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1.
J Neurooncol ; 145(1): 177-184, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31522324

RESUMO

INTRODUCTION: Diffuse intrinsic pontine glioma (DIPG) is a rare clinically, neuro-radiologically, and molecularly defined malignancy of the brainstem with a median overall survival of approximately 11 months. Our aim is to evaluate the current tendency for its treatment in Europe in order to develop (inter)national consensus guidelines. METHODS: Healthcare professionals specialized in DIPG were asked to fill in an online survey with questions regarding usual treatment strategies at diagnosis and at disease progression in their countries and/or their centers, respectively. RESULTS: Seventy-four healthcare professionals responded to the survey, of which 87.8% were pediatric oncologists. Only 13.5% of the respondents biopsy all of their patients, 41.9% biopsy their patients infrequently. More than half of the respondents (54.1%) treated their patients with radiotherapy only at diagnosis, whereas 44.6% preferred radiotherapy combined with chemotherapy. When the disease progresses, treatment strategies became even more diverse, and the tendency for no treatment increased from 1.4% at diagnosis to 77.0% after second progression. 36.5% of the healthcare professionals treat children younger than 3 years differently than older children at diagnosis. This percentage decreased, when the disease progresses. Most of the participants (51.4%) included less than 25% of their patients in clinical trials. CONCLUSION: This survey demonstrates a large heterogeneity of treatment regimens, especially at disease progression. We emphasize the need for international consensus guidelines for the treatment of DIPG, possible by more collaborative clinical trials.

2.
Br J Haematol ; 184(3): 405-417, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30450575

RESUMO

Asparaginase is essential in childhood acute lymphoblastic leukaemia (ALL) treatment, however hypersensitivity reactions to pegylated asparaginase (PEG-asparaginase) hampers anti-neoplastic efficacy. Patients with PEG-asparaginase hypersensitivity have been shown to possess zero asparaginase enzyme activity. Using this measurement to define the phenotype, we investigated genetic predisposition to PEG-asparaginase hypersensitivity in a genome-wide association study (GWAS). From July 2008 to March 2016, 1494 children were treated on the Nordic Society of Paediatric Haematology and Oncology ALL2008 protocol. Cases were defined by clinical hypersensitivity and no enzyme activity, controls had enzyme activity ≥ 100 iu/l and no hypersensitivity symptoms. PEG-asparaginase hypersensitivity was reported in 13·8% (206/1494) of patients. Fifty-nine cases and 772 controls fulfilled GWAS inclusion criteria. The CNOT3 variant rs73062673 on 19q13.42, was associated with PEG-asparaginase allergy (P = 4·68 × 10-8 ). We further identified two signals on chromosome 6 in relation to HLA-DQA1 (P = 9·37 × 10-6 ) and TAP2 (P = 1·59 × 10-5 ). This study associated variants in CNOT3 and in the human leucocyte antigen (HLA) region with PEG-asparaginase hypersensitivity, suggesting that not only genetic variations in the HLA region, but also regulation of these genes are of importance in the biology of this toxicity. Furthermore, our study emphasizes the importance of using asparaginase enzyme activity measurements to identify PEG-asparaginase hypersensitivity.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Hipersensibilidade a Drogas/genética , Predisposição Genética para Doença , Variação Genética , Proteínas de Neoplasias/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras , Membro 3 da Subfamília B de Transportadores de Cassetes de Ligação de ATP/genética , Adolescente , Asparaginase/administração & dosagem , Criança , Pré-Escolar , Cromossomos Humanos Par 19/genética , Cromossomos Humanos Par 6/genética , Feminino , Estudo de Associação Genômica Ampla , Antígenos HLA-DQ/genética , Humanos , Lactente , Masculino , Polietilenoglicóis/administração & dosagem , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Fatores de Transcrição/genética
3.
Cancer Chemother Pharmacol ; 83(1): 53-60, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30324220

