miR 21表达与胃癌细胞阿帕替尼敏感性关系的实验研究#br# #br# #br# #br#

目的探讨miR 21表达与胃癌细胞对阿帕替尼敏感性的关系以及可能作用机制。 方法体外培养人胃癌AGS细胞和耐药AGSAR细胞,分别转染miR 21 inhibitor或miR 21 mimics。采用荧光定量PCR（QPCR）检测AGS和AGSAR细胞miR 21表达水平;QPCR检测不同浓度（0、2、5、10 μmol／L）阿帕替尼对AGS和AGSAR细胞p VEGFR2和p Akt mRNA表达水平的影响,以及不同miR 21表达对AGS和AGSAR细胞p VEGFR2、p Akt、PTEN mRNA表达水平的影响;采用MTT法和划痕实验检测阿帕替尼对AGS、AGSAR细胞增殖和迁移的影响。 结果AGS细胞中miR 21、p VEGFR2和p Akt表达量分别为082±009、073±009和068±008,均高于AGSAR的035±010、033±007和025±004,差异有统计学意义（P＜005）;经阿帕替尼处理后,AGSAR细胞的增殖和迁移活性明显高于AGS细胞（P＜005）。10 μmol／L阿帕替尼处理24 h后,阴性对照组AGS细胞的存活率和迁移距离分别为（3948±745）％和（7044±1157）μm,明显低于miR 21 inhibitor转染AGS细胞的（8063±827）％和（10846±1039）μm,差异有统计学意义（P＜005）;阴性对照组AGSAR细胞存活率和迁移距离（7882±814）％和（9315±986）μm,明显高于miR 21 mimics转染AGSAR细胞的（2995±674）％和（6143±985）μm,差异有统计学意义（P＜005）。转染miR 21 inhibitor后,AGS细胞中p VEGFR2和p Akt mRNA相对表达水平分别为112±013和082±010,明显高于阴性对照组的073±011和064±011,而PTEN mRNA表达水平则下调（018±004 vs. 051±008）,差异均有统计学意义（P＜005）。转染miR 21 mimics后,AGSAR细胞p VEGFR2和p Akt mRNA相对表达水平分别为017±004和012±003,明显低于阴性对照组的030±004和025±002,而PTEN mRNA表达水平则上调（053±006 vs. 044±003）,差异均有统计学意义（P＜005）。 结论上调miR 21表达可增加VEGFR 2和Akt磷酸化水平,从而提高胃癌细胞对阿帕替尼的敏感性。     

甲磺酸伊马替尼治疗国人胃肠间质瘤的临床研究

 目的 观察和评价甲磺酸伊马替尼（Imatinib mesylate）治疗国人胃肠间质瘤（GIST）的有效性和安全性。方法 2002年8月至2004年12月，在本院通过病理形态学及免疫组化确诊的GIST共52例，其中36例应用伊马替尼治疗，用法为伊马替尼400mg，口服，1／日。参照WHO实体瘤客观疗效标准观察和判定疗效，NCI-CTC2．0版抗癌药的毒性标准观察和判定毒性。结果 伊马替尼治疗的36例患者中，包括新辅助治疗和姑息治疗在内可以评价疗效的有28例，用药后获得部分缓解为14例（50％），疾病稳定10例（35．7％），疾病进展4例（14．3％）；即有效率（RR）为50％，疾病控制率（DCR）达到85．7％。36例均可进行毒性评价，除了1例因胃部GIST合并脾脏B细胞型非霍奇金淋巴瘤，姑息切除术后口服格列卫同时进行CHOP方案化疗，结果 发生了Ⅲ级骨髓抑制外，其他35例中毒副反应均为Ⅰ～Ⅱ级，而且大多数毒性可以控制或恢复正常。结论 与国外文献报道一致，甲磺酸伊马替尼治疗国人GIST安全高效，耐受性好。     

