老年人急性髓细胞白血病P-糖蛋白表达的临床意义

目的探讨Ｐ－糖蛋白（Ｐ－ｇｌｙｃｏｐｒｏｔｅｉｎ，Ｐ－ｇｐ）在初治老年人急性髓细胞白血病（ＡＭＬ）中的表达特点及其预后意义。方法采用流式细胞术（ｆｌｏｗｃｙｔｏｍｅｔｒｙ，ＦＣＭ）及抗Ｐ－ｇｐ细胞膜外区域单克隆抗体ＵＩＣ２检测了３７例初治老年人ＡＭＬ白血病细胞Ｐ－ｇｐ表达。结果１６例（４３％）患者Ｐ－ｇｐ阳性（Ｐ－ｇｐ＋），Ｐ－ｇｐ与干细胞或祖细胞抗原ＣＤ３４表达显著相关，与其它免疫表型无关。在可评估疗效的３２例中，Ｐ－ｇｐ＋１５例中的４例（２７％）获得完全缓解（ＣＲ），缓解率显著低于Ｐ－ｇｐ阴性（Ｐ－ｇｐ－）１７例中的１１例（６５％）（Ｐ＜０．０５）。ＣＤ３４阳性（ＣＤ３４＋）１４例中ＣＲ３例（２１％），也显著低于ＣＤ３４阴性（ＣＤ３４－）者１８例中１２例（６７％）（Ｐ＜０．０５）。Ｐ－ｇｐ－及ＣＤ３４－１３例中１１例（８５％）获得ＣＲ。结论Ｐ－ｇｐ阳性及ＣＤ３４阳性是老年人ＡＭＬ预后差的重要指标     

P—糖蛋白表达在急性非淋巴细胞白血病中的意义

为探讨成人急性非淋巴细胞白血病（ＡＮＬＬ）Ｐ－糖蛋白（Ｐ－ｇｐ）表达及其与临床、生物学特征的关系，用单克隆抗体ＵＩＣ２及流式细胞术间接免疫荧光法对１６９例ＡＮＬＬ（初治１５２例，难治７例，缓解１０例）患者Ｐ－ｇｐ进行检测。结果显示：初治者Ｐ－ｇｐ表达率为２９％，明显低于难治者的７１％，而缓解者无Ｐ－ｇｐ表达。ＡＮＬＬ亚型中以杂合型急性白血病及急性单核细胞白血病表达较高，阳性率分别为６７％及４７％。Ｐ－ｇｐ表达与ＣＤ３４、ＣＤ７、ＣＤ１４或ＣＤ４２ｂ／ＣＤ６１高度相关。细胞遗传学研究显示：Ｐ－ｇｐ在染色体预后差组表达最高（５４％），而在预后好组表达低（７％）。Ｐ－ｇｐ＋ＡＮＬＬ的完全缓解率为２３％，明显低于Ｐ－ｇｐ－者的７６％。结果提示：Ｐ－ｇｐ表达是成人初治ＡＮＬＬ化疗耐药的指标，综合免疫分型及核型分析可以更准确地判断预后及指导治疗。     

