伊马替尼或尼洛替尼一线治疗老年慢性髓系白血病慢性期患者疗效及安全性分析

目的：探讨伊马替尼（imatinib,IM）或尼洛替尼（nilotinib,NIL）治疗老年慢性髓系白血病（chronic myeloid leukemia,CML）患者的疗效和安全性。 方法：回顾分析75例一线使用IM或NIL年龄≥60岁的CML患者,IM组43例,NIL组32例,比较两组患者的疗效及安全性。结果：IM组和NIL组间3、6、9、12个月主要分子学反应（major molecular response,MMR）（分别为23.07% vs. 15.00 %,52.38% vs. 52.38%,57.89% vs. 59.09%,54.17% vs. 57.14%）及MR4.0（分别为11.53% vs. 10.00 %,52.38% vs. 47.62%,57.89% vs. 50.00%,54.17% vs. 42.86%）无统计学差异（P＜0.05）;3、6、12、18个月最佳反应率无统计学差异（分别为60.47% vs. 75.00 %,60.47% vs. 71.88%,62.79% vs. 75.00%,72.09% vs. 90.63%,P＞0.05）;总生存（overall survival,OS）、无进展生存（progression?free survival,PFS）及无事件生存（event?free survival,EFS）期无统计学差异（90.70% vs. 93.75%,79.07% vs. 90.62%,34.88% vs. 65.63%,P＞0.05）;NIL组较IM组治疗失败率低（15.63% vs. 44.19%,P=0.009）,但更易发生血液学或心血管不良事件（Adverse Event,AE）（31.25% vs. 6.78%,P=0.006）。结论：IM或NIL一线治疗老年CML均获得良好疗效,NIL治疗失败率低于IM,但NIL较IM更易出现血液学或心血管不良反应。     

舒尼替尼治疗伊马替尼耐药晚期胃间质瘤9例

目的观察舒尼替尼治疗伊马替尼耐药晚期胃间质瘤的疗效及副作用。方法本组采用自身治疗前后对照,选择经胃镜、手术及病理证实为晚期胃间质瘤的患者9例,CT检查：7例肝转移、2例胰腺转移,9例均行姑息切除,术后使用伊马替尼400mg／d口服,治疗6个月无效;而后改为舒尼替尼连续治疗37．5mgl次／d,口服,每阶段治疗4周,停药2周;每阶段结束后复查血常规,肝肾功能,甲状腺功能,心电图,腹部cT,评价疗效及副作用。结果9例患者舒尼替尼中位治疗时间为166周。按Choi标准进行疗效评估,获cR0例（O％）,PR2例（22．2％）,SD4例（44．4％）,PD3例（33．3％）;客观有效率22．2％,疾病控制率为66．7％;治疗期间的主要不良反应有：恶心3例（33．3％）、疲乏4例（44．4％）、中性粒细胞减少2例（22．2％）。结论舒尼替尼治疗伊马替尼耐药胃间质瘤有较好疗效,副作用较少。     

