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CHARGE syndrome is a rare congenital malformation syndrome which may share symptoms with DiGeorge syndrome. Complete DiGeorge syndrome (cDGS) is a severe form of DiGeorge syndrome, characterized by a CD3+ T-cell count of <50/mm3 due to athymia, and is fatal without immunologic intervention. We performed peripheral blood lymphocyte transfusion (PBLT) from an HLA-identical sibling without pretransplant conditioning in a CHARGE/cDGS patient with a novel CHD7 splice site mutation. Cyclosporine and short-term methotrexate were used for graft versus host disease (GVHD) prophylaxis, and neither acute nor chronic GVHD was observed. After PBLT, T-cell proliferative response to phytohemagglutinin and concanavalin A recovered, and intractable diarrhea improved. EBV infection, evidenced by a gradual increase in the viral genome copy number to a maximum of 2861 copies/µgDNA on day 42 after PBLT, resolved spontaneously. HLA A2402 restricted, EBV-specific CTLs were detected from peripheral blood on day 148, and EBV seroconversion was observed on day 181. Thus, EBV-specific immunity was successfully established by PBLT. Our results indicate that PBLT is a simple and effective therapy to reconstitute immune systems in CHARGE/DiGeorge syndrome.
Assuntos
Síndrome CHARGE/terapia , Síndrome de DiGeorge/complicações , Síndrome de DiGeorge/imunologia , Infecções por Vírus Epstein-Barr/prevenção & controle , Transfusão de Linfócitos , Complexo CD3/metabolismo , Proliferação de Células , Concanavalina A/farmacologia , Ciclosporina/administração & dosagem , Diarreia/terapia , Infecções por Vírus Epstein-Barr/imunologia , Evolução Fatal , Doença Enxerto-Hospedeiro , Antígenos HLA/química , Herpesvirus Humano 4/genética , Humanos , Recém-Nascido , Masculino , Metotrexato/administração & dosagem , Mutação , Fenótipo , Fito-Hemaglutininas/química , Irmãos , Linfócitos T/citologiaRESUMO
AIM: To assess the feasibility of transferring to the University of Tsukuba Hospital for proton beam therapy (PBT) during intensive chemotherapy in children with Ewing sarcoma family of tumors (ESFT) who had been diagnosed and started their first-line treatment at prefectural or regional centers for pediatric oncology. BACKGROUND: The treatment of ESFT relies on a multidisciplinary approach using intensive neoadjuvant and adjuvant chemotherapies with surgery and radiotherapy. Multi-agent chemotherapy comprising vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide (VDC-IE) is widely used for ESFT, and the interval between each course is very important for maintaining the intensity and effect of chemotherapy. MATERIALS AND METHODS: Clinical information of patients who received PBT and VDC-IE between April 2009 and May 2016 was collected retrospectively. The intervals between each course of VDC-IE and adverse events were assessed. RESULTS: Fifteen patients were evaluated. No delays in the intervals of chemotherapy due to transfer were observed. There were no adverse events caused during/just after transfer and no increases in adverse events. The estimated 4-year overall and event-free survival rates were 94.6% and 84.8%, respectively. DISCUSSION: Although the results of efficacy are preliminary, survival rates were comparable with past studies. More experience and follow-up are required to further assess the efficacy of PBT for patients with ESFT. CONCLUSION: Multidisciplinary therapy for children with ESFT involving transfer to our hospital for PBT during VDC-IE was feasible without treatment delay or an increase in adverse events.
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BACKGROUND: The rate of childhood cancer survival has recently reached >80%. Various adverse events among childhood cancer survivors (CCS) have been reported. Proton beams are able to avoid unnecessary irradiation to normal/vital organs. We conducted a quality of life (QOL) study for CCS who were treated with proton beam therapy (PBT). METHODS: We included those patients treated with PBT to the brain, head, or neck and who were ≤15 years old at the University of Tsukuba Hospital between 1983 and 2011. Clinical information was collected from medical records. Questionnaires including the Pediatric Quality of Life Inventory (PedsQL) 4.0 Generic Core Scales (which assess health-related quality of life) were sent to the families/patients. RESULTS: Sixty patients were included. Median age at treatment was 6.2 years. The number of patients with status alive/dead/unknown was 32/24/4. Median follow-up period was 63.0 months (range, 48-340 months) for survivors. Questionnaires were sent to 25 families/patients and 19 were returned. PedsQL was assessed for 17 patients. Eleven of 32 living patients had at least one comorbidity grade 3/4. Average QOL score was above that for Japanese schoolchildren and adolescents. There was no correlation with comorbidity, and only longer time from treatment was correlated with a higher PedsQL score (P = 0.006). CONCLUSION: CCS who were treated with multimodal treatment using PBT had a higher QOL score. Higher score was related to longer time since treatment, regardless of comorbidity.