原发性肝癌血清性激素及组织性激素受体的研究

目的研究人体性激素水平变化与原发性肝细胞癌的关系．方法应用放免法测定肝癌组（２０例），肝硬变组（１６例）及正常对照组（２０例）血清雌二醇（Ｅ２）及睾酮（ＴＴＴ）含量，并用放免组化法（ＰＡＰ法）检测肝癌组织及肝硬变组织的雌二醇受体（ＥＲ）及睾酮受体（ＡＲ）含量．结果肝癌组血清Ｅ２含量（４４５５±９３１ｎｇ／Ｌ）明显高于正常对照组（７６６ｎｇ／Ｌ±１７０ｎｇ／Ｌ）而低于肝硬变组（６４９６ｎｇ／Ｌ±１７６ｎｇ／Ｌ）（Ｐ＜００１）；前者ＴＴＴ含量（２５３３００ｎｇ／Ｌ±５６５６０ｎｇ／Ｌ）明显低于后二者（４５８５８０ｎｇ／Ｌ±３４９６０ｎｇ／Ｌ）（Ｐ＜００１）．肝癌组织ＥＲ（８０％）较肝硬变时（４４％）明显增加（Ｐ＜００２５），且与血清Ｅ２含量有明显负相关关系（ｒ＝－０８４７３，Ｐ＜０００１）．ＡＲ阳性百分率在两者无明显差别（ｒ＝－０３１３５，Ｐ＞００５）．结论血清ＴＴＴ含量改变及肝组织ＡＲ浓度改变与肝癌无明显关系，而血清Ｅ２含量改变及肝组织ＥＲ浓度改变与肝癌的发生、发展有密切关系．提示原发性肝细胞癌是一雌激素依赖性肿瘤．     

类风湿关节炎病人血清细胞因子水平以及与炎症指标的相关性

目的：进一步研究细胞因子在类风湿关节炎（ＲＡ）中的作用以及与疾病的关系。方法：随机就诊的７２名门诊及住院ＲＡ病人红细胞沉降率（ＥＳＲ）、Ｃ反应蛋白（ＣＲＰ）以及细胞因子白细胞介素１α（ＩＬ１α）、ＩＬ１β、ＩＬ２、ＩＬ６、肿瘤坏死因子α（ＴＮＦα）、粒细胞单核细胞集落刺激因子（ＧＭＣＳＦ）被测定。全部数据用于ＲＡ病人细胞因子水平的研究，并对细胞因子与炎症指标的相关性进行探讨。结果：ＲＡ病人血清ＧＭＣＳＦ、ＴＮＦα水平较健康对照组明显增高（Ｐ＜０００１）。ＩＬ６、ＧＭＣＳＦ与炎性指标ＥＳＲ（ｒ＝０２６，Ｐ＜００１；ｒ＝０２８，Ｐ＜００２）和ＣＲＰ（ｒ＝０４０，Ｐ＜００００１；ｒ＝０４７，Ｐ＜００００１）呈正相关。结论：ＲＡ病人血清ＩＬ６、ＧＭＣＳＦ、ＴＮＦα较其他细胞因子与ＲＡ疾病有更密切的相关性。细胞因子作为重要的免疫物质参与炎症反应在ＲＡ的病理过程中起到了重要作用。     

MDS患者白细胞介素2受体表达研究

本实验以２８例ＭＤＳ（ＲＡ１８例、ＲＡＥＢ和ＲＡＥＢ－Ｔ１０例）和１０例ＡＮＬＬ为研究对象，采用ＡＰＡＡＰ和ＥＬＩＳＡ法检测患者外周血单个核细胞（ＰＨＡ刺激前后）的ＭＩＬ－２Ｒ和培养血清中ＳＴＬ－ＩＲ，结果表明：经ＰＨＡ刺激培养４８ｈ后，ＭＤＳ和ＡＮＬＬ患者Ｔａｃ抗原阳性率明显低于正常人（Ｐ＜０．０１）ＲＡＥＢ和ＲＡＥＢ－ｔ组Ｔａｃ＋率比ＲＡ低，与ＡＮＬＬ差异无显著性（Ｐ＞０．０５）；血清中ＳＴＬ－２Ｒ在ＭＤＳ各亚型中均高于正常对照组（Ｐ＜０．０５），其中以ＲＡＥＢ及ＲＡＥＢ－ｔ为著。认为ＭＤＳ患者免疫反应及监视能减弱；ＳＴＲ－２Ｒ与ｍＩＬ－２Ｒ无相关；ＩＬ－２Ｒ表达异常可能与造血抑制有关。     