尼洛替尼和伊马替尼一线治疗慢性髓性白血病的疗效及安全性观察

目的:比较尼洛替尼和伊马替尼一线治疗初诊慢性髓性白血病(chronic myeloid leukemia,CML)慢性期(chronic phase,CP)患者的疗效和安全性?方法:65例新诊断的CML-CP患者,接受口服尼洛替尼300~400 mg,每日2次(尼洛替尼组)或口服伊马替尼400 mg,每日1次(伊马替尼组)治疗,比较两组患者的疗效及安全性?结果:65例初发CML-CP患者,确诊CML的中位时间均为19.5(5~39)个月?尼洛替尼组26例,伊马替尼组39例,治疗后3?6?12个月时尼洛替尼组主要分子学反应(major mdecular response,MMR)获得率高于伊马替尼组,分别为23.1% vs. 7.6%?45.5% vs. 21.2%?66.7% vs. 54.8%,且在6个月时有显著差异?Sokal积分低?中和高危组患者12个月MMR的获得率在尼洛替尼组和伊马替尼组分别为81.3% vs. 42.8%?42.8% vs. 57.1%?66.7% vs. 50.0%?3个月获得Bcr-Abl ≤ 10%的发生率在尼洛替尼组为80.8%,显著高于伊马替尼组的41.0%;6个月达Bcr-Abl<1%的比例在尼洛替尼组为77.3%,高于伊马替尼组的48.5%,均有显著差异?12个月Bcr-Abl<0.1%的比例在尼洛替尼组为66.7%,高于伊马替尼组的54.8%,尼洛替尼组达MMR的中位时间短于伊马替尼组(14 vs. 34个月)?尼洛替尼组和伊马替尼组3?6和12个月获得细胞遗传学缓解(complete cytogenetic rewsponse,CCyR)的比例分别为76.9% vs.52.9%?89.5% vs. 70.0%?78.5% vs. 77.3%,达CCyR的中位时间分别为3个月和 6个月?尼洛替尼和伊马替尼组治疗相关的不良反应多为1~2级,患者大多可耐受?结论:尼洛替尼治疗初诊CML-CP较伊马替尼更早达到分子学缓解,安全有效,有可能作为一线用药?     

吉非替尼初治有效的非小细胞肺癌进展后吉非替尼再治疗的疗效评估

1文献来源 Oh I J, Ban H J, Kim KS,et al. Retreatment of Gefitinib in patients with non-small-cell lung cancerwho previously controlled arm, open-label, phase Ⅱ 2012, 77（1）： 121-127. to Gefitinib： A single- study[J]. Lung Cancer. 2 证据水平     

厄洛替尼和吉非替尼靶向治疗非小细胞肺癌脑转移的疗效

目的 分析厄洛替尼和吉非替尼靶向治疗非小细胞肺癌脑转移的疗效.方法 按照数字随机方式将60例非小细胞肺癌脑转移患者分成对照组和试验组各30例,2组患者分别给厄洛替尼和吉非替尼治疗,对比2组患者的临床疗效.结果2组患者的疾病控制率、客观有效率比较差异无统计学意义(P>0.05);试验组不良反应发生率显著低于对照组(P<0.05).结论 在对非小细胞肺癌脑转移患者进行治疗时,厄洛替尼和吉非替尼的治疗效果相当,但是吉非替尼的不良反应发生率更低,临床中应结合患者的肿瘤特征来合理选择药物.     

克唑替尼对MET靶点的抑制作用

1文献来源 研究一：Zou HY,Li Q.An orally available small-molecule inhibitor of c-Met,PF-2341066,exhibits cytoreductive antitumor efficacy throughantiproliferative and antiangiogenic mechanisms[J].Cancer Res,2007,67（9）：4408-4417.     

吉非替尼的合成

吉非替尼(商品名：易瑞沙，Iresa^TM)由阿斯利康公司研制，主要用于非小细胞肺癌治疗，是表皮生长因子受体(EGFR)抑制剂的新型抗肿瘤产品。其化学名为4-(3-氯-4-氟苯胺基)-7-甲氧基-6-(3-吗啉基丙氧基)喹唑啉。     

厄洛替尼挽救治疗吉非替尼治疗失败的晚期非小细胞肺癌疗效观察

目的 评价厄洛替尼作为挽救方案治疗吉非替尼治疗失败的晚期非小细胞肺癌的疗效及不良反应.方法 回顾性分析2005年12月至2009年11月吉非替尼治疗进展后接受厄洛替尼治疗的晚期非小细胞肺癌患者.观察的主要指标为:客观有效率(RR)、疾病控制率(DCR)、疾病无进展生存时间(PFS)、总生存时间(OS)及不良反应.结果 随访至2010年6月,共有22例患者符合入组条件.22例患者均可接受疗效及生存评价,其中部分缓解(PR)2例,稳定(SD)12例,进展(PD)8例,RR为9.1%,DCR为63.6%,中位为PFS 3.0个月,OS为5.5个月.4例患者检测了表皮生长因子受体(EGFR)突变,2例有突变,2例无突变,全部患者均得到疾病控制.1例男性吸烟腺癌合并颅内转移患者原发无效给予厄洛替尼治疗后颅内病灶达到CR.亚组分析显示:吉非替尼治疗疗效SD者DCR显著提高(90% vs 58.3%,P=0.031),其RR、PFS及OS分别为20%、3.0个月及5.5个月.Ⅲ/Ⅳ度不良反应主要是皮疹1/22(4.5%)、肝功能损害1/22(4.5%)及肺间质纤维化1/22(4.5%).结论 吉非替尼治疗失败后的晚期非小细胞肺癌给予厄洛替尼挽救治疗具有较好的临床获益率,其中吉非替尼治疗疗效SD患者显著提高疾病控制率.     

