CYP3A与MDR1基因多态性在儿童急性淋巴细胞白血病的研究进展

儿童急性淋巴细胞白血病(acute lymphoblastic leukemia,ALL)作为一种治愈率较高的疾病,化疗是其主要的治疗方法。CYP3A与MDR1作为决定药物代谢的关键基因,两者参与ALL化疗中大多数药物的代谢;两者基因多态性的表达会影响到药物代谢酶的活性进而影响药物代谢的效率。所以在日益提倡个体化治疗的今天,两者基因多态性的表达就直接关系到儿童ALL的治疗效果、药物毒副作用和预后。我们则可以根据两者基因多态性结合患儿的临床表现及其他实验室检查更为细致的划分出标危、中危和高危,采取不同的化疗方案,为实行个体化治疗提供理论依据。     

ARID5B基因多态性与汉族儿童急性淋巴细胞白血病关联性研究

目的探讨ARID5B基因常见单核苷酸多态性与闽南地区汉族儿童急性淋巴细胞白血病的相关性。方法采用病例-对照研究,对108例急性白血病患儿及116名年龄、性别、种族匹配的对照人群中的ARID5B基因rs7073837和rs10821936多态位点用荧光能量共振转移技术进行检测,分析不同基因型与儿童急性白血病的易感性。结果两位点在两组人群中的基因频率分布符合Hardy-Weinberg平衡(P均0.05)。多态性位点rs7073837在两组间的基因型和等位基因频率分布的差异无统计学意义(P均0.05);病例组rs10821936位点与对照组相比,TT、TC、CC基因型频率的差异有统计学意义(P0.001),ALL组等位基因C频率高于对照组,差异有统计学意义(χ2=16.833,P0.001),提示等位基因C是ALL发生的危险因素(OR=2.203,95%CI:1.507-3.220)。结论 ARID5B基因rs10821936位点是闽南地区汉族儿童急性白血病的一个危险因素,携带突变基因序列C的个体可增加急性白血病的发病风险;而多态性位点rs7073837可能与儿童急性白血病人群无关。     

Diffuse cerebral vasospasm with infarct after intrathecal cytarabine in childhood leukemia

Although the varied neurotoxicity of intrathecal (IT) chemotherapy for treatment of childhood acute leukemia is well known, most are related to transient post‐puncture headache, drug‐induced arachnoiditis, or leukoencephalopathy after methotrexate or cytarabine. Cerebral vasospasm leading to acute infarct after IT chemotherapy is very uncommon in children. Reported herein is a rare case of diffuse cerebral vasospasm with subsequent cerebral infarct after IT cytarabine in a 7‐year‐old boy with acute lymphoblastic leukemia, who successfully recovered with supportive management, and a review of the literature.     

Interphase cytogenetic study of childhood acute lymphoblastic leukemia

We used the fluorescence in situ hybridization (FISH) technique and centromere-specific probes for chromosomes 1, 6, 8, 10, 12, 17, 18, X, and Y to investigate the presence and number of the respective chromosomes in interphase nuclei of 14 cases of childhood acute lymphoblastic leukemia (ALL) which were shown to be hyperdiploid by DNA flow cytometry irrespective of their cytogenetic pattern. Numerical anomalies for one or more chromosomes were detected in all 14 cases. The FISH results were compared with those obtained by conventional cytogenetic analysis. A hyperdiploid karyotype was evident in 5 cases, the others were either normal or lacking cytogenetic results because of technical failure. In the 5 cytogenetically hyperdiploid cases, 14 numerical abnormalities were observed with both techniques, whereas 4 numerical deviations were found only with FISH. In 9 other cases which had a DNA content indicating hyperdiploidy, 34 trisomies and 2 tetrasomies were detected by FISH analysis. Furthermore, in 1 case duplication of the Y chromosome and in 3 male cases duplication of the X chromosome were evident. Double-target FISH experiments in 2 patients allowed the correlation of numerical aberrations of 2 chromosomes in one and the same cell. By such analyses, detection of subpopulations of tumor cells was found to be relatively easy. Our results indicate that the FISH technique with chromosome-specific repetitive centromeric probes is a rapid, simple to use, and easy to interpret technique for the evaluation of numerical chromosomal aberrations in interphase nuclei of leukemias. © 1994 Wiley-Liss, Inc.     

