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4.
Sci Rep ; 10(1): 589, 2020 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-31953453

RESUMO

Through their action on DNA replication, anticancer chemotherapies could increase the basal mutation rate in bacteria and increase the risk of selecting antibiotic resistant mutants. We investigated the impact of several drugs on a beta-lactamase model using KPC-type carbapenemase-producing Enterobacteriaceae. We studied the impact of anticancer chemotherapies used in pediatric hematologic malignancies on 7 clinical isolates of Enterobacteriaceae producing KPC-type carbapenemases. We compared the mutation rates from cultures with/without chemotherapy on ceftazidime-avibactam, rifampicin and ceftazidime-avibactam combined with meropenem media. Mechanisms of ceftazidime-avibactam resistance were explored on a subset of mutants. After exposure to some cytotoxic molecules, the bacterial mutation rates leading to ceftazidime-avibactam and to rifampicin resistance increased up to 104-fold while we observed no emergence of resistant mutants (frequency of <10-10) on a meropenem combined with ceftazidime-avibactam media. Compared to the parental strains, an increased susceptibility to meropenem was observed in the ceftazidime-avibactam resistant mutants. The blaKPC genes of ceftazidime-avibactam mutants harbored either mutations, deletions or insertions, especially in the region encoding the Ω-loop of the KPC-type carbapenemase. Anticancer chemotherapy can increase the mutation rates of bacteria accelerating the extension of KPC-type carbapenemases towards ceftazidime-avibactam, one of the last resort antimicrobial chemotherapy.


Assuntos
Antibacterianos/farmacologia , Antineoplásicos/efeitos adversos , Enterobacteriáceas Resistentes a Carbapenêmicos/efeitos dos fármacos , Mutação , beta-Lactamases/genética , Compostos Azabicíclicos/farmacologia , Proteínas de Bactérias/genética , Enterobacteriáceas Resistentes a Carbapenêmicos/genética , Enterobacteriáceas Resistentes a Carbapenêmicos/isolamento & purificação , Ceftazidima/farmacologia , Combinação de Medicamentos , Farmacorresistência Bacteriana , Infecções por Enterobacteriaceae/microbiologia , Genoma Bacteriano , Humanos , Meropeném/farmacologia , Testes de Sensibilidade Microbiana , Rifampina/farmacologia , Sequenciamento Completo do Genoma
5.
Br J Haematol ; 187(4): 530-542, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31338833

RESUMO

Congenital sideroblastic anaemia (CSA) is a rare disease caused by germline mutations of genes involved in haem and iron-sulphur cluster formation, and mitochondrial protein biosynthesis. We performed a retrospective multicentre European study of a cohort of childhood-onset CSA patients to explore genotype/phenotype correlations. We studied 23 females and 20 males with symptoms of CSA. Among the patients, the most frequently mutated genes were ALAS2 (n = 10; 23·3%) and SLC25A38 (n = 8; 18·6%), causing isolated forms of microcytic anaemia of varying severity. Five patients with SLC19A2 mutations suffered from thiamine-responsive megaloblastic anaemia and three exhibited the 'anaemia, deafness and diabetes' triad. Three patients with TRNT1 mutations exhibited severe early onset microcytic anaemia associated with thrombocytosis, and two exhibited B-cell immunodeficiency, inflammatory syndrome and psychomotor delay. The prognoses of patients with TRNT1 and SLC2A38 mutations were generally dismal because of comorbidities or severe iron overload. No molecular diagnosis could be established in 14/43 cases. This study emphasizes the frequency of ALAS2 and SLC25A38 mutations and provides the largest comprehensive analysis to date of genotype/phenotype correlations in CSA. Further studies of CSA patients with data recorded in an international registry would be helpful to improve patient management and establish standardized guidelines.