RESUMO

PURPOSE: Methotrexate polyglutamates (MTXpg) facilitate incorporation of thioguanine nucleotides into DNA (DNA-TG, the primary cytotoxic thiopurine metabolite and outcome determinant in MTX/6-mercaptopurine treatment of childhood ALL). We hypothesized that mapping erythrocyte levels of MTXpg with 1-6 glutamates and their associations with DNA-TG formation would facilitate future guidelines for maintenance therapy dosing. METHODS AND RESULTS: Summed MTX with 1-6 glutamates resolved by LCMS [median (interquartile): 5.47 (3.58-7.69) nmol/mmol hemoglobin] was in agreement with total MTX by radio ligand assay. In 16,389 blood samples from 1426 ALL maintenance therapy patients, MTXpg3 21.0 (15.2-27.4)% was the predominant metabolite, and MTXpg1 (the maternal drug) constituted 38.6 (27.2-50.2)% of MTXpg1-6. All subsets correlated; the strongest associations were between metabolites with similar polyglutamate lengths. Correlations of MTXpg1 with MTXpg2 and MTXpg3,4,5,6 were rs = 0.68 and rs = 0.25-0.42, respectively. Intercorrelations of MTXpg3,4,5,6 were all rs ≥ 0.51. MTXpg4 accounted for 29.8 (24.7-33.3)% of MTXpg3-6, yet explained 96% of the summed MTXpg3-6 variation. MTXpg1-4, MTXpg1-6, MTXpg2-6 and MTXpg3 were all associated with DNA-TG levels (p < 0.00001), but collinearity precluded identification of the most informative subset. CONCLUSIONS: Measuring erythrocyte MTXpg4 simplifies and can replace longer chain MTXpg monitoring. Resolving individual MTXpg identifies samples that are unsuitable for dose guidance due to high levels of MTXpg1 remaining in the plasma fraction because of recent MTX intake. All tested MTXpg subsets correlated with DNA-TG and may be used for ALL maintenance therapy dose adjustments, but the most informative subset remains to be identified.


Assuntos
Antimetabólitos Antineoplásicos/metabolismo , Eritrócitos/metabolismo , Metotrexato/análogos & derivados , Metotrexato/metabolismo , Ácido Poliglutâmico/análogos & derivados , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Adolescente , Antimetabólitos Antineoplásicos/administração & dosagem , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Lactente , Masculino , Metotrexato/administração & dosagem , Ácido Poliglutâmico/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Prognóstico
4.
Leukemia ; 32(12): 2527-2535, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30201983

RESUMO

The antileukaemic drug 6-mercaptopurine is converted into thioguanine nucleotides (TGN) and incorporated into DNA (DNA-TG), the active end metabolite. In a series of genome-wide association studies, we analysed time-weighted means (wm) of erythrocyte concentrations of TGN (Ery-TGN) and DNA-TG in 1009 patients undergoing maintenance therapy for acute lymphoblastic leukaemia (ALL). In discovery analyses (454 patients), the propensity for DNA-TG incorporation (wmDNA-TG/wmEry-TGN ratio) was significantly associated with three intronic SNPs in NT5C2 (top hit: rs72846714; P = 2.09 × 10-10, minor allele frequency 15%). In validation analyses (555 patients), this association remained significant during both early and late maintenance therapy (P = 8.4 × 10-6 and 1.3 × 10-3, respectively). The association was mostly driven by differences in wmEry-TGN, but in regression analyses adjusted for wmEry-TGN (P < 0.0001), rs72846714-A genotype was also associated with a higher wmDNA-TG (P = 0.029). Targeted sequencing of NT5C2 did not identify any missense variants associated with rs72846714 or wmEry-TGN/wmDNA-TG. rs72846714 was not associated with relapse risk, but in a separate cohort of 180 children with relapsed ALL, rs72846714-A genotype was associated with increased occurrence of relapse-specific NT5C2 gain-of-function mutations that reduce cytosol TGN levels (P = 0.03). These observations highlight the impact of both germline and acquired mutations in drug metabolism and disease trajectory.


