采用噬血细胞综合征-04方案治疗噬血细胞综合征5例

目的观察噬血细胞综合征(HLH)-04方案治疗儿童HLH 5例的早期疗效。方法回顾性分析确诊为HLH患儿5例的临床特点,总结其对以鬼臼乙叉甙(VP16)为基础的免疫化学方案治疗的反应及转归。结果HLH患儿5例中4例在早期治疗阶段完全缓解(CR),CR时间17~22 d(平均18.8 d);另1例规则采用VP16治疗84 d未CR,改用鬼臼甲叉甙(VM26)于d130 CR;病例均存活9~11个月,目前仍CR。1例治疗14 d时出现手足震颤,怀疑为环孢素(CSA)不良反应,改用骁悉替代后手足震颤消失。结论儿童HLH可通过采用HLH-04方案的免疫化学治疗,早期得以有效控制。     

Risk Factors for Early Fatal Outcomes Among Children with Hemophagocytic Lymphohistiocytosis (HLH): A Single-Institution Case-Series in Vietnam

Hemophagocytic lymphohistiocytosis (HLH) is a rare and fatal hematological syndrome that causes a disturbance of the immune system. Overall mortality of HLH is greater than 50% and the majority of patients who die do so within the first 8 weeks of chemotherapy treatment. To find clinical parameters relating to high-risk HLH patients, this study examined associations between an early fatal outcome and potential prognostic clinical factors and laboratory findings on admission. Eighty-nine pediatric HLH patients were prospectively recruited in Children's Hospital No. 1, Ho-Chi-Minh City, Vietnam, during the period from January 2010 to August 2012. Associations between early fatal outcome and clinical and laboratory findings, including a cerebrospinal fluid examination and virological test on admission, were examined. During the 8-week therapy, 25 (28%) HLH patients died. Persistent fever (>2 weeks), severe thrombocytopenia (<75 × 10⁹/L), hyperbilirubinemia, and prolonged activated partial thromboplastin time (APTT) (>33 sec) were significant risk factors of early fatal outcome. Multivariate logistic regression analysis revealed that thrombocytopenia and prolonged APTT (P for trend was 0.054 and 0.013, respectively) were independently associated with the early fatal outcome. Persistent fever, severe thrombocytopenia, hyperbilirubinemia, and prolonged APTT on admission will be useful and practical predictors to determine high-risk HLH patients.     

EB病毒相关噬血细胞性淋巴组织细胞增生症患儿的EB病毒感染特征

目的 了解儿童EB病毒(EBV)相关噬血细胞性淋巴组织细胞增生症(EBV-HLH)患儿的EBV血清学抗体及病毒复制水平等特征.方法 对67例EBV-HLH患儿和60例原发性EBV感染所致的传染性单核细胞增多症(EBV-IM)患儿的临床资料进行分析,EBV特异性抗体和血清EBV DNA载量分别采用间接免疫荧光法和荧光定量PCR测定.结果 EBV-HLH患儿EBV特异性抗体结果:EBV-CA-IgM、EBV-CA-IgG、EBV-EA-IgG和EBV-NA-IgG的阳性率分别为28.8％、100.0％、51.5％和78.8％,EBV-VCA-IgG高亲和力为78.9％,低亲和力为12.1％;血清学抗体结果显示,71.2％的患儿为EBV再激活感染,其余为急性原发EBV感染;45.5％的EBV-HLH患儿可在血清中检测到EBV DNA,其拷贝数中位数为1.976×103 copies·L-1.EBV-IM患儿的EBV-CA-IgM、EBV-CA-IgG、EBV-EA-IgG和EBV-NA-IgG阳性率分别为100.0％、100.0％、58.3％和26.7％,EBV-VCA-IgG高亲和力为18.3％,低亲和力为81.7％,EBV DNA阳性率为10.0％,DNA拷贝数均值为8.495 copies·1-1.IM患儿均为EBV原发感染状态.结论 EBV-HLH可发生在EBV原发感染或既往EBV感染再激活时期,但多数患儿由既往EBV感染再激活所致.EBV-HLH患儿血清中EBV复制水平显著高于EBV-IM患儿.     

