DNA repair gene XRCC1 polymorphisms and susceptibility to childhood acute lymphoblastic leukemia: a meta-analysis

Objective： To estimate the relationship between genetic polymorphisms of X-ray repair cross- complementing group 1 （XRCC1） and the susceptibility to childhood acute lymphoblastic leukemia （ALL）. Methods： Relevant case-control studies were enrolled in the meta-analysis. We applied Rev Man 4.2 software to pool raw data and test studies＇ heterogeneity and to calculate the incorporated odds ratio （OR） and 95% confidence interval （95% CI）. Results： Our data showed that the OR for the Gln allele of the Arg399Gln polymorphism, compared with the Arg allele, was 1.35 （95% CI, 1.16-1.57; P〈0.0001） for childhood ALL patients. Similarly, the homozygous genotype Gln/Gln and heterozygous genotype Arg/Gln both significantly increased the risk of childhood ALL compared with the wild genotype Arg/Arg （OR =1.58; 95% CI, 1.13-2.21; P=0.008; OR =1.51; 95% CI, 1.21-1.87; P=0.0002）. The dominant model of Arg399Gln was associated with childhood ALL risk （OR =1.54; 95% CI, 1.25-1.89; P〈0.0001）. The ethnic subgroup analysis demonstrated that the Gln allele in all five ethnic groups was prone to be a risk factor for childhood ALL just with different degrees of correlation while Arg194Trp SNP showed a protective or risk factor or irrelevant thing in different races. Conclusions： XRCC1 399 polymorphism may increase the risk of childhood ALL. Different ethnic groups with some gene polymorphism have different disease risks.

Maternal alcohol consumption during pregnancy and the risk of childhood acute leukemia:a meta-analysis

Objective： The authors used a meta-analytic technique to quantify the evidence of an association between ma- ternal alcohol consumption during pregnancy and childhood acute leukemia （AL）, which provided a basis for the prevention of childhood AL. Methods： Relevant literatures of maternal alcohol consumption during pregnancy were comprehensively searched and screened. Subgroup meta-analysis was conducted according to the type of leukemia. Results of research data of maternal alcohol consumption during pregnancy were tested for heterogeneity. Combined OR values and 95% CIs were statistically calculated with RevMan 4.2 software; Funnel plots were applied to conduct bias analysis for those included litera- tures. Results： Ten related literatures were included after data screening, 4593 cases in AL group and 6157 cases in control group respectively. According to heterogeneity test result （X2 = 16.26, P 〈 0.05）, the combined OR values and 95% CI were calculated with random effects model, which were 1.02 （0.92-1.14）, Z = 0.41, P = 0.68 〉 0.05, indicating that there was no significant difference between maternal alcohol consumption during pregnancy and the risk of childhood acute leukemia （AL）. Subgroup analysis： for the association between maternal alcohol consumption during pregnancy and childhood acute lympho- blastic leukemia （ALL）, the combined OR value and 95% CI were 0.92 （0.84-1.00）, Z = 1.92, P = 0.05, indicating that there was significant difference between two groups; for the association between maternal alcohol consumption during pregnancy and childhood acute non-lymphoblastic leukemia （ANLL）, the combined OR values and 95% CI were 0.82 （0.61-1.11）, Z = 1.30, P = 0.19 〉 0.05, indicating that there was no significant difference between two groups. Conclusion： Maternal alcohol consumption during pregnancy is a risk factor in childhood ALL, but not in childhood ANLL.

Cytogenetic Characteristics of Childhood Acute Lymphoblastic Leukemia:A Study of 1541 Chinese Patients Newly Diagnosed between 2001 and 2014

Objective:Cytogenetic abnormalities have been proven to be the most valuable parameter for risk stratification of childhood acute lymphoblastic leukemia(ALL).However,studies on the prevalence of cytogenetic abnormalities and their correlation to clinical features in Chinese pediatric patients are limited,especially large-scale studies.Methods:We collected the cytogenetics and clinical data of 1541 children newly diagnosed with ALL between 2001 and 2014 in four Chinese hospitals,and retrospectively analyzed their clinical features,prognosis and risk factors associated with pediatric ALL.

