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1.
J Neurosurg Pediatr ; : 1-9, 2020 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-31952041

RESUMO

OBJECTIVE: Extensive resection of a tumor in the posterior fossa in children is associated with the risk of neurological deficits. The objective of this study was to prospectively evaluate the short-term neurological morbidity in children after medulloblastoma surgery and relate this to the tumor's growth pattern and to the extent of resection. METHODS: In 160 patients taking part in the HIT-SIOP PNET 4 (Hyperfractionated Versus Conventionally Fractionated Radiotherapy in Standard Risk Medulloblastoma) trial, neurosurgeons prospectively responded to questions concerning the growth pattern of the tumor they had resected. The extent of resection (gross, near, or subtotal) was evaluated using MRI. The patients' neurological status before resection and around 30 days after resection was recorded. RESULTS: Invasive tumor growth, defined as local invasion in the brain or meninges, cranial nerve, or major vessel, was reported in 58% of the patients. After surgery almost 70% of all patients were affected by one or several neurological impairments (e.g., impaired vision, impaired extraocular movements, and ataxia). However, this figure was very similar to the preoperative findings. Invasive tumor growth implied a significantly higher number of impairments after surgery (p = 0.03) and greater deterioration regarding extraocular movements (p = 0.012), facial weakness (p = 0.048), and ataxia in the arms (p = 0.014) and trunk (p = 0.025) compared with noninvasive tumor growth. This deterioration was not dependent on the extent of resection performed. Progression-free survival (PFS) at 5 years was 80% ± 4% and 76% ± 5% for patients with invasive and noninvasive tumor growth, respectively, with no difference in the 5-year PFS for extent of resection. CONCLUSIONS: Preoperative neurological impairments and invasive tumor growth were strong predictors of deterioration in short-term neurological outcome after medulloblastoma neurosurgery, whereas the extent of resection was not. Neither tumor invasiveness nor extent of resection influenced PFS. These findings support the continuation of maximal safe resection in medulloblastoma surgery where functional risks are not taken in areas with tumor invasion.

2.
Pharmacogenomics J ; 19(6): 564-569, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30723315

RESUMO

Vincristine is an important drug of acute lymphoblastic leukemia (ALL) treatment protocols that can cause neurotoxicity. Patients treated with LAL/SHOP protocols often suffer from vincristine-related neurotoxicity in early phases of treatment. A genetic variant in CEP72, a gene involved in vincristine pharmacodynamics, was recently associated with neurotoxicity after prolonged vincristine treatment. This association was not replicated in our Spanish population during induction phase. To test the possibility that other variants in genes involved in vincristine pharmacodynamics were associated with vincristine neuropathy in early phases of the treatment, we evaluated the correlation with toxicity of 24 polymorphisms in 9 key genes in a large cohort of 152 Spanish children with B-ALL homogeneously treated. Results showed no association between any genetic variant in the TUBB1, TUBB2A, TUBB2B, TUBB3, TUBB4, MAPT, MIR146a, MIR202, and MIR411 genes and vincristine-related neurotoxicity. These results are in line with the hypothesis that there are different mechanisms causing pheripheral neurotoxicity after prolonged and short-term vincristine treatments.

3.
Pharmacogenomics ; 19(18): 1403-1412, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30479191

RESUMO

AIM: Mucositis, linked to methotrexate, daunorubicin or cyclophosphamide, is a frequent childhood acute lymphoblastic leukemia (ALL) therapy side effect. miRNAs regulate the expression of pharmacokinetic/pharmacodynamic pathway genes. SNPs in miRNAs could affect their levels or function, and affect their pharmacokinetic/pharmacodynamic pathway target genes. Our aim was to determine the association between miRNA genetic variants targeting mucositis-related genes and mucositis-developing risk. PATIENTS & METHODS: We analyzed 160 SNPs in 179 Spanish children with B-cell precursor ALL homogeneously treated with LAL/SHOP protocols. RESULTS: We identified three SNPs in miR-4268, miR-4751 and miR-3117 associated with mucositis, diarrhea and vomiting, respectively. CONCLUSION: The effect of these SNPs on genes related to drug pharmacokinetics/pharmacodynamics could explain mucositis, diarrhea and vomiting development during ALL therapy.


Assuntos
Predisposição Genética para Doença/genética , MicroRNAs/genética , Mucosite/genética , Polimorfismo de Nucleotídeo Único/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Pré-Escolar , Feminino , Humanos , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Estudos Retrospectivos
4.
Oncotarget ; 9(33): 22907-22914, 2018 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-29796161

RESUMO

Acute lymphoblastic leukemia (ALL) is the most common cancer in children. Numerous studies have shown that microRNAs (miRNAs) could play a role in this disease. Nowadays, more than 2500 miRNAs have been described, that regulate more than 50% of genes, including those involved in B-cell maturation, differentiation and proliferation. Genetic variants in miRNAs can alter their own levels or function, affecting their target gene expression, and then, may affect ALL risk. Therefore, the aim of this study was to determine the role of miRNA genetic variants in B-ALL susceptibility. We analyzed all variants in pre-miRNAs (MAF > 1%) in two independent cohorts from Spain and Slovenia and inferred their functional effect by in silico analysis. SNPs rs12402181 in miR-3117 and rs62571442 in miR-3689d2 were associated with ALL risk in both cohorts, possibly through their effect on MAPK signalling pathway. These SNPs could be novel markers for ALL susceptibility.

