酪氨酸激酶抑制剂联合手术治疗转移性胃肠间质瘤

目的 探讨酪氨酸激酶抑制剂（TKI）甲磺酸伊马替尼或舒尼替尼联合手术治疗晚期转移性胃肠间质瘤（GIST）的临床疗效.方法 回顾分析中山大学附属第一医院2007年6月至2009年12月接受TKI治疗后进行手术治疗的转移性GIST患者临床病理资料.结果 共计15例转移性GIST患者在TKI治疗后接受肿瘤切除手术.术前TKI治疗反应分别为疾病控制6例（40.0%）,局限性进展4例（26.7%）,全面性进展5例（33.3%）.手术相关并发症发生率20.0%.全组患者中位无进展生存期18.7个月.其中疾病控制和局限性进展组患者术后无进展中位生存期25.0个月,全面性进展组则仅为3.0个月（P＜0.01）;疾病控制和局限性进展组患者至今仍全部存活,而全面性进展组患者中位总生存期为10.5个月（P＜0.01）.结论 靶向治疗后,疾病控制或局限性进展的晚期转移性GIST患者行手术治疗安全有效,而全面性进展患者手术治疗不能改善其预后,应谨慎选择.     

伊马替尼耐药的复发转移性胃肠道间质瘤再手术的作用

目的 探讨复发转移性胃肠道间质瘤伊马替尼治疗耐药后手术干预的作用价值.方法 回顾分析2005年1月至2011年12月期间15例完全切除原发病灶后出现转移复发、接受伊马替尼治疗后出现耐药患者的临床病理资料、手术及生存情况.结果 7例患者（46.7%）依然存活,其中3例（20%）无瘤生存,4例（26.7%）带瘤生存;有1例患者失访（6.7%）;耐药后的中位生存时间为32个月,1年、2年生存率分别为85.6%和58.2%.9例患者耐药后进行了手术,其中8例患者肿瘤完全切除,1例为减瘤手术;其余6例患者则是接受伊马替尼600 mg/d或改用索坦治疗.生存分析显示,手术干预组总生存期优于未手术者（P=0.041）,中位生存时间分别为44.0个月及19.5个月.结论 对伊马替尼耐药的复发或转移性胃肠道间质瘤患者进行手术干预可能提高患者的总体生存时间,改善患者的预后.     

Rhabdomyosarcomatous differentiation in gastrointestinal stromal tumors after tyrosine kinase inhibitor therapy: a novel form of tumor progression

Approximately 80% of advanced metastatic gastrointestinal stromal tumors (GISTs) respond to treatment with the tyrosine kinase inhibitor (TKI) imatinib mesylate. However, the majority of patients suffer disease progression at a median of 2 years due to drug resistance. In general, progressing GISTs retain their typical morphology. Herein, we report 5 cases of progressing metastatic GIST with heterologous rhabdomyoblastic differentiation after TKI treatment. Histologic, immunohistochemical, and mutational analyses were performed on histologically classic GISTs and components with rhabdomyoblastic differentiation. There were 3 men and 2 women (ranging from 35 to 66 y of age). Three tumors were localized at presentation (2 stomach and 1 small bowel) and 2 presented with metastases. All localized primary tumors were high risk. Two tumors showed spindle cell morphology and 3 were epithelioid, including 1 with marked pleomorphism. After resection of the 3 localized primary tumors, intra-abdominal (2 patients) and liver (1 patient) metastases developed. All patients were treated with imatinib and showed partial clinical responses (4 patient) or stable disease (1 patient). Four patients subsequently progressed; 2 patients were treated with sunitinib after progression with minor responses. Four patients underwent surgical debulking. At last follow-up (range: 20 to 87 mo), 2 patients died of disease, 2 were alive with metastatic disease resistant to TKIs, and 1 was alive without evidence of disease. In all cases, rhabdomyoblastic differentiation was identified adjacent to areas with classic GIST morphology in at least 1 metastatic site; in 1 case, the primary tumor (after treatment with TKIs) showed heterologous differentiation. The rhabdomyoblastic components showed strong and diffuse positivity for desmin and expressed myogenin, whereas KIT was negative in the rhabdomyoblastic component in all cases. Primary KIT mutations were detected in both the conventional GIST and rhabdomyoblastic components from all patients: KIT exon 11 mutations in 4 cases and a platelet-derived growth factor receptor alpha gene exon 18 deletion in 1 case. No secondary mutations of the type associated with TKI resistance were identified in the rhabdomyoblastic areas. This is the first report of rhabdomyoblastic differentiation occurring in GISTs that progressed on TKI therapy. It is associated with loss of KIT expression, but retention of the receptor tyrosine kinase mutation of the precursor GIST. The rhabdomyoblastic differentiation can represent a diagnostic pitfall. The molecular mechanisms for this form of TKI-resistant clonal evolution remain to be determined.     