原发性肝癌雌激素受体表达及内分泌治疗

目的研究原发性肝癌雌激素受体（ＥＲ）的表达及内分泌治疗的临床价值．方法应用Ｌｅｅ氏荧光配体细胞化学法检测４１例手术病理确诊的原发性肝癌ＥＲ的表达．本组男３８例，女３例，年龄２５岁～７２岁．同时检测肝癌的组织类型、分化程度、肿瘤大小、血清ＡＦＰ及ＣＥＡ．６例ＥＲ阳性者采用他莫昔芬治疗（每次２０ｍｇ，２次／ｄ，长期服用）并观察疗效．结果肝癌组织ＥＲ阳性２０／４１例，阳性率４８８％．ＥＲ阳性率与患者年龄、性别、ＡＦＰ、ＣＥＡ含量及组织类型（梁状型ＥＲ阳性４５０％，腺样型３３３％，实体型７１４％，硬化型６６７％，透明细胞型２５０％；Ｐ＞００５）无明显关系，与肿瘤体积（≥１０ｃｍ，ＥＲ阳性率７５０％；＜１０ｃｍ，ＥＲ阳性２３８％；Ｐ＜００１）和分化程度（分化好２６例，ＥＲ阳性３４６％；分化差１５例，ＥＲ阳性７３３％；Ｐ＜００５）有显著关系．本组ＥＲ阳性病例中６例经他莫昔芬内分泌治疗有效５／６（８３３％），其中４例ＡＦＰ下降．结论ＥＲ阳性肝细胞癌患者进行内分泌治疗有一定疗效     

间质性肺疾病患者血清和支气管肺泡灌洗液中内皮素1活性的变化

目的评价内皮素对肺纤维化发生、发展作用的影响。方法利用同位素放射免疫直接测定法,检测１０例肺结节病和８例特发性肺纤维化（ＩＰＦ）患者外周血和支气管肺泡灌洗液（ＢＡＬＦ）中内皮素１（ＥＴ１）的活性,并与８名健康非吸烟者进行对照。结果肺结节病和ＩＰＦ患者血清和ＢＡＬＦ中的ＥＴ１活性分别为（６２±２９）ｎｇ／Ｌ,（１７０±２４）ｎｇ／Ｌ和（７７±７１）ｎｇ／Ｌ、（１０±３）ｎｇ／Ｌ,与正常对照组（２０±８）ｎｇ／Ｌ、（４０±０６）ｎｇ／Ｌ比较,差异有显著性（Ｐ＜００１）;血清中ＥＴ１活性与动脉血氧分压（ＰａＯ２）呈明显负相关（ｒ＝－０５３８,Ｐ＜００１）;结节病组和ＩＰＦ组ＢＡＬＦ中的ＥＴ１水平与ＢＡＬＦ中细胞总数呈正相关（ｒ＝０６４９,Ｐ＜００１）,肺结节病患者、ＩＰＦ患者ＢＡＬＦ中ＥＴ１与淋巴细胞、中性粒细胞呈正相关（ｒ＝０７１２,０８１３,Ｐ均＜００１）。结论ＥＴ１在肺结节病和ＩＰＦ发病机制中起着重要作用,并可作为疾病活动性判定的一项重要参考指标。     