5.
Epigenomics ; 10(4): 409-417, 2018 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-29569486

RESUMO

AIM: Hepatotoxicity is one of the most common drug-related toxicities during the treatment of childhood acute lymphoblastic leukemia (ALL). Many genes involved in liver-specific signaling pathways are tightly controlled by miRNAs, and miRNA function could be modulated by SNPs. As a consequence, we hypothesized that variants in miRNAs could be associated with drug-induced hepatotoxicity. METHODS: We analyzed 213 SNPs in 206 miRNAs in a cohort of 179 children with ALL homogeneously treated. RESULTS: rs2648841 in miR-1208 was the most significant SNP during consolidation phase after false discovery rate correction, probably through an effect on its target genes DHFR, MTR and MTHFR. CONCLUSION: These results point out the possible involvement of SNPs in miRNAs in toxicity to chemotherapy in children with ALL.


Assuntos
Fígado/efeitos dos fármacos , MicroRNAs/genética , Polimorfismo de Nucleotídeo Único , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Antimetabólitos Antineoplásicos/efeitos adversos , Antimetabólitos Antineoplásicos/uso terapêutico , Criança , Pré-Escolar , Feminino , Estudos de Associação Genética , Humanos , Lactente , Masculino , Metotrexato/efeitos adversos , Metotrexato/uso terapêutico , MicroRNAs/química , Conformação de Ácido Nucleico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Estudos Retrospectivos
6.
Pharmacogenomics J ; 18(6): 704-712, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-29282364

RESUMO

Vincristine (VCR), an important component of childhood acute lymphoblastic leukemia (ALL) therapy, can cause sensory and motor neurotoxicity. This neurotoxicity could lead to dose reduction or treatment discontinuation, which could in turn reduce survival. In this line, several studies associated peripheral neurotoxicity and polymorphisms in genes involved in pharmacokinetics (PK) and pharmacodynamics (PD) of VCR. Nowadays, it is well known that these genes are regulated by microRNAs (miRNAs) and SNPs in miRNAs could modify their levels or function. Therefore, the aim of this study was to determine whether SNPs in miRNAs could be associated with VCR-induced neurotoxicity. To achieve this aim, we analyzed all the SNPs in miRNAs (minor allele frequency (MAF) ≥ 0.01) which could regulate VCR-related genes in a large cohort of Spanish children with B-cell precursor ALL (B-ALL) homogeneously treated with LAL/SHOP protocols. We identified the A allele of rs12402181 in the seed region of miR-3117-3p, that could affect the binding with ABCC1 and RALBP1 gene, and C allele of rs7896283 in pre-mature sequence of miR-4481, which could be involved in peripheral nerve regeneration, significantly associated with VCR-induced neurotoxicity. These findings point out the possible involvement of two SNPs in miRNA associated with VCR-related neurotoxicity.


Assuntos
Antineoplásicos Fitogênicos/efeitos adversos , MicroRNAs/genética , Doença dos Neurônios Motores/induzido quimicamente , Doença dos Neurônios Motores/genética , Variantes Farmacogenômicos , Polimorfismo de Nucleotídeo Único , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Transtornos das Sensações/induzido quimicamente , Transtornos das Sensações/genética , Vincristina/efeitos adversos , Transportadores de Cassetes de Ligação de ATP/genética , Idade de Início , Antineoplásicos Fitogênicos/administração & dosagem , Criança , Pré-Escolar , Feminino , Proteínas Ativadoras de GTPase/genética , Frequência do Gene , Predisposição Genética para Doença , Humanos , Lactente , Masculino , Doença dos Neurônios Motores/diagnóstico , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Farmacogenética , Testes Farmacogenômicos , Fenótipo , Leucemia-Linfoma Linfoblástico de Células Precursoras B/diagnóstico , Valor Preditivo dos Testes , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Transtornos das Sensações/diagnóstico , Espanha , Vincristina/administração & dosagem
7.
PLoS One ; 12(5): e0177421, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28481918

RESUMO

The locus CDKN2A/B (9p21.3), which comprises the tumor suppressors genes CDKN2A and CDKN2B and the long noncoding RNA (lncRNA) known as ANRIL (or CDKN2B-AS), was associated with childhood acute lymphoblastic leukemia (ALL) susceptibility in several genome wide association studies (GWAS). However, the variants associated in the diverse studies were different. Recently, new and independent SNPs deregulating the locus function were also identified in association with ALL risk. This diversity in the results may be explained because different variants in each population could alter CDKN2A/B locus function through diverse mechanisms. Therefore, the aim of this study was to determine whether the annotated risk variants in the CDKN2A/B locus affect the susceptibility of B cell precursor ALL (B-ALL) in our Spanish population and explore if other SNPs altering additional regulatory mechanisms could be also involved. We analyzed the four SNPs proposed by GWAs and two additional SNPs in miRNA binding sites in 217 pediatric patients with B-ALL and 330 healthy controls. The SNPs rs2811712, rs3731249, rs3217992 and rs2811709 were associated with B-ALL susceptibility in our Spanish population. ALL subtypes analyses showed that rs2811712 was associated with B-hyperdiploid ALL. These results provide evidence for the influence of genetic variants at CDKN2A/B locus with the risk of developing B-ALL.


