三氧化二砷联合全反式维甲酸治疗急性早幼粒细胞白血病的临床研究

目的 观察三氧化二砷（As2O3）联合全反式维甲酸（ATRA）治疗急性早幼粒细胞白血病（APL）的疗效和不良反应。方法 对APL28例患者用ATRA25mg·m^-2·d^-1，分2～3次服用，As2O3 0．28mg·m^-2·d^-1静脉点滴，并根据外周血白细胞数、不良反应等调整ATRA和As2O3用量直至完全缓解（CR）。结果 28例患者中，2例因发生DIC合并脑出血死亡，26例患者CR，CR率92．9％（26／28）；取得CR所需治疗时间为（22．8±4．5）d（18～36）d。85．7％患者在治疗开始时白细胞升高；46．4％出现肝功异常，多在As2O3减量或停用后1周内恢复。结论 ATRA联合As2O3治疗APL疗效好，不良反应少，CR时间短。     

三氧化二砷治疗急性早幼粒细胞白血病过程中外周血白细胞的变化

全反式维甲酸（all—trans retinoic acid，ATRA）和三氧化二砷（As2O3）开辟了急性早幼粒细胞白血病（APL）诱导分化治疗的新篇章，大大提高了APL患的长期无复发生存率。人们早已注意到ATRA诱导治疗APL时，高白细胞血症及维甲酸综合征（RAS）有一定的发生率，同样As2O3，治疗APL时也有同样的现象。我们详细观察了As2O3治疗APL过程中外周血白细胞数量及形态的变化，并介绍临床处理及转归。     

急性早幼粒细胞白血病缓解过程风险控制的临床疗效观察

目的：探讨全返式维A酸（ATRA）、三氧化二砷（ATO）联合小剂量细胞毒药物（常规剂量的1/4～1/5）在早幼粒细胞白血病（acute promyelocytic leukemia, APL）诱导缓解过程风险控制的临床疗效观察。方法22例APL患者（低、中危险组）随机分成治疗组和对照组。治疗组患者12例,对APL应用常规剂量ATRA 、ATO 联合小剂量细胞毒药物（常规剂量的1/4～1/5）。对照组患者10例, ATRA、ATO同治疗组,联合常规剂量细胞毒药物（按照2011版APL治疗指南）。结果两组患者的完全缓解率90%以上,差异无统计学意义（P＞0.05）;治疗组患者无脏器出血,感染发生率（4/12）33%,对照组患者脏器出血（3/10）30%。感染率（10/10）100%,其中肺炎发生率（2/10）20%,高白细胞发生率8.3%,差异有统计学意义（χ^2=5.632,P＜0.05）;治疗组较对照组明显节约血液制品,血小板输注量减少81.6%,红细胞输注量减少50%,血浆输注量减少79.1%。疗效显著,差异有统计学意义（χ2=2.354,P＜0.05）。结论小剂量细胞毒药物在APL诱导缓解中能有效的降低临床风险、节约血液制品输注。     

集落刺激因子临床研究新进展

目前已有3种不同的重组人生长调节因子：粒细胞集落刺激因子（G－CSF）、粒细胞一巨噬细胞集落刺激因子（GM．CSF）和巨噬细胞集落刺激因子（M－CSF）获得确证和分子克隆，并在世界各国获准用于临床。这些生长因子能影响骨髓造血细胞的功能活性，存活，增殖和分化。G－CSF主要影响定型祖代中性白细胞的增殖，功能性刺激和分化作用。GM－CSF的活性类似于G．CSF，具有使前祖细胞群分化为单核细胞、中性白细胞或粒细胞系的能力。G－CSF和GM－CSF均能刺激多潜能祖细胞和干细胞从骨髓移行进入循环系统。M－CSF主要影响单核细胞和…     

脑梗死及动脉粥样硬化患者血清IL-2、IL-6水平的研究

目的 探讨白细胞介素－２（ＩＬ－２）、白细胞介素－６（ＩＬ－６）在脑醒死发病中的作用。方法 采用放射免疫法检测４８例急性脑梗死患者治疗前后和２０例动脉粥样硬化患者及３０例健康者血清ＩＬ－２、ＩＬ－６水平。结果 脑醒死患者治疗前ＩＬ－２水平显著低于正常对照组（Ｐ〈０．０５）,治疗４周后显著升高（Ｐ〈０．０５）;ＩＬ－６水平治疗前显著高于正常对照组（Ｐ〈０．０５）,治疗４周后显著下降（Ｐ〈０．０５）。     

