两种不同剂型门冬酰胺酶治疗急性淋巴细胞白血病的不良反应比较及其对策

目的比较门冬酰胺酶(L-ASP)和培门冬酶(PEG-ASP)治疗儿童ALL过程中的不良反应,以便及时有效地监测与防范,提高化疗安全。方法回顾性观察诱导缓解和早期巩固治疗期,随机接受ASP或PEG-ASP治疗的135例ALL患儿的临床表现及实验室检查,采用χ2检验及t检验进行分析。结果 ASP、PEG-ASP对ALL患儿的骨髓增殖均有抑制作用,白细胞、中性粒细胞、Hb、血小板及骨髓抑制恢复时间诱导缓解治疗期:ASP组分别为(18.00±5.91)d、(19.70±6.00)d、(21.74±6.97)d、(18.51±8.66)d、(24.04±6.02)d;PEG-ASP组分别为(26.80±6.23)d、(26.40±6.06)d、(30.40±7.31)d、(17.50±8.30)d、(30.30±5.52)d。早期巩固治疗期:ASP组分别为(15.55±3.32)d、(16.68±6.00)d、(2.84±6.58)d、(6.73±8.89)d、(16.61±5.02)d;PEG-ASP组分别为(23.13±13.65)d、(23.78±10.95)d、(11.82±12.61)d、(2.82±7.30)d、(28.12±6.47)d。纤维蛋白原、活化部分凝血活酶时间、抗凝血酶Ⅲ恢复时间,诱导缓解治疗期:ASP组分别为(14.57±7.13)d、(12.15±7.91)d、(12.38±8.15)d。PEG-ASP组分别为(29.70±5.36)d、(24.60±11.37)d、(29.30±8.41)d。早期巩固治疗期:ASP组分别为(11.24±2.90)d、(11.64±2.01)d、(7.13±3.71)d;PEG-ASP组分别为(29.46±7.25)d、(19.05±9.26)d、(30.26±8.56)d。变态反应、总蛋白降低、清蛋白降低发生率,诱导缓解治疗期:ASP组分别为3.77%、56.60%、22.64%;PEG-ASP组分别为0.00%、100.00%、60.00%;早期巩固治疗期:ASP组分别为21.21%、57.58%、30.30%;PEG-ASP组分别为2.56%、84.61%、64.10%。结论 ASP、PEG-ASP均对ALL患儿的骨髓增殖具有抑制作用,其抑制的程度临床相似;PEG-ASP治疗时,骨髓抑制、血常规、血凝恢复正常时间长,蛋白质抑制作用强,变态反应发生率低,余不良反应发生率与ASP相似。     

门冬酰胺酶治疗儿童淋巴系统恶性肿瘤的严重并发症

目的观察门冬酰胺酶(L-ASP)在儿童急性淋巴细胞白血病(ALL)及Ⅲ、Ⅳ期非霍奇金淋巴瘤(NHL)应用中严重并发症，探讨L-ASP化疗顺利完成的有效对策。方法针对L—ASP的各种主要并发症制定相应的检测手段及监测指标，在应用L—ASP期间对患儿进行监测，对出现并发症采取相应的检测。统计各并发症的发生率、发生时间。结果用L—ASP化疗的ALL和NHL患儿总计301例次，其中L-ASP相关严重并发症20例次(6．6％)，高血糖7例次(2．32％)；低血糖1例次(0.33％)；胰腺炎6例次(1．99％)；脑栓塞2例次(0.66％)；弥散性血管内凝血(DIC)6例次(1．99％)；脏器出血4例次(1．32％)；休克7例次(2.3％)；死亡10例(3．3％)。结论L-ASP的细胞毒作用可造成人体各系统的损害，严重者甚至危及生命。严密、合理的监测手段及早期干预可明显降低L-ASP并发症。     

