c-kit基因突变对胃肠道间质瘤预后的影响

目的　探讨c kit基因突变与胃肠道间质瘤 (GIST)临床病理指标和预后的关系 ,为GIST恶性变判断、预后评估提供客观指标。方法　对 82例GIST患者运用聚合酶链反应 单链构象多态性分析、DNA测序的方法筛选c kit基因突变病例 ,采用统计学方法回顾性分析c kit癌基因突变与GIST临床病理特征、生物学行为、复发和病死率的关系。结果　c kit基因突变阳性组与c kit基因突变阴性组间肿瘤大小 (χ2 =16 795 ,P <0 0 1)、增殖细胞核抗原指数 (χ2 =17 0 99,P <0 0 1)、有丝分裂计数 (χ2 =11 2 33,P <0 0 1)、坏死 (χ2 =4 4 0 4 ,P <0 0 5 )、浸润 (χ2 =2 2 391,P <0 0 1)、复发 (χ2 =16 333,P <0 0 1)、转移 (χ2 =12 96 5 ,P <0 0 1)、死亡 (χ2 =11 6 4 6 ,P <0 0 1)差异有显著意义 ,而年龄 (χ2 =0 0 0 0 2 ,P >0 0 5 )、性别 (χ2 =0 14 1,P >0 0 5 )、肿瘤的部位 (χ2 =7 5 2 4 ,P >0 0 5 )、细胞类型 (χ2 =0 82 7,P >0 0 5 )、囊性变 (χ2 =1 6 0 8,P >0 0 5 )、出血 (χ2 =0 6 33,P >0 0 5 )、c kit蛋白表达 (χ2 =0 0 0 0 ,P >0 0 5 )差异无显著意义。结论　c kit基因突变的检测可作为GIST患者预后评估的有意义指标     

DOG1与胃肠道间质瘤关系的研究进展

FLJ10261(TEME16A)是新近发现的与胃肠道间质瘤(GISTs)关系密切的一个基因,由该基因编码的蛋白质DOG1,特异性表达于GISTs中,免疫组化及原位杂交证实,其阳性表达较KIT和PDGFRA更弥漫、更具有特异性,因此可能作为胃肠道间质瘤治疗的另一个靶点。笔者对DOG1与GISTs关系的研究进展进行综述。     

胃肠道间质瘤现代研究进展

摘要：胃肠道间质瘤是一组独立起源于胃肠道间质干细胞的肿瘤，由未分化或多能的梭形或上皮样细胞组成，免疫表型表达c Kit蛋白（CD117），遗传学上有c Kit基因突变。笔者分别从病名简史、组织起源、发病机制、病理特点、临床特点、生物学行为、诊断与鉴别诊断、治疗进展及预后等方面研究进展进行综述。     

胃肠道间质瘤的临床病理研究

目的：探讨胃肠道间质瘤(gastrointestinal stromal tumor，GIST)的临床病理特点。方法：对55例GIST的病例进行分析，并对其进行CD117、CD34、S-100、SMA、vimenfin、desmin、NF共7种免疫组化分析。结果：肿瘤的发生部位：胃38例(69％)，小肠10例(18％)，其他部位7例(13％)。肿瘤直径0．4—40cm(平均6．7cm)。肿瘤最大直径≥5cm、核分裂像数≥5/50 HPF及有溃疡形成3项在良性与恶性之间差异有显著意义。免疫组化的阳性表达结果为：CD117 39例(71％)、CD34 45例(82％)、S-100 19例(35％)、SMA 12例(22％)、vimentin 32例(58％)、desmin 6例(11％)、NF2／4(50％)。13例良性GIST患者全部存活，42例恶性及潜在恶性GIST中有4例发生转移，13例死亡。结论：(1)GIST好发于中老年人，无明显性别差异。(2)其主要恶性指标为：肿瘤最大径≥5cm、核分裂像≥5／50 HPF和有溃疡形成。(3)光镜下很难将平滑肌性肿瘤及神经源性肿瘤与GIST相鉴别。     