胃肠间质瘤外科治疗进展

胃肠问质瘤（gastrointestinal stromal tumor，GIST）是一种发病率相对低的疾病，其年发病率为14．5／1，000，000，但却是胃肠道最常见的问叶性肿瘤。胃肠间质瘤来源于胃肠起搏细胞——Cajal细胞，其发生部位主要是胃约占70％，其次是小肠，约占10％～20％。GIST没有绝对良恶性之分。根据肿瘤的大小、细胞的核分裂数可把GIST分为极低危、低危、中危和高危等类型。     

内镜治疗胃胃肠间质瘤的可行性

近年来,随着消化内镜技术的发展,以内镜黏膜下剥离术（ESD）及其衍生技术包括内镜黏膜下挖除术（ESE）、内镜下全层切除技术（EFR）、内镜经隧道肿瘤切除术（STER）和腹腔镜内镜联合手术（LECS）等的内镜切除技术可治疗绝大多数的胃GIST。本文就内镜治疗胃GIST的指征、方法和疗效评价进行评述。     

复发转移胃肠道间质瘤治疗策略

胃肠道间质瘤（GIST）的检出率逐年升高。大多数GIST可行手术切除,单纯手术后约70％～84％会出现复发转移,术后中位复发转移时间约为2年。中位生存期只有1年左右。伊马替尼应用于GIST治疗可延长至5年。然而,约一半以上的复发转移GIST患者应用药物半年以上后最终出现耐药,故如何合理安排此类患者治疗模式成为当前最迫切的需求。本文从复发转移GIST患者的评估、合理用药、手术干预、药物治疗失败后补救措施、患者依从性管理等方面介绍治疗策略。     

Combined surgical and molecular therapy: the gastrointestinal stromal tumor model

OBJECTIVE: This review describes the pathologic and epidemiologic features of gastrointestinal stromal tumor (GIST) as well as the contemporary management of this tumor. The integration of surgery and treatment with targeted molecular agents in the treatment of GIST is highlighted. SUMMARY BACKGROUND DATA: GIST is the most common mesenchymal tumor of the gastrointestinal tract. Its cellular origin from the interstitial cell of Cajal and distinctness from smooth muscles tumors were only recently appreciated. The discovery of the centrality of KIT proto-oncogene mutations in the pathogenesis of this tumor, and the development of imatinib mesylate, a specific inhibitor of KIT tyrosine kinase function have revolutionized the treatment of GIST. METHODS: We conducted a review of the English literature on GIST. The pathology, epidemiology, diagnosis, and treatment of this tumor are summarized with particular emphasis on recent developments in the field. RESULTS: GIST is a rare tumor that usually arises from the stomach or small intestine. It is characterized by immunohistochemical staining for KIT. Treatment of primary localized tumors is surgical. The benefit of adjuvant treatment with the KIT tyrosine kinase inhibitor imatinib is the subject of investigation. The treatment of unresectable, recurrent, or metastatic GIST is primarily imatinib treatment. The integration of surgery or ablative modalities is often employed, particularly when all disease is amenable to gross resection or destruction, or when GIST becomes resistant to imatinib. Newer tyrosine kinase inhibitors, such as sunitinib are the subject of ongoing investigation. CONCLUSIONS: The treatment paradigm for GIST has required the integration of surgery and molecular therapy and this will likely serve as a paradigm for the treatment of other solid tumors as targeted agents are developed.     

