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1.
Orv Hetil ; 161(3): 103-109, 2020 Jan.
Artículo en Húngaro | MEDLINE | ID: mdl-31928060

RESUMEN

Introduction: Autologous hemopoietic stem cell transplantation remains a promising therapy in certain malignant and non-malignant conditions. The procedure, however, will increase the risk of complications, most notably early and late infections. Aim: To analyze the frequency and spectrum of pathogens in early (<+100 days) post-transplant infections and to evaluate risk factors for mortality. Method: Prospectively collected data from 699 patients undergoing autologous hemopoietic stem cell transplantation between 2007 and 2014 at our center were retrospectively reviewed and analyzed. Results: The median age of 699 patients was 56 (interquartile range: 43-62) years, 54% (376) were male. 25 patients have been transferred to other centers and 19 patients were lost to follow up. Neutropenic fever occurred in 69.8% (488) of patients. In addition, 102 infectious episodes in 96 patients were identified. Most commonly bacteremia occurred (49 episodes) with a median onset of 7 (5-11) days. The majority (33/49) of bacteremias have been observed during the pre-engraftment period. Their incidence proved to be higher in patients with malignant lymphoma compared to individuals with plasma cell disorders (p = 0.0005, OR: 2.41, 95% CI: 1.49-3.99). 12 episodes of viral infections and 8 cases of proven or probable invasive mycoses have been identified. Among the 655 patients with complete follow up, 16 in-hospital deaths (2.4%) occurred, 8 of them were associated with infections. Survival was adversely affected by early infections (p = 0.0001). Conclusion: In autologous stem cell transplantation, microbiologically unconfirmed neutropenic fever is common. Documented early bacteremia, however, is infrequent. Lymphoma patients have a significantly higher chance to develop bloodstream infections compared to individuals with plasma cell disorders. Early infections decrease the chance of survival; thus, an effective prophylaxis and therapy remains of paramount importance. Orv Hetil. 2020; 161(3): 103-109.


Asunto(s)
Infecciones Bacterianas/epidemiología , Infecciones Bacterianas/microbiología , Fiebre/etiología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Neutropenia/microbiología , Trasplante Autólogo/efectos adversos , Adulto , Infecciones Bacterianas/mortalidad , Fiebre/epidemiología , Humanos , Hungría/epidemiología , Linfoma , Masculino , Persona de Mediana Edad , Neutropenia/epidemiología , Estudios Retrospectivos
2.
BMC Med Educ ; 19(1): 452, 2019 Dec 04.
Artículo en Inglés | MEDLINE | ID: mdl-31801502

RESUMEN

BACKGROUND: Proper basic life support (BLS) is key in improving the survival of out-of-hospital cardiac arrest. BLS skills deteriorate in three to 6 months after training. One method to improve skill retention may be using the "testing effect" to test skills at the end of a BLS course. The aim of our study was to investigate whether either testing or the timing of such testing after BLS training have any influence on skill retention. METHODS: This was a post-test only, partial coverage, prospective quasi-experimental study designed to evaluate a BLS training course among 464 fifth year medical students at Semmelweis University in the first semester of 2013/2014. Groups were systematically but non-randomly assigned to either a control group that took no exam or one of two experimental groups that took an exam (N = 179, NoExam group; N = 165, EndExam group - exam at the end of the BLS training; N = 120, 3mExam group - exam 3 months after the BLS training). The ability to perform ten prescribed essential BLS steps was evaluated during a skill retention assessment 2 months after the course in the NoExam, 2 months after the course (and the exam) in the EndExam and 5 months after the course (2 months after the exam) in the 3mExam group to measure skill retention and the effect of our intervention. Scores were calculated for each BLS step, and also summed up as a total score. We used Kruskal-Wallis test to assess differences in skill retention. RESULTS: Overall, NoExam and EndExam groups showed similar skill retention. The mean total score (and many of the sub-scores) of students was significantly higher in the 3mExam group compared to both the NoExam and the EndExam groups, and there was no difference in the total score (and many of the sub-scores) of the latter two groups. The 3mExam group had less variability in total scores (and many of the sub-scores) than the other two groups. CONCLUSION: Our study provides evidence that testing these skills 3 months after BLS training may be more effective than either testing immediately at the end of the course or no testing at all.