尼洛替尼和伊马替尼治疗初诊CML-CP患者的疗效及不良反应比较

目的 比较尼洛替尼和伊马替尼治疗慢性髓系白血病慢性期(CML-CP)的疗效及不良反应.方法 选择2017年1~10月安徽医科大学第一附属医院门诊随访的初诊为CML-CP且初诊时即服用尼洛替尼超过12个月的患者30例为观察组,同时收集30例初诊为CML-CP且初诊时即服用伊马替尼超过12个月的患者为对照组.观察组予尼洛替尼300~400 mg,12小时口服1次,对照组予伊马替尼400 mg,每天口服1次.所有患者服药后3、6、12个月进行BCR-ABLIS转录水平、Ph染色体转录水平及不良反应的检测.比较两组患者服药后早期分子生物学反应获得率(3、6个月),主要分子生物学反应(MMR)获得率(3、6、12个月),完全细胞遗传学缓解(CCyR,Ph=0)获得率(3、6、12个月)及不良反应.结果 在早期分子生物学反应(3、6个月)获得率(80.0%比53.3%,86.7%比63.3%)尼洛替尼组高于伊马替尼组(P<0.05);3、6、12个月的MMR获得率分别为16.7%比6.7%、46.7%比20.0%、60.0%比25.9%,尼洛替尼组高于伊马替尼组,6、12个月时的差异有统计学意义(P<0.05).在细胞遗传学方面,两组患者3、6、12个月的CCyR获得率分别为83.3%比66.7%、90.0%比76.7%、92.0%比85.2%,差异均无统计学意义(P>0.05).两组患者均有血液毒性反应,但Ⅲ~Ⅳ不良反应少见,大多具有自限性.非血液学方面毒副作用尼洛替尼组主要表现为生化指标的异常,伊马替尼组主要表现为水肿,Ⅲ~Ⅳ不良反应少见,多数可自行恢复.结论 尼洛替尼治疗初诊CML-CP疗效更佳,但其生化方面的毒副作用更突出.     

达沙替尼治疗耐伊马替尼慢性粒细胞白血病2例报告

慢性粒细胞白血病(CML)是一种骨髓增殖性疾病,其特征是9号和22号染色体的转位t(9;22)(q34;q11),从而导致BCR-ABL融合酪氨酸激酶的过度表达.小分子酪氨酸激酶抑制剂伊马替尼是目前治疗CML的一线药,可使大多数Ph+的CML慢性期患者获得细胞遗传学的完全缓解,但是约有25％的患者仍然达不到缓解,或在缓解后由于激酶位点的突变或者其他机制而引起耐药性的产生.伊马替尼的耐药在CML加速期和急变期以及Ph+ALL患者中更为突出.     

化疗和厄洛替尼间插联合疗法在晚期非小细胞肺癌患者的随机对照双盲临床试验

1文献来源 Wu YL, Intercalated Lee JS, Thongprasert S, combination of chemotherapy et al. andErlotinib for patients with advanced stage non-smallcell lung cancer （FASTACT-2）： A randomised, double-blind trial[J]. Lancet Oncol, 2013,14（8）： 777-786.     

透过现象看本质：腺癌国际新分类更有利于肺癌个体化治疗吗?

