课件：胃肠道间质瘤.ppt

后面内容直接删除就行 资料可以编辑修改使用 资料可以编辑修改使用,主要经营：网络软件设计、图文设计制作、发布广告等 公司秉着以优质的服务对待每一位客户，做到让客户满意！,致力于数据挖掘，合同简历、论文写作、PPT设计、计划书、策划案、学习课件、各类模板等方方面面，打造全网一站式需求,感谢您的观看和下载,The user can demonstrate on a projector or computer, or print the presentation and make it into a film to be used in a wider field,胃肠道间质瘤 Gastrointestinal stromal tumors,胃肠间质瘤（GIST）身世之谜,Cajal细胞胞,胃肠道间质瘤定义 Gastrointestinal stromal tumors（GIST）,是胃肠道最常见的间叶性肿瘤； 由突变的c-kit或血小板源性生长因子受体-（PDGFRA）基因驱动； 组织学上由梭形细胞、上皮样细胞、偶或多形性细胞，排列成束状或弥漫状图像； 免疫组化检测通常为CD117或DOG-1表达阳性,治 疗,发病机制,病理特点,临床特征,诊 断,内容,P,P,P,P,P,ATP,激酶结构域,有关,c-kit激酶区通过磷酸化激活底物蛋白，如磷酸肌醇-3激酶（ PI3 -K）,激活的底物促发信号传导的级联反应，而调节基因表达、控制细胞生长、增殖和分化。,c-kit基因突变导致酪氨酸激酶持续活化致使突变细胞增殖失控,底物蛋白,发病机制,Go,Heinrich et al. Hum Pathol. 2002;33:484. Corless et al. Proc Am Assoc Cancer Res. 2003;44. Abstract R4447.,GIST中c-kit和 PDGFRA 突变,细胞膜,细胞质,外显子 11 (67.1%),外显子 9 (11%),外显子 13 (0.9%),外显子 17 (0.5%),外显子 12 (0.9%),外显子 18 (6.3%),c-kit,PDGFRA,突变率: 5-10%,外显子 14 (0.3%),突变率: 80%,c-kit基因突变,1998年Hirota发现80-88的GIST存在 c-kit突变 表达c-kit蛋白产物CDll7,PDGFRA -突变,野生型,2004年 Heinrich等在c-kit突变阴性的GIST 中发现了血小板生长因子受体,c-kit和PDGFRA -突变基因均无突变,发病机制,病理特征,一般与周围组织界限清楚，可有或无包膜，切面灰红或灰白色。较大的肿瘤可发生出血坏死或黏液样变性; 可向腔内、腔外生长、壁内生长或同时生长,大体病理特征,病理特征,大体病理特征,病理特征,大体病理特征,病理特征,组织学病理特征,混合型,上皮样细胞,梭形细胞,0% 20% 40% 60% 80% 100%,10%,20%,70%,依据细胞形态可将GIST分为3大类:梭形细胞型、上皮样细胞型和梭形细胞(或上皮样细胞)混合型,梭形细胞,上皮样细胞,病理特征,组织学病理特征,临床特征,年龄,发病人群在40-70岁 中位年龄60岁 男性多于女性,部位,临床表现,消化道出血,腹部隐痛不适、腹痛、急腹症,腹部包块,非特异性症状：乏力、恶心、呕吐、早饱等,常见的转移部位是肝脏和腹腔,无意义,实验室检查：无； 影像学检查：CT、MRI、PET-CT； 内镜：要特征为黏膜下半球形隆起，黏膜 光整，可伴有糜烂和溃疡； 病理诊断:诊断GIST的根本,诊 断,胃,影像学辅助检查,小肠,影像学检查：,内镜检查,回,病理诊断,组织学：由梭形细胞、上皮样细胞组成 免疫组化检测： CD117阳性率约95%,DOG- 1阳性率98%,CD34阳性率70%,-SMA阳性率40%；,c-kit基因的第11913和17号外显子 PDGFRA基因的第12和18号外显子,包括原发肿瘤的部位肿瘤的大小核分裂像以及是否发生破裂等.,基本诊断,基因检测,危险度评估,GIST,诊断,病理诊断思路,DOG-1 检测,CD117免疫组化检测,野生型GIST或其他,PDGFRA基因检测,有可能GIST,c-kit基因检测,GIST,GIST,GIST,（+）是,（+）是,（-）否,（-）否,有突变,有突变,无突变,无突变,回,20.Joensuu H. Hum Path. 2008;39:1411-1419.,NIH原发GIST切除术后的风险分级（2008）,币,恶,黏膜浸润,瘤细胞显著异性,神经浸润,脂肪浸润,淋巴结转移,肿瘤性坏死,肌层浸润,核分裂像大于或等于10个/50 