Assuntos
5-Aminolevulinato Sintetase/genética , Anemia Sideroblástica/genética , Estudos de Associação Genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Proteínas de Transporte da Membrana Mitocondrial/genética , Anemia Sideroblástica/patologia , Criança , Estudos de Coortes , Europa (Continente) , Feminino , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Humanos , Masculino , Mutação , Nucleotidiltransferases/genética , Estudos Retrospectivos
7.
Bull Cancer ; 103(3): 299-311, 2016 Mar.
Artigo em Francês | MEDLINE | ID: mdl-26826739

RESUMO

If acute leukemia is the most frequent cancer in childhood (33%), it remains a very rare diagnosis in infants less than one year old, e.g. less than 5% of cases. At this age, the frequency of acute lymphoblastic leukemia (ALL) (almost all of B-lineage) is quite similar to the one of myeloblastic forms (AML). Infant leukemia frequently presents with high hyperleucocytosis, major tumoral burden and numerous extra-hematological features, especially in central nervous system and skin. Whatever the lineage, the leukemic cell is often very immature cytologically and immunologically. Rearrangements of the Mixed Lineage Leukemia (MLL) gene, located on band 11q23, are the hallmark of these immature leukemias and confer a particular resistance to conventional approaches, corticosteroids and chemotherapy. The immaturity of infants less than 1-year-old is associated to a decrease of the tolerable dose-intensity of some drugs (anthracyclines, alkylating agents) or asks questions about some procedures like radiotherapy or high dose conditioning regimen, responsible of inacceptable acute and late toxicities. The high level of severe infectious diseases and other high-grade side effects limits also the capacity to cure these infants. The survival of infants less than 1-year-old with AML is only 50% but similar to older children. On the other hand, survival of those with ALL is the same, then quite limited comparing the 80% survival in children over one year. Allogeneic stem cell transplantations are indicated in high-risk subgroups of infant ALL (age below 6 months, high hyperleucocytosis >300.10(9)/L, MLL-rearrangement, initial poor prednisone response). However, morbidity and mortality remain very important and these approaches cannot be extended to all cases. During the neonatal period, the dismal prognosis linked to the high number of primary failures or very early relapses and uncertainties about the late toxicities question physicians about ethics. It is an emergency to propose different strategies (targeted therapies) to these infants with acute leukemia as conventional trials failed to improve outcome.


Assuntos
Leucemia Mieloide Aguda , Leucemia-Linfoma Linfoblástico de Células Precursoras , Doenças Raras , Fatores Etários , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/administração & dosagem , Rearranjo Gênico , Humanos , Lactente , Recém-Nascido , Leucemia Aguda Bifenotípica/genética , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/patologia , Leucemia Mieloide Aguda/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Doenças Raras/genética , Doenças Raras/mortalidade , Doenças Raras/patologia , Doenças Raras/terapia , Recidiva , Transplante de Células-Tronco
8.
J Clin Microbiol ; 54(4): 928-33, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26763967

RESUMO

Sensitive molecular assays have greatly improved the diagnosis of viral gastroenteritis. However, the proper preparation of stool samples for clinical testing remains an issue. bioMérieux has developed a stool preprocessing device (SPD) that includes a spoon for calibrated sampling and a vial containing buffer, glass beads, and two filters. The resulting stool filtrate is used for nucleic acid extraction. The purpose of this study was to evaluate the performance of the SPD for the quantification of human adenovirus (HAdV) DNA in stool samples collected from hematopoietic stem cell transplant (HSCT) recipients. HAdV DNA was quantified with the Adenovirus R-gene kit. The suitability of the device to reproducibly quantify HAdV DNA in stools using different extraction platforms (easyMAG and QIAsymphony) was determined using archived HAdV-positive stool samples. Coefficients of variation of HAdV DNA quantifications ranged from 1.79% to 1.83%, and no difference in quantification was observed between the two extraction systems. The HAdV DNA limit of quantification using the SPD was 3.75 log10copies/g of stool. HAdV DNA quantification using the SPD was then compared to that of the routine preprocessing technique on 75 fresh stool samples collected prospectively from pediatric HSCT recipients at risk for HAdV infections. Thirty-eight samples were HAdV DNA positive with both the SPD and routine preprocessing methods. HAdV DNA loads were on average 1.14-log10copies/g of stool higher with the SPD (P< 0.0001) than with routine methods. This new device enabled a standardized preparation of stool samples in <5 min and a reproducible and sensitive quantification of HAdV DNA. The use of the SPD for the detection of other gastrointestinal infections warrants further evaluation.