儿童急性淋巴细胞白血病应用门冬酰胺酶治疗的临床研究

目的回顾性总结和分析应用左旋门冬酰胺酶(L-Asp)治疗儿童急性淋巴细胞白血病(ALL)的经验、不良反应及其应对措施,以期对未来用药提供借鉴。方法 102例ALL患儿入组。分析超敏反应对疗效的影响,总结凝血功能异常及暂时性高血糖(TH)的应对措施,对L-Asp相关胰腺炎(AAP)病例作简要总结。结果(1)34例(33.3%)出现超敏反应,多数程度较轻且发生于诱导期以后的治疗过程中。(2)PT延长16例(20.3%),APTT延长17例(21.5%),FIB不同程度降低,50例(63.3%)低于1g/L,4例(5.I%)低于0.5g/L。(3)70例(68.6%)出现不同程度的血糖升高,11例(10.8%)诊断TH,其中4例(36.4%)有高血糖家族史。(4)4例(3.9%)发生AAP,1例再次应用L-Asp后未出现AAP。结论(1)超敏反应组和无超敏反应组的预计5年OS和EFS差异无显著性。(2)L-Asp治疗过程中出现的凝血功能改变原则上在无严重合并症时可不行预防性凝血因子的替代治疗。(3)高年龄组(≥6岁)及有糖尿病家族史者发生TH的可能性更大。(4)AAP发生后48 h内症状缓解、淀粉酶和脂肪酶低于正常值上限3倍以及影像学未提示假性囊肿或坏死者可尝试再次应用L-Asp化疗。     

左旋门冬酰胺酶治疗小儿白血病时的毒性反应：附4例报告

左旋门冬酰胺酶(L-ASP)治疗急性淋巴细胞白血病(ALL)有明显疗效,且能提高长期存活率,但我院在使用L-ASP过程中有4例出现轻重不一的毒性反应,现报道如下。     

两种门冬酰胺酶对Jurkat和RS4;11细胞的细胞毒性差异研究

目的比较谷氨酰胺酶活性不同的两种门冬酰胺酶(L-ASP)对急性淋巴细胞白血病细胞株Jurkat(L-ASP耐药)和RS4;11 (L-ASP敏感)的细胞毒性,探讨门冬酰胺酶的谷氨酰胺酶活性对抗肿瘤效应的影响。方法 (1)通过基因工程方法获得野生型门冬酰胺酶(WT)和低谷氨酰胺酶活性的突变型门冬酰胺酶(MT)。(2)用CCK-8试剂盒检测WT和MT对Jukat细胞和RS4;11细胞的增殖毒性。(3)绘制WT和MT作用下Jurkat细胞的生长曲线。(4)用流式细胞术检测WT和MT诱导Jurkat细胞凋亡情况。结果 (1)与WT相比,MT的谷氨酰胺酶活性和门冬酰胺酶活性比值明显降低(0.9%±0.1%vs.12.2%±2.8%,P <0.05)。(2) 1.0 IU/mL的WT和MT处理Jurkat细胞48h抑制率分别为(96. 07±1.19)%和(45.60±4.38)%,差异具有显著性(P <0.05);WT和MT对RS4;11细胞的半数抑制浓度(IC50)分别为(0.127±0.012) IU/L和(0.116±0.014)IU/L,差异无显著性(P=0.331)。(3)生长曲线显示0.1 IU/mL的WT显著抑制Jurkat细胞增殖,0.1 IU/mL的MT不能抑制Jurkat细胞增殖。(4) 1.0 IU/mL的WT和MT处理Jurkat细胞24h细胞凋亡率分别为(37.27±6.89)%和(13.02±3.87)%,差异具有显著性(P <0.05)。结论L-ASP的谷氨酰胺酶活性可以增强L-ASP对Jurkat细胞的抗肿瘤效应,但不能增强L-ASP对RS4;11细胞的抗肿瘤效应。     