3.
Pathol Oncol Res ; 25(2): 487-492, 2019 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-29524166

RESUMEN

In antithymocyte globulin (ATG) treated patients occasionally bradycardia has been noticed. Therefore, we retrospectively analyzed the occurrence of bradycardia in ATG-treated children. Using medical records between 2007 and 2012 we identified children undergoing a combined therapy with ATG and glucocorticoids (ATG group, n = 22). The incidence of bradycardia was compared to that registered in children treated with glucocorticoids alone (glucocorticoid alone group, n = 21). Heart rates (HR) were registered before and on days 0-3, 4-7 and 8-14 after the ATG or steroid administration. The rate of bradycardic episodes was higher during ATG therapy than in the steroid alone group, while severe bradycardia occurred only in the ATG group (97 versus 32, p = 0.0037, and 13 versus 0, p = 0.0029, respectively). There was an interaction between the time and treatment group on HR (p = 0.046). Heart rates in ATG and steroid alone groups differed significantly on day 0-3 and day 4-7 (p = 0.046, p = 0.006, respectively). Within the ATG group HR was lower on days 4-7 compared to the days before and the days 8-14 values (p < 0.001, 95%CI: 0.020-0.074). These findings indicate that transient asymptomatic bradycardia is probably more common with ATG therapy than previously reported. HR should be closely monitored during and after ATG therapy.


Asunto(s)
Suero Antilinfocítico/efectos adversos , Bradicardia/inducido químicamente , Inmunosupresores/efectos adversos , Adolescente , Bradicardia/epidemiología , Niño , Preescolar , Femenino , Enfermedad Injerto contra Huésped/prevención & control , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Incidencia , Lactante , Masculino , Metilprednisolona/uso terapéutico , Estudios Retrospectivos
4.
Biol Blood Marrow Transplant ; 24(5): 989-996, 2018 05.
Artículo en Inglés | MEDLINE | ID: mdl-29339271

RESUMEN

Hematopoietic stem cell transplantation (HSCT)-associated thrombotic microangiopathy (TA-TMA) is a multifactorial complication, and its prediction is largely unresolved. Our aim was to analyze changes of complement profile after HSCT to identify potential markers of TA-TMA development. Thirty-three consecutive pediatric patients (9.6 ± 4.4 years old) who underwent allogeneic HSCT due to malignant (n = 17) or nonmalignant (n = 16) indications were included in this study. Graft-versus-host disease (GVHD) was diagnosed using Glucksberg criteria, viral reactivation was monitored, 5 different TA-TMA diagnostic criteria were applied, and all important clinical and laboratory parameters of TA-TMA activity were registered. Complement pathway activities, components and terminal pathway activation marker (sC5b-9) levels were systematically measured before transplantation and on days 28, 56, and 100 after HSCT. During the first 100 days after HSCT, 1 of 33 patients died (day 50, multiple organ failure), whereas 10 subjects met the criteria for TA-TMA, typically on day 61 (range, 16 to 98 days). TA-TMA was preceded by acute GVHD in 3 of 10 patients, by viral reactivation in 2 of 10, or by both in 4 of 10 cases. Baseline sC5b-9 levels did not differ in patients without (200 [interquartile range, 144 to 266] ng/mL), or with (208 [interquartile range, 166 to 271] ng/mL) subsequent TA-TMA; however, on day 28 significant differences were observed (201 [interquartile range, 185 to 290] ng/mL versus 411 [interquartile range, 337 to 471] ng/mL; P = .004). Importantly, all 10 patients with TMA showed increase in sC5b-9 level from baseline level to day 28, whereas in patients without TMA the same tendency was observed for only 9 of 23 patients (P = .031). No additional complement parameters were closely associated with the development of TA-TMA. Development of TA-TMA occurred in 30% of our patients, typically after GVHD and/or viral reactivation. However, early raise of sC5b-9 activation marker was predictive for later development of TA-TMA, and should therefore be considered as an alarming sign necessitating a careful monitoring of all TA-TMA activity markers. Further studies enrolling a higher number of patients are necessary to determine if terminal pathway activation is an independent predictor of TA-TMA.