Assuntos
5'-Nucleotidase/genética , Células Germinativas/metabolismo , Polimorfismo de Nucleotídeo Único/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Adolescente , Antimetabólitos Antineoplásicos/uso terapêutico , Criança , Pré-Escolar , DNA/metabolismo , Feminino , Frequência do Gene/efeitos dos fármacos , Frequência do Gene/genética , Estudo de Associação Genômica Ampla/métodos , Genótipo , Humanos , Lactente , Masculino , Mercaptopurina/uso terapêutico , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Recidiva , Tioguanina/metabolismo
5.
Pediatr Blood Cancer ; 64(10)2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28500740

RESUMO

BACKGROUND: The improved survival rates for childhood acute lymphoblastic leukemia (ALL) may be jeopardized by the development of a second cancer, which has been associated with thiopurine therapy. PROCEDURE: We retrospectively analyzed three sequential Nordic Society of Paediatric Haematology and Oncology's protocols characterized by increasing intensity of thiopurine-based maintenance therapy. We explored the risk of second cancer in relation to protocols, risk group, thiopurine methyltransferase (TPMT) activity, ALL high hyperdiploidy (HeH), and t(12;21)[ETV6/RUNX1]. RESULTS: After median 9.5 years (interquartile range, 5.4-15.3 yrs) of follow-up, 40 of 3,591 patients had developed a second cancer, of whom 38 had non-high-risk B-cell precursor ALL. Patients with standard-risk ALL, who received the longest maintenance therapy, had the highest adjusted hazard of second cancer (hazard ratio [HR], intermediate vs. standard risk: 0.16, 95% CI: 0.06-0.43, P < 0.001; HR, high vs. standard risk: 0.09, 95% CI: 0.02-0.49, P = 0.006); no significant effects of protocol, age, or white blood cell count at diagnosis, ALL HeH, or t(12;21)[ETV6/RUNX1] were observed. A subset analysis on the patients with standard-risk ALL did not show an increased hazard of second cancer from either HeH or t(12;21) (adjusted HR 2.02, 95% CI: 0.69-5.96, P = 0.20). The effect of low TPMT low activity was explored in patients reaching maintenance therapy in clinical remission (n = 3,368); no association with second cancer was observed (adjusted HR 1.43, 95% CI: 0.54-3.76, P = 0.47). CONCLUSIONS: The rate of second cancer was generally highest in patients with low-risk ALL, but we could not identify a subset at higher risk than others.


Assuntos
Segunda Neoplasia Primária/epidemiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/epidemiologia , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Criança , Cromossomos Humanos Par 12/genética , Cromossomos Humanos Par 21/genética , Feminino , Seguimentos , Humanos , Masculino , Metiltransferases/genética , Metiltransferases/metabolismo , Segunda Neoplasia Primária/sangue , Segunda Neoplasia Primária/tratamento farmacológico , Segunda Neoplasia Primária/genética , Ploidias , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangue , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Estudos Retrospectivos , Fatores de Risco , Translocação Genética
6.
Lancet Oncol ; 18(4): 515-524, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28258828