肝转移胃肠道间质瘤c-kit、PDGFRA基因突变研究

目的 探讨肝转移胃肠道间质瘤( GIST)发生的机制.方法 应用聚合酶链反应(PCR)和基因测序法检测12例肝转移GIST c-kit基因第9、11、13、17号外显子和PDGFRA第12、18号外显子序列,总结基因突变规律,分析其与临床病理的关系.结果 本组5例胃部,1例小肠,其他6例.本组c-kit基因突变率为91.7％ (11/12),外显子11为83.3％ (10/12).未检测到PDGFRA基因突变.本组性别、年龄、原发部位、肿瘤大小、核分裂相、NIH危险度分级、肝转移时间、细胞形态、细胞丰富程度、核异型对c-kit基因外显子11突变率及突变形式影响差异无统计学意义(P＜0.05).结论 肝转移GIST基因突变主要集中在c-kit第11号外显子.突变方式有缺失、点突变和缺失伴点突变.缺失突变多见.肝转移GIST临床病理与外显子11突变率、突变形式无明显相关.     

胃肠道间质瘤的分子机制进展

胃肠道间质瘤是人类胃肠道最常见的肿瘤，原癌基因c—kit突变导致酪氨酸激酶持续活化是其发病的主要机制。近年来的研究发现在无c-kit突变的胃肠道间质瘤中，存在PDGFRA基因的突变。此外，尚存在诸多基因和蛋白参与了胃肠道间质瘤的发生和发展，如染色体14q和22q的杂合性缺失导致某些抑癌基因的丢失，HMGB1、COX-2、Hsp90、CA-RP等。本文主要综述胃肠道间质瘤的相关分子机制。     

胃肠道间质瘤c—kit及PDGFRA基因突变及其临床意义

目的探讨胃肠道间质瘤（GIST）中c-kit及PDGFRA基因突变的分子生物学特点及与临床参数间的关系。方法对141例GIST进行基因检测,用PCR扩增和基因测序的方法检测肿瘤c-kit基因第9、11、13和17外显子及PDGFRA基因第12和18外显子的序列,分析基因突变与GIST临床参数之间的关系。结果在141例GIST中共检测到c—kit基因突变108例（76．6％）,其中11号外显子突变99例（70．2％,99／141）;9号外显子突变8例（5．7％,8／141）;13号外显子突变1例（0．7％,1／141）;未检测到17号外显子突变病例。97．0％为杂合性突变,3．0％为纯合性突变,11外显子突变方式以缺失突变最常见65．7％（65／99）,其次为点突变（24．2％）和插入突变（串联重复）（10．1％）;突变位点多集中在5’端的经典热区,其次为3’端的框内串联重复。共检测到4例PDGFRA基因的突变．占无c—kit突变病例的12．1％（4／33）,占CD117阴性GIST的40％（4／10）,均为外显子18的突变。基因突变的发生率在GIST不同原发部位间差异有统计学意义（χ^2=7．229,P=0．027;χ^2=7．000,P=0．03）,而与患者年龄、性别、肿瘤大小、核分裂、恶性潜能分级等均差异无统计学意义。结论GIST中存在c-kit及PDGFRA基因的突变;基因突变的发生率在不同原发部位间有差异。     