Primitive Neuroectodermal Tumor as the Second Malignant Neoplasm in a Long-Term Survivor Child of Acute Lymphoblastic Leukemia: A Case Report

Acute lymphoblastic leukemia(ALL)is a common pediatric cancer.The second malignant neoplasms(SMNs)in long-term survivors of pediatric ALL are relatively rare.Herein we report a 10-year-old girl who was diagnosed as primitive neuroectodermal tumor(PNET)5 years after the initial diagnosis of ALL with radiotherapy・free treatment.PNET is an exceedingly rare neoplasm in SMNs of survivors of childhood ALL.It is predisposed to be misdiagnosed and the pathogenesis is unclear.The outcome is poor.Long-term follow-up is necessary for the survival children of ALL.

A study of the relationship between expression level of TRF1 protein and telomerase activity in human acute leukemia

Objective： To study the expression level of TRF1 （telomeric repeat binding factor 1） protein in human acute leukemia and relationship between expression level of TRF1 protein and telomerase, Methods： A quantitative Western±Blot technique was developed using anti±TRF1^33±277 monoclonal antibody and GST±TRFI purity protein as a standard to further determine the expression level of TRF1 protein in total proteins extracted from clinical specimens. Results： Bone marrow tissues of 20 acute leukemia patients were studied, 11 healthy donors＇ bone marrows were taken as a control. The expression level of TRF1 protein was significantly higher （P〈0.01） in normal bone marrow （（2.2174±0.462） μg/μl） than that of acute leukemia patients （（0.7544±0.343） μg/μl）, But there was no remarkable difference between ALL and ANLL patients （（0.6184±0.285） μg/μl vs （0.8454±0.359） μg/μl, P〉0.05）. After chemotherapy, TRFI expression level of patients with complete remission elevated （（0.7724±0.307）/μg/μl vs （1.6834±0,344）μg/μl, P〈0.01 ）, but lower than that of normal （（2.2174±0.462）/μg/μl, P〈0.01）. There was no significantly difference after chemotherapy （（0.7264±0.411） μg/μl vs （0.895±0.339） μg/μl,p〉0.05）. TRF1 expression level of patients with complete remission is higher than that of patients without complete remission （（1,683±0.344）μg/μl vs （0.895±0.339）μg/μl P〈0.01）. All samples were determined for telomerase activity. It was confirmed that the activity of telomerase in normal bone marrow was lower than that of acute leukemia patients （（0.125±0.078） μg/μl vs （0.765±0.284）μg/μl, P〈0.01）. There was no significant difference of expression level ofTRF I protein between ALL and ANLL patients （（0.897±0.290） μg/μl vs （0.677±0.268） μg/μl, P〉0.05）. After chemotherapy, telomerase activity of patients with complete remission decreased （（0.393±0.125） μg/μl）, but was still higher than that of normal （（0.125±0.078） μg/μl, P〈0.01）. Conclusion： The expression level of TRF1 protein has correlativity to the activity of telomerase （P〈0.001）.

Angiogenic and FLT3 Receptors Expression in Acute Lymphoblastic Leukemia in Pediatric Age Group

Angiogenesis has an important role in pathophysiology of cancer. FMS-like tyrosine kinase 3 (FLT3) is implicated in hematopoietic malignancies. Their role in childhood acute lymphoblastic leukemia (ALL) pathogenesis needs more enlightenment. Expression of vascular endothelial growth factor receptor-1 and -2 (VEGFR-1 and -2), as well as FLT3 were assessed by flow cytometry in bone marrow (BM) blasts of 55 newly diagnosed children with ALL. Patients included B cell ALL (B-ALL) group (n = 41) and T cell ALL (T-ALL) group (n = 14). Comparison between groups revealed a significant increase in blasts percent (%) expressing FLT3 and FLT3 intensity detected in B-ALL group (p = 0.004 and p = 0.02, respectively). In B-ALL patients, a significant positive correlation was seen between blasts % expressing FLT3 and blasts percentage infiltrating BM (r = 0.405;p = 0.009), also positive correlation was seen between % of blasts expressing VEGFR-1 and VEGFR-2 (r = 0.704;p 0.001). In T-ALL group, blast % expressing FLT3 revealed significant positive correlations with blast % expressing VEGFR-1, and those expressing VEGFR-2 (r = 0.627;p = 0.016, and r = 0.654;p = 0.011, respectively). In addition, significant correlation was seen in blasts % expressing all;FLT3, VEGFR-1 and -2, with blasts % expressing stem cell marker CD34 (r = 0.826;p = 0.001, r = 0.596;p = 0.041, and r = 0.798;p = 0.002, respectively). Conclusion: Expression of VEGFR-1, VEGFR-2 and FLT3 were demonstrated and linked on leukemic blasts of ALL which highlights their role in pathogenesis. FLT3 expression plays a role in facilitating blasts proliferation in BM in B-ALL. FLT3, VEGFR-1 and -2 could be used in future profiling of CD34+ leukemic stem cell pool in T-ALL.