三氧化二砷治疗复发急性早幼粒细胞白血病临床观察

应用三氧化二砷注射液治疗7例复发急性早幼粒细胞白血病（APL），复发时间平均为完全缓解（CR）后18（3～30）个月。7例均获再CR，达CR时总剂量10ml×42支（3～62支）。治疗中出现不同程度白细胞升高，达高峰时间14～25天，峰值22．9～255×109／L，均有轻度恶心、纳差，偶有轻度骨髓抑制，ALT及BIL－T轻度升高。随访2～17个月均存活．其中3倒在CR时PML／RARα基因（RT－PCR法）仍阳性。三氧化二砷毒副作用小，疗效好，对于复发及全反式维甲酸（ATRA）再诱导无效的APL尤显其优越性，但关于缓解后PML／RARα残留病灶的变化尚需积累更多病例追踪评判。     

血清降钙素原检测在小儿颅内感染鉴别诊断中的价值分析

目的：探讨血清降钙素原（ PCT）检测在小儿颅内感染鉴别诊断中的应用价值。方法选择2011年5月-2013年5月暨南大学第二临床医学院附属深圳市人民医院儿科收治的颅内感染患儿95例分为急性细菌性脑膜炎组（细菌组,n=46）及病毒性脑炎组（病毒组,n=49）,比较两组治疗前、后脑脊液（CSF）白细胞数、蛋白定量及血清PCT水平的变化,并比较两组不同血清PCT阶梯浓度水平检出分布及阳性率。结果治疗前,细菌组和病毒组CSF白细胞计数、蛋白定量及血清PCT水平差异均有统计学意义（P〈0．01）;治疗后,两组CSF白细胞计数、蛋白定量差异无统计学意义（P〉0．05）,而PCT水平血清差异仍有统计学意义（P〈0．01）;病毒组治疗前、后各指标比较差异均无统计学意义（P〉0．05）,细菌组治疗前、后各指标比较差异均有统计学意义（P〈0．05）。两组不同PCT浓度值检出分布比较差异有统计学意义（Z=6.71, P=0．000）;病毒组及细菌组血清PCT阳性检出率分别为18.4%和80.4%,两组比较差异有统计学意义（χ2=35.60, P=0．000）。结论血清PCT可作为鉴别急性细菌性脑膜炎及病毒性脑炎的重要指标,其检测程序简便、快捷,值得临床广泛开展。     

全反式维甲酸联合三氧化二砷治疗急性早幼粒细胞白血病血清血脂变化规律的研究

目的探讨全反式维甲酸(ATRA)联合三氧化二砷(ATO)治疗急性早幼粒细胞白血病(APL)过程中血清血脂的变化规律。方法回顾分析经全反式维甲酸联合三氧化二砷诱导完全缓解后,两种药物联合巩固治疗2个周期的急性早幼粒细胞白血病住院患者49例。分别于治疗前、完全缓解后(CR)、联合用药巩固治疗第1个周期结束及第2周期结束,检测血清血脂指标-血清三酰甘油(TG)、血清总胆固醇(TC)。并对血脂指标进行统计学分析。结果经ATRA联合ATO治疗完全缓解后,患者血脂与治疗前比较,差异无统计学意义(P>0.05)。完全缓解后巩固治疗1个周期,血清TG及TC水平升高(P<0.05)。完全缓解后巩固治疗2个周期,分别与治疗前、完全缓解后及巩固治疗1个周期比较,血清TG及TC升高(P<0.01)。结论 APL患者经ATRA联合ATO治疗会导致血脂升高。     

