大剂量甲氨蝶呤治疗急性淋巴细胞白血病血药浓度及不良反应观察

 目的　探讨大剂量甲氨蝶呤（HD-MTX）治疗急性淋巴细胞白血病（ALL）的血药浓度与患者不良反应的关系。方法　分析12例完全缓解期的ALL患者HD-MTX化疗后不良反应。结果　HD-MTX化疗后患者以骨髓抑制（7／12）、胃肠道反应（8／12）、肝损害（5／12）为常见的不良反应。化疗后24 h MTX血药浓度为（23.688±9.607）μmol／L,经甲酰四氢叶酸钙（CF）解救后,44、68 h血药浓度降低为（0.338±0.247）μmol／L,（0.045±0.033）μmol／L。结论　HD-MTX治疗时保证充分水化、碱化,正确使用CF解救是保证HD-MTX方案顺利进行的关键因素。     

大剂量甲氨蝶呤治疗成人急性淋巴细胞白血病的药物代谢研究

目的：研究大剂量甲氨蝶呤（HD-MTX）治疗成人急性淋巴细胞白血病时的药物代谢作用及不同解救方案的价值。方法回顾性分析2003至2010年收治的124例成人患者（共190例次 HD-MTX 治疗）的临床和实验室资料。结果190例次患者的甲氨蝶呤血药浓度降至0.1μmol/L 以下的中位时间是72 h（48～342 h）,76例次（40%）发生延迟排泄;延迟排泄组患者的不良反应显著增高（P＜0.05）,其体质指数和甲氨蝶呤治疗第7日的血清肌酐水平均显著高于正常排泄组（分别为 P=0.046和 P＜0.001）。甲酰四氢叶酸钙联合左旋门冬酰胺酶解救不优于单用亚叶酸钙（P=0.849）。缩短甲氨蝶呤输注时间并提前亚叶酸钙的解救时机不能改善甲氨蝶呤的延迟排泄,但可减轻血液学不良反应。结论体质指数、血清肌酐水平影响甲氨蝶呤的代谢。适度缩短甲氨蝶呤输注时间和提前亚叶酸钙的解救时机或能改善甲氨蝶呤的排泄和不良反应。     

大剂量甲氨蝶呤治疗儿童急性淋巴细胞白血病的临床观察

目的探讨大剂量甲氨蝶呤(MTX)治疗儿童急性淋巴细胞白血病的临床效果。方法选取2011年1月至2013年12月间收治的急性淋巴细胞白血病患儿96例,采用随机数字表法分为对照组和治疗组,每组48例,对照组患者采用VDLP方案[长春新碱(VCR)、柔红霉素(DXR)、左旋门冬酰胺酶(L-ASP)、泼尼松(Pre)]进行治疗,治疗组患者采用大剂量MTX治疗,观察两组患儿治疗后的疗效、安全性,并对治疗组患儿血浆MTX的血药浓度进行监测。结果治疗组完全缓解率和总有效率分别为66.7%(32/48)和89.6%(43/48),显著高于对照组的37.5%(18/48)和70.8%(34/48),差异有统计学意义(P<0.05);治疗组患者不良反应发生率为20.8%,对照组患者不良反应发生率为35.4%,差异有统计学意义(P<0.05);治疗组患儿48 h血浆MTX浓度<0.25μmol/L者39例,占81.3%;患儿48 h血浆MTX浓度≥1μmol/L者3例,占6.3%。结论大剂量MTX治疗儿童急性淋巴细胞白血病临床效果显著,在血浆MTX浓度监测下,实施个体化甲酰四氢叶酸钙解救,毒副反应轻微,值得临床推广。     

大剂量甲氨蝶呤治疗儿童急性淋巴细胞白血病的安全性观察

目的 观察大剂最甲氨蝶呤(HD-MTX)治疗儿童急性淋巴细胞白血病(ALL)的毒副反应.方法 全组35例缓解期ALL患儿累计给予HD-MTX治疗210例次,治疗结束后观察并记录毒副反应的发生情况及处理措施.结果 HD-MTX常见的毒副反应为骨髓抑制、胃肠道反应、口腔黏膜溃疡、肝功能损害及肾功能损害等,多为轻度.全组毒副...     