Evolution of the Outcomes of Children with Acute Leukemia in Congo

Background: To lower the mori-mortality related to the aggressiveness of acute leukemia’s chemotherapy regimens, we have implemented in 2017 two low toxicity chemotherapy regimens and new supportive care strategies. The aim of the study is to evaluate our new treatments. Materials and Method: A retrospective study was carried out from January 2014 to May 2021 in the hematology department of the teaching hospital in Brazzaville. The study concerned 47 children diagnosed with acute leukemia. Participants were divided into two groups: acute leukemia diagnosed before 2017 (group 1: 23 children) and after 2017 (group 2: 14 children). They were compared using the chi-square. Results: The median age was 10.0 ± 5.01 years. Features and outcomes of group 2 were better. The median duration of symptoms was shorter: 2.45 ± 2.87 months (p = 0.036). The Karnosky score was higher (p = 0.002) and white blood cell count lower (p = 0.331). Both groups started the treatment with a delay of 6 days. The induction treatment was completed in 69.6% before 2017 versus 93.3% after. The rate of relapse was more important for group 1: 85.7% versus 14.3% (p = 0.01). Conclusion: Trainings of professionals have improved the characteristics outcomes of our patients and should be pursued. Considering the high relapse rate, our protocol will need to be intensified.

Effect of Factor V Leiden on Thrombosis in Childhood Leukemia

Thromboembolism is an important complication in children undergoing therapy for ALL as it has the potential to impact adversely on both their survival and quality of life. The incidence of thrombosis in children with ALL varies between 1.1% and 36.7% and the actual mean is 3.2%. The aim of our study is to review the available reported data on the effect of FVL on thrombotic risk in pediatric patients with acute leukemia.

Outcome of childhood acute lymphoblastic leukemia： a report of 121 patients treated at Wuhan Union Hospital of China

Prognostic factors are biological or physical characteristics of a patient or the patient＇s cancer that can be used to predict the outcome of the individual. The prognosis of childhood acute lymphoblastic leukemia （ALL） has been improved greatly in the past 40 years, reaching a long-term event free survival （EFS） of about 75% and overall survival of about 80% in developed countries.3-6 The same result has also been achieved in China. The ALL-XH-99 Protocol at Shanghai Children＇s Medical Center adopted early intensification treatment and triple intrathecal chemotherapy with high-dose methotrexate treatment for all patients and intensive chemotherapy in median risk （MR） and high risk （HR） patients. More intensive chemotherapy might cause more complications. In order to reevaluate the outcome of childhood ALL treated with the ALL-XH-99 Protocol and to fully elucidate the prognostic factors and the sequelae, a retrospective analysis was carried out to evaluate patients diagnosed with childhood ALL who were treated with the ALL-XH-99 Protocol in the past decade.

急性白血病异基因造血干细胞移植后的维持治疗研究进展

急性白血病(acute leukemia,AL)是来源于造血干细胞的恶性克隆性疾病,分为急性淋巴细胞白血病(acute lymphoblastic leukemia,ALL)和急性髓细胞白血病(acute myeloid leukemia,AML)两大类。异基因造血干细胞移植(allogeneic hematopoietic stem cell transplantation,allo-HSCT)是AL患者获得长期生存有力的手段,但移植后复发仍然是导致其死亡的主要原因。移植前状态、移植预处理、移植后复发防治均影响移植后的复发。目前,有部分患者移植后维持治疗的研究开展,包括表观遗传学药物、靶向药物、免疫药物等移植后维持治疗。本文主要讨论移植后维持治疗与预后的关系,综述近年来急性白血病allo-HSCT后维持治疗的方法、治疗结局和潜在的不良反应。