人粒细胞-巨噬细胞集落刺激因子基因转移表达及对慢性乙型肝炎细胞免疫功能影响的实验研究

为了探讨人GM－CSF基因转移表达对慢性乙型肝炎患者细胞免疫功能的影响，运用携带人GM－CSF基因的重组腺病毒转染慢性乙型肝炎患者PBMCs，表明以重组腺病毒为载体的人GM－CSF基因在转染细胞中，可持续表达1．26±0．065～2．09±011ngs·ml-1·24h－1水平26天左右。通过观察慢性乙型肝炎患者PBMCs在GM－CSF基因转架前后及分泌GM－CSF细胞和慢性乙型肝炎患者PBMCs已共同培养前后淋巴细胞增殖反应和CD3、CD4、CD8、CD16、CD19淋巴细胞比率的变化，提示GM－CSF基因转染的淋巴细胞及与分泌GM－CSF细胞共同培养的淋巴细胞增殖反应增强（P＜0．01），CD3、CD4、CD8、CD16、CD19淋巴细胞比率无明显变化（P＞0．05）．小剂量IL－2（25IU／ml）存在时，GM-CSF基因转染及与分泌GM－CSF细胞共同培养的PBMCs中CD3、CD4、CD16淋巴细胞比率升高（P＜0.01），CD8、CD19淋巴细胞比率未见明显变化（P＜0.05）。     

氯雷他定对变应性鼻炎患儿外周血 T细胞17的影响

目的：观察氯雷他定对变应性鼻炎患儿外周血T细胞17（Th17）阳性率及白细胞介素（ IL）－17及IL－23水平的影响。方法试验组为80例急性发作期变应性鼻炎患儿,每日给予氯雷他定糖浆5 mL,睡前口服,2周为1个疗程;对照组为30例健康儿童,不予任何药物。用流式细胞术及酶联免疫吸附试验（ELISA）法检测试验组治疗前、治疗后1,2周以及对照组的外周血Th17细胞阳性率及IL－17、IL－23水平。结果试验组患儿治疗前血清中Th17细胞阳性率及IL－17、IL－23的含量较对照组明显升高（P＜0．05）。治疗2周后,Th17细胞阳性率及IL－17、IL－23的含量较对照组仍升高,但差异缩小（ P＜0．05）。治疗1周后,试验组Th17细胞阳性率及IL－17、IL－23的含量较治疗前降低,差异无统计学意义（ P ＞0．05）。治疗2周后,试验组 Th17细胞阳性率及 IL －17、IL－23的含量较治疗前明显降低（ P＜0．05）。结论氯雷他定糖浆可以通过调节患者外周血Treg／Th17平衡,降低IL－17和IL－23 mRNA的表达水平来抑制变应性鼻炎的炎症反应。     

全反式维甲酸与亚砷酸联合化疗对急性早幼粒细胞白血病高危患者的疗效

目的观察全反式维甲酸(ATRA)与亚砷酸(ATO)联合化疗对急性早幼粒细胞白血病(APL)患者的疗效。方法回顾性分析86例不同危险分级的初治APL患者的临床资料。根据治疗前白细胞和血小板数将APL患者分为低、中、高危三组。采用ATRA+ATO+蒽环类药诱导缓解,蒽环类药+阿糖胞苷巩固治疗,ATRA+ATO+甲氨蝶呤(MTX)[部分加用6-巯基嘌呤(6-MP)]维持治疗。结果治疗后,完全缓解(CR)率高达95.3%(82/86)。中位随访37个月,高危组和中低危组无事件生存率及中枢神经系统累积复发率差异均无统计学意义(P>0.05)。维持治疗单用MTX者或MTX+6-MP者CR率均为100%。结论 APL患者尤其是高危患者可以从ATO+ATRA+化疗中受益;该方案作为初治APL的一线治疗方案优势明显。     

Arsenic trioxide in hematological malignancies: the new discovery of an ancient drug