急性淋巴细胞白血病患儿血浆中甲氨蝶呤血药浓度的监测

目的 建立甲氨蝶呤血药浓度测定方法.方法 采用高效液相色谱法.色谱柱:C18反相柱(200 nm×4.6 nm,5 μm),流动相:甲醇:磷酸缓冲液(pH 7.2)为17:83,流速:1.0 mL/min,柱温35℃,检测器波长306 nm.结果 线性范围0.25～100.0 μg/mL,线性关系良好,回收率101.74%,精密度RSD＜5%.结论 该方法简单快捷,灵敏度高,结果准确,适用于甲氨蝶呤血药浓度监测.     

大剂量甲氨蝶呤治疗成人急性淋巴细胞白血病的临床观察

探讨使用大剂量甲氨蝶呤(HD-MTX)在成人急性淋巴细胞白血病(acute lymphoblastic bukemia．ALL)维持强化治疗过程中的疗效和毒副反应，采用甲氨蝶呤(MTX)1～3g/m^2．24h持续静脉滴入，用来成人ALL的强化治疗，并用四氢叶酸钙(CF)解救。结果呈缓解状态86．0％(49／57)．骨髓复发7．0％(4/57)．中枢神经系统白血病(CNS-L)1．8％(1／57)，死亡5．2％(3／57)。初步研究结果提示，HD-MTX治疗成人ALL疗效肯定．相对骨髓抑制较轻．黏膜皮肤损害较突出。毒副反应可以耐受。     

大剂量甲氨蝶呤治疗成人急性淋巴细胞白血病的临床观察

探讨使用大剂量甲氨蝶呤(HD -MTX)在成人急性淋巴细胞白血病(acute lymphoblastic leukemia,ALL)维持强化治疗过程中的疗效和毒副反应,采用甲氨蝶呤(MTX)1~3 g/m2,24 h持续静脉滴入,用来成人ALL的强化治疗,并用四氢叶酸钙(CF)解救。结果呈缓解状态86 .0%(49/57),骨髓复发7 0%(4/57),中枢神经系统白血病(CNS L)1 .8%(1/57),死亡5. 2%(3/57)。初步研究结果提示,HD- MTX治疗成人ALL疗效肯定,相对骨髓抑制较轻,黏膜皮肤损害较突出,毒副反应可以耐受。     

急性淋巴细胞白血病小鼠甲氨蝶呤化疗后血及脑组织药物浓度的对比研究

 目的　探索急性淋巴细胞白血病小鼠不同剂量甲氨蝶呤（MTX）化疗后血和脑组织药物浓度的关系。方法　4周龄清洁级普通昆明小鼠80只：建立急性淋巴细胞白血病小鼠模型,随机抽取20只小鼠经股骨取骨髓行骨髓细胞学检查作模型验证;依据MTX化疗剂量与标本采取时间点的不同将余60只急性淋巴细胞白血病小鼠分为六组,每组10只,分别为A、B、C、D、E、F组;各组均取0.5 ml血液及0.4 g脑组织,血液离心,脑组织匀浆后离心,取上清用荧光偏振免疫方法检测药物浓度。结果　A、B、C、D、E、F六组平均MTX血药浓度分别为（39.08±5.18）μmol／L、（15.86±1.02）μmol／L、（8.67±5.43）μmol／L、（68.29±5.19）μmol／L、（29.55±6.22）μmol／L、（13.98±1.12）μmol／L,组间比较差异有统计学意义（P＜0.05）;各组脑组织平均MTX浓度依次为：（1.05±0.26）μmol／L、（0.61±0.25）μmol／L、（0.48±0.25）μmol／L、（2.07±0.35）μmol／L、（1.27±0.21）μmol／L、（0.59±0.69）μmol／L,组间比较差异有统计学意义（P＜0.05）;六组血与脑组织药物浓度相关系数依次为：0.82、0.75、0.19、0.81、0.55、0.43。结论　急性淋巴细胞白血病小鼠经大剂量MTX（HD-MTX）方案化疗后,于0.5 h出现血及脑组织药物浓度峰值,5 g／m2较3 g／m2能更好地透过血脑屏障使脑组织药物浓度达到有效治疗浓度。     