胃肠道间质瘤的基因研究进展

胃肠道间质瘤（GISTs）是消化道最常见的间叶源性肿瘤,其发生主要源自于KIT基因或血小板源性生长因子受体α（PDGFRA）基因的突变。但约10%~15%的GISTs不存在KIT或PDGFRA基因的突变,被称为野生型GISTs,主要包括琥珀酸脱氢酶功能缺失型GISTs、BRAF突变型GISTs,以及Ⅰ型神经纤维瘤病型GISTs。GISTs相关的基因研究可以为其诊断及治疗提供新思路,笔者就GISTs发生、发展、诊断、治疗及预后等相关的基因研究进展进行综述。 胃肠道间质瘤（GISTs）是消化道最常见的间叶源性肿瘤,其发生主要源自于KIT基因或血小板源性生长因子受体α（PDGFRA）基因的突变。但约10%~15%的GISTs不存在KIT或PDGFRA基因的突变,被称为野生型GISTs,主要包括琥珀酸脱氢酶功能缺失型GISTs、BRAF突变型GISTs,以及Ⅰ型神经纤维瘤病型GISTs。GISTs相关的基因研究可以为其诊断及治疗提供新思路,笔者就GISTs发生、发展、诊断、治疗及预后等相关的基因研究进展进行综述。     

胃肠道间质瘤c-kit基因突变的研究进展

目的探讨胃肠道间质瘤（gastrointestinal stromal tumor,GIST）c-kit基因突变特征与临床病理、分子靶向治疗及预后的相关性。方法采用文献复习的方法,对研究胃肠道间质瘤分子遗传学机理的相关文献加以综述。结果 c-kit基因突变可能是GIST发生的早期事件,是GIST的普遍现象,不能作为GIST预后判断的指标。然而,c-kit突变位点和方式是否影响GIST的生物学行为,能否作为评估预后的指标仍存在争议。结论基因突变检测对从分子水平上研究疾病、判断预后以及指导用药具有重要意义,需要不断地深入研究。     

胃肠道间质瘤的诊治理念

胃肠道间质瘤(GIST)是一种具有基因和分子特征性的肿瘤。胃肠道间叶源性肿瘤中最常见。GIST均具有生物学的侵袭行为,因此治疗原则应以手术切除为主,且必须遵循无瘤操作以及防止瘤体破溃的原则。GIST常发生肝转移和腹膜转移,少有淋巴结转移,故除非术中发现有淋巴结转移,一般不常规行淋巴结清扫。其切除范围和术式应根据瘤体大小、解剖部位并结合对肿瘤恶性潜能的评估再作抉择。GIST对常规化疗和放疗不敏感,以格列卫为代表的分子靶向治疗是一种较好的辅助治疗。应强调指出:若拟行格列卫新辅助治疗或术中已有多处无法切除的转移灶而拟行术后化疗时方可考虑活检,但禁忌术前经皮穿刺活检,以免瘤体破溃酿成腹膜转移。     

胃肠间质瘤基因突变和分子靶向治疗相关研究进展

胃肠管间质瘤是最常见的胃肠管原发的间叶源性肿瘤.胃肠管间质瘤的发生是由KIT基因突变导致KIT蛋白的组成性激活引起的.血小板源性生长因子受体α(platelet-derived growth factor receptor alpha,PDGFRA)也与胃肠管间质瘤的发病机制有关.KIT的突变位点主要是exon11、exon9、exon13和exon17;PDGFRA的突变位点主要是exon18、exon12和exon14.胃肠间质瘤的临床病理参数、对甲磺酸依马替尼的反应与突变所在的位置及突变类型相关.甲磺酸伊马替尼是一个选择性的小分子酪氨酸激酶抑制剂,其临床应用是胃肠管间质瘤分子靶向治疗的里程碑.本文就胃肠管间质瘤基因突变和分子靶向治疗的研究进展概述.     

Management of gastrointestinal stromal tumors

A gastrointestinal stromal tumor (GIST) is a rare mesenchymal malignancy of the gastrointestinal (GI) tract. Malignant GISTs were first defined as a separate entity from a collection of nonepithelial malignancies of the GI tract in the 1980s and 1990s based on pathologic and clinical behavior. The discovery of activating KIT mutations as a near-uniform occurrence in these tumors greatly influenced the classification [1] and revolutionized therapeutic management of these tumors. To meet the next challenges, newer tyrosine kinase inhibitors and targeted agents are being developed with the goal of providing improved response rates or alternative therapies for patients progressing on established agents. In this article, the authors describe the management of GISTs, concentrating on surgical management and targeted therapies.     