Outcome following surgical therapy for gastrointestinal stromal tumors

We have pursued an approach of complete resection for patients with gastrointestinal stromal tumors (GISTs), including multivisceral resection, for patients with disease involving adjacent organs. We have also extended the limits of resection to include patients with metastatic disease who were treated with imatinib mesylate. The aim of this study is to report the outcomes and prognostic factors associated with this clinical approach. Study subjects were identified using the pathology database at our institution; for inclusion in the study group, patients must have undergone surgical resection for a KIT-positive gastrointestinal stromal tumor between January 1992 and March 2004. We calculated survival by using the Kaplan-Meier method. Univariate and multivariate analysis was performed using log-rank analysis and the Cox proportional hazards model. Thirty-four patients met the study criteria. Fifty-nine percent of patients had GISTs of gastric origin, 20.6% had duodenal GISTs, and the remainder was comprised of a variety of other sites. Twenty-two (64.7%) patients underwent single-organ resection, and 12 patients (35.3%) underwent multivisceral resection. Estimated actuarial survival at 5 years was 65.2%. Seven patients (five patients with metastases, one patient with locally advanced disease, and one patient with organ-confined disease) received imatinib mesylate. Independent predictors of poor survival included incomplete resection, metastatic disease at presentation, and high mitotic index. Mitotic index and the presence of metastases remain the primary predictors of postoperative survival. Complete surgical resection, even if multivisceral resection is required, is associated with improved survival. Presented at the Forty-Sixth Annual Meeting of The Society for Surgery of the Alimentary Tract, Chicago, Illinois, May 14–19, 2005 (poster presentation).     

胃肠道间质瘤的辅助治疗

原发性胃肠道间质瘤（GIST）手术切除率约为85％,术后5年的复发率为50％,5年总体生存率约为50％。术后应根据肿瘤大小、核分裂像数目、原发肿瘤的部位以及术中情况（肿瘤破裂、出血、坏死、浸润、淋巴结转移征象）来仔细评估GIST的复发风险。伊马替尼辅助治疗可改善GIST术后中高复发风险的无复发生存率,基因检测指导辅助治疗已得到初步结果,但辅助治疗最适疗程尚无定论。在GIST的辅助治疗领域,仍有很多尚未解决的问题需要进一步研究。     

Transvaginal resection of a rectal gastrointestinal stromal tumor

We herein report a case in which a rectal gastrointestinal stromal tumor (GIST) was resected transvaginally. The patient, a 45-year-old female, had a rectal GIST on the anterior wall of the lower rectum. The tumor was within 6?cm of the anal verge, a location which would normally require performing an ultra-low anterior resection using the Double Staple Technique, and a diverting stoma. To minimize the invasiveness of treatment and to reduce the postoperative morbidity, a transvaginal resection was performed. Under general anesthesia, the posterior vaginal mucosa was incised vertically. The tumor was then excised en bloc with the overlying rectovaginal septum and rectal mesenchymal tissue. The defect was repaired primarily, and a diverting stoma was not required. The procedure was uncomplicated, and the patient was discharged home with an intact anal sphincter function and no abdominal incisions. In female patients, transvaginal resection of low anterior rectal lesions may provide a minimally invasive alternative to the traditional ultra-low anterior resection.     

胃肠间质瘤新辅助与术后辅助治疗

胃肠间质瘤（gastrointestinal stromal tumor，GIST）是一类发生在胃肠道，组织形态及免疫组化表现特殊的间质肿瘤，在约95％的GIST中酪氨酸激酶受体蛋白（KIT、CD117）存在阳性表达。一般认为，GIST的发生与c—KIT基因突变有关：c—KIT基因突变导致KIT受体结构异常，从而无须干细胞因子（SCF）的参与也能持续激活KIT信号传导通路，导致GIST肿瘤细胞不断增殖。GIST对一般的放化疗不敏感，但随着伊马替尼为代表的选择性酪氨酸激酶抑制剂（TKI）的问世，GIST的治疗获得了极大进展，应用TKI制剂进行辅助与新辅助治疗也是目前GIST治疗领域研究的热点问题。     

胃肠间质瘤靶向治疗的影像学评价

影像学是评价胃肠间质瘤（GIST）靶向治疗疗效的重要手段。RECIST形态学标准在靶向治疗中的应用存在一定限度．主要表现为基于传统径线评效不能准确地反映疗效变化。结合肿瘤径线及CT值变化率的Choi评效标准．拓展了影像学在GIST靶向治疗评价疗效的应用价值。新近的研究显示．磁共振扩散加权成像（DWI）表观扩散系数（ADC）值的变化,可早期反映GIST靶向治疗疗效．有效者在初始治疗后1周内即可出现ADC值的显著改变。通过基于肿瘤生物学行为影像因素的综合分析,可为胃肠间质瘤靶向治疗评效提供新的途径。     

Laparoscopic-assisted resection of a bleeding gastrointestinal stromal tumor.

The authors report a case of a 29-year-old male patient with a severe lower gastrointestinal hemorrhage in whom a successful laparoscopic diagnosis and resection (assisted) of an ileal gastrointestinal stromal tumor (GIST) was performed. Laparoscopy can be very useful in the diagnosis and treatment of selected cases of lower gastrointestinal bleeding.