Asunto(s)
Complejo de Ataque a Membrana del Sistema Complemento/análisis , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Microangiopatías Trombóticas/etiología , Adolescente , Biomarcadores/análisis , Niño , Preescolar , Enfermedad Injerto contra Huésped , Humanos , Valor Predictivo de las Pruebas , Microangiopatías Trombóticas/diagnóstico , Factores de Tiempo , Activación Viral
5.
J Immunother ; 41(3): 158-163, 2018 04.
Artículo en Inglés | MEDLINE | ID: mdl-29239916

RESUMEN

Viral reactivation is a frequent complication of allogeneic hematopoietic stem cell transplantation especially in children. For refractory cases, rapid virus-specific T-cell therapy would be ideally implemented within a few days. Over the course of a year in our pediatric cohort of 43 allogeneic transplantation, 9 patients fulfilled criteria for virus-specific T-cell therapy. Viral infections were due to cytomegalovirus (CMV) in 3, Epstein-Barr virus (EBV) in 2, and adenovirus (AdV) in 1 case, whereas >1 virus was detected in 3 cases. Viral diseases necessitating a T-cell therapy were CMV pneumonitis and colitis, AdV enteritis and cystitis, and EBV-induced posttransplantation lymphoproliferative disease. Cells were produced by the CliniMACS Prodigy CCS (IFN-gamma) System within 24 hours after mononuclear leukapheresis. Eight patients became completely asymptomatic, whereas 7 also cleared the virus. Six patients are alive without viral illness or sequelae demonstrating viral DNA clearance in peripheral blood with a median follow-up of 535 (350-786) days. One patient with CMV pneumonitis died of respiratory insufficiency. In 2 cases the viral illness improved or cleared, however, the patients died of invasive aspergillosis. No cases of graft-versus-host disease, rejection, organ toxicity, or recurrent infection were noticed. Virus-specific T-cell therapy implemented by the CliniMACS Prodigy CCS (IFN-gamma) System is an automated, fast, safe, and probably effective way to control resistant viral diseases after pediatric hematopoietic stem cell transplantation.


Asunto(s)
Trasplante de Células Madre Hematopoyéticas/efectos adversos , Especificidad del Receptor de Antígeno de Linfocitos T , Linfocitos T/inmunología , Virosis/etiología , Adolescente , Adulto , Factores de Edad , Antivirales/farmacología , Antivirales/uso terapéutico , Niño , Preescolar , Citocinas/metabolismo , Femenino , Humanos , Inmunoterapia Adoptiva , Lactante , Masculino , Persona de Mediana Edad , Linfocitos T/metabolismo , Donantes de Tejidos , Trasplante Homólogo , Carga Viral , Virosis/diagnóstico , Virosis/terapia
6.
Orv Hetil ; 158(27): 1043-1050, 2017 Jul.
Artículo en Húngaro | MEDLINE | ID: mdl-28670985

RESUMEN

Hematopoietic stem cell transplantation associated thrombotic microangiopathy is a multifactorial complication, and has variable incidence in study populations due to different diagnostic criteria. The diversity of activity parameters, like elevated laktát-dehidrogenáz, hematological parameters and kidney function are not specific variables after stem cell transplantation. Dysregulation of the classical and alternative pathway can play an important role in the pathomechanism of thrombotic microangiopathy, but the understanding of the role of complement activation under transplantation conditions requires further investigation. Monitoring of complement parameters, including terminal complement pathway activation complex during transplantation may help physicians to improve diagnostic strategy, to evaluate therapeutical options and to predict and follow up efficacy of complement blockade methods and supportive therapy. This review focuses on the development of diagnostic criteria and therapeutical options in thrombotic microangiopathy, and presents some preliminary findings while using different diagnostic criteria in pediatric patients. Orv Hetil. 2017; 158(27): 1043-1050.