Assuntos
Neoplasias Encefálicas/epidemiologia , Neoplasias Encefálicas/radioterapia , Sobreviventes de Câncer , Neoplasias de Cabeça e Pescoço/epidemiologia , Neoplasias de Cabeça e Pescoço/radioterapia , Terapia com Prótons , Qualidade de Vida , Adolescente , Criança , Pré-Escolar , Comorbidade , Feminino , Seguimentos , Humanos , Lactente , Recém-Nascido , Japão/epidemiologia , MasculinoRESUMO
The pharmacokinetics among children has been altered dynamically. The difference between children and adults is caused by immaturity in things such as metabolic enzymes and transport proteins. The periods when these alterations happen vary from a few days to some years after birth. We hypothesized that the effect of gene polymorphisms associated with the dose of medicine could be influenced by age. In this study, we analyzed 51 patients with childhood acute lymphoblastic leukemia (ALL) retrospectively. We examined the associations between the polymorphism in NUDT15 and clinical data, especially the dose of 6-mercaptopurine (6-MP). Ten of the patients were heterozygous for the variant allele in NUDT15. In patients under 7 years old with NUDT15 variant allele, the average administered dose of 6-MP was lower than that for the patients homozygous for the wild-type allele (P=0.04). Genotyping of NUDT15 could be a beneficial to estimate the tolerated dose of 6-MP for patients with childhood ALL, especially at a preschool age in Japan. Furthermore, the analysis with stratification by age might be useful in pharmacogenomics among children.
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Antimetabólitos Antineoplásicos/administração & dosagem , Genótipo , Mercaptopurina/administração & dosagem , Farmacogenética , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Pirofosfatases/genética , Adolescente , Fatores Etários , Alelos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Criança , Pré-Escolar , Feminino , Frequência do Gene , Estudos de Associação Genética , Humanos , Lactente , Masculino , Metiltransferases/genética , Polimorfismo GenéticoRESUMO
BACKGROUND: Management of the adverse effects of chemotherapy is essential to improve outcome of children with leukemia. Some genetic polymorphisms can predict treatment-related toxicity, and be used individually in dose modification of 6-mercaptopurine (6-MP) and methotrexate (MTX) in maintenance therapy for childhood acute lymphoblastic leukemia (ALL). We investigated associations between clinical course and candidate gene polymorphisms less evaluated in Japanese patients. METHODS: Fifty-three children who received maintenance chemotherapy were enrolled in this study. The scheduled dose of oral 6-MP was 40 mg/m(2) daily and that of oral MTX was 25 mg/m(2) weekly. The doses were adjusted according to white blood cell count (target range, 2.5-3.5 × 10(9) /L) and aspartate aminotransferase and alanine aminotransferase level (< 750 IU/L). Eight polymorphisms in six candidate genes, TPMT, ITPA, MRP4, MTHFR, RFC1, and SLCO1B1, were genotyped using the Taqman PCR method. Clinical course was reviewed retrospectively from medical records. RESULTS: The average dose of 6-MP was lower in the patients with at least one variant allele at SLCO1B1 c.521 T > C than in the patients with wild homozygous genotype. The other analyzed polymorphisms were not associated with toxicity, 6-MP, or MTX dose. CONCLUSIONS: Polymorphism of SLCO1B1 c.521 T > C could be a strong predictor of 6-MP dose reduction in maintenance chemotherapy in childhood ALL.