大肠癌P53蛋白PCNA和CEA的表达与淋巴结转移的关系

目的研究大肠癌Ｐ５３蛋白、增殖细胞核抗原（ＰＣＮＡ）和ＣＥＡ的表达与淋巴结转移的关系．方法应用链霉菌素生物素（ＳＰ）免疫组化法，观察４４例大肠癌Ｐ５３，ＰＣＮＡ的阳性率和ＣＥＡ的表达型式．结果大肠癌Ｐ５３阳性率为５２３％；大肠癌Ｐ５３阳性表达与性别、年龄及肿瘤的部位、分化程度和浸润深度无关（Ｐ＞００５）；大肠癌Ｐ５３阳性者其淋巴结转移率较阴性者高（１４／２３，６０９％ｖｓ６／２１，２８６％，Ｐ＜００５）；Ｐ５３阳性表达及有淋巴结转移者其细胞增殖活性分别较Ｐ５３阴性表达及无淋巴结转移者高（５５９±１７ｖｓ３７９±１４，Ｐ＜００５；５６２±１５ｖｓ３９６±１７，Ｐ＜００５）；Ｐ５３阳性表达及有淋巴结转移者其ＣＥＡ表型均以胞质型和间质型为主（２１／２３，９１３％ｖｓ１３／２１，６１９％，Ｐ＜００５；１９／２０，９５０％ｖｓ１５／２４，６２５％，Ｐ＜００５）．结论检测Ｐ５３和ＰＣＮＡ表达及ＣＥＡ表型对判断大肠癌的恶性程度，预测其淋巴结转移趋势和预后及指导临床治疗有重要价值．     

~(131)I抗AFP抗体-MMC双弹头导向治疗肝癌31例

目的观察化疗兼内照射的新型双弹头免疫导向治疗肝癌的疗效．方法以马抗人ＡＦＰ多克隆抗体（抗ＡＦＰＡｂ）和大鼠抗人ＡＦＰ单克隆抗体（抗ＡＦＰＭｃＡｂ）为载体，核素１３１Ｉ和丝裂霉素（ＭＭＣ）为双弹头，采用改良氯胺Ｔ法制备１３１Ｉ抗ＡＦＰＭｃＡｂＭＭＣ（双弹头１）和１３１Ｉ抗ＡＦＰＡｂＭＭＣ（双弹头２），静脉滴注，每月１次，治疗不能切除中晚肝癌３１例（治疗组）．治疗１，２，３次分别占４，１７和１０例，放射剂量（ＭＢｑ／例）均值依次为１９３５１±３７７４，６５１９±２３２４和９９２０±２３０５．结果治后肿瘤缩小率、血清ＡＦＰ下降率和１，２年生存率分别高于同期经动脉插管灌注（ＴＡＩ）或化疗栓塞（ＴＡＣＥ）的对照组（５００％，１５／３０比３００％，９／３０Ｐ＜００５；６６７％，１８／２７比２８０％，７／２５Ｐ＜００１和５００％比３３０％，３４０％比３３％Ｐ＜００１），治疗组病例的进展率（１００％）明显低于对照组（４００％，Ｐ＜００１）．结论双弹头疗效提高，由于抗体、核素１３１Ｉ和抗癌药的协同作用而增强了对癌细胞的杀伤力所致．     

p53 C-myc和P-gp蛋白在胃癌细胞中表达

目的研究胃癌组织中ｐ５３和Ｃｍｙｃ的表达与多药耐药性（ＭＤＲ）的关系．方法应用ＬＳＡＢ免疫组织化学方法研究６７例（男４１例，女２６例，平均年龄４６±１５８岁）胃癌标本中ｐ５３，Ｃｍｙｃ和Ｐｇｐ的表达．结果本组胃癌中ｐ５３阳性３２例（４７８％），Ｃｍｙｃ阳性３７例（５５２％），Ｐｇｐ阳性３９例（５８２％）．淋巴结转移阳性胃癌ｐ５３阳性率（５６９％）和Ｃｍｙｃ阳性率（６４７％）显著高于淋巴结转移阴性的胃癌（Ｐ＜００５）．ｐ５３的异常表达与ｍｄｒ１基因表达呈显著正相关（ｒ＝０６３，Ｐ＜００５），而Ｃｍｙｃ和ｍｄｒ１的表达无明显相关．结论ｐ５３异常表达可增加ｍｄｒ１基因的表达，从而使胃癌细胞获得ＭＤＲ表型     

Clinical significance of multidrug resistance P-glycoprotein expression on acute nonlymphoblastic leukemia cells at diagnosis.