急性淋巴细胞白血病患儿大剂量静脉滴注门冬酰胺酶治疗后脑脊液门冬酰胺浓度

目的　测定急性淋巴细胞白血病 (ALL)患儿大剂量静注门冬酰胺酶 (ASP)治疗前、后脑脊液 (CSF)中门冬酰胺 (ASN)浓度 ,从临床及药代动力学方面 ,探讨ASP在中枢神经系统 (CNS)白血病治疗中的药理作用及最佳给药方式。方法　 10例ALL患儿分别 4次接受德国小儿白血病协作组多中心协作治疗方案 (COALL 97)中的主要药物ASP(每隔 4～ 6周 1次静脉注射 4 0 0 0 0U/m2 )的联合化疗。在静脉注射L ASP前及给药后第1、3、4、5周采集CSF ,用安捷伦高效流相色谱仪检测CSF中ASN浓度 ,并观察临床疗效。结果　CSF中ASN浓度分别为 :给药前 1.894± 0 .5 8μmol/L ;给药后第 1周 0 .0 5 6± 0 .0 13μmol/L ;第 3周 0 .117± 0 .0 0 0 0 8μmol/L ;第 4周 0 .2 12± 0 .0 13μmol/L ;第 5周 0 .897± 0 .0 89μmol/L。ALL患儿应用L ASP后CSF中ASN浓度明显降低 (P <0 .0 5 ) ,同时测定CSF中谷氨酰胺浓度在给药前后均无显著变化。结论　 1次注射 4 0 0 0 0U/m2 ASP后能使CSF中ASN浓度降低并持续至第 5周后回升。这种用药方法有预防或治疗CNS白血病的作用     

左旋门冬酰胺酶治疗白血病患儿对凝血功能的影响

目的探讨左旋门冬酰胺酶(L-ASP)对凝血功能影响;比较国产与进口不同产品对凝血功能影响,静脉滴注与肌肉注射不同应用方式对凝血功能的影响。方法应用L-ASP化疗的急性淋巴细胞白血病(ALL)76例患儿,检测其治疗前后血纤维蛋白原(FIB)、活化部分凝血活酶时间(APTT)、凝血酶原时间(PT)变化。结果47.4%出现APTT延长;其中国产44.4%,进口50.0%,无显著性差异(P>0.05);静脉滴注54.2%,肌肉注射35.7%,无统计学差异(P>0.1)。42.1%出现FIB降低;其中国产44.4%,进口40.0%,无显著性差异(P>0.5);静脉滴注47.9%,肌肉注射32.1%,无显著性差异(P>0.1)。颅内出血1例(1.3%)。结论1.L-ASP可影响凝血功能;2.国产和进口、静脉滴注和肌肉注射L-ASP对凝血功能的影响均无显著性差异。     

COALL-97方案治疗急性淋巴细胞白血病临床及实验室研究

目的　引用德国儿童急性淋巴细胞白血病协作组 (cooperativeALLstudygroup ,COALL)的COALL 97方案治疗急性淋巴细胞白血病 (ALL) ,从临床疗效防治及目前国内外选用有效治疗ALL的药物 ,左旋门冬酰胺酶 (L Asp)的药代动力学方面 ,探讨在我国治疗儿童ALL的最佳方案及L Asp的最佳给药方式。方法　ALL患儿 1 2例自愿接受COALL 97方案在我院完成早期强化治疗后 ,回当地继续口服巯基嘌呤 (6 MP) /硫鸟嘌呤 (6 TG)加甲氨蝶呤 (MTX)持续治疗 ,每隔 3个月、半年来院复查 ,总疗程 1 .5～ 2 .0年。结果　诱导治疗后d1 4做骨髓检查 8例呈缓解骨髓像 ,治疗 2 8d后 1 2例均完全缓解 (CR) ,CR率1 0 0 % ,HR ALL患儿 1例CR后 1 0个月时骨髓复发并重症感染死亡。应用高压液相色谱技术 (HR HPLC)检测 1次注射 40 0 0 0U/m2 L Asp后能使血清和脑脊液 (CSF)中门冬酰胺 (ASN)浓度降低 ,并持续至第 5周后回升。 结论　COALL 97方案可被我国ALL患儿所接受 ;在治疗ALL的临床实践中 ,该方案确有可借鉴之处 ;1次 / 2～ 6周静脉注射 40 0 0 0U/m2 L Asp联合化疗的用药方式不仅作用强、持续时间长 ,耐药性小、不良反应少 ,且避免患儿每天或隔天静脉注射痛苦及患儿家长的经济和精神负担。     