RESUMO

BACKGROUND: Adjustment of mercaptopurine and methotrexate maintenance therapy of acute lymphoblastic leukaemia by leucocyte count is confounded by natural variations. Cytotoxicity is primarily mediated by DNA-incorporated thioguanine nucleotides (DNA-TGN). The aim of this study was to establish whether DNA-TGN concentrations in blood leucocytes during maintenance therapy are associated with relapse-free survival. METHODS: In this substudy of the NOPHO ALL2008 phase 3 trial done in 23 hospitals in seven European countries (Denmark, Estonia, Finland, Iceland, Lithuania, Norway, and Sweden), we analysed data from centralised and blinded analyses of 6-mercaptopurine and methotrexate metabolites in blood samples from patients with non-high-risk childhood acute lymphoblastic leukaemia. Eligible patients were aged 1·0-17·9 years; had been diagnosed with non-high-risk precursor B-cell or T-cell leukaemia; had been treated according to the Nordic Society of Pediatric Hematology and Oncology ALL2008 protocol; and had reached maintenance therapy in first remission. Maintenance therapy was (mercaptopurine 75 mg/m2 once per day and methotrexate 20 mg/m2 once per week, targeted to a leucocyte count of 1·5-3·0 × 109 cells per L). We measured DNA-TGN and erythrocyte concentrations of TGN nucleotides, methylated mercaptopurine metabolites, and methotrexate polyglutamates. The primary objective was the association of DNA-TGN concentrations and 6-mercaptopurine and methotrexate metabolites with relapse-free survival. The secondary endpoint was the assessment of DNA-TGN concentration and 6-mercaptopurine and methotrexate metabolites during maintenance therapy phase 2. FINDINGS: Between Nov 26, 2008 and June 14, 2016, 1509 patients from the NOPHO ALL2008 study were assessed for eligibility in the DNA-TGN substudy, of which 918 (89%) of 1026 eligible patients had at least one DNA-TGN measurement and were included in the analyses. Median follow-up was 4·6 years (IQR 3·1-6·1). Relapse-free survival was significantly associated with DNA-TGN concentration (adjusted hazard ratio 0·81 per 100 fmol/µg DNA increase, 95% CI 0·67-0·98; p=0·029). In patients with at least five blood samples, erythrocyte concentrations of TGN, methylated mercaptopurine metabolites, and methotrexate polyglutamates were associated with DNA-TGN concentration (all p<0·0001). INTERPRETATION: Our results suggest the need for intervention trials to identify clinically applicable strategies for individualised drug dosing to increase DNA-TGN concentration, and randomised studies to investigate whether such strategies improve cure rates compared with current dose adjustments based on white blood cell counts. FUNDING: Danish Cancer Society, Childhood Cancer Foundation (Denmark), Childhood Cancer Foundation (Sweden), Nordic Cancer Union, Otto Christensen Foundation, University Hospital Rigshospitalet, and Novo Nordic Foundation.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/sangue , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , DNA/química , Recidiva Local de Neoplasia/mortalidade , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Tioguanina/sangue , Adolescente , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Lactente , Masculino , Mercaptopurina/administração & dosagem , Metotrexato/administração & dosagem , Metotrexato/análogos & derivados , Recidiva Local de Neoplasia/sangue , Recidiva Local de Neoplasia/tratamento farmacológico , Estadiamento de Neoplasias , Ácido Poliglutâmico/administração & dosagem , Ácido Poliglutâmico/análogos & derivados , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangue , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Prognóstico , Estudos Prospectivos , Taxa de Sobrevida , Tioguanina/química
7.
Eur J Haematol ; 96(2): 160-9, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25867866

RESUMO

OBJECTIVES: Cure rates improve when adolescents and young adults with acute lymphoblastic leukemia (ALL) are treated according to pediatric protocols. Assumed risks of toxicities and associated delays in treatment have played a role in setting upper age limits. The aim of this study was to examine the toxicity profile and treatment delays in NOPHO ALL2008 comparing children and adults. METHODS: We collected information on 19 treatment-related toxicities, systematically captured at 3-month intervals throughout therapy, and time intervals between 12 consecutive treatment phases for 1076 patients aged 1-45 yrs treated according to the Nordic/Baltic ALL2008 protocol. RESULTS: No adults died during induction. The duration of induction therapy and postinduction treatment phases did not differ between children and adults, except for patients 18-45 yrs being significantly delayed during two of nine high-risk blocks (median number of days for patients 1-9, 10-17, and 18-45 yrs; the glucocorticosteroid/antimetabolite-based block B1: 24, 26, and 29 d, respectively, P = 0.001, and Block 5 (in most cases also a B block): 29, 29, and 37 d, respectively, P = 0.02). A higher incidence of thrombosis with increasing age was found; highest odds ratio 5.4 (95% CI: (2.6;11.0)) for patients 15-17 yrs compared with children 1-9 yrs (P < 0.0001). Risk of avascular osteonecrosis was related to age with the highest OR for patients 10-14 yrs (OR = 10.4 (95% CI: (4.4;24.9)), P < 0.0001). CONCLUSION: Adults followed and tolerated the NOPHO ALL2008 protocol virtually as well as children, although thrombosis and avascular osteonecrosis was most common among adolescents.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Osteonecrose/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Trombose/diagnóstico , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/toxicidade , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Metotrexato/administração & dosagem , Metotrexato/toxicidade , Pessoa de Meia-Idade , Osteonecrose/induzido quimicamente , Osteonecrose/genética , Osteonecrose/patologia , Cromossomo Filadélfia , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Prednisona/administração & dosagem , Prednisona/toxicidade , Prognóstico , Indução de Remissão , Trombose/induzido quimicamente , Trombose/genética , Trombose/patologia , Resultado do Tratamento , Vincristina/administração & dosagem , Vincristina/toxicidade
8.
Pediatr Blood Cancer ; 62(3): 427-33, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25418987