中剂量甲氨蝶呤联合VDP方案对急性淋巴细胞白血病缓解后治疗的疗效观察

随着化疗的进展 ,急性白血病 (ＡＬ)缓解率大大地提高。如何防治ＡＬ髓内、外的复发 ,延长生存期 ,已成为ＡＬ治疗的重要组成部分。为此 ,我们从 1995年 8月——— 1999年 3月 ,对 13例缓解后的急性淋巴细胞白血病 (ＡＬＬ)患者 ,采用了中剂量甲氨蝶呤 (ＭＤ ＭＴＸ)联合ＶＤＰ方案 ,即长春新碱(ＶＣＲ)加柔红霉素 (ＤＮＲ)加泼尼松 (Ｐｒｅｄ)强化治疗 ,疗效较好。材料和方法一　研究对象　治疗组 (ＭＤ ＭＴＸ ＶＤＰ) 13例中 ,男 9例 ,女 4例 ,年龄 13— 5 7岁 ,中位年龄 2 4岁。ＦＡＢ分型 :Ｌ1 3例、Ｌ2 8例、Ｌ32例。初发 12例 ,复发 …     

儿童急性淋巴细胞白血病的药学监护

目的 探讨儿童急性淋巴细胞白血病(ALL)行维持化疗时,大剂量甲氨蝶呤(HD-MTX)方案实施过程中进行的基于血药浓度监测的药学监护。方法 回顾性分析2021年1月至12月郑州大学第二附属医院实施药学监护的2例ALL患儿的病例资料,包括基本资料、MTX用药情况、合并用药、相关检查指标、MTX血药浓度监测结果和不良反应,讨论可能引起排泄延迟的相关因素。结果 2例患儿均出现MTX排泄延迟和不同程度的不良反应,对症处理后,均顺利完成此次化疗。结论 对使用HD-MTX治疗的ALL患儿可以实施基于血药浓度监测的药学监护,且效果良好。     

正元胶囊辅助甲氨蝶呤治疗儿童急性淋巴细胞白血病的有效性和安全性分析

目的探讨正元胶囊辅助甲氨蝶呤治疗儿童急性淋巴细胞白血病的有效性和安全性以及对血清中B淋巴细胞刺激因子(BAFF)和增殖诱导配体(APRIL)水平的影响。方法 78例儿童急性淋巴细胞白血病随机分为对照组和观察组,各39例。对照组采取甲氨蝶呤治疗,观察组在对照组基础上于缓解期口服正元胶囊,1~3粒/次,3次/天,共治疗8周。比较2组近期疗效、治疗过程中不良反应。检测2组患儿血清中BAFF和APRIL水平。结果观察组近期总缓解率为89.74%,显著高于对照组的61.54%(P<0.01)。观察组患儿的口腔黏膜损害、肝功能损害、感染、骨髓抑制、胃肠道反应及皮肤损害发生少于对照组,但组间差异无统计学意义(P>0.05)。治疗后,观察组患儿血清中BAFF和APRIL水平显著低于对照组,差异有统计学意义(P<0.01)。结论金正元胶囊辅助甲氨蝶呤治疗儿童急性淋巴细胞白血病的疗效确切,安全性好,降低患儿血清中BAFF和APRIL水平可能与其疗效有关。     

Karyotypic Evolution: Cytogenetics Follow-Up Study In Childhood Acute Lymphoblastic Leukemia