国际肺癌研究协会（International Association for the Study of Lung Cancer,IASLC）／美国胸科学会（American Thoracic Society,ATS）／欧洲呼吸学会（European Respiratory Society,ERS）于今年2月份颁布了肺腺癌的国际多学科分类新标准（Travis,et al．JTO 2011）。     

基于SUV的PET对 4周期化疗后的弥漫大B细胞淋巴瘤患者预后的评估

在过去的十来年中,18氟脱氧葡萄糖（fluorodeoxyglucose,FDG）PET已经成为多种淋巴瘤疗效评价的有力工具,它主要通过视觉分析来评估疗效。修订后的判读标准适合评估化疗结束后的疗效。而不适用于化疗期间的疗效评价。     

Effect of ALA-PDT on the expressions ofMMP-9, MMP-13 TIMP-1 of hypertrophic scar model in rabbit ears

Objective： To investigate the effect of 5-aminolevulinic （ALA）-photodynamic therapy （PDT） on the expressions of MMP-9, MMP-13 and TIMP-1 of hypertrophic scar model in rabbit ears, and analyze the possible therapeutic mechanisms of ALA-PDT treatment to hypertrophic scars of rabbit ears. Methods： The experimental animals were randomly divided into normal control negative control, high concentration of ALA-PDT, low concentration of ALA-PDT and PDT groups. The latter three groups received ALA-PDT treatment or PDT treatment once a week for 3 weeks. The specimens of the rabbits were collected respectively 1, 2 and 3 months after treatment to be used for RT-PCR and Western-blot test. Results： 1, 2 and 3 months after PDT treatment, the expressions of MMP-9 and MMP-13 （including mRNA and protein） in hypertrophic scar tissues of three treatment groups were significantly higher than those of the negative control group （P〈0.01）, and the expression of TIMP-1 mRNA and protein of three treatment groups were significantly lower than that of the negative control group （P〈0.01）. There were also significant differences between high-concentration ALA-PDT treatment group and the low one （P〈0.05）. Conclusion： ALA-PDT is effective in treating hypertrophic scars of rabbit ears, and its possible therapeutic mechanisms are that ALA-PDT treatment generates oxidation activation effect to activate the activity of MMPs and induces the photoaging of fibroblasts of hypertrophicscar tissues of rabbit ears to inhibit the activity of TIMPs, which causes the up-regulation of MMPs and the down-regulation of TIMPs. Because of this, the degradation of collagen and ECM is accelerated and the formation of scars is suppressed     

HIV-Specific IL-2^＋ and/or IFN-γ^＋ CD8^＋ T Cell Reponses during Chronic HIV-1 Infection in Former Blood Donors

Objective Conflicting data have been generated from previous studies to determine which kind of relationship exists between HIV-1 specific CD8 Tcell responses and HIV-1 viral load or CD4 count over the course of infection.In this study,153 HIV-1 infected LTNPs were enrolled to investigate the role of HIV-1 specific CD8 T-cell responses in chronic HIV-1 infection among HIV-1 infected former blood donors.Methods The patients were stratified into three groups according to CD4 count：CD4≥500 cells/μL;350 cells/μL≤CD4〈500 cells/μL;CD4〈350 cells/μL.PBMCs were isolated from the patients＇ anticoagulated blood samples.IL-2 and IFN-γ secretions of CD 8 T cells against 17 HIV-1 consensus B full peptide pools were analyzed by using ICS assay.Results An overall inverse correlation were observed between CD4 count and plasma viral load.Although no significant difference was observed during the comparisons of frequency/breadth of HIV-1 specific CD8 T cell responses,CD4 count stratification analysis showed that different correlation pattern existed in three strata：as for patients whose CD4 counts were less than 350 cells/μL,no significant correlations were identified between frequency/breadth of HIV-1 specific CD8 T cell responses and CD4 count/viral load;as for patients whose CD4 counts ranged from 350 cells /μL to 500 cells/μL,significant correlation was only observed between the response breadth of IL-2＋IFN-γ＋ CD8 T cells and CD4 count;however,as for patients whose CD4 counts were more than 500 cells/μL,direct correlations were identified between IL-2＋IFN-γ＋/IL-2＋/IFN-γ＋ CD8 T cells and viral load or CD4 count.Conclusions Universal consistent inverse correlation was only indentified between CD4 count and viral load.The relationship between HIV-1 specific CD8 T cell responses and CD4 count/viral load varied in different CD4 strata,which showed that better preserved CD4 T cells were correlated with better CD8 T cell functions.     