Assuntos
Inibidor de Quinase Dependente de Ciclina p15/genética , Inibidor de Quinase Dependente de Ciclina p18/genética , Leucemia de Células B/genética , Mutação , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Adolescente , Criança , Pré-Escolar , Inibidor p16 de Quinase Dependente de Ciclina , Feminino , Genótipo , Humanos , Lactente , Masculino , Espanha
8.
Pharmacogenet Genomics ; 26(11): 517-525, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27649261

RESUMO

OBJECTIVES: Methotrexate (MTX), the key drug in childhood B-cell acute lymphoblastic leukemia (B-ALL) therapy, often causes toxicity. An association between genetic variants in MTX transport genes and toxicity has been found. It is known that these transporters are regulated by microRNAs (miRNAs), and miRNA single nucleotide polymorphisms (SNPs) interfere with miRNA levels or function. With regard to B-cell ALL, we have previously found rs56103835 in miR-323b that targets ABCC4 associated with MTX plasma levels. Despite these evidences and that nowadays a large amount of new miRNAs have been annotated, studies of miRNA polymorphisms and MTX toxicity are almost absent. Therefore, the aim of this study was to determine whether there are other variants in miRNAs associated with MTX levels. PATIENTS AND METHODS: Blood samples of 167 Spanish patients with pediatric B-cell ALL treated with the LAL-SHOP protocol were analyzed. We selected all the SNPs described in pre-miRNAs with a minor allele frequency more than 1% (213 SNPs in 206 miRNAs) that could regulate MTX transporters because the miRNAs that target MTX transporter genes are not completely defined. Genotyping was performed with VeraCode GoldenGate platform. RESULTS: Among the most significant results, we found rs56292801 in miR-5189, rs4909237 in miR-595, and rs78790512 in miR-6083 to be associated with MTX plasma levels. These miRNAs were predicted, in silico, to regulate genes involved in MTX uptake: SLC46A1, SLC19A1, and SLCO1A2. CONCLUSION: In this study, we detected three SNPs in miR-5189, miR-595, and miR-6083 that might affect SLC46A1, SLC19A1, and SLCO1A2 MTX transport gene regulation and could affect MTX levels in patients with pediatric B-cell ALL.


Assuntos
Antimetabólitos Antineoplásicos/efeitos adversos , Metotrexato/efeitos adversos , MicroRNAs/genética , Polimorfismo de Nucleotídeo Único , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Antimetabólitos Antineoplásicos/uso terapêutico , Criança , Pré-Escolar , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Humanos , Masculino , Metotrexato/uso terapêutico , Transportadores de Ânions Orgânicos/genética , Transportador de Folato Acoplado a Próton/genética , Proteína Carregadora de Folato Reduzido/genética , Estudos Retrospectivos , Espanha
9.
J Neurooncol ; 129(3): 515-524, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27423645

RESUMO

The HIT-SIOP-PNET4 randomised trial for standard risk medulloblastoma (MB) (2001-2006) included 338 patients and compared hyperfractionated and conventional radiotherapy. We here report the long-term outcome after a median follow up of 7.8 years, including detailed information on relapse and the treatment of relapse. Data were extracted from the HIT Group Relapsed MB database and by way of a specific case report form. The event-free and overall (OS) survival at 10 years were 76 ± 2 % and 78 ± 2 % respectively with no significant difference between the treatment arms. Seventy-two relapses and three second malignant neoplasms were reported. Thirteen relapses (18 %) were isolated local relapses in the posterior fossa (PF) and 59 (82 %) were craniospinal, metastatic relapses (isolated or multiple) with or without concurrent PF disease. Isolated PF relapse vs all other relapses occurred at mean/median of 38/35 and 28/26 months respectively (p = 0.24). Late relapse, i.e. >5 years from diagnosis, occurred in six patients (8 %). Relapse treatment consisted of combinations of surgery (25 %), focal radiotherapy (RT 22 %), high dose chemotherapy with stem cell rescue (HDSCR 21 %) and conventional chemotherapy (90 %). OS at 5 years after relapse was 6.0 ± 4 %. In multivariate analysis; isolated relapse in PF, and surgery were significantly associated with prolonged survival whereas RT and HDSCR were not. Survival after relapse was not related to biological factors and was very poor despite several patients receiving intensive treatments. Exploration of new drugs is warranted, preferably based on tumour biology from biopsy of the relapsed tumour.