甲磺酸伊马替尼治疗复发或转移性胃肠间质瘤

目的 评价甲磺酸伊马替尼进行术前辅助治疗及治疗术后复发和(或)转移性胃肠间质瘤(GISTs)的临床疗效及不良反应。方法 经病理组织学证实的GISTs 30例,其中29例CD117阳性。行术前辅助化疗2例,术后复发或已转移并失去手术机会者28例,给予甲磺酸伊马替尼200～600mg／d口服。结果 30例患者中,3例失访,25例可评价客观疗效。部分缓解(PR)15例,占60．0％;病情稳定(SD)5例,占20．0％;疾病进展(PD)5例,占20．0％。患者获益(CR PR SD)率80．0％,获益者中位无进展生存期(TTP)超过13个月。随访1年以上者22例,1年生存率为86．4％。27例可评价不良反应,其中轻度水肿23例(85.2％),Ⅰ、Ⅱ度白细胞减少11例(40．7％),Ⅰ、Ⅱ度乏力8例(29．6％),轻度腹痛4例(14．8％),Ⅰ、Ⅱ度恶心呕吐5例(18．5％),轻度皮疹3例(11．1％),出血2例(7．4％)。结论 甲磺酸伊马替尼治疗进展期GISTs疗效肯定,不良反应较轻．患者能够耐受,可以较长时期用于转移性和(或)不能手术的GISTs治疗。     

甲磺酸伊马替尼治疗胃肠间质瘤毒副作用的深化研究*

目的　进一步观察甲磺酸伊马替尼治疗胃肠间质瘤（ＧＩＳＴ）患者的毒副反应。方法　入组１２８例患者,均口服甲磺酸伊马替尼剂量４００ｍｇ／天,病情进展患者部分加量至６００ｍｇ／天。自服药起观察毒副反应,直至患者死亡或随访结束。结果　甲磺酸伊马替尼毒副反应多发生于治疗的最初１年内,大多数长期服药患者的毒副反应发生率及严重程度增加不显著。常见毒副反应多为１～２级,高剂量组毒副反应未见明显增加。新观察到的毒副反应包括记忆力下降、语言迟缓、阴囊水肿、指甲凸凹不平、皮下瘀斑、肾病综合征样表现,未出现消化道大出血及肿瘤溶解综合征。原发部位、剂量水平、有无肝转移对毒副反应的发生率无显著影响（Ｐ＞０.０５）;性别和年龄对毒副反应的发生率有显著影响（Ｐ＜０.０５）。结论　甲磺酸伊马替尼毒副反应轻微,患者耐受性较好,但药物说明书和文献未提及的毒副反应尤其值得关注。     

甲磺酸伊马替尼治疗手术无法切除的晚期胃肠间质瘤

目的：探讨甲磺酸伊马替尼用于治疗晚期胃肠间质瘤的疗效及生存获益。方法：收集2004年9 月至2015年6 月天津医科大学肿瘤医院收治的无法手术切除的61例晚期胃肠间质瘤患者的临床资料,接受初始剂量400 mg/d 的口服甲磺酸伊马替尼治疗,定期随访,评价生存获益及药物不良反应。结果：61例患者开始接受治疗1 年后,治疗有效率为57.4%（35/ 61）,疾病控制率为88.5%（54/ 61）,Logic二元回归分析显示性别、年龄和腹盆腔多发病灶是影响治疗有效率的因素（P < 0.05）。 本组患者5 年累积生存率为53% ,Cox 回归模型分析提示腹盆腔的多发病灶是影响患者生存获益的重要因素（P < 0.05）。 除2 例患者出现出血,其余患者不良反应轻微。结论：甲磺酸伊马替尼显著改善晚期胃肠间质瘤的生存获益,可作为无法手术切除的晚期胃肠间质瘤的首选治疗。     

不同基因型伊马替尼耐药的胃肠间质瘤二线靶向治疗选择

胃肠间质瘤（gastrointestinal stromal tumor ,GIST）是胃肠道最常见的间叶组织来源肿瘤。伊马替尼是转移或不可切除GIST的标准一线治疗药物。但随着临床应用时间的延长,伊马替尼耐药病例在逐渐增加。对于这组伊马替尼耐药的GIST患者二线如何选择合理的诊疗策略,是临床亟待解决的问题。目前,指南推荐二线可选择增加伊马替尼剂量和直接换用舒尼替尼治疗。针对患者个体时,是选择伊马替尼加量,还是直接换用舒尼替尼治疗,这是临床医生关注的焦点。该文对一线标准剂量伊马替尼治疗失败的不同基因型GIST患者二线靶向治疗选择进行综述。     