CCLG-ALL-2008方案治疗169例儿童急性淋巴细胞白血病长期随访结果

目的回顾和分析CCLG-ALL-2008方案治疗儿童初诊急性淋巴细胞白血病（acute lymphoblastic leukemia,ALL）的长期随访结果。方法总结2008年4月至2014年4月期间,于武汉协和医院儿科接受CCLG-ALL-2008方案治疗的169例初诊ALL患儿的临床资料,采用Kaplan-Meier生存分析评估患儿总体生存率（OS）和无事件生存率（EFS）,运用COX回归比例风险模型分析影响预后的因素。结果169例ALL患儿中,第33天完全缓解（CR）率为96.3%,5年OS为（84.72±4.10）%,5年EFS为（81.53±3.80）%,其中标危、中危及高危组患儿5年EFS分别为（89.15±2.80）%、（87.44±3.10）%及（56.64±9.30）%;复发19例（11.2%）,复发中位时间为CR后16个月（2-36个月）;死亡29例（17.2%）,死亡中位时间为诊断后15个月（1-38个月）。多因素回归分析显示危险度分组诊疗有利于延长患儿EFS。结论 CCLG-ALL-2008方案治疗儿童ALL的CR率高,长期随访5年OS、EFS接近发达国家水平,严格的分型诊疗和微小残留病灶（MRD）监控有利于患儿的个性化治疗,改善预后。

SIL-TAL1融合基因阳性的儿童急性T淋巴细胞白血病的临床特征及其治疗研究

目的:探讨SIL-TAL1融合基因阳性儿童急性T淋巴细胞白血病(T-cell acute lymphoblastic leukemia,TALL)的临床特征、治疗方案及预后。方法:收集2005年4月至2012年11月间来我院治疗的101例T-ALL患儿的临床资料,比较SIL-TAL1阳性和SIL-TAL1阴性患儿的常见临床特征、早期治疗反应、微小残留病(minimal residual disease,M RD)、无事件生存率(event free survival,EFS)、无复发生存率(relapse free survival,RFS)及SIL-TAL1阳性T-ALL采用BCH-2003方案和CCLG-2008方案治疗的疗效。结果:在101例患儿中共22例携带SIL-TAL1融合基因(21.9%)。SIL-TAL1阳性(22例)和阴性患儿(79例)初诊时性别、年龄、对泼尼松反应及中枢神经系统累及均无明显差异,但SIL-TAL1阳性患儿初诊时外周血白细胞水平明显高于SIL-TAL1阴性患儿(P=0.009)。两组患儿在诱导缓解治疗后、延迟强化治疗Ⅱ前、维持治疗前的MRD水平无明显差异,但SIL-TAL1阳性患儿中巩固治疗前的MRD高水平者明显多于SIL-TAL1阴性患儿(P<0.05),延迟强化治疗I前的MRD高水平者似有增多的趋势(P>0.05)。两组患儿的5年EFS和RFS没有明显差异。将22例SIL-TAL1阳性患儿按CCLG-2008方案的分型标准重新划分危险度,BCH-2003组(10例)的危险度明显高于CCLG-2008组(12例,P=0.029),但两组患儿在常见临床特征、早期治疗反应、MRD水平、长期预后等方面均无明显差异。结论:SIL-TAL1阳性患儿初诊时外周血白细胞水平较高,临床疗效与SIL-TAL1阴性患儿没有显著差异。同时,SIL-TAL1阳性患儿对早期强化治疗可能反应性较差,BCH-2003方案可能更适于这一亚型的患儿。

1例口服雄黄制剂致白血病患儿急性砷中毒死亡原因分析

目的 探讨雄黄制剂致急性砷中毒的原因。方法 回顾性分析1例口服雄黄制剂致白血病患儿急性砷中毒的诊治过程,总结雄黄制剂治疗儿童白血病的砷中毒特点及治疗注意事项。结果 患儿雄黄日用量为1 g,远高于单味日用量50~100 mg;临床症状为多器官功能衰竭,尿砷含量为33.56μmol/L,远超过人体尿砷正常值1.8μmol/L,诊断为急性砷中毒。结论 该患儿雄黄日用量属超剂量用药。雄黄制剂的剂量和疗程应符合药品说明书要求,不可长期和超量服用,一旦出现心律失常和心电图QT间期延长等砷中毒症状时应立即停药,保证用药安全。