Genetic polymorphisms and haplotypes of DNA repair genes in childhood acute lymphoblastic leukemia

BACKGROUND: Polymorphisms of DNA repair genes can alter protein structure and may impair DNA repair capacity. Defects in repairing damaged DNA lead to genetic instability and carcinogenesis. This study was performed to evaluate the effect of the polymorphisms of DNA repair genes on risk of childhood acute lymphoblastic leukemia (ALL). PROCEDURES: We genotyped polymorphisms of X-ray repair cross-complimenting group 1 (XRCC1) codon 194 (Arg to Trp), 280 (Arg to His) and 399 (Arg to Gln), and xeroderma pigmentosum group D (XPD) codon 312 (Asp to Asn) and 715 (Lys to Gln) in 108 children with ALL and 317 healthy controls using PCR-RFLP method. The allele, genotype, and haplotype frequencies of these polymorphisms were compared between cases and controls using Chi-square or Fisher's exact test. PHASE computer software was used to analyze estimated haplotypes of the XRCC1 and XPD polymorphisms. RESULTS: The frequency of XRCC1 194Trp allele in patients was significantly lower than that in controls (odds ratio (OR) 0.67; 95% confidence interval (CI), 0.47-0.97). Individuals with XRCC1 194 Trp/Trp genotype had a significantly reduced risk of ALL (OR 0.22; 95% CI, 0.05-0.96). The frequency of the XRCC1 haplotype B (194Trp-280Arg-399Arg) was significantly lower in children with ALL when compared to controls. The XRCC1 399Gln allele was associated with a significantly increased risk of ALL (OR 1.67; 95% CI, 1.20-2.33). The frequency of the XRCC1 haplotype C (194Arg-280Arg-399Gln) was significantly higher in patients. There was no difference of allele frequencies of the XRCC1 280 (Arg to His), XPD 312 (Asp to Asn), or XPD 715 (Lys to Gln) between cases and controls. CONCLUSION: The XRCC1 194Trp allele and haplotype B showed a protective effect against development of childhood ALL. In contrast, individuals with the XRCC1 399Gln allele and haplotype C were associated with increased risk for this disease.     

Moyamoya syndrome following childhood acute lymphoblastic leukemia

BACKGROUND: Long-term survivors of childhood acute lymphoblastic leukemia (ALL) sometimes suffer from adverse long-term sequelae. We analyzed the incidence, clinical course and prognosis of moyamoya syndrome (MoS) following childhood ALL. PROCEDURE: A total of 1,846 ALL patients were treated with four consecutive TCCSG ALL protocols (L84-11, L89-12, L92-13, and L95-14) between 1984 and 1999. We surveyed the MoS cases among these patients in the follow-up studies. RESULTS: Six patients with MoS were identified: four boys and two girls whose ages ranged from 2 years and 1 month (abbreviated as "2y1m") to 14y 1 m at diagnosis of ALL. None of the patients had central nervous system (CNS) leukemia. All six patients received prophylactic cranial irradiation with a dosage of 18 or 24 Gy. Although one patient died of brain infarction due to MoS, no leukemic relapse was observed in the group. The cumulative incidence of MoS in our series was 0.46 +/- 0.02% at 8 years. Among several clinical characteristics, use of cranial irradiation was the only factor that appeared to be significantly related to the development of MoS. CONCLUSIONS: MoS occurs with increased frequency in children treated for ALL, and might be associated with cranial irradiation. Prophylactic cranial irradiation should be used cautiously in ALL patients who can be cured by other CNS-directed therapies.     

药物代谢酶基因多态性与甲氨蝶呤治疗儿童急性淋巴细胞白血病不良反应

随着白血病药物基因组学的研究进展,人们发现儿童急性淋巴细胞白血病药物代谢酶相关基因的多态性与不良反应相关.如何寻找有效预测甲氨蝶呤不良反应的基因型,进行个体化治疗是当前研究的热点.该文主要阐述三种药物代谢酶即亚甲基四氢叶酸还原酶、还原叶酸载体和谷胱甘肽S-转移酶基因多态性与甲氨喋呤相关不良反应之间的关系.     