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Antineoplásicos/administração & dosagem , DNA de Neoplasias/genética , Leucemia/tratamento farmacológico , Transportador 1 de Ânion Orgânico Específico do Fígado/genética , Quimioterapia de Manutenção/métodos , Polimorfismo Genético , Adolescente , Alelos , Criança , Pré-Escolar , Relação Dose-Resposta a Droga , Feminino , Seguimentos , Genótipo , Humanos , Lactente , Leucemia/genética , Leucemia/metabolismo , Transportador 1 de Ânion Orgânico Específico do Fígado/metabolismo , Masculino , Estudos Retrospectivos , Fatores de TempoRESUMO
Anti-nuclear matrix protein 2 (NXP2) antibody-positive dermatomyositis (DM) is characterized by extensive and severe myositis. In this study, we evaluated which cytokines/chemokines involved with the activity of the myositis. We performed quantitative immunoassays using the MILLIPLEX® Multiplex Assays Using Luminex to evaluate serum levels of interferon-γ, interleukin (IL)-1ß, IL-6, IL-8, IL-12p40, and tumor necrosis factor-α in samples collected over time from a 9-year-old female with anti-NXP2 antibody-positive DM. In our case, the serum level of IL-8 was elevated when the myositis worsened, and decreased in accordance with the improvement of myositis, suggesting that the serum IL-8 levels were correlated with the myositis activity. Serum levels of IL-8 in samples from five patients with anti-NXP2 antibody-positive DM and five patients with anti-transcriptional intermediary factor 1γ (TIF1γ) antibody-positive DM without both interstitial lung disease (ILD) and malignancy before starting treatments, along with five healthy controls, were also evaluate by an enzyme-linked immunosorbent assay. Serum IL-8 levels were significantly elevated in anti-NXP2 or anti-TIF1γ antibody-positive DM patients with myositis but not ILD, than healthy controls. It was suggested that serum levels of IL-8 correlate with the activity of myositis in DM including anti-NXP2 antibody-positive DM.
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Autoanticorpos , Dermatomiosite , Interleucina-8 , Adulto , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adenosina Trifosfatases , Autoanticorpos/sangue , Biomarcadores/sangue , Dermatomiosite/imunologia , Dermatomiosite/sangue , Proteínas de Ligação a DNA , Interleucina-8/sangue , Miosite/imunologia , Miosite/sangue , Proteínas de Ligação a RNA/imunologia , Fatores de Transcrição/sangue , Fatores de Transcrição/imunologiaRESUMO
Maturity-onset diabetes of the young type 3 (MODY3) is caused by hepatocyte nuclear factor 1α gene mutation and is clinically characterized by young onset and insufficient insulin secretion. We report a 19-month-old Japanese boy with a family history of young-onset diabetes who was initially diagnosed with type 1 diabetes. Mutational analysis of the hepatocyte nuclear factor 1α gene revealed a novel heterozygous frameshift mutation (c.593delA p.Lys198fs) resulting in a truncated protein in the patient and his father. The patient was diagnosed as having MODY3 and was successfully treated with insulin glargine. We could not determine the genetic or environmental factors to explain the difference in the age of disease onset within the same family. This is the youngest case of a MODY3 child presenting with overt diabetes. Our experience suggests that clinicians should always consider the possible diagnosis of MODY3 in a diabetic child with a family history of young-onset diabetes and should perform molecular investigations.
Assuntos
DNA/genética , Diabetes Mellitus Tipo 2/genética , Mutação da Fase de Leitura , Fator 1-alfa Nuclear de Hepatócito/genética , Idade de Início , Análise Mutacional de DNA , Diabetes Mellitus Tipo 2/sangue , Fator 1-alfa Nuclear de Hepatócito/sangue , Humanos , Lactente , Insulina/sangue , Masculino , LinhagemRESUMO
Introduction: Physical examinations to assess pubertal development are challenging in large epidemiological surveys. This study aimed to assess the reliability of judgment of pubertal onset in Japanese children by the original pubertal self-assessment sheet. Methods: A total of 144 children aged 10 or 12 years were recruited between March 2019 and September 2020 from the pediatric endocrine outpatient clinics of participating institutions. Agreement between the physician- and participantassessed pubertal onsets was determined using unweighted kappa (UK) and Gwet's agreement coefficient (AC1). Results: The physician's assessment of pubertal onset was in slight agreement with that of the self-assessment sheet in 10-year-old boys (UK: 0.23 and AC1: 0.14), whereas the agreement between the physician's assessment and self-assessment sheet results was good and the physician's assessment was fair (UK: 0.64 and AC1: 0.94) in 12-year-old boys. The physician's assessment of pubertal onset were in good and moderate agreement with the self-assessment sheet in 10-year-old girls (UK/AC1: 0.74/0.78, respectively). In 12-year-old girls, although it showed poor agreement with UK (0.46), there was a very good agreement with AC1 (0.88). Conclusions: Although self-assessment of breast development was in good agreement with that of the physician's assessment for determining pubertal onset in girls, large-scale epidemiological studies are difficult to conduct for adolescent boys, especially for those in the early pubertal stage.
