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.     

甲磺酸伊马替尼治疗不能切除和/或转移的胃肠道间质瘤的临床分析

目的：评价甲磺酸伊马替尼(ST1571)治疗不能手术切除和／或转移的胃肠道间质瘤疗效和毒性。方法：口服甲磺酸伊马替尼400mg/日治疗10例不能手术切除和／或转移的胃肠道间质瘤患者。结果：9例可评价疗效，4例部分缓解，4例稳定。10例评价不良反应，非血液学毒性有水肿(主要是眼眶周围水肿)、腹痛、腹泻、恶心呕吐、乏力、腹腔肿瘤出血、间歇性肌肉痉挛和结膜炎，大多为I～Ⅱ度。血液学毒性少见。结论：酪氨酸激酶抑制剂甲磺酸伊马替尼治疗不能手术切除和／或转移的胃肠道间质瘤有一定疗效，且毒性可耐受。     

伊马替尼治疗晚期胃肠间质瘤的疗效分析及不良反应

目的 评价靶向药物伊马替尼治疗晚期(不可切除或复发转移)胃肠间质瘤(GIST)患者的临床疗效并总结所有胃肠间质瘤患者服用伊马替尼后的不良反应.方法 回顾分析我院自2004年6月至2009年12月接受伊马替尼治疗的GIST患者154例,其中晚期患者96例.完全切除术后辅助治疗58例.对晚期患者的治疗疗效进行分析,并统计所有患者服药后的不良反应.结果 资料完整的晚期患者73例,接受伊马替尼治疗中位时间23个月,其中完全缓解0例,部分缓解53例(72.6%),疾病稳定15例(20.5%),原发耐药疾病进展5例(6.8%),客观有效率为72.6%,疾病控制率为93.2%.中位无进展生存期45.0个月,患者1、3、5年无进展生存率分别为86%、61%和34%,患者1、3、5年总体生存率分别为98%、88%和72%.154例患者接受过至少一次伊马替尼治疗,起始剂量400 mg/d,绝大多数患者不良反应为1～2级,耐受良好.最常见的不良反应分别为水肿(75.3%)、消化道反应(37.7%)和贫血(22.7%).3级或以上不良反应发生率15.6%(24/154).结论 伊马替尼治疗晚期GIST疗效肯定;患者对于400 mg/d的治疗剂量耐受良好.     

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。     

伊马替尼治疗晚期胃肠道间质瘤

背景与目的:胃肠道间质瘤(gastrointestinal stromal tumors,GISTs)是胃肠道最常见的间叶源性肿瘤,对传统的化疗耐药.本研究评价选择性的酪氨酸激酶抑制剂伊马替尼治疗晚期胃肠道间质瘤的效果.方法:入组60例患者,男性43例,女性17例,95.0%的患者体能状况评分(ECOG)0～2分.中位年龄53岁(23～80岁).所有患者口服伊马替尼400 mg/d,评价抗肿瘤疗效和安全性,主要的入选标准是晚期胃肠道间质瘤,有可测量病灶.结果:1例无法评价疗效,无CR,PR 35例(59.3%,35/59),SD持续6个月以上者13例(22.0%,13/59),6个月内PD 11例(18.6%,11/59).不良反应较轻,最常见的Ⅲ～Ⅳ度毒性有出血(6.7%,4/60)、贫血 (5.0%,3/60)、水肿(3.3%,2/60)、腹痛 (3.3%,2/60)、腹泻 (3.3%,2/60)和恶心(3.3%,2/60).结论:酪氨酸激酶抑制剂伊马替尼治疗晚期胃肠道间质瘤有一定疗效,且毒性可耐受.     

Preoperative imatinib mesylate for unresectable or locally advanced primary gastrointestinal stromal tumors (GIST)

Aim

To explore the effect of preoperative imatinib mesylate (IM) in patients with unresectable or locally advanced primary gastrointestinal stromal tumor (GIST).

Methods

From January 2003 to January 2008, all patients affected by bulky localized GIST who presented at our institution were considered for preoperative IM with cytoreductive intent. Clinical, pathological and molecular characteristics were assessed and the rate of response recorded. Progression-free survival (PFS) was calculated according to Kaplan–Meier analysis.

Results

Fifteen patients (1 esophageal, 7 gastric, 3 duodenal, 4 rectal GISTs) received preoperative IM for a median of 9 months. All patients had tumor shrinkage, with a median size reduction of 34%. One patient had radiological complete response. In all cases an improvement of the originally planned surgical procedure was obtained: 3 patients initially considered unresectable underwent complete surgery; 7 patients with initial indication for extensive surgery were more conservatively operated on; 4 patients initially deemed at high perioperative risk underwent safe surgery. Due to the small sample size, no association between tumor shrinkage and tumor site, size, IM duration, mutational status and pathological response could be formally explored. PFS at 3 years from IM onset was 77%.

Conclusions

In unresectable or locally advanced GISTs, preoperative IM is a useful tool both to improve resectability and reduce surgical morbidity. It should be therefore always be considered before embarking on a major surgical procedure. The long-term impact of IM on PFS and survival is presently under investigation in multicenter prospective randomized trials.     

Imatinib mesylate in clinically suspected gastric stromal tumors

Gastrointestinal stromal tumors （GISTs） occur most frequently in the stomach.Diagnosis of gastric GIST is not always clear before surgery.Flexible endoscopy may suggest the nature of the lesion （a bulky tumor with preserved mucosa）; however,biopsy is rarely diagnostic.Therefore,diagnostic medication with safe drugs may provide a feasible way under such conditions after an informed consent is obtained.Based on the excellent efficacy of imatinib mesylate （IM） in the treatment of GIST,we successfully applied it in the diagnostic medication of two patients with clinically suspected gastric stromal tumors.In conclusion,the diagnostic medication with IM can be an alternative option for patients with suspected GIST that can not be confirmed pathologically.     