Adrenal axis function after high-dose steroid therapy for childhood acute lymphoblastic leukemia

Background A 4‐week course of high‐dose glucocorticoids may cause prolonged adrenal suppression even after a 9‐day tapering phase. In this study, adrenal function and signs and symptoms of adrenal insufficiency were prospectively assessed in children with acute lymphoblastic leukemia (ALL) after induction treatment including high‐dose prednisone (PDN) or dexamethasone (DXM). Procedures Sixty‐four children with ALL, treated according to the AIEOP ALL 2000 Study protocol, underwent low dose ACTH (LD‐ACTH) stimulation 24 hr after the last tapered steroid dose. In those with impaired cortisol response, additional LD ACTH tests were performed every 1–2 weeks until cortisol levels normalized. Signs and symptoms of adrenal insufficiency were recorded during the observation period. Results All patients had normal basal cortisol values at diagnosis. Twenty‐four hours after last glucocorticoid dose, morning cortisol was reduced in 40/64 (62.5%) patients. LD‐ACTH testing showed adrenal suppression in 52/64 (81.5%) patients. At the following ACTH test 7–14 days later, morning cortisol values were reduced in 8/52 (15.4%) patients and response to the test was impaired in 12/52 (23%). Adrenal function completely recovered in all patients within 10 weeks. No difference was found between patients treated with PDN or DXM. Almost 35% of children with impaired cortisol values at the first test developed signs or symptoms of adrenal insufficiency. One child developed a severe adrenal crisis during adrenal suppression. Conclusions High‐dose glucocorticoid therapy in ALL children may cause prolonged adrenal suppression and related clinical symptoms. Laboratory monitoring of cortisol levels and steroid coverage during stress episodes may be indicated. Pediatr Blood Cancer 2008;50:537–541. © 2007 Wiley‐Liss, Inc.     

Clinical relevance of in vitro drug resistance testing in childhood acute lymphoblastic leukemia: The state of the art

Nowadays about two-thirds of children with acute lymphoblastic leukemia (ALL) can be cured with chemotherapy, but one-third die from the disease. The clinical response of leukemic cells to chemotherapy is roughly due to two factors: the effective drug levels reaching the cells and the resistance of these cells to the drugs. The clinical value of cellular drug resistance in children with ALL is not known. We developed an in vitro assay to study drug resistance in these children. In this article, the main results obtained with this MTT assay on samples from 137 children with ALL are summarized: (1) patients whose cells are resistant to several drugs at initial diagnosis have a poor prognosis; (2) relapsed leukemias show a considerable drug resistance which might partly explain the poor prognosis. Relapsed cases differ in their type and degree of resistance; (3) the poor outcome of high risk groups as defined by age and immunophenotype can partly be explained by specific patterns of drug resistance; (4) P-glycoprotein-mediated multidrug resistance is not an important cause of resistance in childhood ALL; and (5) no relation exists between the activities of the purine enzymes HGPRT, 5′NT, ADA, and PNP and drug resistance in childhood ALL. The conclusion is that in vitro drug resistance data have clinical relevance and can be used to develop more effective and less toxic treatment strategies in childhood ALL. © 1994 Wiley-Liss, Inc.     

Insulin‐dependent diabetes: A chronic complication to acute pancreatitis in childhood acute lymphoblastic leukemia

Pancreatitis is a frequent toxicity to acute lymphoblastic leukemia (ALL) treatment, significantly associated with asparaginase use, and may be followed by severe complications such as acute hyperglycaemia, need for mechanical ventilation, pseudocysts, and death. Here, we provide novel data on seven patients diagnosed with diabetes after pancreatitis and still requiring insulin treatment after a median follow‐up of 4.2 years (range: 1.7–9.2). We describe the clinical course of pancreatitis and illustrate the association between pancreatic pseudocysts, older age, and development of insulin‐dependent diabetes. Together, this study documents the persisting burden of pancreatitis in childhood ALL and underlines the need for plasma glucose level monitoring.     

Induction toxicity in childhood acute lymphoblastic leukemia: A comparison of two schedules of daunorubicin administration

The haematological toxicity of the induction phase of chemotherapy for acute lymphoblastic leukaemia (ALL) was compared in two cohorts of patients. The principal difference between these two cohorts was the mode of administration of the anthracycline, daunorubicin (DNR). Both groups received four-drug induction chemotherapy, which produced a high remission rate. Those receiving DNR on days 1 and 2 experienced a profound but shorter period of neutropenia and more severe thrombocytopenia than those who received the DNR weekly. The pattern of hospitalisation and support facilities in the individual unit may determine which regimen is to be preferred. These observations are relevant for the newly diagnosed patient in whom an anthracycline is retained in the induction therapy for ALL. © 1995 Wiley-Liss, Inc.