Protective Effects of Sphingosine 1-phosphate and FTY720 on Rat Pulmonary Microvascular Endothelial Cells Stimulated by TNFα

Objective In this study, the effects of sphingosine 1-phosphate （S1P） and its analogue FTY720 on lactate dehydrogenase （LDH）, prostacyclin and PGE2 release, monolayer paracellular permeability, and F-actin structural changes of cultured rat pulmonary microvascular endothelial cells stimulated by TNFα were examined. Methods Rat pulmonary microvascular endothelial cells（rPMECs） were isolated, cultured and identified by immunofluorescent stain of yon Willebrand-associatedan-antigen （vWF）. Incubation with TNFα at a dose of 150 ng/ml for 12 hours induced a significant increase in paracellular permeability determined by measurement of a paracellular solute flux, 3-kDa FD-3. Results PGE2, PGF2α and LDH productions by cell cultures exposed to TNFα for 12 hours increased significantly compared with control cells. Also, the 12-hour exposure to TNFα resulted in reorganization and retraction of the rat pulmonary microvascular endothelial cells that was visible both by phase contrast microscopy and cytoskeletal F-actin stain. Paracellular permeability of the monolayers, PGE2, PGFα and LDH productions were significantly reduced following pretreatment with S 1P or FTY-720. Moreover, S 1P or FTY-720 pretreatment prevented the changes of morphologic and cytoskeletal F-actin induced by TNFa. Conclusion S 1P and FTY-720 can inhibited the LDH, PGF2α and PGE2 release by strengthening the cytoskeleton and protecting the barrier function, and may represent a novel therapeutic method for pulmonary vascular barrier damage.     

吉非替尼或紫杉醇-卡铂治疗肺腺癌

1文献来源 Mok TS, Wu YL, Thongprasert S, et at.Gefitinib or Carboplatin-Paclitaxel in pulmonaryadenocarcinoma [J]. N Engl J Med, 2009,361（10）：947-957.     

Protective effect of autophagy inhibition on ischemia-reperfusioninduced injury of N2a cells

Autophagy is a conserved and programmed catabolic process that degrades damaged pro- teins and organelles. But the underlying mechanism and functions of autophagy in the ische- mia-reperfusion （IR）-induced injury are unknown. In this study, we employed simulated IR of N2a cells as an in vitro model of IR injury to the neurons and monitored autophagic processes. It was found that the levels of Beclin-1 （a key molecule of autophay complex, Beclin-1/elass III PI3K） and LC-3 II （an autophagy marker） were remarkably increased with time during the process of ischemia and the process of reperfusion after 90 min of ischemia, while the protein kinases pTOS6K and roTOR which are involved in autophagy regulation showed delayed inactivation after reperfusion. Admini- stration of 3-methyladenine （3MA）, an inhibitor of class III PI3K, abolished autophagy during reper- fusion, while employment of rapamycin, an inhibitor of mTORC1 （normally inducing autophagy）, surprisingly weakened the induction of autophagy during reperfusion. Analyses of mitochondria function by relative cell viability demonstrated that autophagy inhibition by 3-MA attenuated the de- cline of mitochondria function during reperfusion. Our data demonstrated that there were two distinct dynamic patterns of autophagy during IR-induced N2a injury, Beclin-1/class III PI3K com- plex-dependent and mTORCl-dependent. Inhibition of over-autophagy improved cell survival. These suggest that targeting autophagy therapy will be a novel strategy to control IR-induced neuronal damage.     

脑胶质瘤放化疗后复发和假性进展的鉴别

1病历摘要 患者男性,66岁,因“右颞间变型少突星形细胞瘤Ⅲ级术后10个月”入院。患者曾于2012—03．23因“左下肢乏力3天,伴全身抽搐1次”收住我院神经外科。2012—04—16在全麻下行右颞开颅肿瘤切除术,