HPF,围绕血管呈古钱币样生长,血管浸润,恶性GIST诊断标准,外科治疗,分子靶向治疗,1,2,治 疗,GIST对于放疗、化疗几乎不敏感,Go,Go,Go,应该注意不适当的活检可能引起肿瘤的破溃出血和增加肿瘤播散的危险性;尤其对于部位较深的,如肿瘤位于十二指肠,进行活检需慎重,.,活检原则,手术适应证,手术原则,外科治疗,外科治疗原则,根据肿瘤的大小、位置 复发或转移 急诊手术,Go,手术基本原则 腹腔镜、胃、小肠等,回,初发且疑似GIST者,术前需明确性质,首选超声内镜引导下穿刺活检,需要联合多脏器切除者,或手术后影响相关脏器功能者, 考虑活检,无法切除或估计难以获得R0切除的病变,拟采用术前药物治疗者,经皮穿刺,适用于肿瘤已经播散或复发的患者,活检原则,对于大多数可以完整切除的GIST,手术前不推荐常规活检或穿刺,对于直肠和盆腔肿物,如需术前活检,推荐经直肠前壁穿刺活检,活检原则,返回,手术适应症,回,手术中触摸肿瘤不当造成破溃出血、术中播散,初次手术仅为R1切除,预计再次手术难度低且风险可控制, 考虑二次手术,GIST很少发生淋巴结转移,除非有明确淋巴结转移,一般不必常规清扫,对于术后切缘阳性,目前国内外学者倾向于采用分子靶向药物治疗,手术适应症,手术目标是尽量争取达到R0切除,腹腔镜手术容易引起肿瘤破裂和导致腹腔种植,所以不推荐常规应用,手术原则,胃外GIST手术,GIST内镜下治疗,腹腔镜GIST手术,小肠GIST手术,胃GIST手术,十二指肠与结肠,手术原则,返回,33,何谓肿瘤分子靶向治疗？,肿瘤分子靶向治疗是针对可能导致细胞癌变的环节，如细胞信号传导通路、原癌基因和抑癌基因、细胞因子及受体、抗肿瘤血管形成、自杀基因等，从分子水平来逆转这种恶性生物学行为，从而抑制肿瘤细胞生长，甚至使其完全消退的一种全新的生物治疗模式。,传统治疗模式,个体化治疗,特异性地作用于肿瘤细胞,肿瘤分子靶向治疗,伊马替尼,激酶区,伊马替尼占据了ATP在KIT激酶区的结合位点 从而阻止了底物磷酸化及信号转导 信号缺失抑制了细胞的增殖和存活,Savage and Antman. N Engl J Med. 2002;346:683. Scheijen and Griffin. Oncogene. 2002;21:3314.,伊马替尼的作用机制,回,通用名：甲磺酸伊马替尼 商品名：格列卫 剂量/剂型：100mg x 60片/盒 价格：12000/60片/盒 英文商用名： Imatinib Mesylate Capsules,伊马替尼（格列卫）,伊马替尼（imatinib）：一种选择性抑制bcr-abl酪氨酸激酶，同时还是PDGFR和干细胞因子受体c-kit的强抑制剂。,Joensuu et al. N Engl J Med. 2001;344:1052-1056.,治疗4周后,2000年2月伊马替尼治疗的第一例GIST,减小肿瘤体积,降低临床分期;缩小手术范围,避免不必要的联合脏器切除,降低手术风险,同时增加根治性切除机会,.,术前治疗,术后辅助治疗,转移或复发,靶向治疗,分子靶向治疗,Go,Go,Go,适应症 时限 剂量,估计需要进行多脏器联合切除手术,术前估计难以达到R0切除,肿瘤体积巨大(大于10 cm),术中易出血破裂,可能造成医源性播散,肿瘤虽可以切除,但估计手术风险较大,术后复发率死亡率较高,术前治疗适应症,特殊部位的肿瘤(如十二指肠低位直肠等),手术易损害重要脏器的功能,术前治疗的适应证,其他,推荐初始剂量,术前治疗时间,术前停药时间,伊马替尼400mg,6个月,1周,术前治疗,back,术后辅助治疗,辅助治疗适应证,辅助治疗时限,辅助治疗剂量,推荐有中高危复发风险患者作为辅助治疗的适合人群.,中危患者,应至少给予伊马替尼辅助治疗1年 高危患者,辅助治疗时间为3年,建议初始剂量为400 mg/d 如果 KIT 外显子9阳性，则初始剂量为800 mg/d,天,转移复发或不可切除GIST的治疗,一线治疗,二线治疗,三线治疗,伊马替尼是转移复发或不可切除GIST的一线治疗药物,初始推荐剂量为400 mg/d.,伊马替尼标准剂量失败后的治疗选择； 伊马替尼增加剂量；舒尼替尼治疗,伊马替尼与舒尼替尼治疗失败后的维持治疗 建议参加新药临床研究 也可以考虑使用其他分子靶向药物,如索拉非尼,天,back,原发局部疾病,可切除,手术,术后给予伊马替尼,无法切除或需要扩大手术方能切除或存在器官功能障碍的危险,伊马替尼,仍无法切除,伊马替尼,若有微转移疾病，可考虑切除原发灶，尤其是有症状时,复发或转移性疾病,缓解/ 