甲磺酸伊马替尼治疗晚期胃肠间质瘤的疗效及预后因素

目的:探讨口服甲磺酸伊马替尼治疗晚期胃肠间质瘤患者的疗效及预后相关因素。方法:102例复发和(或)转移性胃肠间质瘤患者接受甲磺酸伊马替尼口服治疗(起始剂量为400mg/d,病情进展者加量至600mg/d)。结果:99例患者可评价疗效,其中8例(8.1%)完全缓解,68例(68.7%)部分缓解,20例(20.2%)疾病稳定,3例(3.0%)疾病进展;客观缓解率(完全缓解+部分缓解)为76.8%。中位无进展生存期(progression-free survival,PFS)为32.0个月,1、2和3年生存率分别为96.1%、81.2%和70.8%。居住在城市、美国东部肿瘤协作组(Eastern Cooperative Oncology Group,ECOG)体能状况(performance status,PS)<2分或客观缓解的患者有更长的PFS(P<0.05),而年龄<65岁、居住在城市、ECOG PS<2分、单纯肝转移或治疗后病灶密度降低的患者有更长的总生存期(P<0.05)。结论:口服甲磺酸伊马替尼治疗晚期胃肠间质瘤患者安全而有效。年龄、基线PS、近期疗效和治疗后病灶密度的变化是晚期胃肠间质瘤预后的重要相关因素。     

甲磺酸伊马替尼治疗胃肠道间质瘤的研究进展

胃肠道间质瘤（GIST）是胃肠道及腹腔最常见的间叶源性肿瘤,对常规的放疗、化疗均不敏感。外科手术是局限性GIST患者的主要治疗方式,但术后复发率较高。对于术前、术后辅助、复发、转移及不能手术切除的患者,酪氨酸激酶抑制剂甲磺酸伊马替尼对其有较好的治疗效果。本文对甲磺酸伊马替尼治疗胃肠道间质瘤的研究进展作一综述。     

甲磺酸伊马替尼一线治疗复发／转移胃肠间质瘤患者的临床分析

目的 回顾性分析国人复发／转移的胃肠间质瘤（GISTs）患者一线应用甲磺酸伊马替尼的有效性、安全性以及预后的影响因素。方法 对2003年4月至2012年3月接受伊马替尼400mg／d一线治疗的患者进行随访,按RECIST 1.0版进行疗效评价,根据NCI CTC 3.0版标准进行毒副反应评价。应用SPSS 13.0统计学软件进行数据处理,分层分析影响国人肿瘤进展时间（TTP）和总生存时间（OS）的相关因素。结果 接受一线治疗的复发／转移GISTs 患者共105例,中位随访时间126个月（范围：44～348个月）,至随访截止日期死亡36例。获CR 8例（7.6％）,PR 62例（59.0％）,SD 14例（13.3％）,PD 21例（20.0%）;有效率为66.6％,疾病控制率为79.9％。全组患者的中位TTP为61.5个月,中位OS为600个月（95％CI：52.1～67.8个月）。接受辅助治疗与未接受辅助治疗、接受二线治疗与未接受二线治疗的患者比较,中位TTP和OS差异均无统计学意义;停药3～12个月组与停药3个月内组、未停药组的中位TTP差异均有统计学意义（P＜0.05）,而停药3个月内组与未停药组的差异无统计学意义;停药3～12个月组与停药3个月内组、未停药组的中位OS差异均有统计学意义（P＜0.05）,而停药3个月内组与未停药组的差异无统计学意义。主要毒副反应为乏力、皮肤黏膜水肿、白细胞减少、腹泻等,多为1～2级,未发生治疗相关性死亡。结论 对于复发／转移的GISTs患者,一线应用伊马替尼400mg／d治疗安全有效。结合中国患者的依从性和经济等因素,是否接受辅助治疗以及是否接受二线治疗对TTP和OS的影响可能不大,而中断治疗超过3个月可能会导致疾病进展,并最终转化为OS的劣势。     

甲磺酸伊马替尼治疗胃肠道间质瘤的疗效及安全性分析

胃肠道间质瘤(gastrointestinalStromal tumor,GIST)是最常见的消化道间质肿瘤,这些肿瘤通常存在酪氨酸受体激酶KIT(75%～80%)或PDGFRA(5%～10%)激活性突变[1].激活性突变使配体独立激活,然后激发KIT或PDG-FRA组成性激活介导的信号转导通路,从而发生不可控制的细胞增生,同时抑制细胞凋亡,最终GIST形成.GIST对传统的化疗和放疗高度耐药,在甲磺酸伊马替尼(imatinibmesvlate.Glivec,preyiotislv called STI571)出现以前,手术是治疗GIST的主要方式,但手术治疗往往并不足够,甚至完全切除肿瘤后,大部分晚期GIST患者还是出现复发,而出现复发和(或)转移的患者往往预后不良[2].GIST分子遗传学与靶向治疗方面的相互结合,使小分子激酶抑制剂伊马替尼治疗复发性或转移性胃肠道问质瘤,成为其他实体瘤靶向治疗的典范.到日前为此,甲磺酸伊马替尼在美国、中国及许多国家被批准用于不可切除和(或)转移性GIST治疗的一线药物.本文回顾性分析复旦大学附属肿瘤医院甲磺酸伊马替尼治疗的39例GIST患者,并就伊乌替尼疗效和安全性作一总结.     