To evaluate the clinical value of the expression of multidrug resistance P-glycoprotein (P-170) on the surface of acute nonlymphoblastic leukemia (ANLL) cells, we analyzed specimens from 150 newly diagnosed patients for staining with MRK16, a monoclonal antibody (MoAb) that binds to an external epitope of P-170. Other surface markers (CD13, CD14, CD15, and CD34) were studied by the same technique. A marker was considered positive when 20% or more cells were stained. Of 150 samples, 71 were P-170-positive. These cases did not differ from P-170-negative cases with regard to age, sex, initial white blood cell (WBC) counts, or French-American-British (FAB) type (except for M3 ANLL, which were more frequently negative). However, leukemias arising from previous myelodysplastic syndrome (MDS) and therapy-induced leukemias were more frequently P-170-positive. CD34 and P-170 expression were significantly associated. All patients were treated by intensive chemotherapy. Complete remission (CR) rates were significantly lower in P-170-positive (23/71, 32%) than in P-170-negative cases (64/79, 81%) (P less than 10(-5)). CD34 positivity was also associated with a low remission rate (P less than 10(-5)). Survival was shorter for P-170- and CD34-positive patients (P less than 10(-5)). The prognostic value of both markers was confirmed in multivariate analysis. CR duration was also shorter for P-170-positive cases, but the difference is less significant (P = .05). It is concluded that P-170 analysis may be an important tool for predicting the outcome of intensive chemotherapy in ANLL patients.     

人肝癌细胞中COX-2与MDR/P-gp表达相关性研究

观察人肝癌细胞中特异性环氧合酶-2(Cyclooxygenase-2,COX-2)与MDR／P—gp表达变化,探讨二者在Celecoxib诱导细胞凋亡中的意义。采用免疫组化法、流式细胞技术以及RT-PCR观察Celecoxib诱导肝癌细胞凋亡过程中COX-2与MDR／P—gP表达的变化。Celecoxib诱导肝癌细胞呈时间、剂量依赖性;细胞周期分布改变,G0／G1期细胞比例增加;COX-2与MDR／P—gp表达减弱,但非线性相关。Celecoxib可能通过降低COX-2、MDR／P—gp表达,影响细胞周期分布,发挥抗肿瘤作用。     

Patients hospitalized with pulmonary tuberculosis presenting Koch's bacillus in direct sputum examination. Clinical, radiologic and bacteriologic characteristics

To determine the influence of socio-economic, clinical and radiological factors on the detection of a Mycobacterium tuberculosis-positive direct sputum smear, we studied 531 patients hospitalized for pleuropulmonary tuberculosis over a 5 year period. M. tuberculosis positivity of the expectorate smear was found more frequently in clinically detected (43%) than in radiologically detected (26%) tuberculosis (P less than 0.001). On admission, a M. tuberculosis-positive sputum smear was more common in patients under 40 years old (P less than 0.02), blacks (P less than 0.05) and alcoholics (P = 0.001). M. tuberculosis positivity on direct sputum smears was more often associated with general (asthenia, sweating, fever greater than 38 degrees C) and functional respiratory symptoms (cough and sputum production) (P less than 0.003), bilateral diffusion of lung lesions and/or excavation on chest roentgenography (P less than 0.0001). Nevertheless, 21% of the asymptomatic radiologically detected tuberculosis patients had positive direct expectorate smears and should be considered contagious.     

Overexpression of multidrug resistance-associated p170-glycoprotein in acute non-lymphocytic leukemia.