Asunto(s)
Trasplante de Células Madre Hematopoyéticas/efectos adversos , Microangiopatías Trombóticas/diagnóstico , Microangiopatías Trombóticas/etiología , Anticuerpos Monoclonales Humanizados/administración & dosificación , Enfermedad Injerto contra Huésped/diagnóstico , Enfermedad Injerto contra Huésped/etiología , Humanos , Microangiopatías Trombóticas/tratamiento farmacológico
7.
Oncotarget ; 8(6): 9388-9398, 2017 Feb 07.
Artículo en Inglés | MEDLINE | ID: mdl-27566582

RESUMEN

Inter-individual differences in toxic symptoms and pharmacokinetics of high-dose methotrexate (MTX) treatment may be caused by genetic variants in the MTX pathway. Correlations between polymorphisms and pharmacokinetic parameters and the occurrence of hepato- and myelotoxicity were studied. Single nucleotide polymorphisms (SNPs) of the ABCB1, ABCC1, ABCC2, ABCC3, ABCC10, ABCG2, GGH, SLC19A1 and NR1I2 genes were analyzed in 59 patients with osteosarcoma. Univariate association analysis and Bayesian network-based Bayesian univariate and multilevel analysis of relevance (BN-BMLA) were applied. Rare alleles of 10 SNPs of ABCB1, ABCC2, ABCC3, ABCG2 and NR1I2 genes showed a correlation with the pharmacokinetic values and univariate association analysis. The risk of toxicity was associated with five SNPs in the ABCC2 and NR1I2 genes. Pharmacokinetic parameters were associated with four SNPs of the ABCB1, ABCC3, NR1I2, and GGH genes, and toxicity was shown to be associated with ABCC1 rs246219 and ABCC2 rs717620 using the univariate and BN-BMLA method. BN-BMLA analysis detected relevant effects on the AUC0-48 in the following SNPs: ABCB1 rs928256, ABCC3 rs4793665, and GGH rs3758149. In both univariate and multivariate analyses the SNPs ABCB1 rs928256, ABCC3 rs4793665, GGH rs3758149, and NR1I2 rs3814058 SNPs were relevant. These SNPs should be considered in future dose individualization during treatment.


Asunto(s)
Antimetabolitos Antineoplásicos/administración & dosificación , Neoplasias Óseas/tratamiento farmacológico , Metotrexato/administración & dosificación , Osteosarcoma/tratamiento farmacológico , Variantes Farmacogenómicas , Polimorfismo de Nucleótido Simple , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Adolescente , Factores de Edad , Antimetabolitos Antineoplásicos/efectos adversos , Antimetabolitos Antineoplásicos/farmacocinética , Área Bajo la Curva , Teorema de Bayes , Neoplasias Óseas/genética , Neoplasias Óseas/metabolismo , Neoplasias Óseas/patología , Distribución de Chi-Cuadrado , Niño , Femenino , Genotipo , Semivida , Humanos , Masculino , Tasa de Depuración Metabólica , Metotrexato/efectos adversos , Metotrexato/farmacocinética , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/genética , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/metabolismo , Análisis Multivariante , Oportunidad Relativa , Osteosarcoma/genética , Osteosarcoma/metabolismo , Osteosarcoma/patología , Farmacogenética , Fenotipo , Receptor X de Pregnano , Receptores de Esteroides/genética , Receptores de Esteroides/metabolismo , Factores de Riesgo , Resultado del Tratamiento , gamma-Glutamil Hidrolasa/genética , gamma-Glutamil Hidrolasa/metabolismo
8.
J Pediatr Hematol Oncol ; 38(5): 334-40, 2016 07.
Artículo en Inglés | MEDLINE | ID: mdl-27050122