左旋门冬酰胺酶诱发儿童急性胰腺炎19例分析

目的：分析左旋门冬酰胺酶（L-ASP）诱发急性胰腺炎的临床特点，以利早期诊断和治疗。方法：对1996-2001年应用L-ASP进行化疗方案治疗的675例次中发生急性胰腺炎的19例的临床特点、血液学和影象学及治疗预后作了总结分析。结果:L-ASP诱发急性胰腺炎的发生率为2.8%。临床表现中有腹痛17例，伴恶心17例、呕吐16例；发烧13例、腹胀13例、休克11例。首发症状中主要为腹痛，其次为休克。血液检查19例中血淀粉酶升高16例、高血糖11例、低血钠11/18例、低血钙9/18例、低蛋白血症8/16例、酸中毒7/18例及肾功能不良3例，凝血功能异常10/16例。合并症中有肝损害或脂肪肝、腹膜炎、感染。B超或CT检查;16/18例（89％）有异常。抢救休克和抑制胰酶分泌是最重要的非手术治疗措施；出血坏死性胰腺炎及早手术。19例胰腺炎中12例治愈，其中10例水肿型均痊愈；9例出血坏死型中7例死于休克。结论：结合L-ASP的用药史，监测病人腹痛或休克表现，检测血淀粉酶及腹部B超可以使早期诊断成为可能。抢救休克、抑制胰酶分泌及手术是最主要的治疗措施。     

左旋门冬酰胺酶致儿童继发性糖尿病临床观察

在小儿急性淋巴细胞白血病及淋巴瘤的治疗中，左旋门冬酰胺酶(L-ASP)是国内、外用于儿童急性淋巴细胞白血病和Ⅲ和Ⅳ期T细胞性非霍奇金淋巴瘤(NHL)联合化疗方案中首选的有效的治疗药物。但在应用过程中左旋门冬酰胺酶诱发的继发性糖尿病，尤其是糖尿病酮症酸中毒，若不及时处理，可导致死亡。我们分析了应用该药后导致继发性糖尿病6例以期早期诊断。     

Erfahrungen mit der L-Asparaginase im Kindesalter

Zusammenfassung Bei der Behandlung der ersten 10 Kinder mit unreifzelliger Leukose wurden durch L-Asparaginase 3 Voll- und 3 Teilremissionen erzielt. Die Vollremissionen hielten 10 Wochen, 6 Wochen und 7 Tage an. — Das Spektrum der möglichen Nebenwirkungen der Asparaginasetherapie und die Häufigkeit ihres Auftretens bei unseren Patienten werden geschildertAuszugsweise vorgetragen auf der Tagung der Rheinisch-Westfälischen Kinderärzte, Dortmund 3. 5. 1969, und der Tagung der Deutschen Arbeitsgemeinschaft für Leukämie-Forschung und-Behandlung im Kindesalter, Frankfurt 5. 7. 1969.     

左旋门冬酰胺酶治疗小儿白血病的应用研究

目的 　通过研究左旋门冬酰胺酶 (L -asp)的药代动力学特点 ,探讨其治疗小儿急性白血病的合理用药时间。方法 　检测 1 5例应用常规剂量L -asp [1 0 0 0 0U (m2 ·次 ) ]的急性淋巴细胞白血病患儿 ( 340份外周血样本 )治疗前、治疗中及治疗后多个时间点下患儿血浆L -asp活性 ,动态观察用药过程中血浆L -asp活性及停药后L -asp维持有效作用活性的持续时间。结果 　用药过程中 ,血L -asp活性峰值逐渐增高的趋势 ,到第 8次用药开始达到高峰。用药疗程后 ,血L -asp活性持续 7天维持 1 0 0U L以上 ,随后逐渐下降至用药前水平。结论 　研究结果表明 ,目前L -asp治疗小儿急性淋巴细胞白血病的用药方案 [1 0 0 0 0U (m2 ·次 ) ,隔天一次 ,用 8～ 1 0次 ]有其药代动力学依据 ,但仍可作出进一步改善。     