Resistance to several cytotoxic agents, including anthracyclines, vinca alkaloids and epipodophylline derivatives (multidrug resistance, or MDR) can develop in tumor cells by overexpression of a 170-kd glycoprotein (p170) which is an essential component of a membrane transport system leading to increased drug efflux and decreased intracellular drug concentration. By means of a p170-directed monoclonal antibody (MRK-16) and immunocytochemistry (alkaline phosphatase anti-alkaline phosphatase technique), we investigated the expression of p170 in marrow blast cells of 59 cases (38 at diagnosis and 21 in relapse) of acute-non-lymphocytic leukemia (ANLL). The proportion of strongly MDR-positive cells was higher in relapse that at diagnosis (median 15.5% vs 1.5%). Out of 31 patients who were evaluable for the results of first remission induction, failure of first-line treatment (including Daunorubicin, standard-dose and high-dose Arabinosyl Cytosine, and sometimes also Mitoxantrone) occurred in 8/22 MDR-positive cases and in 1/9 MDR-negative ones (p = 0.21). Failure of first-line treatment was always associated with a progressive increase of p170 expression. Total failures (no remission plus early relapse) were more frequent (p = 0.001) among MDR-positive cases (16/22) than among the others (2/9). These data show that MDR is very frequent in ANLL also at diagnosis and suggest that MDR can contribute to early failure of standard treatment.     

胃肠道外间质瘤预后因素分析

目的探讨胃肠道外间质瘤（EGIST）的临床特征及影响预后的因素。 方法回顾性分析2006年11月至2017年5月间辽宁省肿瘤医院收治的首次进行外科治疗且经病理证实的47例胃肠道外间质瘤患者的临床及随访资料,与本中心的254例胃肠间质瘤（GIST）患者资料进行对比。 结果EGIST与GIST患者在年龄（χ²=6.394,P<0.011）,肿瘤大小（χ²=60.941,P<0.001）,组织学类型（χ²=30.081,P<0.001）,CD117表达（χ²=52.99,P<0.001）,CD34表达（χ²=37.21,P<0.001）、Dog-1表达（χ²=24.57,P<0.001）,是否坏死（χ²=10.38,P=0.006）、改良NIH危险度分级（χ²=56.12,P<0.001）之间差异有统计学意义。EGIST患者1、2、3年生存率分别为84.6%、78.3%、63.4%;接受R0切除的EGIST患者25例（53.2%）。R0切除患者的生存率明显高于非R0切除患者（χ²=5.104,P=0.024）。其中,25例R0切除的患者中显示不同核分裂像、不同肿瘤直径大小、是否伴坏死与EGIST患者的预后未体现统计学意义（χ²=2.067,P=0.151;χ²=1.355,P=0.244;χ²=0.912,P=0.34）。 结论EGIST患者症状隐匿,不易早诊断,首次就诊时肿瘤体积往往较大。是否R0切除关系到患者的预后。     

Multidrug resistance analysis in lymphoproliferative disease of large granular lymphocytes

Multi-drug resistance (MDR) phenotype contributes to the ineffectiveness of chemotherapy. P-glycoprotein (PgP) and lung resistance protein (LRP) are proteins implicated in chemoresistance. We analysed the expression of PgP and LRP respectively in 17 and 15 cases of lymphoproliferative disease of granular lymphocytes (LDGL) including 10 cases of clonal large granular lymphocytic (LGL) leukaemia, six cases of oligoclonal ( n  = 5) and polyclonal ( n  = 1) CD3⁺ lymphoproliferation and one case of CD3⁻ NK lymphocytosis. Functional PgP activity, as determined by Rh123 dye efflux assay, was found in all the patients. The mean percentage of effluxing cells was 47 ± 22%, compared to 35 ± 8% on normal lymphocytes ( P  < 0.04). The efflux was blocked in the presence of verapamil, a PgP revertant agent. A high proportion of CD57⁺ cells (66 ± 10%) from these patients expelled Rh123. Functional PgP activity was associated with expression of MDR1 mRNA. By using immunocytochemistry, LRP expression was detected in 11/15 patients (73%). 7/10 LGL leukaemia patients presented a LRP⁺/Efflux⁺ phenotype and 5/7 had LRP⁺/Efflux⁺/MDR1 mRNA⁺ phenotype. These findings suggest that the PgP⁺/LRP⁺ phenotype is frequently observed in LDGL. Its clinical relevance in aggressive cases remains to be determined.     