Mechanisms of resistance to imatinib and sunitinib in gastrointestinal stromal tumor

Gastrointestinal stromal tumor (GIST), the most common mesenchymal neoplasm of the GI tract and one of the most common sarcomas, is dependent on the expression of the mutated KIT or platelet-derived growth factor receptor in most cases. Imatinib mesylate potently abrogates the effects of KIT signaling by directly binding into the ATP-binding pocket of the kinase. It is becoming increasingly apparent that the binding affinity of imatinib for the receptor is dependent on the type and location of mutation. Within KIT, patients whose tumor has an exon 9 mutation are treated by many clinicians with higher doses of imatinib than those patients with mutations within exon 11. Additionally, there are over 400 unique mutations within exon 11 that may have distinctly different binding affinity for imatinib as well as other kinases. Secondary KIT mutations generally occur at a codon where imatinib binds resulting in KIT reactivation and resistance. Sunitinib malate, a second-generation KIT inhibitor is active in imatinib-resistant disease and is FDA-approved for use in this setting. In this review, we describe the biology of the genes and gene mutations responsible for GIST and discuss known and potential clinical implications.     

Patterns of progression in gastrointestinal stromal tumor treated with imatinib mesylate

BACKGROUND: Although most patients with gastrointestinal stromal tumor (GIST) treated with imatinib mesylate achieve remission or disease stabilization, a significant proportion show progressive disease (PD) with or without initial favorable responses. We evaluated and categorized the patterns of progression of metastatic or unresectable GIST treated with imatinib to identify the prognostic significance and contribution to further treatment decision-making. METHODS: We prospectively gathered clinical data from 62 GIST patients treated with imatinib mesylate (400 mg/day) over a median period of 26 months. Twenty-one of these patients showed evidence of PD based on Response Evaluation Criteria in Solid Tumor criteria. RESULTS: Four patterns of PD were defined: focal progression (FP, N = 4), general progression (GP, N = 6), new cystic lesion (NCL, N = 6) and new solid lesion (NSL, N = 5). The groups were found to differ in terms of time to progression and prior response to imatinib. The proportion of patients who responded to escalated doses of imatinib (600-800 mg/day) was significantly higher in NCL patients (P = 0.04). Overall survival and survival from the confirmation of PD were significantly better in NCL or FP patients compared with NSL or GP patients (P = 0.0157, P = 0.0013). CONCLUSIONS: We identified four patterns of disease progression based on radiographic criteria with different clinical characteristics and impact on survival. Knowledge of these patterns was relevant for early detection and may be helpful in further treatment decision-making.     

１８例胃肠道间质瘤伊马替尼辅助治疗的临床观察

目的　探讨伊马替尼在胃肠道间质瘤（ＧＩＳＴ）辅助治疗中的地位。方法　收集２００３年至２００９年在苏州大学附属第一医院治疗的３５例ＧＩＳＴ患者的随访资料,１８例术后接受伊马替尼４００ｍｇ／ｄ辅助治疗,１７例仅术后观察,主要的观察指标为２年无复发生存率（ＲＦＳ）。结果　３５例ＧＩＳＴ患者的中位随访时间为２８.３个月;伊马替尼治疗时间１２～３６个月,平均治疗时间为２４个月;治疗组和观察组２年ＲＦＳ分别为７２.２％和４１.２％（Ｐ＜０.０１）;治疗组患者均可评价不良反应,其中１～２级白细胞减少７例,轻度腹泻２例,恶心呕吐６例,眼眶周围水肿１例,轻度皮疹８例,轻度乏力２例。结论　ＧＩＳＴ患者术后给予伊马替尼辅助治疗能提高患者２年ＲＦＳ,且不良反应轻,患者耐受性良好。     