Assuntos
Infecções por Adenoviridae/diagnóstico , Fezes/virologia , Gastroenterite/diagnóstico , Técnicas de Diagnóstico Molecular/métodos , Manejo de Espécimes/métodos , Infecções por Adenoviridae/virologia , Pré-Escolar , Gastroenterite/virologia , Humanos , Lactente , Recém-Nascido , Técnicas de Diagnóstico Molecular/normas , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Manejo de Espécimes/normas , Carga Viral/métodos
9.
J Pediatr Hematol Oncol ; 37(2): e102-10, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25171452

RESUMO

In the European Union, the pediatric medicines regulation in 2007 modified significantly the access to new agents in pediatric oncology. Early oncology trials are still thought to be associated with limited benefit and substantial risk. We report the characteristics and outcome of patients below 21 years enrolled in investigational trials in the Pediatric and Adolescent Department at Gustave Roussy between January 2000 and December 2012. A total of 235 patients (median age, 10.4 [0.8 to 20.7] y) were included in 26 trials (16 cytotoxic and 10 targeted agents) for a total of 260 inclusions. A total of 117 patients (50%) had brain tumors and 68 (29%) had various soft tissue and bone sarcoma. Thirteen of the 106 patients in a phase I trial experienced dose-limiting toxicity. Main severe toxicity was hematologic; none had toxic death. Grade 3 to 4 toxicities were associated with combination trials, cytotoxic agent, and at least 1 previous line of therapy. Thirty patients (12%) had objective response and 42 (16%) had stable disease for >4 months. Median overall survival was 9.0 months (95% CI, 7.5-10.5) and 73% of patients received further anticancer treatment. Phase I to II pediatric oncology trials are safe, associated with clinical benefit, and can be successfully integrated in current relapse strategies.


Assuntos
Hospitalização/estatística & dados numéricos , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/terapia , Neoplasias/mortalidade , Neoplasias/terapia , Adolescente , Adulto , Criança , Pré-Escolar , Terapia Combinada , Feminino , Seguimentos , Humanos , Lactente , Recém-Nascido , Masculino , Metanálise como Assunto , Prognóstico , Taxa de Sobrevida , Fatores de Tempo , Adulto Jovem
10.
Br J Haematol ; 166(2): 229-39, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24702221

RESUMO

The interplay between immune recovery, cytomegalovirus (CMV)-reactivation, CMV-driven immunity and graft-versus-leukaemia effect (GVL) was analysed in 108 children (median age: 8 years) who underwent haematopoietic-stem cell transplantation (HSCT) for acute leukaemia. Follow-up was 2 years unless death or relapse occurred. CMV-polymerase chain reaction (PCR) was programmed weekly until month +3 post-HSCT. Immunomonitoring consisted of sequential lymphocyte subset enumerations and analyses of T-cell proliferative and γ-interferon responses to CMV and to adenovirus. In the 108 recipients, the 2-year relapse rate (RR) was 25% (median time to onset 4·5 months; range: 24 d-17 months). CMV reactivation occurrence was 31% (median time to onset 26 d). Donor/recipient CMV serostatus did not influence RR. Among the 89 recipients disease-free after day +120, i) early CMV-reactivation before day +30 was more frequent (P = 0·01) in the relapse recipient group opposed to the non-relapse group. ii) CD8(+) /CD28(-) and CD4(+) CD45RA(-) T-cell expansions induced by CMV did not influence RR, iii) Recovery of anti-CMV and also anti-adenovirus immunity and of naïve CD4(+) T-cells was faster in the non-relapse group (P = 0·008; 0·009 and 0·002 respectively). In contrast to adult acute myeloid leukaemia, CMV reactivation was associated with increased RR in this paediatric series. Accelerated overall immune recovery rather than CMV-driven immunity had a favourable impact on RR.