Hyperferritinemia in Malignant Histiocytosis, Virus-Associated Hemophagocytic Syndrome and Familial Erythrophagocytic Lymphohistiocytosis

ABSTRACT. Data on 28 patients with malignant histiocytosis (MH), fourteen patients with virus-associated hemophagocytic syndrome (VAHS) and two patients with familial erythrophagocytic lymphohistiocytosis (FEL) were collected from 21 hospitals in Japan to study the serum ferritin levels and clinical features. At diagnosis, the serum ferritin values were a median of 3000 ng/ml (range, 59–270000 ng/ml) in MH and 10500 ng/ml (range, 44–68600 ng/ml) in VAHS/FEL. Clinical signs and symptoms were not substantially different between MH and VAHS/FEL. Thus, serum ferritin markedly increased in the majority of MH/VAHS/FEL patients and should be a useful marker of disease activity in either neoplastic or reactive histiocytic proliferative disorders.     

Hematologic and Bone Marrow Changes in Children with Protein-Energy Malnutrition

Background: All systems in an organism are affected by protein-energy malnutrition (PEM), but one of the worst affected is the hematopoietic system. Today PEM remains a very serious problem in developing countries. We examined the relationships between clinical features, hematological, and bone marrow changes with severe PEM from Turkey. Method: We evaluated 34 (11 females and 23 males) consecutive cases of severe PEM, with no underlying diseases aged 3–20 months. The clinical nutritional conditions of the patients were determined using the Wellcome-Trust PEM classification. Ten of the patients were in the Marasmic-Kwashiorkor (M-K) group, 10 were in the Kwashiorkor (KW) group, and 14 were in the Marasmic (M) group. Full blood count, protein, albumin, serum iron (SI), iron-binding capacity (TIBC), ferritin, vitamin B12, folic acid, complement-3 (C3), complement-4 (C4), and bone marrow were investigated in all groups. Results: Anemia was detected in 97% of patients. We determined serum iron levels were low in 67.6% of the patients, TS levels were low in 76.4% of the patients and ferritin levels were low in 20.5%. The level of vitamin B12 was normal in all patients. Bone marrow analysis showed erythroid series hypoplasia in 28.5% of patients in the M group, 50% in the KW group, and 30% in the M-K group. Marrow iron was absent in 58.8% of patients. Conclusion: The most common hematologic change in the children with PEM was anemia and major cause of anemia was iron deficiency in this study. Patients with severe PEM have normal Vit B12 and serum folate levels. Most of the patients with severe PEM had normal cellularity with megaloblastic and dysplastic changes in bone marrow due to the inadequate and imbalanced intake of protein and energy.     

再生障碍性贫血患儿外周血淋巴细胞表型分析

目的　探讨再生障碍性贫血 (再障 )患儿外周血淋巴细胞表型的变化 ,了解其在发病中的作用及临床意义。方法　将 1 1 5名确诊为再障的患儿取外周血作淋巴细胞表型分析并与正常组比较。结果　再障组CD4 % ,CD8 % ,CD4/CD8分别为 2 9.53± 8.94,34 .2 5± 1 0 .38,0 .96± 0 .53 ,对照组为 35 .2 5± 5 .1 6 ,2 5 .0 8± 4 .34 ,1 .48± 0 .46 ,两者比较有显著差异 (P <0 .0 0 5) ,而重型再障的细胞表型CD4/CD8、γδT细胞百分率、HLA DR %则更高于慢性再障 ,两者有显著差异。CD3 %两组分别为 69.53± 2 4 .35和 69.98± 5 .79,两者比较无显著差异 (P <0 .0 5)。结论　再障患儿存在严重的免疫异常 ,且与疾病严重程度呈正相关 ,临床可行免疫抑制治疗。     

儿童血液病并发绿脓杆菌败血症的临床特点分析

目的研究儿童血液病并发绿脓杆菌败血症的临床特点及治疗效果。方法回顾性总结了1995～2005年入院的24例儿童白血病或再生障碍性贫血患儿并发绿脓杆菌败血症的临床资料,并结合血培养、药敏试验结果综合分析。结果①绿脓杆菌败血症主要发生于中性粒细胞低下的住院病人;②起病急、发展快、病情重,100%的患儿有发热,87.5%有寒战,25.0%出现感染性休克,8.3%出现DIC,20.8%出现坏疽性深脓疱;③药敏监测显示对碳青霉烯类、头孢他定等有较高的敏感率;④24例患儿中治愈22例,死亡2例,患儿在24h内应用碳青霉烯类抗感染治疗,可明显缩短发热时间和病程;中性粒细胞绝对值(ANC)<0.5×109/L、持续时间≥7d的患儿,发热持续时间及感染灶恢复时间较ANC<0.5×109/L、持续时间<7d的病人明显延长。结论绿脓杆菌败血症在粒细胞低下的血液病患儿进展极其迅速,及时有效的抗生素应用是改善预后的关键。     