ALL-2005方案治疗儿童T系急性淋巴细胞白血病35例疗效总结

目的研究ALL-2005方案治疗儿童T系急性淋巴细胞白血病(T-ALL)的疗效。方法对2005年5月-2009年4月初发的35例T-ALL患儿采用ALL-2005方案进行分层治疗及疗效分析。结果 T-ALL患儿35例,男30例(86%),女5例(14%),发病时中位年龄8.3(2.0～15.6)岁。其中>10岁患儿14例,占40%。起病时外周血白细胞≥50×109/L者24例,占69%,起病时6例患儿有纵隔增宽。泼尼松治疗第8天时泼尼松试验反应好者22例(63%)。诱导治疗第35天有29例获完全缓解(83%),骨髓微小残留病(MRD)≤0.01%者共20例(67%)。治疗第55天时MRD≤0.01%共26例(87%)。4例复发,3例失访,6例死亡(包括3例复发和3例第1疗程未缓解而放弃治疗者)。随访至2011年6月31日,中位随访时间39(1～71)个月,5年无事件生存率为73.5%。结论 ALL-2005方案治疗儿童T-ALL疗效较好。

应用MALDI-TOF-MS法筛选儿童急性淋巴细胞白血病潜在标记物

本研究旨在分析儿童急性淋巴细胞白血病(c-ALL)的肿瘤特异性蛋白,寻找新的肿瘤蛋白分子标志物。应用双向凝胶电泳(2-DE)及基质辅助激光解吸电离飞行时间质谱分析(MALDI-TOF-MS)及联网检索数据库,鉴定表达上调的差异蛋白,并应用细胞免疫组织化学法验证相关蛋白。结果表明,获得了4个表达上调的蛋白点,经质谱分析初步鉴定出其中2个表达上调的差异蛋白为谷胱甘肽S转移酶P和阻殖蛋白;细胞免疫组织化学法检测发现,二者在儿童ALL细胞内的表达阳性率明显高于对照组,差异具有统计学意义(P<0.05)。结论:谷胱甘肽S转移酶P和阻殖蛋白有望成为儿童ALL新的诊断标志物和药物靶点。

儿童急性淋巴细胞白血病在德国的治疗——COALL-92方案521例临床及疗效分析

目的 :总结分析德国应用COALL 92方案 (CooperativemulticentertreatmentstudyforchildhoodwithacutelymphoblasticleukemiaoftheGermanPediatricOncologyandHematologySocietyCOALL 92 Study/GPOH)治疗儿童急性淋巴细胞白血病的临床疗效。方法 :1992～ 1997年间在德国 19所儿童肿瘤治疗中心共同合作采用统一的诊断标准及治疗方案 (COALL 92 STUDY/GPOH)治疗儿童急性淋巴细胞白血病 (acutelymphoblasticleukemiaALL) 5 2 1例 ,其中高危急淋 (High Risk ALLHR ALL) 2 74例 ,低危急淋 (Low Risk ALLLR ALL) 2 47例。结果 :完全缓解率 (CompleteRemissionCR)分别为 98% ,99.6 % ,长期无病生存 (Event FreeSurvivalEFS)率和生存 (Sur vivalS)率分别为 71% ,78%和 79% ,82 %。结论 :按照复发因素分型选用相应的治疗方案 ,早期采用由多种非交叉耐药性抗肿瘤药物交替 ,联合的强化疗 ,避护所预防治疗及完善的辅助治疗方法及措施是减少白血病复发 。

CCLG-ALL2008诱导缓解方案化疗儿童急性淋巴细胞白血病的效果观察

目的探讨CCLG-ALL2008诱导缓解方案化疗儿童急性淋巴细胞白血病(ALL)的效果。方法回顾性选取ALL患儿134例,其中67例(观察组)给予CCLG-ALL2008诱导缓解方案化疗,另67例(对照组)给予常规多药联合化疗。观察并比较两组患儿疗效、化疗不良发应发生率、化疗后热休克蛋白90(Hsp90)表达水平、5年生存率。结果观察组患儿治疗有效率高于对照组(P<0.05),化疗不良反应发生率与对照组比较差异无统计学意义(P>0.05),化疗后Hsp90 m RNA和蛋白表达水平均低于对照组(均P<0.05),5年生存率高于对照组(P<0.05)。结论 CCLG-ALL2008诱导缓解方案化疗儿童ALL,效果确切,预后相对较佳,值得临床应用。