Assuntos
Neoplasias Encefálicas/radioterapia , Terapia Combinada/métodos , Meduloblastoma/radioterapia , Resultado do Tratamento , Adolescente , Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/mortalidade , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Humanos , Estudos Longitudinais , Imagem por Ressonância Magnética , Masculino , Meduloblastoma/diagnóstico por imagem , Meduloblastoma/genética , Meduloblastoma/mortalidade , Mutação/genética , Proteína Proto-Oncogênica N-Myc/genética , Recidiva Local de Neoplasia , Dosagem Radioterapêutica , Recidiva , Análise de Regressão , Prevenção Secundária , Adulto Jovem , beta Catenina/genética
10.
Pharmacogenomics ; 17(7): 731-41, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-27180762

RESUMO

AIM: Vincristine is an important component of acute lymphoblastic leukemia (ALL) treatment protocols that can cause neurotoxicity. Patients treated with LAL/SHOP protocols often suffer from vincristine-related neurotoxicity in early phases of treatment. Recently, a genome-wide association study connected a SNP in CEP72, involved in vincristine pharmacodynamics, with neurotoxicity during later phases of therapy, which was not replicated during induction phase. These results, together with previous studies indicating that polymorphisms in pharmacokinetic genes are associated with drug toxicity, suggest that changes in the activity or levels of vincristine transporters or metabolizers could work as predictors of vincristine-related neurotoxicity in early phases of treatment in pediatric ALL. PATIENTS & METHODS: We analyzed 150 SNPs in eight key genes involved in vincristine pharmacokinetics and in 13 miRNAs that regulate them. We studied their correlation with neurotoxicity during induction phase in 152 ALL patients treated with LAL/SHOP protocols. RESULTS: The strongest associations with neurotoxicity were observed for two SNPs in ABCC2. The genotypes rs3740066 GG and rs12826 GG were associated with increased neurotoxicity. CONCLUSION: Polymorphisms in ABCC2 could be novel markers for vincristine-related neurotoxicity in pediatric ALL in early phases.


Assuntos
Antineoplásicos Fitogênicos/efeitos adversos , Antineoplásicos Fitogênicos/farmacocinética , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Variantes Farmacogenômicos , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/metabolismo , Vincristina/efeitos adversos , Vincristina/farmacocinética , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Criança , Pré-Escolar , Feminino , Haplótipos , Humanos , Masculino , Redes e Vias Metabólicas/genética , MicroRNAs/genética , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Síndromes Neurotóxicas/etiologia , Testes Farmacogenômicos , Polimorfismo de Nucleotídeo Único , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Estudos Retrospectivos
11.
Rev. iberoam. micol ; 32(3): 190-196, jul.-sept. 2015. tab, ilus
Artigo em Inglês | IBECS | ID: ibc-142080

RESUMO

Background. Fungi of the genus Fusarium are primarily plant pathogens and saprobes that produce disseminated infections in immunologically deficient humans. After aspergillosis, disseminated fusariosis is the second most common cause of invasive infection by filamentous fungi in patients with hematologic malignancies or those undergoing transplants of hematopoietic progenitors. Aims. Disseminated fusariosis (DF) is considered an extremely rare infection and has reached a stable incidence rate, but its high mortality rate and the lack of an optimal management protocol have raised increasing interest in this mycosis. Methods. We present three cases of DF produced by Fusarium oxysporum species complex, Fusarium solani species complex and the highly unusual Fusarium dimerum in patients with advanced hematological malignancies diagnosed in our hospital between 2007 and 2011. The species level identification of the Fusarium isolates was established by sequencing their TEF1 gene. Results. The isolates showed low susceptibility to most of the antifungal agents analyzed, except that observed for F. dimerum to amphotericin B (AmB) and terbinafine, and F. oxysporum species complex to AmB. Interestingly, the strain of F. solani species complex exhibited high MIC values for AmB and voriconazole, notwithstanding these drugs were used for treatment with good results. Other relevant aspects to be considered in the treatment of DF are surgically cleaning foci of infection, withdrawing presumably contaminated catheters and recovery from neutropenia. Conclusions. The prevention of infection in colonized patients, the maintenance of a high level of diagnostic suspicion for early diagnosis, and the combined, vigorous and prolonged use of L-AmB and voriconazole are essential to decrease the mortality rate of this devastating infection (AU)


Antecedentes. Los hongos del género Fusarium son principalmente patógenos vegetales que producen infecciones diseminadas en personas con deficiencias inmunológicas. Tras la aspergilosis, la fusariosis diseminada es la segunda causa de infección invasora por hongos filamentosos en pacientes con enfermedades hematológicas malignas o en receptores de trasplantes de progenitores hematopoyéticos. Objetivos. La fusariosis diseminada es muy infrecuente y ha alcanzado una tasa de incidencia estable. Sin embargo, el interés por estas micosis se ha incrementado debido a su alta tasa de mortalidad y a la falta de un tratamiento óptimo. Métodos. Se presentan tres casos de fusariosis diseminada por Fusarium oxysporum species complex (SC), Fusarium solani SC y Fusarium dimerum en pacientes de nuestro hospital con enfermedades hematológicas avanzadas, diagnosticados entre 2007 y 2011. Los aislamientos de Fusarium se identificaron mediante secuenciación del gen TEF1. Resultados. La sensibilidad a los antifúngicos ensayados fue baja salvo a la anfotericina B (AmB) y la terbinafina en F. dimerum, y a la AmB en F. oxysporum SC. Aunque F. solani SC mostró valores altos de CMI para la AmB y el voriconazol, su uso para el tratamiento del paciente dio buenos resultados. Otros aspectos relevantes para el tratamiento de la fusariosis diseminada son la limpieza quirúrgica de los focos de infección, la retirada de catéteres presumiblemente contaminados y la recuperación de la neutropenia. Conclusiones. La prevención de la infección en pacientes colonizados, el mantenimiento de un alto grado de sospecha para un diagnóstico temprano y el uso combinado, vigoroso y prolongado de L-AmB y voriconazol son esenciales para disminuir la mortalidad de esta infección devastadora (AU)