疾病稳定,局灶进展,弥漫性进展,手术 肝动脉栓塞术 射频消融术,舒尼替尼 其它新药,继续使用伊马替尼,GIST的治疗规程,Company Logo,GIST:药物疗效的判断,GIST靶向治疗Choi疗效评价标准32,32.Choi H. Oneologist.2008;13(Suppl 12):4-7.,Diagram,Text in here,Text in here,Text in here,Title,Title,ThemeGallery is a Design Digital Content & Contents mall developed by Guild Design Inc.,ThemeGallery is a Design Digital Content & Contents mall developed by Guild Design Inc.,Diagram,Description of the contents,Title in here,Title in here,ThemeGallery is a Design Digital Content & Contents mall developed by Guild Design Inc.,Before,After,ThemeGallery is a Design Digital Content & Contents mall developed by Guild Design Inc.,Description of the contents,ThemeGallery is a Design Digital Content & Contents mall developed by Guild Design Inc.,Click to edit title style,2. Describe contents for a Chart Description of the companys sub contents Description of the companys sub contents,1. Describe contents for a Chart Description of the companys sub contents Description of the companys sub contents,Chart Title in here,2003,2004,2005,2006,30,50,70,120,2.0cm,2.0cm,急诊手术,对于肿瘤最大径线超过2 cm的局限性GIST,原则上可行手术切除; 不能切除的局限性GIST,或临界可切除,但切除风险较大或严重影响脏器功能者,宜先行术前药物治疗,待肿瘤缩小后再行手术,对于肿瘤最大径线小于或等于2 cm的可疑局限性GIST,有症状者应进行手术 位于胃的无症状GIST,一旦确诊后,应根据其表现确定超声内镜风险分级；如合并不 良因素,应考虑切除;如无不良因素,可定期复查超声内镜 直肠的GIST, 肿瘤一旦增大,保留肛门功能的手术难度增大,倾向于及早手术切除,手术适应症,急诊手术适应证:在GIST引起完全性肠梗阻消化道穿孔保守治疗无效的消化道大出血以及肿瘤自发破裂引起腹腔大出血时,须行急诊手术,复发或转移,分多种情况区别对待（略）,1,2,3,4,返回,返回,Diagram,- ThemeGallery is a Design Digital Content & Contents mall developed by Guild Design Inc.,- ThemeGallery is a Design Digital Content & Contents mall developed by Guild Design Inc.,- ThemeGallery is a Design Digital Content & Contents mall developed by Guild Design Inc.,Description of the companys sub contents,Description of the companys sub contents,Description of the companys sub contents,Diagram,4. Description of the business,5. Description of the business,1. 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