The role of imatinib plasma level testing in gastrointestinal stromal tumor

The management of patients with gastrointestinal stromal tumor (GIST) has markedly advanced over the past 10 years. Imatinib has exceptional activity in controlling gastrointestinal stromal tumor (GIST) due to inhibition of the constitutively active conformation of KIT and PDGFRA which is found in the majority of patients with GIST. Although some patients may experience prolonged disease control while on imatinib, most patients will develop imatinib resistance within 2-3 years on therapy. A recent retrospective analysis demonstrated a relationship between imatinib plasma levels and progression-free survival in patients with advanced GIST. Plasma imatinib levels in this study were unrelated to the daily administered dose of imatinib. A prospective trial is underway in order to evaluate whether modification of imatinib dose to achieve a target imatinib plasma level will impact patient outcome when compared to standard imatinib dosing in GIST ( http://www.clinicaltrials.gov , NCT01031628). This review will explore the current available data on the relationship between imatinib plasma levels, response to treatment, and other prognositic factors as well as discuss the implications of this data for possible future therapeutic approaches.     

Interruption of imatinib in advanced gastrointestinal stromal tumor after prolonged imatinib maintenance in the absence of gross tumor lesions

Gastric Cancer - Current guidelines recommend indefinite imatinib treatment for advanced gastrointestinal stromal tumor (GIST) patients. Imatinib-refractory progression-free survival (PFS) and...     

多层螺旋ＣＴ评价伊马替尼治疗胃肠间质瘤疗效的价值

目的：同时采用ＲＥＣＩＳＴ标准和Ｃｈｏｉ标准,探讨和比较多层螺旋ＣＴ用于分子靶向治疗药物甲磺酸伊马替尼（格列卫）治疗胃肠间质瘤（ＧＩＳＴ）疗效评价的临床价值。方法：２００４年２月～２００８年２月的４年间,本院收治和应用格列卫治疗的ＧＩＳＴ患者６２例,定期进行临床和多层螺旋ＣＴ检查,严密随访,动态观察病灶的大小、形态及密度变化,分别根据ＲＥ-ＣＩＳＴ标准和Ｃｈｏｉ标准评价疗效,进行分析比较。结果：６２例ＧＩＳＴ患者中,格列卫治疗前、后按照ＲＥＣＩＳＴＣＴ标准评价,获得ＰＲ３７例（５９.７％）,ＳＤ１８例（２９％）,ＰＤ７例（１１.３％）;而依据Ｃｈｏｉ标准,ＣＴ的Ｈｕ值明显下降的有１１例,略微下降的１９例,基本一致的２８例,增高的有４例。其中,有５例肝脏多发转移ＧＩＳＴ,格列卫治疗半年后,原肝内多发低密度的转移灶发生囊性变。结论：多层螺旋ＣＴ扫描是诊断和随访ＧＩＳＴ的最常用和有价值的影像学手段。按照Ｃｈｏｉ标准,通过ＣＴ同时观察Ｈｕ值和大小变化来监测和评价格列卫的疗效,更加客观和全面,对于指导临床治疗具有重要意义。     

Post-operative imatinib in patients with intermediate or high risk gastrointestinal stromal tumor

Aims

This study aims to determine whether adjuvant treatment with imatinib improves recurrence-free survival (RFS) in Chinese patients undergoing complete resection of localized primary gastrointestinal stromal tumor (GIST) compared with those not receiving adjuvant therapy. We also sought a correlation between c-KIT mutations and RFS.

Methods

Patients who had undergone complete tumor resection with intermediate or high risk of recurrence were enrolled in a single-center, non-randomized, prospective study. Patients either received adjuvant imatinib therapy (400 mg once-daily) for 3 years or did not. Mutation analyses of c-KIT were performed on available archival tumor samples.

Results

105 patients were enrolled: 56 in the treatment group and 49 in the control group. Median follow-up was 45(43.1-46.9) months. RFS at 1, 2 and 3 years were higher in the treatment group than in the control group (100% vs. 90% at 1 year; 96% vs. 57% at 2 years; 89% versus 48% at 3 years, P < 0.001, HR = 0.188). Subgroup analyses showed that adjuvant therapy significantly decreased the risk of recurrence in patients whether at high risk or at intermediate risk compared with control patients (3-year RFS: 95% vs. 72%, in intermediate risk; 85% versus 31% in high risk; P < 0.001). In addition, imatinib adjuvant treatment decreased the risk of death (P = 0.039, HR = 0.254).

Conclusions

Adjuvant imatinib can improve 1-, 2- and 3-year RFS rates in patients at intermediate or high risk of recurrence after complete tumor resection.Clinical Trials Registration Number: ChiCTR-TCC-00000582