Assuntos
Adolescente , Adulto , Humanos , Masculino , Pessoa de Meia-Idade , Fusariose/complicações , Fusarium/patogenicidade , Neoplasias Hematológicas/complicações , Antifúngicos/uso terapêutico , Fungemia/complicações , Anfotericina B/uso terapêutico , Hospedeiro Imunocomprometido , Análise de Sequência de DNA
12.
Rev Iberoam Micol ; 32(3): 190-6, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25936697

RESUMO

BACKGROUND: Fungi of the genus Fusarium are primarily plant pathogens and saprobes that produce disseminated infections in immunologically deficient humans. After aspergillosis, disseminated fusariosis is the second most common cause of invasive infection by filamentous fungi in patients with hematologic malignancies or those undergoing transplants of hematopoietic progenitors. AIMS: Disseminated fusariosis (DF) is considered an extremely rare infection and has reached a stable incidence rate, but its high mortality rate and the lack of an optimal management protocol have raised increasing interest in this mycosis. METHODS: We present three cases of DF produced by Fusarium oxysporum species complex, Fusarium solani species complex and the highly unusual Fusarium dimerum in patients with advanced hematological malignancies diagnosed in our hospital between 2007 and 2011. The species level identification of the Fusarium isolates was established by sequencing their TEF1 gene. RESULTS: The isolates showed low susceptibility to most of the antifungal agents analyzed, except that observed for F. dimerum to amphotericin B (AmB) and terbinafine, and F. oxysporum species complex to AmB. Interestingly, the strain of F. solani species complex exhibited high MIC values for AmB and voriconazole, notwithstanding these drugs were used for treatment with good results. Other relevant aspects to be considered in the treatment of DF are surgically cleaning foci of infection, withdrawing presumably contaminated catheters and recovery from neutropenia. CONCLUSIONS: The prevention of infection in colonized patients, the maintenance of a high level of diagnostic suspicion for early diagnosis, and the combined, vigorous and prolonged use of L-AmB and voriconazole are essential to decrease the mortality rate of this devastating infection.


Assuntos
Fusariose/complicações , Neoplasias Hematológicas/complicações , Adolescente , Adulto , Anfotericina B/uso terapêutico , Antifúngicos/uso terapêutico , Fusariose/diagnóstico , Fusariose/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Voriconazol/uso terapêutico
13.
Cancer Genet ; 207(4): 164-7, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24767712

RESUMO

The identification of new cryptic deletions and duplications can be used to improve prognostic classification in cancer. To obtain accurate results, it is necessary to discriminate between somatic alterations in the tumor cell and germline polymorphisms. For this purpose, copy number variation (CNV) public databases have been used as a reference. Nevertheless, the use of these databases may lead to erroneous results. Our main goal was to explore the limitations of the use of CNV databases, such as the Database of Genomic Variants (DGV), as the reference. To that end, we used pediatric acute lymphoblastic leukemia (ALL) as a model. We analyzed the genome-wide copy number profile of 23 ALL patients and conducted a comparison of the results obtained using the DGV with those obtained using the normal sample from the patient as the reference. Using only the DGV, 19% of alterations and 41% of polymorphisms were erroneously catalogued. Our results support the hypothesis that with the use of databases such as the DGV as the reference, a high percentage of the variations can be erroneously classified.


Assuntos
Variações do Número de Cópias de DNA , Bases de Dados Genéticas/estatística & dados numéricos , Bases de Dados Genéticas/normas , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Criança , Dosagem de Genes , Humanos , Mutação , Polimorfismo Genético , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Prognóstico , Padrões de Referência , Reprodutibilidade dos Testes
14.
Pediatr Res ; 75(6): 767-73, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24618566