Differential actions of naftopidil,doxazosin and nifedipine on platelet thromboxane generation and platelet-derived growth factor efflux in vitro

We examined the effects of the f 1 -adrenoreceptor blockers naftopidil and doxazosin and the Ca 2+ antagonist nifedipine on platelet function with reference to stimulus-induced thromboxane (TxB 2 ) generation and platelet-derived growth factor (PDGF) efflux. Collagen (5 w g/ml) caused a 12.5-fold increase in TxB 2 generation, from a basal level of 7.69 - 1.28 ng/10 8 platelets to 96.34 - 13.37 ng/10 8 platelets ( P <0.001). Adrenaline (16 w M) increased TxB 2 production 3-fold from 2.44 - 0.61 to 8.02 - 1.08 ng/10 8 platelets ( P <0.01). Adrenaline-induced TxB 2 generation was inhibited 42.5 - 10.3% ( P <0.05) and 81.8 - 7.5% ( P <0.05) by 10 and 40 w M naftopidil, respectively. Collagen-stimulated TxB 2 generation was inhibited 59.5 - 9.2% ( P <0.01) by 40 w M naftopidil and 53.7 - 11.3% ( P <0.01) by 28 w M nifedipine. Doxazosin (7.5 and 30 w M) did not influence adrenaline- or collagen-induced TxB 2 synthesis. Collagen increased PDGF efflux from 1.17 - 0.39 to 4.25 - 0.51 ng/10 8 platelets ( P <0.01), whilst adrenaline raised concentrations from 1.08 - 0.19 to 5.37 + 1.02 ng/10 8 platelets ( P <0.01). Naftopidil had no effect on collagen-induced PDGF release. Adrenaline-stimulated PDGF efflux was, however, inhibited 82.9 - 13.7% ( P <0.001) and 125.7 - 16.3% ( P <0.001) by 10 and 40 w M naftopidil, respectively. Doxazosin (30 w M) inhibited adrenaline-induced PDGF release by 70.3 - 31.5% ( P <0.05), whilst nifedipine (28 w M) had no effect on collagen-stimulated release. We conclude that naftopidil, like nifedipine, may block stimulated TxB 2 generation via inhibition of phospholipase A 2 , the Ca 2+ -dependent, rate-limiting enzyme in thromboxane synthesis. Although adrenaline-induced PDGF release was inhibited by naftopidil and doxazosin, collagen-induced release was unaffected by either f 1 -adrenoreceptor blocker or nifedipine, indicating that platelet f -granular release is not dependent on Ca 2+ mobilisation or thromboxane generation. Thus, the effects of these drugs on PDGF release may be mediated through alternative cellular signalling mechanisms.     

Frequency and clinical significance of the expression of the multidrug resistance proteins MDR1/P-glycoprotein, MRP1, and LRP in acute myeloid leukemia: a Southwest Oncology Group Study.