Forty seven children affected with acute lymphoblastic leukemia (ALL) were cytogenetically investigated ‍at diagnosis and all through different stages of the disease (remission and relapse). A clonal karyotypic abnormality ‍was found in 32% at diagnosis (mainly comprised of cALLa+). A hyperdiploid mode with chromosome counts ‍ranging from 47-58, was found to be most prominent among cALLa+ patients. The most common numerical ‍aberrations were gain of chromosomes 2, 5, and 21. The structural aberrations at diagnosis were found to be ‍del(9)(p22), inv(9)(p11q13) and del(19)(p12). None of the children showed ph+ chromosome. A good prognosis ‍was found in cALLa+ children with an abnormal karyotype at diagnosis and of these children, those who ‍showed karyotypic instability , had a significantly longer first remission time. The karyotypic evolution ‍through remission(s) and relapse(s) revealed the occurrence of structural alterations , including changes in ‍chromosomes 3, 6, 9, 21 and 22. However, irrespective of the karyotypic clonal nature at diagnosis, ‍chromosome 9 was the most commonly involved chromosome through the course of disease. ‍     

Glutathione S-Transferase P1 Genotypes,Genetic Susceptibility and Outcome of Therapy in Thai Childhood Acute Lymphoblastic Leukemia

Glutathione S-transferases (GSTs) are enzymes that involved in bio- transformation by conjugation ofelectrophillic compounds to glutathione. Polymorphisms within genes that encode GSTs may affect the functionof the enzymes. Polymorphisms of GSTP1 at codon 105 residue forms GSTP1 active site for binding of hydrophobicelectrophiles, and the Ile-Val substitution affect substrate specific catalytic activity of this enzyme andmay associate with susceptibility to malignant human disease, especially acute lymphoblastic leukemia (ALL),which is the most common leukemia in children younger than 15 years old.Genetic polymorphisms within theGSTP1 gene of childhood ALL patients were studied. In addition, the association of genetic polymorphism ofGSTP1 and genetic susceptibility of acute lymphoblastic leukemia (ALL) was also determined using Chi-squareand Odds ratio. PCR-RFLP was used to study genetic polymorphism of GSTP1 in 100 ALL patients and 100healthy individuals.The results show that there is no statistically significant association between each genotypesand genetic susceptibility of acute lymphoblastic leukemia (ALL) (OR=0.92, P –value=0.886). Moreover, thereis no statistically significant association between each genotypes and demographic data of acute lymphoblasticleukemia (ALL). However, there are 2 cases of ALL with BM relapse show the polymorphic genotypes of GSTP1.It may suggest that GSTP1*V105 may be involved in relapse of ALL.     

p73基因失活在儿童急性淋巴细胞白血病发病和预后中的意义

目的 探讨p73基因mRNA失表达与儿童急性淋巴细胞白血病(ALL)的发病和预后的关系。方法 采用反转录聚合酶链反应(RT-PCR)方法检测了34例ALL患儿骨髓单个核细胞内p73 mRNA的表达情况，并分析了p73 mRNA失表达与化疗的反应及复发的关系。结果 儿童ALL患者中p73 mRNA失表达率达26．5％(9/34)，且与诱导缓解治疗的反应和复发显著相关(P＜0．05)。结论 p73m RNA失表达在小儿ALL的发病过程中起重要作用，p73 mRNA检测对评估儿童ALL预后，指导临床治疗有一定临床意义。     

Acute Complications and Survival Analysis of Childhood Acute Lymphoblastic Leukemia: A 15-year Experience