Currently, Arsenic Trioxide (ATO) is considered the treatment of choice for patients with relapsed acute promyelocytic leukemia (APL). Recently, a durable remission with minimal toxicity by single agent ATO or ATO + ATRA in newly diagnosed APL was reported by different groups. These regimens have minimal toxicity and can be administered on an outpatient basis after remission induction, thus they could become a real, less toxic and more economic option to ATRA + anthracyclines in particular in low risk APL, or in patients that cannot undergo chemotherapy because of age or comorbid conditions and in patients that refuse chemotherapy. Significantly, these therapies are a successful attempt to cure a tumoral disease without chemotherapy. The results of clinical trials of ATO administration as single agent in multiple myeloma (MM) and myelodisplastic syndromes (MDS) were encouraging and showed clinical effects but they were not close to APL success. On the contrary, results of clinical trials to treat non-APL acute myeloid leukemia (AML) were disappointing. We suggest that a combination therapy with drugs targeting specific pro-survival molecules or capable to enhance pro-apoptotic pathways may lead to an improvement of ATO efficacy against hematological malignancies, in particular AML. Our pre-clinical studies showed that ATO is capable to induce cell death in acute leukemia cells but the apoptotic function is limited since it can induce also a mechanism of cell defense by activating pro-survival molecules such as MEK-ERK, Bcl-xL, Bcl-2. By combining ATO with specific MEK inhibitors, we demonstrated that the block of MEK-ERK phosphorylation, the induction of Bad de-phosphorylation, and activation of p53AIP1 apoptotic pathway interrupt the pro-survival mechanisms of ATO and kill the leukemic cells by apoptotic synergism. Our results provide an experimental basis for combined or sequential treatment with MEK inhibitors and ATO in AML. The renaissance of ATO as a drug in moderne medicine may be considered, together with ATRA success, a victory of empirical analysis, that had (and has) great impact on Chinese culture.     

粒细胞集落刺激因子治疗肾移植后白细胞减少症

目的：评价重组人粒细胞集落刺激因子（Ｇ＿ＣＳＦ）在治疗肾移植后白细胞减少症中的效果及安全性。方法：应用Ｇ＿ＣＳＦ治疗肾移植后白细胞减少症１０例（男性６例，女性４例，年龄３８±ｓ１１ａ），每例注射Ｇ＿ＣＳＦ１５０μｇ，ｓｃ，ｑｄ，直至白细胞计数＞４×１０９／Ｌ。结果：１０例接受Ｇ＿ＣＳＦ的剂量为２２５±１０６μｇ，治疗前白细胞计数基值为（２．２±０．４）×１０９／Ｌ，治疗后白细胞峰值为（１０．６±２．６）×１０９／Ｌ（Ｐ＜０．０１），开始治疗至出现峰值时间为３．６±１．３ｄ，治疗前血清肌酐为２３５±１３５μｍｏｌ／Ｌ，治疗后２ｗｋ内最高血清肌酐为２３４±１２５μｍｏｌ／Ｌ（Ｐ＞０．０５）。结论：Ｇ＿ＣＳＦ治疗肾移植后白细胞减少症疗效显著，且不引起排斥反应     

Auranofin induces apoptosis and when combined with retinoic acid enhances differentiation of acute promyelocytic leukaemia cells in vitro

1. Acute promyelocytic leukaemia (APL) is characterized by a block in differentiation at the promyelocyte stage. Here, we describe the effects of auranofin (AF), a coordinated gold compound, on apoptosis and differentiation of APL cells. 2. Nucleosomal DNA fragmentation assay and Hoechst 33342 staining indicated that AF induced apoptosis in APL-derived NB4 cells at low concentrations (0.5-1.0 microm). The AF-induced apoptosis involved caspase-3 activation and specific cleavage of poly-ADP-ribose polymerase. 3. The AF-treated NB4 cells also produced reactive oxygen species (ROS) and cotreatment with N-acetyl-l-cysteine protected the NB4 cells from AF-induced apoptosis. 4. Expression of the CD11b cell surface marker and C/EBPepsilon was increased when the cells were treated for 4 days with 0.3 microm AF and a physiological concentration of all-trans retinoic acid (ATRA, 5 nm). Treatment with AF in combination with ATRA markedly increased the number of cells with differentiated features, such as lobed or multiple nuclei and numerous granules and vacuoles. At these low concentrations, neither AF nor ATRA alone induced significant cell differentiation. 5. These findings suggest not only that AF induces caspase-3-dependent apoptosis via a mechanism involving ROS, but also that the combined treatment with AF and ATRA induces differentiation of NB4 cells. Our results demonstrate a novel characteristic of AF from which an effective drug treatment of APL might be developed.     