儿童ALL的HLA-1类抗原表达及机体免疫功能探讨

目的通过研究儿童急性淋巴细胞性白血病人的白血病细胞及对照组外周血白细胞HLA-1类抗原表达情况,探讨儿童急性淋巴细胞性白血病发病机制及机体免疫状态。方法采用流式细胞术检测儿童急性淋巴细胞性白血病初发病人42例、完全缓解期病人36例、对照组34例儿童HLA-A2、HLA-B抗原表达。结果①三组儿童HLA-A2抗原均为高表达,阳性率均数均在90%以上,组间比较无显著性差异(P>0.05)。②初发组白血病细胞表面HLA-B抗原表达明显下调,完全缓解组外周血白细胞表面HLA-B抗原表达略下降;初发组与完全缓解组或对照组比较,具有显著性差异(P<0.01)。完全缓解组与对照组比较无显著性差异(P>0.05)。结论急性淋巴细胞性白血病人白血病细胞表面HLA-B抗原表达下调,其作为靶细胞提呈抗原能力下降,可能是白血病细胞逃脱机体免疫监视的主要机制之一。

PRPS2 mutations drive acute lymphoblastic leukemia relapse through influencing PRPS1/2 hexamer stability

Tumor relapse is the major cause of treatment failure in childhood acute lymphoblastic leukemia(ALL),yet the underlying mechanisms are still elusive.Here,we demonstrate that phosphoribosyl pyrophosphate synthetase 2(PRPS2)mutations drive ALL relapse through influencing PRPS1/2 hexamer stability.Ultra-deep sequencing was performed to identify PRPS2 mutations in ALL samples.The effects of PRPS2 mutations on cell survival,cell apoptosis,and drug resistance were evaluated.In vitro PRPS2 enzyme activity and ADP/GDP feedback inhibition of PRPS enzyme activity were assessed.Purine metabolites were analyzed by ultra-performance liquid-chromatography tandem mass spectrometry(UPLC–MS/MS).Integrating sequencing data with clinical information,we identified PRPS2 mutations only in relapsed childhood ALL with thiopurine therapy.Functional PRPS2 mutations mediated purine metabolism specifically on thiopurine treatment by influencing PRPS1/2 hexamer stability,leading to reduced nucleotide feedback inhibition of PRPS activity and enhanced thiopurine resistance.The 3-amino acid V103-G104-E105,the key difference between PRPS1 and PRPS2,insertion in PRPS2 caused severe steric clash to the interface of PRPS hexamer,leading to its low enzyme activity.In addition,we demonstrated that PRPS2 P173R increased thiopurine resistance in xenograft models.Our work describes a novel mechanism by which PRPS2 mutants drive childhood ALL relapse and highlights PRPS2 mutations as biomarkers for relapsed childhood ALL.

急性早幼粒细胞白血病患儿组织砷残留和生活质量的横断面研究

目的调查接受砷剂(ATO和RIF)治疗的急性早幼粒细胞白血病(APL)患儿组织中砷浓度和健康相关生活质量。方法于2022年7月11日—2022年9月7日开展一项横断面研究,期间36名APL患儿和17名健康儿童(对照组)纳入该研究。收集研究对象血浆、尿液、头发和指甲样本,测定各组织砷浓度。采用中文版PedsQL4.0普适性核心量表测定APL患儿健康相关生活质量。结果仅在停用砷剂(ATO和RIF)治疗不足3个月时,APL患儿各组织砷浓度高于健康儿童,有统计学差异。26例APL患儿完成了中文版PedsQL4.0普适性核心量表,在生理功能、情感功能、社会功能、学校表现四个类目及总分维度,不同砷浓度组别间无统计学差异,各类目总体得分基本接近正常人群。结论在使用砷剂(ATO和RIF)后,3个月内APL患者组织中的砷浓度会高于正常水平,之后会恢复正常。在不同砷残留水平的APL患儿之间未观察到健康相关生活质量的差异,提示APL患儿组织中的砷残留不是健康相关生活质量的直接影响因素。