BACKGROUND:In metastasized GISTs, resistance to imatinib after initial tumour response has been associated with observation of secondary mutations in the activation loop of KIT. The aim of the current study was to evaluate the tumour response and observance of secondary KIT mutations in a case of GIST undergoing neoadjuvant imatinib therapy. METHODS:We report on a case of an initially unresectable gastric GIST with curative resection after 10 months of neoadjuvant imatinib therapy. Mutation analysis of KIT was performed on a pretherapeutic biopsy specimen, as well as on the resected tumour specimen. RESULTS:The pretherapeutic biopsy revealed cKit positive tumour cells with mutation of KIT exon 11 Del 560-576. The remaining tumour mass after neoadjuvant imatinib therapy almost exclusively consisted of hypocellular myxohyalinale stroma with rare microfoci of cKit positive tumour cells. Laser microdissection of several tumour microfoci revealed two additional point mutations located in the activation loop of KIT exon 17, C809G and N822Y, each observed separately in a distinct microfocus. Neither of these two point mutations has been reported in a GIST so far. CONCLUSIONS:Neoadjuvant imatinib therapy successfully reduces tumour size in GISTs. Since resistance relevant secondary mutations of the activation loop of KIT may be observed after neoadjuvant imatinib therapy, the time elapse with preoperative imatinib therapy should be chosen as short as curative tumour resection or function sparing surgery can be carried out. The determination of the optimal time point for surgery is therefore a critical event and will be discussed.

译文

背景:在转移的GIST中,初始肿瘤反应后对伊马替尼的耐药性与观察到的KIT激活环中的继发突变有关。本研究的目的是评估在接受新辅助伊马替尼治疗的GIST病例中的肿瘤反应和对继发性KIT突变的观察。
方法:我们报告了在新辅助伊马替尼治疗10个月后最初无法切除的胃GIST并进行根治性切除的病例。在治疗前的活检标本以及切除的肿瘤标本上进行了KIT的突变分析。
结果:治疗前的活检显示cKit阳性肿瘤细胞具有KIT外显子11 Del 560-576突变。新辅助伊马替尼治疗后剩余的肿瘤块几乎完全由具有cKit阳性肿瘤细胞稀有微灶的低细胞粘液性角质层基质组成。几个肿瘤微灶的激光显微切割揭示了位于KIT外显子17,C809G和N822Y激活环中的另外两个点突变,分别在不同的微焦点处分别观察到。到目前为止,这两个点突变均未在GIST中报告。
结论:新辅助伊马替尼治疗可成功减少GISTs的肿瘤大小。由于在新辅助伊马替尼治疗后可能会观察到与耐药相关的KIT激活环的继发突变,因此应选择术前伊马替尼治疗的时间,因为可以进行根治性肿瘤切除或可以保留功能的手术。因此,确定手术的最佳时间点是关键事件,将进行讨论。

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