胃肠道间质瘤的预后

随着对胃肠道间质瘤（gastrointestinal stromal tumor，GIST）分子生物学的认识和激酶抑制剂类靶向治疗药物的诞生，GIST的预后也发生了明显改善，疾病缓解率和手术切除率显著提高，生存期延长。不同的临床病理因素和治疗方法对GIST病人生存期具有根本影响。     

胃肠道间质瘤的内科治疗

胃肠道间质肿瘤（gastrointestinal stromal tumor，GIST）是胃肠道中一种特殊的肿瘤。近年来随着对GIST分子病理的深入研究和靶向药物的应用，GIST越发引起人们的关注。在GIST传统治疗中，手术切除至今仍是GIST惟一根治性治疗手段。但复发率极高。而放射治疗很少应用于GIST的治疗，因为其邻近器官对射线过于敏感，而肿瘤本身对射线抵抗，仅应用于减少盆腔等部位复发转移所致的疼痛或不适。多种化疗方案被试用于残留、复发的以及转移的GIST，但不论是阿霉索、异环磷酰胺、丝裂霉素、氮希咪胺、足叶乙甙、顺铂及其他细胞毒药物单药还是联合化疗，客观有效率均〈7％。目前未发现单药有效率超过10％的药物，所以不主张化学治疗GIST。对于局限在腹膜的病人术后加用腹腔内化疗，仅适用于对格列卫耐药的病人。     

Laparoscopic management of gastrointestinal stromal tumors

Background Surgery remains the standard for nonmetastatic gastrointestinal stromal tumors (GISTs). Laparoscopic surgery should be considered for these tumors as their biologic behavior lends them to curative resection without requiring large margins or extensive lymphadenectomies. Methods A retrospective review was performed of patients who underwent laparoscopic treatment of GISTs by surgeons at the Mount Sinai Medical Center from 2000-2005. Records were reviewed with respect to patient demographics, medical history, diagnostic workup, operative details, postoperative course, and pathologic characteristics. Results Laparoscopic surgery was attempted in 43 patients with GISTs. The average age was 65 years and 21 were women. Fifty-six percent of patients presented with anemia or gastrointestinal bleeding. The tumors were located in the stomach (65%) and in the small bowel (35%). The mean tumor sizes were 4.6 cm (stomach) and 3.7 cm (small bowel). Gastric operations included laparoscopic wedge (29%), sleeve (21%), and partial (29%) gastrectomies. The three gastric conversions were due to local invasion of tumor into adjacent organs or proximity to the gastroesophageal junction. Small bowel operations included laparoscopic resections with extracorporeal (47%) and intracorporeal anastamoses (33%). Conversion in small bowel operations was associated with coincidental pathology in addition to the GIST. This consisted of an associated bowel perforation and a synchronous colonic carcinoma. There was one mortality and a 9% morbidity rate, including an evisceration requiring reoperation. All tumors were pathologically confirmed with CD117 immunohistochemistry. Conclusions In light of their biologic behavior, GISTs should be considered for laparoscopic resection. This minimally invasive approach to these tumors can be performed safely and reliably.     

Laparoendoscopic management of gastrointestinal stromal tumors

Gastrointestinal stromal tumors (GISTs) account for 1% to 3% of all resected gastric tumors and are the most common submucosal mass found in the stomach. The preoperative characterization of malignancy is often difficult, and excision is the most common management option. Reported techniques are endoscopic, laparoendoscopic, and laparoscopic. The excision can be intracorporeal or extracorporeal, intragastric or transgastric. Different methods are used based on the location of the tumor. We present two cases of a three-port laparoendoscopic transgastric technique. This method can be used safely for both anteriorly and posteriorly located lesions.     