Assuntos
Infecções por Citomegalovirus/imunologia , Citomegalovirus/fisiologia , Efeito Enxerto vs Leucemia/imunologia , Leucemia/imunologia , Adolescente , Criança , Pré-Escolar , Citomegalovirus/isolamento & purificação , Infecções por Citomegalovirus/complicações , Feminino , Transplante de Células-Tronco Hematopoéticas , Humanos , Imunidade Celular , Lactente , Recém-Nascido , Leucemia/complicações , Leucemia/terapia , Masculino , Recidiva , Estudos Retrospectivos , Fatores de Risco , Subpopulações de Linfócitos T/imunologia , Resultado do Tratamento , Viremia/complicações , Viremia/imunologia , Ativação Viral
11.
Antimicrob Agents Chemother ; 58(6): 3191-9, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24663023

RESUMO

An increase in vancomycin dose has been proposed in adults with malignant hematological disease. As pediatric data are limited, our aim was to evaluate the population pharmacokinetics of vancomycin in order to define the appropriate dosing regimen in children with malignant hematological disease. Vancomycin concentrations were collected prospectively during therapeutic monitoring. Population pharmacokinetic analysis was performed using NONMEM software. Seventy children (age range, 0.3 to 17.7 years) were included. With the current recommended dosing regimen of 40 to 60 mg/kg/day, 53 children (76%) had subtherapeutic steady-state trough concentrations (Css/min of <10 mg/liter). A one-compartment model with first-order elimination was developed. Systematic covariate analysis identified that weight significantly influenced clearance (CL) and volume of distribution (V) with power functions of 0.677 for CL and 0.838 for V. Vancomycin CL also significantly increased with increases in creatinine clearance and seemed to be higher in children with malignant hematological disease than in the general pediatric population. The model was validated internally. Its predictive performance was further confirmed in an external validation by Bayesian estimation. A patient-tailored dosing regimen was developed based on the final pharmacokinetic model and showed that a higher proportion of patients reached the target Css/min than with the traditional mg/kg-basis dose (60% versus 49%) and that the risks associated with underdosing or overdosing were reduced. This is the first population pharmacokinetic study of vancomycin in children with malignant hematological disease. An optimized dosing regimen, taking into account patient weight, creatinine clearance, and susceptibility of the pathogens involved, could routinely be used to individualize vancomycin therapy in this vulnerable population.


Assuntos
Antibacterianos/administração & dosagem , Antibacterianos/farmacocinética , Neoplasias Hematológicas/metabolismo , Vancomicina/administração & dosagem , Vancomicina/farmacocinética , Adolescente , Criança , Pré-Escolar , Simulação por Computador , Creatinina/sangue , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Humanos , Lactente , Masculino , Modelos Estatísticos , Medicina de Precisão
12.
J Pediatr Hematol Oncol ; 35(3): 188-92, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23042014

RESUMO

INTRODUCTION: The patients receiving hematopoietic stem cell transplantation (HSCT) require routine management: the role of the pharmacist has not been extensively considered. This study had 2 aims: to explore the knowledge of community pharmacists relating to pediatric HSCT and to evaluate their expectations in terms of training needs. MATERIALS AND METHODS: We interviewed 40 community pharmacists in May and June 2010 in Paris (France) with a 3 parts questionnaire: information concerning the community pharmacy, analysis of 2 pediatric prescriptions and knowledge about HSCT and professional training. RESULTS: Twenty-nine (72.5%) of the 40 community pharmacies agreed to participate in the study. When asked what pharmacological advice they would give for an episode of fever, 13% of the pharmacists asked said that they would deliver acetaminophen without asking any further questions. Concerning hypertrichosis in patients treated with corticosteroids and ciclosporin, none mentioned the role of ciclosporin. The erroneous indications for HSCT given included road accidents (1 pharmacist; 3.4%) and hemophilia (3 pharmacists; 10.3%). Almost 80% of the pharmacists questioned considered their HSCT knowledge insufficient for their professional practice. An E-learning session adapted to their needs was of interest to almost three quarters of the pharmacists questioned.


Assuntos
Serviços Comunitários de Farmácia/tendências , Educação Continuada em Farmácia , Conhecimentos, Atitudes e Prática em Saúde , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas , Farmacêuticos , Competência Profissional , Humanos , Inquéritos e Questionários
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