RESUMO

BACKGROUND: L-Asparaginase is an effective drug in the treatment of childhood acute lymphoblastic leukemia (ALL). The use of L-asparaginase may be limited by serious adverse events of which allergy is the most frequent. The objective of this study was to describe the clinical aspects of PEG-asparaginase allergy in children treated according to the Nordic Society of Paediatric Haematology and Oncology (NOPHO) ALL2008 protocol. PROCEDURE: Children (1-17 years) enrolled in the NOPHO ALL2008 protocol between July 2008 and August 2011, who developed PEG-asparaginase allergy were identified through the NOPHO ALL2008 toxicity registry. In the NOPHO ALL2008 protocol, patients are randomized to 8 or 15 doses of intramuscular PEG-asparaginase (Oncaspar®) 1,000 IU/m(2) /dose administered at 2 or 6 weeks intervals during a total period of 30 weeks. (Clinical trials.gov no: NCT00819351). RESULTS: Of 615 evaluable patients, 79 patients developed clinical PEG-asparaginase allergy (cumulative risk; 13.2%) and discontinued PEG-asparaginase therapy for that reason. PEG-asparaginase allergy occurred after a median of two doses (75% range 2-4, max 14). In 58% of PEG-asparaginase hypersensitive patients, the clinical allergic reactions appeared within 2 hr after PEG-asparaginase administration and ranged from mild symptoms to systemic anaphylaxis. Nine patients experienced an anaphylactic reaction within 1 hr and 50 min from asparaginase administration; none were fatal. Four of 68 patients (6%) who subsequently received Erwinase therapy also reacted allergic to Erwinase. CONCLUSION: Clinical allergy to PEG-asparaginase occurred early in treatment, was in general moderate in severity, and mostly developed within 2 hr after PEG-asparaginase administration. The risk of subsequent Erwinase allergic reactions was low.


Assuntos
Antineoplásicos/administração & dosagem , Asparaginase/administração & dosagem , Polietilenoglicóis/administração & dosagem , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Adolescente , Adulto , Anafilaxia/induzido quimicamente , Antineoplásicos/efeitos adversos , Asparaginase/efeitos adversos , Criança , Pré-Escolar , Hipersensibilidade a Drogas/etiologia , Feminino , Seguimentos , Humanos , Lactente , Masculino , Polietilenoglicóis/efeitos adversos , Fatores de Risco
9.
Br J Haematol ; 168(4): 547-52, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25288392

RESUMO

We present a prospective multicentre cohort of 20 children with acute lymphoblastic leukaemia (ALL) and cerebral sinus venous thrombosis (CSVT). The study covers a period of 5 years and comprises 1038 children treated according to the Nordic Society of Paediatric Haematology and Oncology (NOPHO) ALL 2008 protocol. The cumulative incidence of CSVT was 2%. Sixteen of the thromboses were related to asparaginase and 16 to steroids. Most CSVTs occurred in the consolidation phase. Nearly all were treated with low molecular weight heparin without bleeding complications. Mortality related to CSVT directly or indirectly was 10%, emphasizing the importance of this complication.


Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Trombose dos Seios Intracranianos/etiologia , Adolescente , Corticosteroides/efeitos adversos , Anticoagulantes/efeitos adversos , Anticoagulantes/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Asparaginase/administração & dosagem , Asparaginase/efeitos adversos , Países Bálticos/epidemiologia , Criança , Pré-Escolar , Quimioterapia de Consolidação , Feminino , Humanos , Incidência , Lactente , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Estudos Prospectivos , Fatores de Risco , Países Escandinavos e Nórdicos/epidemiologia , Trombose dos Seios Intracranianos/tratamento farmacológico , Trombose dos Seios Intracranianos/epidemiologia , Resultado do Tratamento
10.
Eur J Cancer ; 50(2): 251-9, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24231337

RESUMO

The European Clinical Trials Directive of 2004 has increased the amount of paper work and reduced the number of initiated clinical trials. Particularly multinational trials have been delayed. To meet this challenge we developed a novel, simplified, fast and easy strategy for on-line toxicity registration for patients treated according to the Nordic/Baltic acute lymphoblastic leukaemia protocol, NOPHO ALL 2008, for children and young adults, including three randomisations. We used a risk-assessment based approach, avoiding reporting of expected adverse events and instead concentrating on 20 well-known serious, but rarer events with focus on changes in therapy introduced in the treatment protocol. This toxicity registration strategy was approved by the relevant regulatory authorities in all seven countries involved, as compliant within the EU directive of 2004. The centre compliance to registration was excellent with 98.9% of all patients being registered within 5weeks from the requested quarterly registration. Currently, four toxicities (thrombosis, fungal infections, pancreatitis and allergic reactions) have been chosen for further detailed exploration due to the cumulative fraction of patients with positive registrations exceeding 5%. This toxicity registration offers real-time toxicity profiles of the total study cohort and provides early warnings of specific toxicities that require further investigation.


Assuntos
Ensaios Clínicos como Assunto/normas , Guias de Prática Clínica como Assunto/normas , Medição de Risco/normas , Adolescente , Criança , Pré-Escolar , Ensaios Clínicos como Assunto/métodos , União Europeia , Humanos , Hipersensibilidade/etiologia , Lactente , Micoses/etiologia , Pancreatite/etiologia , Relatório de Pesquisa/normas , Medição de Risco/métodos , Fatores de Risco , Trombose/etiologia
11.
Hum Vaccin Immunother ; 8(4): 465-9, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22370511

RESUMO

Group A rotaviruses (RVA) are a major cause of acute gastroenteritis in children ≤ 5 y worldwide which could be prevented with two recently introduced vaccines - monovalent Rotarix (live-attenuated G1P[8] strain) and pentavalent RotaTeq (human-bovine reassortant containing serotypes G1, G2, G3, G4 and P[8]). Prior to implementation of vaccines into national immunization program we aimed to describe RVA genotype distribution in hospitalized children aged < 5 y in Estonia during 2007-2008. A total of 671 children with confirmed RVA gastroenteritis from three major pediatric hospitals were prospectively enrolled. G- and P-genotypes were detected from 124 stool samples by semi-nested reverse transcription-PCR. Severity of disease was assessed using Clark scoring system. The majority of cases (65%) occurred in infants aged 7 to 24 mo and were of moderate severity (mean Clark score 12.1 (SD 3.2)). The prevailing strain was G2P[4] (34.7%), causing significantly more cases than G4P[8] (12.9%), G1P[8] or G9P[8] (both 4.0%), G3P[8] (1.6%). Yearly differences in genotype distribution occurred, as G2P[4] (52.8%) dominated in 2007, but G4P[8] (26.9%) in 2008. One third of strains remained non-typeable. The distribution of RVA genotypes in Estonia differs from that seen in other Central and Eastern European countries, although one should bear in mind the large proportion of P-untypeable strains and natural fluctuations of dominating RVA genotypes. Nevertheless, considering the high genotype-independent efficacy of the vaccines, introduction of national immunization should be considered.


Assuntos
Gastroenterite/epidemiologia , Gastroenterite/virologia , Infecções por Rotavirus/epidemiologia , Infecções por Rotavirus/virologia , Rotavirus/classificação , Rotavirus/genética , Criança Hospitalizada , Pré-Escolar , Estônia/epidemiologia , Fezes/virologia , Feminino , Gastroenterite/patologia , Genótipo , Humanos , Lactente , Masculino , Epidemiologia Molecular , Reação em Cadeia da Polimerase/métodos , Prevalência , Estudos Prospectivos , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Rotavirus/isolamento & purificação , Infecções por Rotavirus/patologia , Índice de Gravidade de Doença
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