A study on the antitumoral and differentiation effects of peganum harmala derivatives in combination with atra on leukaemic cells

Plant derived agents may exert a new approach to the treatment of leukaemia. The present study was an evaluation of proliferation, cytotoxicity and differentiation of harmine and harmaline on HL60 cells, alone or in combination with ATRA and G-CSF. Counting of cells, viability, MTT assay, morphology, NBT reduction and flow cytometry analysis were performed using CD11b and CD 14 monoclonal antibodies. The data showed that harmine and harmaline reduced proliferation in dose and time dependent manner. Optimal antiproliferative concentration of these agents was chosen. However, both agents in higher doses were cytotoxic. Combination of ATRA, G-CSF and each agent alone, particularly harmaline in optimal dose, resulted in partially additive decrease in cell proliferation. Cells treated with both harmaline and ATRA demonstrated some morphological changes and NBT positivity, but the extent of changes observed following treatment with harmaline was less than ATRA. Flow cytometric analysis showed that ATRA induced a neutrophilic differentiation, while harmaline led to a predominantly monocytic differentiation. Combination of harmine and harmaline with ATRA and G-CSF did not change the extent of differentiation, and the cells differentiated into the neutrophilic lineage. This shows that the direction of differentiation is dominantly determined by ATRA. These preliminary data implies a new approach in treatment of leukemia.     

三氧化二砷联合全反式维甲酸治疗初发急性早幼粒细胞白血病临床分析

目的三氧化二砷联合全反式维甲酸治疗初发急性早幼粒细胞白血病的临床疗效(即完全缓解率和融合基因PML-RARα转阴情况)及不良反应。方法 46例初发APL患者随机分成研究组予As2O3联合ATRA治疗24例,对照组仅予ATRA治疗22例,均治疗直至CR。根据外周血白细胞计数、维甲酸综合征以及肝功能变化调整两药物的剂量。观察CR率、获得CR和不良反应。结果 46例初发APL患者,ATRA联合As2O3组24例患者中,CR23例,1例未缓解,缓解率95.8%,ATRA单药组22例患者中,CR17例,5例未缓解,缓解率77.3%。两组间CR率差异有统计学意义。65.0%患者在治疗开始后出现白细胞升高,63.8%出现肝功能异常,多在减量或停用后1周内恢复。所有患者融合基因PML-RARα初发时均为阳性,CR时9.8%转阴。结论 As2O3联合ATRA治疗初发APL疗效好,不良反应少。长期完全缓解时间需要进一步观察。     

Pathogenesis and treatment of leukemia: an Asian perspective

INTRODUCTION: Leukemias occur worldwide, but there are important geographic differences in incidences. AREAS COVERED: Three leukemias with special Asian perspectives, acute promyelocytic leukemia (APL), T-cell large granular lymphocyte (T-LGL) leukemia and NK-cell leukemia. EXPERT OPINION: In APL, China has made contributions in discovering the efficacy of all-trans retinoic acid (ATRA) and arsenic trioxide. Some APL patients are potentially curable after treatment with ATRA or arsenic trioxide as a single agent. Combined treatment of APL with ATRA and arsenic trioxide induces remission with deeper molecular response. An oral formulation of arsenic trioxide is available, making outpatient treatment feasible. Future regimens for APL should examine how ATRA and arsenic trioxide can be optimally combined with other synergistic drugs. Asian patients with T-LGL leukemia present more frequently with pure red cell aplasia, but less frequently with neutropenia, recurrent infection, splenomegaly and rheumatoid arthritis as compared with Western patients. These differences have potential effects on treatment and disease pathogenesis. NK-cell leukemia is rapidly fatal and occurs almost exclusively in Asian and South American patients. Conventional anthracycline-based chemotherapy designed for B-cell lymphomas do not work in NK-cell leukemias. Novel therapeutic approaches targeting cellular signaling pathways or preferentially upregulated genes are needed to improve outcome.     

