervoso Central/prevenção & controle , Criança , Pré-Escolar , Terapia Combinada , Intervalo Livre de Doença , Feminino , Humanos , Lactente , Masculino , Recidiva Local de Neoplasia/prevenção & controle , Neoplasias Ovarianas/prevenção & controle , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/radioterapia , Neoplasias Testiculares/prevenção & controle , Resultado do Tratamento , Adulto Jovem
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