儿童白血病感染与血浆纤维结合蛋白的关系

研究纤维结合蛋白和白血病发生感染的关系，其是体内重要的生物活性物质。采用Ｌａｕｒｅｌｌ‘ｓ火箭免疫电泳法检测３５例急性白血病患儿血中纤维结合蛋白水平，重点观察各种感染时的变化。急性白血病患儿无发生感染时血中纤维结合蛋白含量与正常对照无差别，有感染发生者Ｆｎ即显著降低，感染越严重血中Ｆｎ下降就越显著。血浆Ｆｎ水平动态监测不仅对了解急性白血病理生理机制有益，而且对临床监测病情有帮助，更重要的是为临床治     

Low Expression of Basic Fibroblastic Growth Factor in Mesenchymal Stem Cells and Bone Marrow of Children with Aplastic Anemia

Background: Our previous experiments with gene chip suggested that basic fibroblastic growth factor (FGF2) levels were lower in mesenchymal stem cell (MSC) from aplastic anemia patients. The purpose of this study was to determine the expression of FGF2 in MSC and in bone marrow of children with aplastic anemia to better understand the role of low FGF2 expression in the pathogenesis of aplastic anemia. Procedure: MSCs from the bone marrow of aplastic anemia children and control group were cultured in vitro. Growth curves of primary and passage MSC were plotted. FGF2 gene expression in MSCs was detected using quantitative real-time polymerase chain reaction (RT-PCR). FGF2 protein expression in mononuclear cells and FGF2 protein level in extracellular fluid of bone marrow were also investigated. Result: Decreased growth of MSCs from aplastic anemia children was observed after passage 8 in serial subcultivation, and FGF2 gene expression was downregulated. Within the patients’ bone marrow, low FGF2 expression was validated both in mononuclear cells and in the extracellular fluid. Conclusion: Low FGF2 gene expression in MSCs and low FGF2 protein level in bone marrow of aplastic anemia may involve to pathogenesis of aplastic anemia.     

Immunosuppressive treatment of aplastic anemia in Chinese children with antithymocyte globulin and cyclosporine

Fifty-one children with aplastic anemia (AA) from 1993 to 2004 in the authors' institution were treated by 3 therapies: 11 patients in group 1 received the SSL-6 protocol; 16 patients in group 2 had CsA alone, where the dose of CsA began from 9-12 mg/kg in the initial 2 weeks and tapered off to 5 mg/kg later; 24 patients in group 3 were treated combining rabbit ATG (Pasteur, Merieux) 2.5 mg/kg for 5 days with CsA, which was the same dose as in group 2. The response was 27, 50, and 79%, respectively. The statistical analysis showed that the protocol of intensive immunosuppressive treatment (IST) was the most effective one and CsA was better than that of SSL-6. None of our patients developed clone diseases although the follow-up was as long as more than to 9 years. The data suggest that children with AA should receive IST as first-line therapy in developing countries.

Hematopoietic stem cell transplantation (HSCT) is effective treatment for patients with aplastic anemia (AA). However, HSCT is not widely used in China for economic reasons and lack of donors. Immunosuppressive therapy (IST) is now the mainstay treatment for AA. To evaluate the effect of immunosuppressive therapy, combining antithymocyte globulin (ATG) with cyclosporine (CsA), a retrospective study on 51 children with AA from January 1993 to December 2004 treated in the authors' department was performed.     