RESUMO

BACKGROUND: Evidence for an inherited genetic risk for pediatric acute lymphoblastic leukemia has been provided in several studies. Most of them focused on coding regions. However, those regions represent only 1.5% of the entire genome. In acute lymphoblastic leukemia (ALL), it has been suggested that the expression of microRNAs (miRNAs) is dysregulated, which suggests that they may have a role in ALL risk. Changes in miRNA function may occur through single-nucleotide polymorphisms (SNPs). Therefore, the aim of this study was to evaluate whether polymorphisms in pre-miRNAs, and/or miRNA-processing genes, contribute to a predisposition for childhood ALL. METHODS: In this study, we analyzed 118 SNPs in pre-miRNAs and miRNA-processing genes in 213 B-cell ALL patients and 387 controls. RESULTS: We found 11 SNPs significantly associated with ALL susceptibility. These included three SNPs present in miRNA genes (miR-612, miR-499, and miR-449b) and eight SNPs present in six miRNA biogenesis pathway genes (TNRC6B, DROSHA, DGCR8, EIF2C1, CNOT1, and CNOT6). Among the 118 SNPs analyzed, rs12803915 in mir-612 and rs3746444 in mir-499 exhibited a more significant association, with a P value <0.01. CONCLUSION: The results of this study indicate that SNP rs12803915 located in pre-mir-612, and SNP rs3746444 located in pre-mir-499, may represent novel markers of B-cell ALL susceptibility.


Assuntos
Predisposição Genética para Doença/genética , Polimorfismo de Nucleotídeo Único/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , RNA não Traduzido/genética , Criança , Estudos de Associação Genética , Humanos , MicroRNAs/genética
15.
PLoS One ; 9(3): e91261, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24614921

RESUMO

Despite the clinical success of acute lymphoblastic leukemia (ALL) therapy, toxicity is frequent. Therefore, it would be useful to identify predictors of adverse effects. In the last years, several studies have investigated the relationship between genetic variation and treatment-related toxicity. However, most of these studies are focused in coding regions. Nowadays, it is known that regions that do not codify proteins, such as microRNAs (miRNAs), may have an important regulatory function. MiRNAs can regulate the expression of genes affecting drug response. In fact, the expression of some of those miRNAs has been associated with drug response. Genetic variations affecting miRNAs can modify their function, which may lead to drug sensitivity. The aim of this study was to detect new toxicity markers in pediatric B-ALL, studying miRNA-related polymorphisms, which can affect miRNA levels and function. We analyzed 118 SNPs in pre-miRNAs and miRNA processing genes in association with toxicity in 152 pediatric B-ALL patients all treated with the same protocol (LAL/SHOP). Among the results found, we detected for the first time an association between rs639174 in DROSHA and vomits that remained statistically significant after FDR correction. DROSHA had been associated with alterations in miRNAs expression, which could affect genes involved in drug transport. This suggests that miRNA-related SNPs could be a useful tool for toxicity prediction in pediatric B-ALL.


Assuntos
MicroRNAs/biossíntese , MicroRNAs/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Criança , Feminino , Técnicas de Genotipagem , Humanos , Desequilíbrio de Ligação/genética , Masculino , MicroRNAs/metabolismo , Farmacogenética , Polimorfismo de Nucleotídeo Único/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Processamento Pós-Transcricional do RNA/genética
16.
J Cancer Res Clin Oncol ; 139(11): 1879-86, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24013273

RESUMO

PURPOSE: Single-nucleotide polymorphisms (SNPs) in AT-rich interactive domain 5B (ARID5B) have been associated with risk for pediatric acute lymphoblastic leukemia (ALL). After reviewing previous studies, we realized that the most significant associations were restricted to intron 3, but the mechanism(s) by which those SNPs affect ALL risk remain to be elucidated. Therefore, the aim of this study was to analyze the association between genetic variants of the intron 3 region of ARID5B and the incidence of B-ALL in a Spanish population. We also aimed to find a functional explanation for the association, searching for copy number variations (CNVs), and changes in ARID5B expression associated with the genotypes of the SNPs. METHODS: We analyzed 10 SNPs in intron 3 of ARID5B in a Spanish population of 219 B-ALL patients and 397 unrelated controls with the Taqman Open Array platform. CNVs were analyzed in 23 patients and 17 controls using the Cytogenetics Whole-genome 2.7 M platform. Expression of ARID5B transcript 1 was quantified by qPCR and related to SNPs genotype in seven ALL cell lines. RESULTS: Association between intron 3 and B-ALL risk was confirmed for all of the SNPs evaluated in our Spanish population. We could not explain this association by the presence of CNVs. We neither detected changes in the expression of ARID5B isoform associated with the genotype of the SNPs. CONCLUSIONS: The intron 3 of ARID5B gene was found to be strongly associated with B-ALL risk in the Spanish population examined. However, neither CNVs nor changes in mRNA expression were found to be responsible for this association.


Assuntos
Proteínas de Ligação a DNA/genética , Íntrons , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Fatores de Transcrição/genética , Criança , Pré-Escolar , Proteínas de Ligação a DNA/biossíntese , Diploide , Feminino , Dosagem de Genes , Predisposição Genética para Doença , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Fatores de Transcrição/biossíntese
17.
Pharmacogenet Genomics ; 23(2): 53-61, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23222202