Imatinib mesylate for the treatment of gastrointestinal stromal tumor

Gastrointestinal stromal tumors (GISTs) are rare neoplasms of mesenchymal origin arising in the GI tract. These tumors are characterized by activating mutations of either receptor tyrosine kinase KIT or PDGFRA, which are found in 85% of cases. The introduction of imatinib mesylate (IM), which targets the kinases presenting with these molecular alterations, has dramatically changed the management of these rare tumors, which were resistant to conventional cytotoxic chemotherapy, both in advanced and localized phases. IM is orally available, has a favorable safety profile and induces partial responses and disease stabilization in up to 80% of patients with advanced GIST. Recently, IM was approved for the postoperative treatment of patients with completely resected localized GIST.     

Imatinib inhibits various types of activating mutant kit found in gastrointestinal stromal tumors

Mutations of proto-oncogene c-KIT in gastrointestinal stromal tumors (GISTs) are considered to cause a constitutive activation of KIT responsible for their oncogenesis. Imatinib has therapeutic potential for GISTs because of its inhibitory effect on KIT kinase activity. To investigate the effect of Imatinib on various c-KIT mutations found in GISTs, we examined kinase activity of KIT, cell proliferation and tumorigenicity of transfectants with various c-KIT mutations. Murine lymphoid Ba/F3 cells transfected with one of the three types of mutants (KIT(del559-560), KIT(642Glu), and KIT(820Tyr)) or wild-type KIT were used for the experiments. Phosphorylation of KIT, mitogen-activated protein (MAP) and Akt was studied by immunoblotting with or without immunoprecipitation. In vitro studies on cell proliferation using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenylcetrazolium bromide colorimetric assay and in vivo tumorigenicity assay using nude mice were also carried out. Imatinib could inhibit the KIT, MAP and Akt phosphorylation of all the transfectants but had a weaker effect on KIT(820Tyr). Imatinib potently inhibited the proliferation of cells transfected with KIT(820Tyr) at the concentration of 10 microM whereas it inhibited the other 3 types at 1 microM. Moreover, Imatinib could inhibit the tumor formation in nude mice transplanted with transfectants. In various types of activating mutant KIT, Imatinib could inhibit the constitutive activation of KIT signal transduction and cell proliferation both in vitro and in vivo although the effect of Imatinib on KIT(820Tyr) was weaker than that on KIT(del559-560) or KIT(642Glu).     

Imatinib as adjuvant therapy for gastrointestinal stromal tumors: a systematic review

The high risk of recurrence in resected gastrointestinal stromal tumor (GIST) highlights the need for effective adjuvant treatment. This review evaluates the clinical efficacy and safety of imatinib for adjuvant treatment of localized KIT (CD117)-positive resected GIST. Relevant studies were identified by searching several electronic databases from inception to August 2009. Searches were supplemented by examining bibliographies of included studies, searching conference proceedings and consulting experts. All study types were included. Methodological quality was assessed using published criteria. Sixteen studies met the eligibility criteria, comprising one randomized controlled trial (RCT), three phase II studies, three cohort studies and nine case reports. In the RCT, the estimated 1-year recurrence-free survival was 98% [95% confidence interval (CI), 96-100] in the imatinib group versus 83% (95% CI, 78-88) in the placebo group, corresponding to a 65% reduction in the risk of disease recurrence (hazard ratio, 0.35; 95% CI, 0.22-0.53; p < 0.0001) with an absolute recurrence-free survival difference of 15% at 1 year. Other nonrandomized studies reported similar outcomes demonstrating that imatinib used in the adjuvant setting improved recurrence-free survival. The optimum duration of adjuvant treatment, safety and efficacy is currently under investigation with two ongoing RCTs (EORTC 62024 and SSG XV111) and two nonrandomized studies (NCT00867113 and NCT00171977). This study adds to the evidence (based on one RCT and a number of observational studies) that GIST patients treated with adjuvant imatinib therapy show an improvement in recurrence-free survival compared to placebo or no treatment after resection of KIT-positive localized GIST with tolerable toxicity.     

十二指肠间质瘤的临床病理学特点和外科治疗进展

十二指肠胃肠道间质瘤（gastrointestinal stromal tumors,GISTs）是起源于消化道卡哈尔间质细胞（interstitial cells of Cajal,ICCs）一种少见的亚群。虽然影像学、内镜技术和病理免疫组织化学已经取得显著的进步,但术前仍很难达到完全确诊。内镜超声下细针穿刺活检被认为是诊断的金标准,具有很高的敏感性和特异性,GISTs诊断率高达80%。对于非转移性原发的十二指肠GISTs,获得显微镜下阴性切缘的手术切除仍是潜在治愈性治疗手段,但由于胰十二指肠区域的复杂解剖,最佳治疗策略仍具有挑战性。复发风险和无瘤生存时间取决于肿瘤大小、核分裂数和美国国立卫生研究院（national institutes of health,NIH）复发风险分层,而不是手术方式。伊马替尼作为新辅助治疗,对治疗复发和转移性GISTs起到重要作用。对十二指肠GISTs的病理生理和治疗方式的全面深入研究将有利于发现更新且更有效的治疗方式。