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To assess whether adiponectin gene (ADIPOQ) polymorphism is associated with intrauterine fetal growth and cord blood adiponectin, we investigated eight single-nucleotide polymorphisms (SNPs; rs182052, rs710445, rs16861205, rs12495941, rs1501299, rs3774261, rs2082940 and rs266729) in ADIPOQ and birth weight and cord blood adiponectin in 526 healthy neonates. We found that the neonates carrying the G allele of rs266729 had a significantly greater birth weight s.d. score than those homozygous for the C allele (CC: -0.06±0.75 versus CG: 0.20±0.64 versus GG: 0.07±0.78; P=1.65 × 10(-3), adjusted P=9.90 × 10(-3)). However, this difference was not significant after adjustment for cord blood adiponectin (P=0.04, adjusted P=0.26). The rs266729 SNP was strongly associated with cord blood adiponectin; neonates with rs266729 GG had the highest adiponectin (CC: 34.1±20.2 versus CG: 44.3±26.1 versus GG: 54.1±36.7 µg ml(-1), P=2.80 × 10(-9), adjusted P=1.68 × 10(-8)). This association remained after adjustment for birth weight s.d. score (P=6.63 × 10(-8), adjusted P=3.98 × 10(-7)). Our results suggest that the influence of the rs266729 SNP in ADIPOQ on birth weight may be dependent on circulating adiponectin.
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Adiponectina/sangue , Adiponectina/genética , Sangue Fetal/metabolismo , Desenvolvimento Fetal/genética , Polimorfismo de Nucleotídeo Único , Peso ao Nascer/genética , Feminino , Estudos de Associação Genética , Genótipo , Humanos , Recém-Nascido , MasculinoRESUMO
BACKGROUND The interference of biotin administration with thyroid function tests has been reported; however, it remains unclear in clinical practice. In this report, we present the case of a neonate with a diagnosis of pontocerebellar hypoplasia type 6 (PCH6) treated with biotin who developed biotin interference with laboratory thyroid function tests. CASE REPORT A 1-day-old male infant with hypothermia, tachypnea, and lactic acidosis had a suspected diagnosis of mitochondrial disease. Biotin and several vitamins were administered to improve his condition. On day 14, his laboratory tests revealed a free triiodothyronine level of 4.7 pg/mL, free thyroxine level of 3.7 ng/dL, thyroid-stimulating hormone level of 0.07 µIU/mL, and thyroid-stimulating hormone receptor antibody (TRAb) level of 37.6 IU/L, suggesting Graves' disease. No goiter or tachycardia developed. The maternal thyroid function was not measured during pregnancy, while the maternal TRAb was negative on the same day. After methimazole administration, the patient's thyroid function normalized, and methimazole was therefore discontinued. All thyroid function tests were conducted using immunoassay methods with avidin and biotin. Later, reduced oxygen consumption under aerobic conditions in skin fibroblasts and compound heterozygous variants of the mitochondrial arginine tRNA synthetase gene were identified, and the patient was diagnosed with PCH6. CONCLUSIONS In this case, the clinical symptoms and physical findings were incompatible with the thyroid function. These laboratory findings could have mimicked Graves' disease due to the biotin interference with immunoassays. Therefore, caution is required when evaluating similar cases.