BackgroundWe evaluated the acute complications that occurred during the treatment of childhood acute lymphoblastic leukemia (ALL) and documented the survival rates of children with ALL.Materials and MethodsWe retrospectively evaluated 110 children with a diagnosis of ALL treated with the Children’s Oncology Group protocol from 1999 to 2014. The demographic, clinical, and laboratory data of 110 patients and acute complications of eligible and evaluable 105 patients were recorded.ResultsOf the 110 patients, 65 were male and 45 were female. The mean age at admission was 8.3 ± 5.2 years. Ninety-seven patients (88.2%) had been diagnosed with pre–B-cell ALL, 11 (10%) with T-cell ALL, 1 (0.9%) with mixed phenotype acute leukemia, and 1 (0.9%) with mature B-cell acute leukemia. Of the 110 patients, 40 (36.3%) were in the standard-risk group and 70 (63.7%) were in high-risk group. Of the 110 patients, 105 had been followed up regularly and evaluated for acute complications. Infection was the most common complication (n = 93; 88.5%), followed by gastrointestinal (n = 29; 27.6%), neurologic (n = 28; 26.6%), metabolic/endocrine (n = 16; 15.2%), drug-related hypersensitivity (n = 16; 15.2%), avascular necrosis (n = 13; 12.3%), thrombotic (n = 11; 10.4%), severe psychiatric (n = 2; 1.9%), and various other (n = 12; 11.4%) complications. Of the 110 patients, 98 were assessed in terms of survival analysis. The 5- and 10-year overall survival rates were both 85.9% (standard error [SE], 3.6%). The relapse-free survival rates at 1, 3, and 5 years were 97.9% (SE, 1.5%), 91.3% (SE, 3%), and 86.3% (SE, 3.7%), respectively.ConclusionChildhood ALL, although categorized as curable malignancy owing to the improvements in treatment strategies in recent years, can cause acute complications affecting various systems. Thus, patients should be treated and followed up by multidisciplinary medical teams with high expertise.     

急性淋巴细胞白血病TPMT基因多态性的研究

目的 分析急性淋巴细胞白血病TPMT基因多态性与6-MP不良反应的相关性.方法 收取急性淋巴细胞白血病患儿48例作为研究对象,对其TPMT基因型及6-MP不良反应进行分析.结果 48例患儿中31.25％按照常规6-MP使用剂量完成维持治疗,68.75％患儿出现不耐受后调整为低剂量完成维持治疗.常规剂量组重度不良反应发生率高于低剂量组,但差异无统计学意义(P＞0.05).6-MP所致骨髓抑制及肝功能损害发生率分别为93.75％及83.33％.仅有1例患儿发生杂合型TPMT×3C点突变,突变发生率为2.08％,该患儿同时发生4级骨髓抑制及4级肝功能损害.结论 TPMT×3C基因突变可能与6-MP所致重度不良反应有关,但6-MP所致重度不良反应可能是多种因素共同作用的结果.     

NET1 Enhances Proliferation and Chemoresistance in Acute Lymphoblastic Leukemia Cells

Acute lymphoblastic leukemia (ALL) is the most prevalent of pediatric cancers. Neuroepithelial cell-transforming 1 (NET1) has been associated with malignancy in a number of cancers, but the role of NET1 in ALL development is unclear. In the present study, we investigated the effect of NET1 gene in ALL cell proliferation and chemoresistance. We analyzed GEO microarray data comparing bone marrow expression profiles of pediatric B-cell ALL samples and those of age-matched controls. MTT and colony formation assays were performed to analyze cell proliferation. ELISA assays, Western blot analyses, and TUNEL staining were used to detect chemoresistance. We confirmed that NET1 was targeted by miR-206 using Western blot and luciferase reporter assays. We identified NET1 gene as one of the most significantly elevated genes in pediatric B-ALL. MTT and colony formation assays demonstrated that NET1 overexpression increases B-ALL cell proliferation in Nalm-6 cells. ELISA assays, Western blot analyses, and TUNEL staining showed that NET1 contributes to ALL cell doxorubicin resistance, whereas NET1 inhibition reduces resistance. Using the TargetScan database, we found that several microRNAs (miRNAs) were predicted to target NET1, including microRNA-206 (miR- 206), which has been shown to regulate cancer development. To determine whether miR-206 targets NET1 in vitro, we transfected Nalm-6 cells with miR-206 or its inhibitor miR-206-in. Western blot assays showed that miR-206 inhibits NET1 expression and miR-206-in increases NET1 expression. Luciferase assays using wild-type or mutant 3 -untranslated region (3 -UTR) of NET1 confirmed these findings. We ultimately found that miR-206 inhibits B-ALL cell proliferation and chemoresistance induced by NET1. Taken together, our results provide the first evidence that NET1 enhances proliferation and chemoresistance in B-ALL cells and that miR-206 regulates these effects by targeting NET1. This study therefore not only contributes to a greater understanding of the molecular mechanisms underlying B-ALL progression but also opens the possibility for developing curative interventions.     