RESUMO

OBJECTIVES: Methotrexate (MTX) is an important component of therapy for pediatric acute lymphoblastic leukemia (ALL). Treatment with MTX often causes toxicity, which can necessitate dose reduction or treatment cessation. Interindividual differences in adverse reactions can be due to different factors, including polymorphisms in key genes. Recently, we confirmed the association between SLCO1B1 rs11045879 polymorphism and toxicity previously proposed by Treviño and colleagues. As SLCO1B1 is a transporter involved in MTX elimination, other polymorphisms in genes from this pathway could also have a role in MTX toxicity. The aim of the present study was to analyze in depth the role of polymorphisms in the genes of the MTX transport pathway as putative toxicity predictors in pediatric ALL. METHODS: We analyzed 384 single nucleotide polymorphisms in 12 transporter genes (SLCO1B1, SLCO1B3, SLCO1A2, ABCB1, ABCG2, ABCC1, ABCC2, ABCC3, ABCC4, SLC19A1, SLC22A6 and SLC22A8) and their correlation with different toxicity parameters in 151 pediatric ALL patients treated using the LAL/SHOP protocol. RESULTS: A significant association with MTX plasma levels was found for 21 polymorphisms from seven genes and 15 haplotypes. After correction, rs9516519 in ABCC4, rs3740065 in ABCC2, and haplotype GCGGG in ABCC2 remained significantly associated. CONCLUSION: Our results suggest that polymorphisms in ABCC4 and ABCC2 could be novel markers for MTX toxicity in pediatric ALL.


Assuntos
Antimetabólitos Antineoplásicos/efeitos adversos , Biomarcadores Tumorais/genética , Haplótipos/genética , Metotrexato/efeitos adversos , Polimorfismo de Nucleotídeo Único/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Antimetabólitos Antineoplásicos/sangue , Criança , Feminino , Humanos , Masculino , Metotrexato/sangue , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangue , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Prognóstico , Estudos Retrospectivos
18.
J Clin Oncol ; 30(26): 3187-93, 2012 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-22851561

RESUMO

PURPOSE: To compare event-free survival (EFS), overall survival (OS), pattern of relapse, and hearing loss in children with standard-risk medulloblastoma treated by postoperative hyperfractionated or conventionally fractionated radiotherapy followed by maintenance chemotherapy. PATIENTS AND METHODS: In all, 340 children age 4 to 21 years from 122 European centers were postoperatively staged and randomly assigned to treatment with hyperfractionated radiotherapy (HFRT) or standard (conventional) fractionated radiotherapy (STRT) followed by a common chemotherapy regimen consisting of eight cycles of cisplatin, lomustine, and vincristine. RESULTS: After a median follow-up of 4.8 years (range, 0.1 to 8.3 years), survival rates were not significantly different between the two treatment arms: 5-year EFS was 77% ± 4% in the STRT group and 78% ± 4% in the HFRT group; corresponding 5-year OS was 87% ± 3% and 85% ± 3%, respectively. A postoperative residual tumor of more than 1.5 cm(2) was the strongest negative prognostic factor. EFS of children with all reference assessments and no large residual tumor was 82% ± 2% at 5 years. Patients with a delay of more than 7 weeks to the start of RT had a worse prognosis. Severe hearing loss was not significantly different for the two treatment arms at follow-up. CONCLUSION: In this large randomized European study, which enrolled patients with standard-risk medulloblastoma from more than 100 centers, excellent survival rates were achieved in patients without a large postoperative residual tumor and without RT treatment delays. EFS and OS for HFRT was not superior to STRT, which therefore remains standard of care in this disease.


Assuntos
Neoplasias Cerebelares/radioterapia , Fracionamento da Dose de Radiação , Meduloblastoma/radioterapia , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quimioterapia Adjuvante , Criança , Pré-Escolar , Terapia Combinada , Irradiação Craniana , Intervalo Livre de Doença , Feminino , Perda Auditiva/etiologia , Humanos , Masculino , Radioterapia Adjuvante , Recidiva , Taxa de Sobrevida
19.
Med. clín (Ed. impr.) ; 139(4): 141-149, jul. 2012. tab, ilus
Artigo em Espanhol | IBECS | ID: ibc-101841

RESUMO

Fundamento y objetivo: La leucemia linfoblástica aguda (LLA) es el cáncer más frecuente en la edad pediátrica, con tasas de curación del 80-85%. En la LLA de fenotipo T (LLA-T, 15% de casos) los factores pronósticos no están bien definidos. Nuestro objetivo es analizar la supervivencia y los factores pronósticos clínicos en una serie de pacientes con LLA-T. Pacientes y método: Se analizaron los niños con LLA-T (1-18 años) tratados según los protocolos SHOP/LLA-89/LLA-94/LLA-99/LLA-2005 (desde febrero de 1989 hasta noviembre de 2009) en 37 instituciones. Resultados: Se incluyeron 218 pacientes con LLA-T sobre un total de 1.652 LLA pediátricas. De ellos, 164 (75%) eran varones. La edad mediana fue de 7,8 años (extremos 1,3-18,6). La mediana de leucocitos fue 78,2×109/l (extremos 0,8-930). Quince niños (6,8%) tuvieron infiltración del sistema nervioso central (SNC). En cuanto a la respuesta al tratamiento de inducción, 150 (75%) pacientes tenían menos de 5% de blastos en médula ósea del día +14 y 199 alcanzaron la remisión completa. La supervivencia global (SG) media (DE) a 60 meses para los protocolos SHOP/LLA-89, LLA-94 y LLA-99 fue del 48 (8), 49 (6) y 70 (6) %, respectivamente, y la SG a 48 meses para el protocolo SHOP/LLA-05 (protocolo en curso) del 74 (8) %. La mediana de seguimiento fue de 206, 152, 74 y 17 meses, respectivamente. El análisis de factores pronósticos no mostró diferencias significativas en cuanto a sexo ni edad. Resultaron significativos la cifra de leucocitos mayor o igual a 200×109/l (p=0,024), la infiltración del SNC al diagnóstico (p<0,006), la respuesta al tratamiento (médula ósea día +14) (p=0,005) y la remisión completa al final de la inducción (p=0,0000). Conclusiones: Los resultados obtenidos en la LLA-T con los protocolos SHOP/LLA-89 y SHOP/LLA-94 fueron inferiores a otros protocolos contemporáneos, pero la supervivencia mejoró en los 2 últimos protocolos. En concordancia con otras series de LLA-T, la respuesta al tratamiento fue el principal factor pronóstico (AU)