胃肠道间质瘤的规范化治疗

Gastrointestinal stromal tumors (GISTs) is a subset of mesenchymal tumors and represents the most common mesenchymal neoplasm of gastrointestinal tract.In the last decade,GISTs has become well known because of the effectiveness of imatinib mesylate.The molecular targets for tyrosine kinase receptor inhibitor are not only of importance for the treatment of patients but also useful for the development of a novel drug modalities and new strategies in basic cancer therapy.The improved understanding of the molecular mechanism of GISTs has made its diagnosis standardized.Many multicenter phase Ⅱor phase Ⅲ clinical trials have been completed to establish the role of adjuvant and neoadjuvant therapy.It is important to select the correct management strategy,which is multidisciplinary,integrated,and individualized.This paper provides an overview of the rational treatment of GISTs at present.     

胃肠道间质瘤的临床研究

目的探讨胃肠道间质瘤（GIST）临床病理特点、手术治疗及预后。方法对1997年4月至2008年6月间84例手术切除的GIST患者的临床病理资料进行回顾性分析,并评价预后。结果84例GIST位于胃42例,小肠24例,食管5例,直肠6例,胃肠道外7例;肿瘤直径（5．6±4．8）cm,肿瘤组织免疫组织化学检测CD117阳性表达率为96．4％。79例行肿瘤完全切除,5例行姑息切除或肿瘤活检。78例获随访患者1、3、5年生存率分别为92．0％、79．2％和72．0％,根据肿瘤直径和核分裂像计数分级的Fletcher恶性程度风险分级与生存率有密切关系（P〈0．01）,极低度风险组、低度风险组生存率与高度风险组生存率间差异有统计学意义（P值分别为0．003及0．000）。结论GIST的Fletcher分级与患者术后生存率有关。对高度风险者,需积极施行切除范围较大的手术。     

Laparoscopic resection of gastrointestinal stromal tumors

BACKGROUND: Laparoscopic resection has become an accepted approach to gastrointestinal stromal tumors (GISTs), with acceptable early results published in the literature. Long-term recurrence rates, however, are still unclear, and the management of tumors in challenging locations requires exploration. METHODS: A retrospective analysis of all patients undergoing a laparoscopic resection of gastric GIST in our institution between November 1997 and July 2004 was performed. RESULTS: A total of 14 patients with 15 tumors were evaluated, 5 of which were located high on the lesser curve. All the patients had an attempted laparoscopic approach, with the following procedures performed: stapled wedge excision (n = 8), excision and manual sewing technique (n = 4), and distal gastrectomy (n = 1). Overall, there was a 15% (n = 2) conversion rate. Lesions found in the fundus and greater curvature areas were easily resected via simple stapled wedge excision. High lesser curve tumors were more difficult to manage and required a combination of methods for complete excision and preservation of the gastrointestinal junction including intraoperative gastroscopy, excision and manual sewing technique, and reconstruction over an esophageal bougie. There were no postoperative complications, and the length of hospital stay was 4.6 +/- 1.9 days. At a median follow-up period of 46.5 months (mean, 37.4 +/- 26 months), one patient experienced a recurrence (18 months postoperatively), with eventual disease-related death. CONCLUSION: The laparoscopic approach to gastric GIST tumors is safe and associated with acceptable short- and intermediate-term results. High lesser curve GISTs can be safely approached laparoscopically using various techniques to ensure an adequate resection margin without compromise of the GE junction.     

胃肠间质瘤的外科治疗

近年来,关于胃肠间质瘤(gastrointestinal stromal tumor,GIST)的研究已越来越受到国内外医学界的重视。2005年美国NCI(National Cancer Institute)的一项回顾性调查报告显示,年发病率为0.68/10万;瑞典报道年发病率为14.5/100万。我国尚无GIST发病率的调查数据。GIST具有肿瘤边界清楚、质地较脆、常有假包膜、淋巴转移少