Biodistribution characteristics of all-trans retinoic acid incorporated in liposomes and polymeric micelles following intravenous administration

The aim of this study was to investigate the biodistribution characteristics of all-trans retinoic acid (ATRA) incorporated in liposomes and polymeric micelles following intravenous administration. [3H] ATRA were incorporated in distearoylphosphatidylcholine (DSPC)/cholesterol (6:4) liposomes. Two types of block copolymers, poly (ethylene glycol)-b-poly-(aspartic acid) derivatives with benzyl (Bz-75) groups, were synthesized to prepare the polymeric micelles for [(3)H]ATRA incorporation. ATRA were dissolved in mouse serum to analyze their inherent distribution. After intravenous administration, the blood concentration of [3H] ATRA in liposomes and polymeric micelles (Bz-75) was higher than that of inherent [3H]ATRA, suggesting that liposomes and polymeric micelles (Bz-75) control the distribution of ATRA. Pharmacokinetic analysis demonstrated that [3H]ATRA incorporated in polymeric micelles (Bz-75) exhibit the largest AUC(blood) and lowest hepatic clearance of ATRA, suggesting that polymeric micelles (Bz-75) are an effective ATRA carrier system for acute promyelocytic leukemia (APL) therapy. These results have potential implications for the design of ATRA carriers for APL patients.     

Tamibarotene

Tamibarotene is a new synthetic retinoid drug recently approved for relapsed or refractory acute promyelocytic leukemia (APL) in Japan. It is a specific agonist for retinoic acid receptor alpha/beta. Compared to all-trans retinoic acid (ATRA), a natural retinoid indicated for a first-line treatment of APL, tamibarotene is chemically more stable and several times more potent as an inducer of differentiation in promyelocytic leukemia cells. In contrast to ATRA, whose plasma concentration declines considerably during daily administration, tamibarotene sustains plasma level probably due to a lower affinity for cellular retinoic acid binding protein. Furthermore, adverse side effects were milder than those of ATRA in clinical trials. Clinical trials held in Japan showed that tamibarotene had efficacy in APL patients who had relapsed from ATRA-induced complete remission. Recently, better understanding of the various mechanisms of action of retinoids has stimulated great interest in its potential use for treatment of various diseases. Tamibarotene is being investigated for treatment of multiple myeloma and Crohn's disease in clinical trials. This review focuses on tamibarotene's mechanisms of action, chemical properties, pharmacokinetics and its use in APL as well as its potential use in various disorders.     

三氧化二砷治疗急性早幼粒细胞白血病疗效观察

目的 :观察三氧化二砷 (As2 O3)治疗急性早幼粒细胞白血病的完全缓解率、高白细胞发生率、肝功损害及融合基因转阴率 ,并与维甲酸 (ATRA )的治疗情况进行比较。方法 :随机分为两组 ,As2 O3组 17例 ,ATRA组 2 1例 ,分别选用 0 .1% As2 O310 m L/ d,静脉滴注 ;ATRA2 5 mg· m- 2 · d- 1 ,分 3次服用。分别观察两组的完全缓解率 (CR)、不良反应以及融合基因转阴率。结果 :As2 O3组 15 / 17例 (88.2 % )获 CR,获得 CR时间为 (2 8.1± 4 .6 ) d;ATRA组 19/2 1例 (90 .4 % )获 CR,获得 CR时间为 (39.4± 8.6 ) d,两组之间 CR无明显差别 ,但 As2 O3组获得 CR时间明显缩短。高白细胞发生率 As2 O3组 10 / 15例 (6 6 .7% ) ,ATRA组 18/ 19例 (94 .7% ) ,P<0 .0 5。肝功能异常 ,As2 O3组 11/ 17例(6 4 .7% ) ,ATRA组 13/ 19例 (6 8.4 % ) ,P>0 .0 5。所有患者治疗前 PML- RARα融合基因阳性。 As2 O3组 CR时 ,2 /14例 (14 % )转阴 ,ATRA组 2 / 19例 (10 .5 % )转阴 ,P<0 .0 5。CR后 1a,As2 O3组 5 / 8例 (6 2 .5 % )转阴 ,ATRA组 4 /11例 (36 .3% )转阴 ,P<0 .0 5。As2 O3组 15例获 CR者 ,无 1例复发。ATRA组 19例获 CR者 ,4例 (2 1% )复发。结论 :与 ATRA相比 As2 O3获得 CR时间缩短 ,高白细胞发生率低 ,CR及 CR