不同来源门冬酰胺酶在儿童急性淋巴细胞白血病应用的对照研究

目的观察菊欧文菌源性门冬酰胺酶(asp)及大肠杆菌源性asp在儿童急性淋巴细胞白血病(ALL)治疗中的药物疗效及不良反应。方法随机选取新诊断的ALL患儿15例,其中9例患儿接受国产菊欧文菌源性asp治疗,6例患儿接受大肠杆菌源性asp治疗,化疗前后对两组患儿血浆内L-asp活性及门冬酰胺(ASN)水平进行检测,同时对两组患儿不良反应进行比较。结果在用药前,两组患儿血浆内L-asp活性与ASN水平差异无显著性;用药期间两组患儿血浆内的asp活性逐渐升高,ASN水平差异无显著性(P>0.05);停药后,L-asp活性及ASN水平在一周后可缓慢恢复至用药前水平。结论国产菊欧文菌源性asp有望成为ALL患儿化疗方案中有效的备选用药。     

Experience with generic pegylated L-asparaginase in children with acute lymphoblastic leukemia and monitoring of serum asparaginase activity

Abstract

Background: Pegylated asparaginase (P-Asp) though integral to acute lymphoblastic leukemia (ALL) therapy is often not accessible to patients in developing countries. We share our clinical experience with generic P-Asp along with monitoring of asparaginase activity. Methods: In this prospective observational study, patients ≤18?years of age with ALL were assigned to receive either generic P-Asp or native asparaginase (N-Asp) in a non-randomized manner. Treatment protocol was based on ALL BFM-95 backbone. The dose of P-Asp was 1500?IU/m² by intravenous route during induction (Ia) and re-induction (IIa) phase of therapy. Results: N-Asp or P-Asp was administered to 52 and 54 of the 106 eligible patients respectively. Demographic and disease characteristics were comparable in both arms. The mean trough levels for N-Asp and P-Asp were 156.87?±?22.35?IU/L and 216.03?±?73.40?IU/L, respectively (p value <0.001) and all patients achieved therapeutic levels during Ia. Incidence of asparaginase-attributable toxicity was similar in the two arms in both phases of treatment, although hospitalization due to noninfectious causes was more common in P-Asp arm during Ia (13% versus 0%, p value, 0.01). Clinical hypersensitivity and silent inactivation were not observed during Ia while these occurred in 13% and 5% of patients in the N-Asp arm and P-Asp arms of IIa, respectively. The 2-year event free survival for P-Asp and N-Asp groups was 84% and 80.7%, respectively (p value 0.85). Conclusion: Generic P-Asp was observed to be efficacious and well tolerated in our patients and adequate therapeutic levels were sustained for 2 weeks.     

Bibliometric data: a disaster for many non-American biomedical journals

Bibliometric data published by the Institute of Scientific Information in Philadelphia (ISI), and which was previously discussed in Acta Paediatrica , has increasingly been used despite all the relevant and severe criticism that has been raised against this method of evaluating individual research results and grading scientific journals. It is obvious that the present trend regarding the use of bibliometric data as a basis for priorities and funding of research and for the promotion of individual scientists favours American-oriented research projects at the expense of those that are based on concepts of predominantly European relevance.

Conclusion: For the future of non-American research, it is important that no single super-power, i.e. the USA, should dominate scientific priorities. The condition for efficient European competition is that European Centres with high levels of competence for creative research and training of scientists from all over the world are established. In addition, it is important that the results of European research are published in prestigious European journals, as was the situation before World War II.     

The importance of different immunosuppressive regimens in the development of posttransplant diabetes mellitus