RESUMEN

We investigated whether an altered individual glucocorticoid sensitivity due to particular glucocorticoid receptor single-nucleotide polymorphisms (SNPs) (N363S, ER22/23EK, and Bcl-1) influences the susceptibility to steroid-related toxicities, prognostic factors, and survival rates in children with acute lymphoblastic leukemia. In total, 346 pediatric patients with acute lymphoblastic leukemia were enrolled in our study. Their carrier status was investigated by allele-specific polymerase chain reaction analysis. Clinical and laboratory signs of glucocorticoid-related toxicities, day-8 prednisone response, 5-year event-free survival, and 5-year overall survival rates were analyzed and compared retrospectively. Hepatotoxicity occurred significantly more often in 363S carriers (P=0.004), and glucose metabolism abnormalities were more common in 363S carriers (P=0.001), but did not occur in patients with the ER22/23EK SNP. Hypertension and central nervous system/behavioral changes did not occur in patients with the ER22/23EK SNP. None of the patients with the N363S SNP, the ER22/23EK polymorphism, or the GG genotype for the Bcl-1 polymorphism had a poor prednisone response. The 363S carriers had significantly better 5-year event-free survival (P=0.012) and 5-year overall survival (P=0.013) rates compared with noncarriers. The Bcl-1 SNP was not associated with any of the toxicities investigated or survival. Children with the N363S polymorphism in the glucocorticoid receptor gene were more prone to steroid-related toxicities, whereas those with the ER22/23EK polymorphism were less susceptible. Children with the N363S polymorphism may have more favorable survival rates.


Asunto(s)
Polimorfismo Genético , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicaciones , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Receptores de Glucocorticoides/genética , Esteroides/toxicidad , Adolescente , Niño , Preescolar , Ciclina D1/genética , Supervivencia sin Enfermedad , Glucocorticoides/uso terapéutico , Glucocorticoides/toxicidad , Humanos , Lactante , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidad , Prednisona/uso terapéutico , Prednisona/toxicidad , Pronóstico , Esteroides/uso terapéutico , Tasa de Supervivencia
9.
PLoS One ; 10(10): e0140136, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-26457809

RESUMEN

L-asparaginase (ASP) is a key element in the treatment of paediatric acute lymphoblastic leukaemia (ALL). However, hypersensitivity reactions (HSRs) to ASP are major challenges in paediatric patients. Our aim was to investigate genetic variants that may influence the risk to Escherichia coli-derived ASP hypersensitivity. Sample and clinical data collection was carried out from 576 paediatric ALL patients who were treated according to protocols from the Berlin-Frankfurt-Münster Study Group. A total of 20 single nucleotide polymorphisms (SNPs) in GRIA1 and GALNT10 genes were genotyped. Patients with GRIA1 rs4958351 AA/AG genotype showed significantly reduced risk to ASP hypersensitivity compared to patients with GG genotype in the T-cell ALL subgroup (OR = 0.05 (0.01-0.26); p = 4.70E-04), while no such association was found in pre-B-cell ALL. In the medium risk group two SNPs of GRIA1 (rs2055083 and rs707176) were associated significantly with the occurrence of ASP hypersensitivity (OR = 0.21 (0.09-0.53); p = 8.48E-04 and OR = 3.02 (1.36-6.73); p = 6.76E-03, respectively). Evaluating the genders separately, however, the association of rs707176 with ASP HSRs was confined only to females. Our results suggest that genetic variants of GRIA1 might influence the risk to ASP hypersensitivity, but subgroups of patients can differ significantly in this respect.


Asunto(s)
Antineoplásicos/efectos adversos , Asparaginasa/efectos adversos , Hipersensibilidad a las Drogas/etiología , Predisposición Genética a la Enfermedad , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicaciones , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Adolescente , Alelos , Antineoplásicos/administración & dosificación , Asparaginasa/administración & dosificación , Niño , Preescolar , Femenino , Estudios de Asociación Genética , Genotipo , Humanos , Lactante , Masculino , Polimorfismo de Nucleótido Simple , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Estudios Retrospectivos
10.
Br J Haematol ; 166(3): 410-20, 2014 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-24712521