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Biotina , Atrofias Olivopontocerebelares , Feminino , Humanos , Recém-Nascido , Laboratórios , Masculino , Gravidez , Testes de Função TireóideaRESUMO
The severity of the poststreptococcal acute glomerulonephritis is considered to be modulated by the immune response of each individual, although there had been few reports regarding specific factors. Renal cell carcinoma is a cancer frequently associated with paraneoplastic syndrome, characterized by fever, leukocytosis, elevated cytokines, and elevated hormone levels. All of these symptoms resolve after tumor resection. A girl with renal cell carcinoma developed renal failure rapidly, which resolved promptly right after nephrectomy for the carcinoma. She was diagnosed as having poststreptococcal acute glomerulonephritis according to the results of pathological and serological examinations. In addition, elevated serum interleukin-6 level before the surgery was detected. Six and a half years after the diagnosis, the patient's renal function was within normal range and she was tumor free. Because of the quick resolution of her renal dysfunction after the nephrectomy, paraneoplastic syndrome induced by renal cell carcinoma seemed to play a key role in the accentuation of poststreptococcal acute glomerulonephritis.
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Carcinoma de Células Renais/complicações , Glomerulonefrite/complicações , Nefrectomia/efeitos adversos , Síndromes Paraneoplásicas/complicações , Doença Aguda , Adolescente , Carcinoma de Células Renais/diagnóstico , Carcinoma de Células Renais/cirurgia , Feminino , Glomerulonefrite/diagnóstico , Glomerulonefrite/microbiologia , Humanos , Neoplasias Renais/patologia , Nefrectomia/métodos , Síndromes Paraneoplásicas/diagnóstico , Síndromes Paraneoplásicas/metabolismo , Insuficiência Renal/diagnóstico , Insuficiência Renal/etiologia , Insuficiência Renal/fisiopatologia , Índice de Gravidade de Doença , Infecções Estreptocócicas/complicações , Resultado do TratamentoRESUMO
BACKGROUND & AIMS: Genetic factors in class II human leukocyte antigen (HLA) have been reported to be associated with inter-individual variation in hepatitis B virus (HBV) vaccine response. However, the mechanism underlying the associations remains elusive. In particular, the broad linkage disequilibrium in HLA region complicates the localization of the independent effects of genetic variants. Thus, the present study aimed to identify the most probable causal variations in class II HLA loci involved in the immune response to HBV vaccine. METHODS: We performed a case-control study to assess whether HLA-DRB1, -DQB1, and -DPB1 4-digit alleles were associated with the response to primary HBV vaccination in 574 healthy Japanese students. To identify causative variants, we next assessed independently associated amino acid variants in these loci using conditional logistic regression analysis. Furthermore, to clarify the functional effects of these variants on HLA proteins, we performed computational structural studies. RESULTS: HLA-DRB1∗01:01, HLA-DRB1∗08:03, HLA-DQB1∗05:01, and HLA-DPB1∗04:02 were significantly associated with sufficient response, whereas HLA-DPB1∗05:01 was associated with poor response. We then identified amino acids independently associated with sufficient response, namely, leucine at position 26 of HLA-DRß1 and glycine-glycine-proline-methionine at positions 84-87 of HLA-DPß1. These amino acids were located in antigen-binding pocket 4 of HLA-DR and pocket 1 of HLA-DP, respectively, which are important structures for selective binding of antigenic peptides. In addition, the detected variations in HLA-DP protein were responsible for the differences in the electrostatic potentials of the pocket, which can explain in part the sufficient/poor vaccine responses. CONCLUSION: HLA-DRß1 position 26 and HLA-DPß1 positions 84-87 are independently associated with anti-HBs production against HBV vaccine. Our results suggest that HBsAg presentation through these HLA pocket structures plays an important role in the inter-individual variability of HBV vaccination.