Solid-organ transplantation is the optimal long-term treatment for most patients with end-stage organ failure. After solid-organ transplantation, short-term graft survival significantly improved (1). However, due to chronic allograft nephropathy and death with functioning graft, long-term survival has not prolonged remarkably (2). Posttransplant immunosuppressive medications consist of one of the calcineurin inhibitors in combination with mycophenolate mofetil (MMF) or azathioprine (Aza) and steroids. All of them have different adverse effects, among which posttransplant diabetes mellitus (PTDM) is an independent risk factor for cardiovascular (CV) events and infections causing the death of many transplant patients and it may directly contribute to graft failure (3). According to the criteria of the American Diabetes Association (4), diabetes mellitus (DM) is defined by symptoms of diabetes (polyuria and polydipsia and weight loss) plus casual plasma glucose concentration ≥ 11.1 mmol/L or fasting plasma glucose (FPG) ≥ 7.0 mmol/L or 2-h plasma glucose level ≥ 11.1 mmol/L following oral glucose tolerance test (OGTT). This metabolic disorder occurring as a complication of organ transplantation has been recognized for many years. PTDM, which is a combination of decreased insulin secretion and increased insulin resistance, develops in 4.9/15.9% of liver transplant patients, in 4.7/11.5% of kidney recipients, and in 15/17.5% of heart and lung transplants [cyclosporine A (CyA)/tacrolimus (Tac)-based regimen, respectively] (5). Risk factors of PTDM can be divided into non-modifiable and modifiable ones (6), among which the most prominent is the immunosuppressive therapy being responsible for 74% of PTDM development (7). Emphasizing the importance of the PTDM, numerous studies have determined the long-term outcome. On the basis of these studies, graft and patient survival is tendentiously (8) or significantly (9, 10) decreased for those developing PTDM.     

alpha -SMOOTH MUSCLE ACTIN DISTRIBUTION IN THE PULMONARY VASCULATURE COMPARING HYPOPLASTIC AND NORMAL FETAL LUNGS

We investigated the intra-acinar pulmonary vascular muscularization in the developing human fetal lung between the 17th and 24th gestational weeks, that is, during the canalicular phase of lung development. Fifteen hypoplastic and 25 normal developed lungs were included in this study using monoclonal alpha -smooth muscle (sm) actin antibodies for smooth muscle detection. Computer-aided image analysis was performed for morphometrical measurements and statistical evaluation. Alphasm-actin-immunoreactive intra-acinar vessels down to a luminal diameter of less than 10 mu m were detected in hypoplastic as well as in normally developed lungs. Crucial differences presented as follows: significantly higher density of intra-acinar vessels, especially due to alpha -sm-actin-negative vessels less than 30 mu m in luminal diameter, in the control group; significantly higher alpha -sm-actin immunoreactivity per section unit as well as per vessel in the hypoplastic lung group. As suggested by others, alpha-sm-actin-positive cells of the intra-acinar vessel wall in the developing human lung were demonstrated to be smooth muscle cells, their immediate precursors, and pericytes. We conclude that the increased alpha -sm-actin immunoreactivity represents muscularization of the vessel wall in functional terms and may be regarded as one structural cause among others for the establishment of persistent fetal circulation in hypoplastic lungs.     

Whole-body mineral measurements in Swedish adolescents at 17 years compared to 15 years of age

Aim: To provide reference data for bone mineral variables in 15- and 17-y-old adolescents and to analyse the relationships between these variables and measures of bone and body size, gender, puberty, growth, various lifestyle and environmental factors and socioeconomic background.

Methods: In the same 321 randomly selected adolescents (147 boys and 174 girls) living in two different regions of Sweden, the total bone mineral content (TBMC), bone area (BA) and total bone mineral density (TBMD) were assessed by dual-energy X-ray absorptiometry at ages 15 and 17 y. The effects of bone and body size, gender, growth, sexual maturity, physical activity, region of domicile, social conditions, food habits, smoking and alcohol intake on TBMC and TBMD were examined in multivariate analyses.

Results: In the 15-y-old adolescents, BA, height, gender, physical activity, maturity and weight explained 91% and 48%, of the variance in TBMC and TBMD, respectively. In similar analyses in the 17-y-olds, the corresponding figures were 92% and 62%, respectively, when BA, height, growth, physical activity, gender and region emerged as significant in the model. In all these analyses, BA explained most of the variance in TBMC and TBMD. No significant reduction of variance was found when different measures of social conditions, smoking, food habits, alcohol or dietary intakes of energy, calcium or vitamin D were included in the models. The reason why region of domicile had a significant impact on TBMC in the 17-y-olds is not known. The fact that the normal fluoride concentration in drinking water (1.1 mg/L) is 10 times higher in the region where TBMC was higher than in the other region is an interesting observation.

Conclusion: Almost 90% of the variance in TBMC and 50% of that in TBMD was explained by measures of bone and body size and only a few percent by gender, physical activity, Tanner stage, growth and region of domicile.