RESUMEN

High-dose methotrexate (HD-MTX) plays an important role in the consolidation therapy of acute lymphoblastic leukaemia (ALL) in many treatment regimens worldwide. However, there is a large interpatient variability in the pharmacokinetics and toxicity of the drug. We investigated the influence of single nucleotide polymorphisms (SNPs) in genes of the folate metabolic pathway, transporter molecules and transcription proteins on the pharmacokinetics and toxicity of MTX and 7-hydroxy-methotrexate (7-OH-MTX). 63 SNPs of 14 genes were genotyped and a total of 463 HD-MTX courses (administered according to the ALL-BFM 95 and ALL IC-BFM 2002 protocols) were analysed. Haematological, hepatic and renal toxicities, estimated by routine laboratory parameters were evaluated. Random forest and regression trees were used for variable selection and model building. Linear mixed models were established to prove the significance of the selected variables. SNPs (rs4948502, rs4948496, rs4948487) of the ARID5B gene were associated with the serum levels of MTX (P < 0·02), serum levels and area under the curve of 7-OH-MTX (P < 0·02) and with hypoproteinaemia (P = 0·004). SLCO1B1 rs4149056 also showed a significant association with serum MTX levels (P < 0·001). Our findings confirm the association of novel genetic variations in folate-related and ARID5B genes with the serum MTX levels and acute toxicity.


Asunto(s)
Proteínas de Unión al ADN/genética , Variación Genética , Metotrexato/efectos adversos , Metotrexato/farmacocinética , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Factores de Transcripción/genética , Adolescente , Alelos , Antimetabolitos Antineoplásicos/administración & dosificación , Antimetabolitos Antineoplásicos/efectos adversos , Antimetabolitos Antineoplásicos/farmacocinética , Niño , Preescolar , Proteínas de Unión al ADN/metabolismo , Femenino , Ácido Fólico/metabolismo , Frecuencia de los Genes , Genotipo , Humanos , Lactante , Masculino , Metotrexato/administración & dosificación , Farmacogenética , Polimorfismo de Nucleótido Simple , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Factores de Transcripción/metabolismo
11.
Anticancer Drugs ; 24(2): 189-97, 2013 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-23187460

RESUMEN

We carried out a detailed comparative study of the pharmacokinetics and toxicity of methotrexate (MTX) and 7-hydroxy-methotrexate (7-OH-MTX) after high-dose intravenous methotrexate (HD-MTX) in children with acute lymphoblastic leukemia (ALL). Overall, 65 children were treated with 5 g/m2/24 h MTX and 88 children were treated with 2 g/m2/24 h MTX according to ALL-BFM 95 and ALL IC-BFM 2002 protocols (mean age: 6.4 years, range 1.0-17.9 years). A total of 583 HD-MTX courses were analyzed. Serum MTX and 7-OH-MTX levels were measured at 24, 36, and 48 h, and cerebrospinal fluid (CSF) MTX levels were determined 24 h after the initiation of the infusion. The area under the concentration-time curve was calculated. Hepatotoxicity, nephrotoxicity, and bone marrow toxicity were estimated by routine laboratory tests. We investigated pharmacokinetics and toxicity in distinct age groups (< 6 and > 14 years). 5 g/m2/24 h treatments resulted in higher serum and CSF MTX and 7-OH-MTX levels (P < 0.05). The CSF penetration rate of MTX was independent of the MTX dose [2.3% (95% confidence interval: 1.7-2.5%) vs. 2.8% (95% confidence interval: 2.4-3%)]. The CSF MTX concentration was correlated with the 24 h MTX serum level (r = 0.38, P < 0.0001). Repeated treatments did not alter MTX or 7-OH-MTX levels. 7-OH-MTX levels were correlated with nephrotoxicity (r = 0.36, P < 0.0001). Higher MTX levels and toxicity occurred more frequently in children aged older than 14 years (P < 0.05). Therapeutic serum and CSF MTX concentrations can be achieved more reliably with 5 g/m2/24 h treatments. To predict the development of toxicity, monitoring of the level of the 7-OH-MTX is useful. Monitoring of pharmacokinetics is essential to prevent the development of severe adverse events in adolescents.