Background and objectives: Acute lymphoblastic leukemia (ALL) is the most frequent cancer in childhood, with cure rates of 80-85%. In T-cell ALL (15% of ALL), prognostic factors are ill defined. We aimed to describe the event-free survival (EFS) and analyze clinical prognostic factors in a series of pediatric T-ALL of 4 consecutive clinical trials. Patients and methods: Children with T-ALL aged 1-18 years treated in 37 institutions in Spain were enrolled in 4 consecutive trials from February-1989 to November-2009. Results: A total of 218 T-ALL patients out of 1,652 pediatric ALL were evaluable during the study period (SHOP/ALL-89: 35, ALL-94: 63, ALL-99: 62, ALL-2005: 58). There were 164 boys (75%). Median age (years) was 7.8 range (1.3-18.6). Median leukocytes (109/L) was 78.2, range 0.8-930. Fifteen (6.8%) children had central nervous system (CNS) involvement at diagnosis. Regarding response to induction treatment, 150 (75%) patients had less than 5% blasts on day-14 bone marrow and 199 achieved complete remission at the end of induction. Overall survival (OS) at 60 months for SHOP/ALL-89, ALL-94, ALL-99 was 48 (8), 49 (6), 70 (6) %, respectively, and at 48 months for SHOP/ALL-2005 (ongoing protocol) was 74 (8) %. Median follow-up (months) was 206, 152, 74 and 17 respectively. Analysis of prognostic factors revealed no statistical differences regarding sex or age. Leukocyte count over 200×109/l (P=.024), CNS infiltration at diagnosis (P<.006) and treatment response had prognostic significance (end-induction complete remission) (P=.0000), day 14-bone marrow (P=.005). Conclusions:Results for the SHOP/ALL-89 and ALL-94 protocols were inferior to other contemporary protocols but there has been an improvement in survival in the 2 last trials. In line with other T-ALL series, response to treatment had the strongest prognostic impact (AU)


Assuntos
Humanos , Masculino , Feminino , Lactente , Pré-Escolar , Criança , Adolescente , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamento farmacológico , Infiltração Leucêmica/patologia , Quimioterapia de Indução/métodos , Protocolos Clínicos , Taxa de Sobrevida , Prognóstico , Progressão da Doença , Distribuição por Idade e Sexo , Resultado do Tratamento
20.
Clin Transl Oncol ; 14(5): 396-8, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22551548

RESUMO

INTRODUCTION: The Li-Fraumeni syndrome (LFS) is an autosomal dominant hereditary disorder associated with different tumor types in childhood and young adults. Approximately 70% of LFS cases contain germline mutations in the TP53 gene. We report a case of a family suspected of LFS. MATERIALS AND METHODS: The proband and four members of the family affected were diagnosed with cancer at an early age and they all died except the proband. Exons 5-9 from TP53 gene were analysed by direct amplification and sequencing in 7 family members. RESULTS: The analysis revealed a germline nonsense mutation in exon 8 at codon 306 of the codified region of the TP53 gene, causing a change of CGA to TGA (Arg→Stop) in the proband, her mother, her cousin and her maternal uncle. Proband's maternal grandmother and aunt do not have the mutation. CONCLUSIONS: The members of this family that were studied meet the criteria of classic LFS and the described mutation increases their susceptibility to develop cancer. The proband's maternal grandfather died of lung cancer in 1993, and we believe that he was the carrier of the mutation in this family.


Assuntos
Códon sem Sentido/genética , Éxons/genética , Mutação em Linhagem Germinativa/genética , Síndrome de Li-Fraumeni/genética , Proteína Supressora de Tumor p53/genética , Adulto , Criança , DNA de Neoplasias/genética , Feminino , Seguimentos , Genótipo , Heterozigoto , Humanos , Incidência , Lactente , Síndrome de Li-Fraumeni/epidemiologia , Masculino , Pessoa de Meia-Idade , Linhagem , Reação em Cadeia da Polimerase , Prognóstico , Estudos Prospectivos , Taxa de Sobrevida
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