Frequency and Correlation of Common Genes Copy Number Alterations in Childhood Acute Lymphoblastic Leukemia with Prognosis

Objective: It was shown by genomic profiling that despite no detectable chromosomal abnormalities a proportion of children with pre-B acute lymphoblastic leukemia harbors copy number alterations (CNA) of genes playing role in B-cell development and function. The aim of the study was to determine the frequency of CNA in pediatric acute lymphoblastic leukemia and correlate these findings with clinical outcome. Methods: DNA extracted from peripheral blood or bone marrow at diagnosis/relapse of fifty newly diagnosed children with precursor B-cell acute lymphoblastic leukemia was analyzed for CNA with multiplex ligation-dependent probe amplification. Results: The analysis revealed 76 CNA in 24 patients most frequently found in PAR1 (17%), CDKN2A/B (15.7%) and PAX5 (14.4%) genes. There were significant CNA co-occurrences between PAX5, CDKN2A/B, BTG1, ETV6, PAR1 or XP22 genes, (p <0.020) and the high-risk group. There was a significant correlation between EBF1, RB1, and IKZF1 alterations and bone marrow relapse. Patients with CNA in screened genes are more likely to succumb to their disease except for those with PAR1 or XP22 genes (p <0.050). Conclusion: The multiplex ligation-dependent probe amplification could be considered as an independent diagnostic tool allowing prompt identification of patients at high risk of treatment failure and, subsequently, a more adequate treatment approach.     

MTRR基因A66G多态性与儿童急性淋巴细胞白血病关系的Meta分析

目的 评估甲硫氨酸合成酶还原酶（MTRR）基因A66G多态性与儿童急性淋巴细胞白血病（ALL）发生风险的关系。方法 全面检索PubMed、Elsevier、Embase、中文期刊全文数据库（CNKI）和万方数据库,收集探索MTRR基因A66G多态性与儿童ALL发生关系的病例对照研究,纳入符合入选标准的文献并评估其质量。优势比（ORs）及95%可信区间（CIs）评估关联强度。应用RevMan 5.2软件对纳入研究进行异质性检验和效应值合并,漏斗图评估发表性偏倚,敏感性分析采用逐一排除的方法以评估结果的稳定性。结果 共纳入7篇文献,包括儿童ALL患者2 326例,对照3 090例。异质性检验结果表明纳入研究间无显著异质性,采用固定效应模型合并数据。Meta分析结果示,在整体人群纯合子模型和显性模型发现MTRR A66G多态性与儿童ALL风险有关联（GG vs. AA: OR=0.81, 95%CI: 0.69~0.95, P=0.009; AG+GG vs. AA: OR=0.87, 95%CI: 0.77~0.98, P=0.03）;根据种族 进行亚组分析时在白种人群中发现显著性关联（AG vs. AA: OR=0.84, 95%CI: 0.72~0.99, P=0.04; GG vs. AA: OR=0.79, 95%CI: 0.66~0.95, P=0.01; AG+GG vs. AA: OR=0.82, 95%CI: 0.71~0.96, P=0.01）。漏斗图未检测出显著性发表性偏倚,敏感性分析表明结果稳定可靠。结论 目前Meta分析表明MTRR基因A66G多态性与儿童ALL发生风险存在关联,尤其在白种人群。