Asunto(s)
Antimetabolitos Antineoplásicos/efectos adversos , Antimetabolitos Antineoplásicos/farmacocinética , Metotrexato/análogos & derivados , Metotrexato/efectos adversos , Metotrexato/farmacocinética , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Adolescente , Antimetabolitos Antineoplásicos/sangre , Antimetabolitos Antineoplásicos/líquido cefalorraquídeo , Área Bajo la Curva , Líquido Cefalorraquídeo/metabolismo , Niño , Preescolar , Relación Dosis-Respuesta a Droga , Humanos , Lactante , Infusiones Intravenosas , Metotrexato/sangre , Metotrexato/líquido cefalorraquídeo , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangre , Leucemia-Linfoma Linfoblástico de Células Precursoras/líquido cefalorraquídeo
12.
BMC Med Genomics ; 5: 42, 2012 Sep 28.
Artículo en Inglés | MEDLINE | ID: mdl-23021489

RESUMEN

BACKGROUND: We carried out a candidate gene association study in pediatric acute lymphoblastic leukemia (ALL) to identify possible genetic risk factors in a Hungarian population. METHODS: The results were evaluated with traditional statistical methods and with our newly developed Bayesian network based Bayesian multilevel analysis of relevance (BN-BMLA) method. We collected genomic DNA and clinical data from 543 children, who underwent chemotherapy due to ALL, and 529 healthy controls. Altogether 66 single nucleotide polymorphisms (SNPs) in 19 candidate genes were genotyped. RESULTS: With logistic regression, we identified 6 SNPs in the ARID5B and IKZF1 genes associated with increased risk to B-cell ALL, and two SNPs in the STAT3 gene, which decreased the risk to hyperdiploid ALL. Because the associated SNPs were in linkage in each gene, these associations corresponded to one signal per gene. The odds ratio (OR) associated with the tag SNPs were: OR = 1.69, P = 2.22x10(-7) for rs4132601 (IKZF1), OR = 1.53, P = 1.95x10(-5) for rs10821936 (ARID5B) and OR = 0.64, P = 2.32x10(-4) for rs12949918 (STAT3). With the BN-BMLA we confirmed the findings of the frequentist-based method and received additional information about the nature of the relations between the SNPs and the disease. E.g. the rs10821936 in ARID5B and rs17405722 in STAT3 showed a weak interaction, and in case of T-cell lineage sample group, the gender showed a weak interaction with three SNPs in three genes. In the hyperdiploid patient group the BN-BMLA detected a strong interaction among SNPs in the NOTCH1, STAT1, STAT3 and BCL2 genes. Evaluating the survival rate of the patients with ALL, the BN-BMLA showed that besides risk groups and subtypes, genetic variations in the BAX and CEBPA genes might also influence the probability of survival of the patients. CONCLUSIONS: In the present study we confirmed the roles of genetic variations in ARID5B and IKZF1 in the susceptibility to B-cell ALL. With the newly developed BN-BMLA method several gene-gene, gene-phenotype and phenotype-phenotype connections were revealed. We showed several advantageous features of the new method, and suggested that in gene association studies the BN-BMLA might be a useful supplementary to the traditional frequentist-based statistical method.


Asunto(s)
Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Análisis Multinivel , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Adolescente , Teorema de Bayes , Estudios de Casos y Controles , Niño , Preescolar , Supervivencia sin Enfermedad , Femenino , Frecuencia de los Genes/genética , Haplotipos/genética , Humanos , Lactante , Desequilibrio de Ligamiento/genética , Modelos Logísticos , Masculino , Polimorfismo de Nucleótido Simple/genética , Factores de Riesgo , Análisis de Supervivencia , Factores de Tiempo
13.
J Cancer Res Clin Oncol ; 138(10): 1697-702, 2012 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-22652833