An Effective Salvage Regimen with Aclarubicin for Daunorubicin-Resistant Acute Non-Lymphocytic Leukemia in Children

We evaluated the efficacy and toxicity of aclarubicin for acute non-lympkocytic leukemia (ANLL) refractory to daunorubicin in childhood. Twenty-four patients were treated with aclarubicin and prednisolone with or without 6-mercaptopurine and behenoyl-cytosine arabinoside daily for 5 to 14 days. Of 21 evaluable patients, 14 (67%) responded: 12 obtained complete remission and 2 partial remission. The median time to reach complete remission was 37 days (range, 16 to 60 days), and the median duration of complete remission was 5.5 months (range, 2 to 41 months). The cumulative dose of anthracycline administered before the study was not considered significant for the response. The only major complication was severe bone marrow suppression; infectious episodes occurred in 14 patients (58%) and three died of sepsis and/or bleeding. The observed non-hematologic toxicities included hematuria, an elevation of serum amylase, nausea/vomiting, and angitis. In addition, one patient showed abnormal cardiac function. Aclarubicin is therefore considered a highly active drug for remission reinduction of previously treated children suffering from ANLL with an acceptable toxicity.     

急性粒细胞性白血病预后因素分析

目的　探讨儿童急性粒细胞性白血病 (AML)预后的相关因素。方法　回顾分析AML 84例患儿多种因素与 3年长期无病生存率 (EFS)的关系 ,并进行统计学分析。结果　 3年EFS为 47.6 % ,统计学分析包括性别、FAB分型中M3型和M5型、ETO阳性M2 、PML RAR阳性M3型、1个月时骨髓未缓解、复杂异常型染色体等 ,其 3年EFS与对照组比较有显著性差异(P均 <0 .0 5)。结论　儿童AML的EFS与发病时多种因素有关。其中男童、M5型、1个月时骨髓未缓解、复杂异常型染色体为预后差的相关因素。ETO阳性M2 、PML RAR( )的M3型预后好。     

不典型再生障碍性贫血患儿骨髓巨核细胞、骨髓小粒和骨髓活检分析

目的分析不典型再生障碍性贫血（AA）息儿的骨髓巨核细胞、骨髓小粒的特点,对其诊断进行探讨。方法对16例不典型AA初诊、15例慢性AA（CAA）和30例同龄正常骨髓标本进行骨髓有核细胞分类,每例随机选择10个骨髓小粒作有核细胞面积（％）评估及小粒中巨核细胞和组织嗜碱细胞计数,并将两组AA骨髓活检结果进行比较。结果骨髓巨核细胞不典型AA组（21．18±12．02）与CAA组（1．93±1．48）、淋巴细胞不典型AA组（27．82±9．89）与CAA组（43．78±12．47）比较,差异均有统计学意义（P均〈0.001）;骨髓小粒有核细胞面积和组织嗜碱细胞计数比较,两组差异均无统计学意义（P均〉0．05）;不典型AA骨髓小粒巨核细胞检出率（6．88％）与正常骨髓小粒检出率（92％）比较,差异有统计学意义（x^2=319．88,P〈0．001）;不典型AA组骨髓小粒组织嗜碱细胞（1～12个／粒）检出率为91.88％,正常骨髓检出率为0％;不典型AA和CAA组骨髓活检均示脂肪组织增多,造血组织减少,巨核细胞缺如。结论骨髓小粒有核细胞面积减少、巨核细胞缺如或罕见、检出组织嗜碱细胞为不典型AA的特征,活检示造血组织被脂肪组织代替。     

化疗对肝功能异常的噬血细胞性淋巴组织细胞增生症的有效性及安全性观察

目的初步评价化疗对并肝功能异常的噬血细胞性淋巴组织细胞增生症(HLH)患儿的有效性及安全性。方法选取对2004年3月-2008年4月收治的非肿瘤相关HLH患儿,参照由地塞米松、依托泊苷、环孢素组成的HLH-04化疗方案指南,在化疗后第8周对疗效进行评估,并在治疗前、治疗后2周、治疗后8周末监测血清ALT、血清清蛋白(Alb)、血浆纤维蛋白原(Fib)等指标变化。结果共60例HLH患儿在接受免疫化疗前并肝功能异常,其中ALT增高47例,Alb降低58例,Fib降低38例。病毒感染相关42例(70%),真菌感染相关1例(1.7%),不明原因17例(28.3%)。60例患儿中55例在诱导治疗4周中临床有效,15例患儿放弃治疗,45例患儿按统一方案完成了8周诱导治疗(其中42例无活动性病变,3例存在活动性病变),该45例患儿治疗后2周、8周,ALT、Alb、Fib监测指标均明显改善,与治疗前比较,组间差异均有统计学意义(Pa<0.01)。结论HLH-04化疗方案治疗HLH临床疗效显著,同时对化疗前肝功能异常患儿同样具有较好的安全性。病初肝功能异常并非免疫化疗的禁忌证,在监测肝功能的基础上应尽可能按时足量应用。     