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Aminoácidos/genética , Apresentação de Antígeno/genética , Antígenos de Superfície da Hepatite B/imunologia , Vacinas contra Hepatite B/imunologia , Antígenos de Histocompatibilidade Classe II/genética , Adulto , Aminoácidos/metabolismo , Povo Asiático , Sítios de Ligação , Estudos de Casos e Controles , Feminino , Voluntários Saudáveis , Vacinas contra Hepatite B/administração & dosagem , Antígenos de Histocompatibilidade Classe II/química , Antígenos de Histocompatibilidade Classe II/metabolismo , Humanos , Masculino , Modelos Moleculares , Conformação Proteica , Adulto JovemRESUMO
OBJECTIVE: To clarify the impact of a mild form of gestational diabetes mellitus (GDM) on neonatal birth size, and on insulin-related hormones and adiponectin (AdipoQ) in cord blood. METHODS: Two hundred and sixteen Japanese pregnant women diagnosed as having normal glucose tolerance according to the JSOG criteria were enrolled. Of the 216 women, 38 women were reclassified into a mild GDM (mGDM) group according to the IADPSG criteria. Of the remaining 178 women, 135 women with normal 50-g glucose challenge test were reclassified into a normal glucose tolerance (NGT) group. Cord blood insulin-like growth factor (IGF)-1, IGF-binding proteins (IGFBPs) and AdipoQ were measured in the offspring of the two groups. RESULTS: Birth weight and its SD scores were larger in the mGDM group than in the NGT group. The incidence of large-for-gestational age (LGA) newborns was higher in the mGDM than in the NGT group. No differences in cord blood free IGF-1, IGFBP-1, IGFBP-2 or AdipoQ levels were observed between the mGDM and NGT groups. CONCLUSIONS: Our study suggests that mild GDM reclassified according to the IADPSG criteria influences neonatal birth size, but neither the IGF-IGFBP axis nor AdipoQ can account for the changes of birth size in offspring of women with mild GDM.
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Adiponectina/sangue , Peso ao Nascer , Diabetes Gestacional/sangue , Proteínas de Ligação a Fator de Crescimento Semelhante a Insulina/sangue , Fator de Crescimento Insulin-Like I/metabolismo , Adulto , Biomarcadores/sangue , Feminino , Sangue Fetal/metabolismo , Humanos , Recém-Nascido , Masculino , GravidezRESUMO
BACKGROUND: It is poorly understood whether dipeptidyl peptidase 4 (DPP4) activity is altered and how DPP4 contributes to glycemic control in patients with type 1 diabetes mellitus (T1DM). AIM: The aim of this study was to measure serum DPP4 activity and to assess its relationships to metabolic variables in T1DM children. METHODS: Serum DPP4 activity was determined using a fluorometric assay in 43 T1DM and 26 control children. RESULTS: Serum DPP4 activity was significantly higher in T1DM children than in controls (3.57 ± 0.99 vs. 2.67 ± 0.77 U/mL, p<0.001). In the T1DM children, DPP4 activity was not correlated with HbA1c, blood glucose, or diabetes duration. A significant negative correlation was found between DPP4 activity and serum adiponectin levels in the T1DM group (r=-0.35, p<0.05). CONCLUSIONS: Serum DPP4 activity was increased in the T1DM children, whereas it was not associated with glycemic control. Given the negative correlation between serum DPP4 and adiponectin levels, further investigations are warranted to elucidate the role of DPP4 on insulin sensitivity in T1DM children.
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Diabetes Mellitus Tipo 1/enzimologia , Dipeptidil Peptidase 4/sangue , Estudos de Casos e Controles , Criança , Feminino , Humanos , MasculinoRESUMO
Backgrounds. Outcome of childhood malignancy has been improved mostly due to the advances in diagnostic techniques and treatment strategies. While methotrexate (MTX) related polymorphisms have been under investigation in childhood malignancies, many controversial results have been offered. Objectives. To evaluate associations of polymorphisms related MTX metabolisms and clinical course in childhood lymphoid malignancies. Method. Eighty-two acute lymphoblastic leukemia and 21 non-Hodgkin's lymphoma children were enrolled in this study. Four single nucleotide polymorphisms in 2 genes (MTHFR (rs1801133/c.677C>T/p.Ala222Val and rs1801131/c.1298A>C/p.Glu429Ala) and SLCO1B1 (rs4149056/c.521T>C/p.V174A and rs11045879/c.1865+4846T>C)) were genotyped by Taqman PCR method or direct sequencing. Clinical courses were reviewed retrospectively. Results. No patient who had the AC/CC genotype of rs1801131 (MTHFR) had relapsed or died, in which distribution was statistically different among the AA genotype of rs1801131 (P = 0.004). Polymorphisms of SLCO1B1 (rs11045879 and rs4149056) were not correlated with MTX concentrations, adverse events, or disease outcome. Conclusions. Polymorphisms of MTHFR (rs1801131) could be the plausive candidate for prognostic predictor in childhood lymphoid malignancies.