RESUMEN

PURPOSE: High-dose methotrexate (HD-MTX) with leucovorin rescue is widely used to treat osteosarcoma. Our objectives were to assess correlations between pharmacokinetic parameters and the outcome of osteosarcoma and to analyze the relation between HD-MTX exposure and toxicity. METHODS: Pharmacokinetic data of 105 patients with osteosarcoma treated with 989 HD-MTX courses were evaluated. Pharmacokinetic parameters (clearance, half-life and AUC) were calculated based on methotrexate (MTX) serum levels measured at 6, 24, 36, 48 h after the initiation of the infusion. Clinical data were collected by retrospective chart review. Hepato-, nephro- and bone marrow toxicity parameters were categorized according to Common Toxicity Criteria v.3.0, and MTX dose intensity was calculated. Event-free survival (EFS) and overall survival (OS) were estimated according to the Kaplan-Meier method. RESULTS: Patients with serious hepatotoxicity had higher mean peak MTX concentrations (p < 0.0001), 24-h (p = 0.001) and 48-h MTX serum levels (p = 0.008) and AUC(0-48) (p < 0.0001), and lower MTX clearance (p = 0.0002). No significant association was found between toxicity and age, gender, presence of metastases or histological tumor response. Patients with higher 48-h MTX serum levels had significantly better OS and EFS. Higher dose intensity was associated with better EFS (p = 0.0504). There was no association between presence of toxicity and survival. CONCLUSION: There was correlation between MTX exposure and the incidence of toxicity. Higher serum concentrations at 48 h were associated with a better 5-year OS and EFS. These results suggest that higher MTX exposure may lead to serious side effects, but it also improves treatment outcome.


Asunto(s)
Neoplasias Óseas/tratamiento farmacológico , Neoplasias Óseas/metabolismo , Metotrexato/administración & dosificación , Metotrexato/farmacocinética , Osteosarcoma/tratamiento farmacológico , Osteosarcoma/metabolismo , Adolescente , Antimetabolitos Antineoplásicos/administración & dosificación , Antimetabolitos Antineoplásicos/efectos adversos , Antimetabolitos Antineoplásicos/sangre , Antimetabolitos Antineoplásicos/farmacocinética , Médula Ósea/efectos de los fármacos , Neoplasias Óseas/sangre , Supervivencia sin Enfermedad , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Hígado/efectos de los fármacos , Metotrexato/efectos adversos , Metotrexato/sangre , Osteosarcoma/sangre , Estudios Retrospectivos , Resultado del Tratamiento
14.
Orv Hetil ; 152(40): 1609-17, 2011 Oct 02.
Artículo en Húngaro | MEDLINE | ID: mdl-21945870

RESUMEN

UNLABELLED: Monitoring the pharmacokinetic parameters of different anticancer drugs is necessary because they might have several side effects. AIM: Pharmacokinetic and toxicity evaluation of high-dose methotrexate treatments in children with acute lymphoblastic leukemia. PATIENTS AND METHODS: 43 children (28 boys, 15 girls, mean age: 7.03 years) in 147 cases were treated with 5 g/m2/24h MTX according to ALL-BFM 1995 and 2002 protocols. Methotrexate and 7-hydroxi-methotrexate levels were measured with high pressure liquid chromatography at 24, 36, 48 hours. Authors registered the development of hepatotoxicity, nephrotoxicity, grade III/IV oral mucositis. RESULTS: Therapeutic methotrexate serum concentrations (30-100µmol/l) were achieved in 72.5% of the cases. Repeated treatments resulted similar serum levels. Hepatotoxicity and hypoproteinemia occurred in 17% and in 48.9% of the cases. There was significant correlation between serum 7-hydroxi-methotrexate and creatinine levels (p<0.05). CONCLUSION: 5 g/m2 methotrexate resulted reliable therapeutic serum levels with mild and reversible toxicity. 7-hydroxi-methotexate measurements might be more useful than methotrexate levels to detect toxicity.


Asunto(s)
Antimetabolitos Antineoplásicos/administración & dosificación , Antimetabolitos Antineoplásicos/farmacocinética , Metotrexato/análogos & derivados , Metotrexato/administración & dosificación , Metotrexato/farmacocinética , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Adolescente , Antimetabolitos Antineoplásicos/sangre , Proteínas Sanguíneas/metabolismo , Niño , Preescolar , Cromatografía Líquida de Alta Presión , Creatinina/sangre , Esquema de Medicación , Femenino , Humanos , Riñón/efectos de los fármacos , Riñón/metabolismo , Hígado/efectos de los fármacos , Hígado/metabolismo , Fallo Hepático/inducido químicamente , Fallo Hepático/prevención & control , Masculino , Metotrexato/sangre , Metotrexato/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangre , Insuficiencia Renal/inducido químicamente , Insuficiencia Renal/prevención & control , Estomatitis/inducido químicamente , Factores de Tiempo , Resultado del Tratamiento
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