Therapeutic resistance is a major obstacle in the treatment of acute myeloid leukemia (AML). Such resistance has been associated with rapid drug efflux mediated by the multidrug resistance gene 1 (MDR1; encoding P-glycoprotein) and more recently with expression of other novel proteins conferring multidrug resistance such as MRP1 (multidrug resistance-associated protein 1) and LRP (lung resistance protein). To determine the frequency and clinical significance of MDR1, MRP1, and LRP in younger AML patients, we developed multiparameter flow cytometric assays to quantify expression of these proteins in pretreatment leukemic blasts from 352 newly diagnosed AML patients (median age, 44 years) registered to a single clinical trial (SWOG 8600). Protein expression was further correlated with functional efflux by leukemic blasts [assessed using two substrates: Di(OC)(2) and Rhodamine 123] and with the ability of MDR-reversing agents to inhibit efflux in vitro. MDR1/P-glycoprotein expression, which was highly correlated with cyclosporine-inhibited efflux, was noted in only 35% of these younger AML patients, distinctly lower than the frequency of 71% we previously reported in AML in the elderly (Blood 89:3323, 1997). Interestingly, MDR1 expression and functional drug efflux increased with patient age, from a frequency of only 17% in patients less than 35 years old to 39% in patients aged 50 years (P =.010). In contrast, MRP1 was expressed in only 10% of cases and decreased with patient age (P =. 024). LRP was detected in 43% of cases and increased significantly with increasing white blood cell counts (P =.0015). LRP was also marginally associated with favorable cytogenetics (P =.012) and French-American-British (FAB) AML FAB subtypes (P =.013), being particularly frequent in M4/M5 cases. Only MDR1/P-glycoprotein expression and cyclosporine-inhibited efflux were significantly associated with complete remission (CR) rate (P(MDR1) =.012; P(efflux) =.039) and resistant disease (RD; P(MDR1) =.0007; P(efflux) =.0092). No such correlations were observed for MRP1 (P(CR) =.93; P(RD) =.55) or LRP (P(CR) =.50; P(RD) =.53). None of these parameters were associated with overall or relapse-free survival. Unexpectedly, a distinct and nonoverlapping phenotype was detected in 18% of these cases: cyclosporine-resistant efflux not associated with MDR1, MRP1, or LRP expression, implying the existence of other as yet undefined efflux mechanisms in AML. In summary, MDR1 is less frequent in younger AML patients, which may in part explain their better response to therapy. Neither MRP1 nor LRP are significant predictors of outcome in this patient group. Thus, inclusion of MDR1-modulators alone may benefit younger AML patients with MDR1(+) disease.     

Improvement in exercise capacity and associated changes in hemodynamics and left ventricular function after the addition of metoprolol to nifedipine in patients with stable exertional angina

In 10 men with stable exertional angina, the changes in exercise capacity, hemodynamics, and left ventricular (LV) function were measured after 20 mg sublingual nifedipine (N) and again after adding 100 mg oral metoprolol (M). Nifedipine alone did not significantly improve exercise workloads (+18%) and duration (+21%), but the addition of metoprolol increased both parameters by a further 37 and 32%, respectively (both p less than 0.005 vs. N). After nifedipine the onset of angina was slightly delayed (5.14 +/- 2.41 min placebo (P), 6.00 +/- 2.31 min N, p less than 0.1) and occurred at higher workloads (36 +/- 17 W P, 43 +/- 8 W N, p less than 0.1). After the addition of metoprolol, the onset of angina was delayed substantially more (9.57 +/- 2.22 min, p less than 0.001 vs. P and N) and occurred at much higher workloads (62 +/- 20 W, p less than 0.001 vs. P and N). At rest (R) and during exercise (E), nifedipine decreased systemic vascular resistance (-36% R, -27% E, both p less than 0.001) and mean arterial pressure (-18% R, -21% E, both p less than 0.001), and increased heart rate (+15% R, +11% E, both p less than 0.001), Pulmonary artery wedge pressure on exercise increased less (22 +/- 7 mmHg P, 13 +/- 5 mmHg N, p less than 0.001). After adding metoprolol, the major change was a reduced heart rate (-25% vs. N at R and E, both p less than 0.001), and arterial pressure was unaltered. Pulmonary artery wedge pressure on exercise increased to 18 +/- 5 mmHg (p less than 0.05 vs. N). Exercise LV ejection fraction and volume did not change significantly after adding metoprolol despite marked improvement in angina. In this acute exercise study in patients with stable exertional angina, metoprolol added to nifedipine markedly improved exercise capacity by preventing the increase in heart rate seen with nifedipine. In our patients with relatively normal LV function at rest, the combination was safe and produced no deleterious effects on LV function.