Prognostic Significance of Adenosine Deaminase in Children with Malignancies

In 33 children, 23 with acute lymphoblastic leukemia (ALL) and 10 with solid tumors, the phenotype of the enzyme adenosine deaminase (ADA) was detected in the erythrocytes by electrophoresis in cellulose acetate. In all children the ADA enzyme activity was also determined in the plasma by spectrophotometry at the onset of the disease, during remission, at the end of the therapy, and during relapse. The phenotype in all children was ADA1-1. There was a difference in enzyme activity between the mean values of children with ALL and those with solid tumors. There were also differences among the subtypes of ALL and also among the stages of ALL and the stages of solid tumors. In 23 children with ALL the mean value (MV) and the corresponding standard error (SEM) of enzyme activity at the onset of the disease were MV ± SEM = 60.2 ± 6.2 IU/L. This was higher than that of the control group (control group: MV ± SEM = 27.8 ± 3.3 WIL). During remission the enzyme activity was lower than that of the control group (MV ± SEM = 19.6 ± 1.7 IU/L); at the end of the therapy it was MV ± SEM = 24.0 ± 1.3 IU/L, which is close to that of the control group; and during relapse it was much higher compared with the control group (MV ± SEM = 73.1 ± 4.6 IU/L). These values are discussed in connection to the leukaemic subtypes. In 10 children with solid tumors the mean value of enzyme activity at the onset of the disease was MV ± SEM = 48.8 ± 2.4 IU/L. During therapy it was MV ± SEM = 32.4 ± 1.9 IU/L and at the end of therapy MV ± SEM = 22.1 ± 2.5 IU/L. The aim of this work is to study the qualitative isoenzyme abnormalities to better understand the biological nature of the malignancies, to distinguish main groups and subsets of ALL and solid tumors on an enzymatic basis, and to identify possible sensitive key enzymes as targets for chemotherapy.     

Growth in Children Treated for Acute Lymphoblastic Leukemia with and without Prophylactic Cranial Irradiation

ABSTRACT. Growth and weight gain were studied longitudinally over a period of four years in thirty-nine children treated for acute lymphoblastic leukemia. The children were divided into two groups according to treatment. Twenty-eight children were given prophylactic cranial irradiation and eleven children were treated without such irradiation. The duration of cytostatic treatment was three years in all cases. Average growth during the first two years was similar in the two groups, and the standard deviation scores (SDS) were below average. The rate of growth (in height) during the fourth year was significantly higher among those children who had not received cranial irradiation ( p <0.01). After four years the average attained height had declined 0.5 SD for children treated with cranial irradiation and 0.2 SD for children without such treatment. Weight velocity was significantly greater than the expected mean in the non-irradiated group during the first year and in the irradiated group during the fourth year of the study. Attained weight after four years had increased 0.4 SD more among those children who had not received irradiation. The results suggest that prophylactic cranial irradiation is responsible for the greater part of the prepubertal growth inhibition in these children.     

再生障碍性贫血患儿骨髓祖细胞培养的临床意义

目的探讨再生障碍性贫血(AA)患儿红细胞集落生成单位(CFU-E)、爆式红细胞集落生成单位(BFU-E)、粒细胞-单核细胞集落生成单位(CFU-GM)及巨核细胞集落生成单位(CFU-Meg)骨髓祖细胞培养情况,了解骨髓祖细胞在AA发病中的作用及意义。方法抽取28例AA患儿骨髓3～4mL,以淋巴细胞分离液提取单个核细胞,用磷酸盐缓冲液(PBS)洗涤2次,调节单个核细胞水平为106/mL,取0.3mL分别接种于红系、粒-单核系、巨核系培养基分别作4类祖细胞培养,在7、14d测定其集落数。结果28例AA中,4类集落数均值与对照组比较,差异有显著意义(P<0.01或P<0.001)。集落数随病情加重而逐步下降。4类集落数低于对照组患儿下限所占百分比分别为BFU-E35.71%、CFU-E85.71%、CFU-GM75.00%、CFU-Meg89.29%。治愈及进步者4类集落数接近对照组水平,治疗无效及进展者与治疗前比较无变化。结论动态监测AA患儿骨髓4类祖细胞集落数变化对辅助诊断、观察疗效及预后判断均有指导意义。