进展期胃肠间质瘤的诊治进展

目的总结进展期胃肠间质瘤(GIST)的诊断及治疗进展。方法通过检索相关文献资料,就近年来关于进展期GIST的诊断及治疗进展情况进行综述。结果进展期GIST的诊断主要依靠CT、MRI等影像学以及内镜或超声内镜等辅助检查,考虑术前行伊马替尼治疗的GIST患者可以行穿刺活检确定诊断。目前,对于进展期GIST患者来说,伊马替尼为一线靶向治疗药物,其次为舒尼替尼和其他新型靶向药物。在靶向药物治疗的基础上联合手术、射频消融、栓塞化疗等多学科综合治疗能给进展期GIST患者带来更多的临床获益。结论 GIST易转移,临床医生应做到早诊断、早治疗。在靶向药物治疗的基础上根据患者的具体情况采取个体化治疗。     

伊马替尼在进展期胃肠间质瘤的应用分析

目的探讨伊马替尼治疗进展期胃肠间质瘤（GIST）患者的临床疗效及其影响因素。方法回顾性分析2004年4月至2010年1月间在中山大学附属第一医院接受伊马替尼治疗的73例成人进展期GIST患者的临床资料。分析其治疗效果和影响疗效的因素。结果73例GIST患者接受伊马替尼治疗后完全缓解1例,部分缓解53例,疾病稳定14例,疾病进展5例。全组均获随访,随访时间12～76（中位随访32）个月,中位无进展生存期45．0个月（95％CI：34．2～55．8个月）,1、3、5年无进展生存率（PFS）分别为87．7％、63．6％和39．6％。多因素分析显示,基因突变情况和治疗前体力状态评分是伊马替尼治疗疗效的独立影响因素：c-kit外显子11突变患者PFS优于外显子9突变者;治疗前体力状态低评分者优于高评分者（均P〈0．01）。结论伊马替尼治疗进展期GIST疗效肯定,c-kit外显子9突变和体力状态不良的患者接受伊马替尼治疗效果不佳。     

进展期胃肠间质瘤的合理诊疗策略

随着对胃肠间质瘤（GIST）认识的提高。临床上诊断为GIST患者的比例逐年升高。早期GIST行手术完整切除预后良好,而进展期GIST无论是在单纯手术治疗阶段、单纯伊马替尼靶向治疗阶段还是手术联合伊马替尼治疗阶段,手术后再复发、伊马替尼耐药和靶向药物多重耐药等问题仍然是目前治疗的难点。大量的临床证据显示．合理的治疗策略可以改善进展期GIST患者的预后。进展期GIST绝不能单纯认为是内科或者外科疾病,需要包括肿瘤外科、肿瘤内科、病理科、影像科和介入科等多学科协作组的综合诊疗。本文结合目前国内外最新研究进展．基于循证医学证据和笔者经验．提出进展期GIST的合理诊疗策略．以期达到早期发现、初期预防和恰当管理的目标．从而改善患者预后．延长生存期．     

伊马替尼耐药晚期胃肠间质瘤治疗策略

胃肠间质瘤（GIST）是消化道最常见的间叶组织来源肿瘤。目前伊马替尼是转移或不可切除GIST的标准一线治疗药物。近10年随着伊马替尼进入GIST的治疗领域,以往不可治愈GIST病人的预后得到明显改善。然而,多数伊马替尼初始治疗有效的晚期GIST,会在2～3年内发展成伊马替尼继发耐药,原因可能与肿瘤中存在继发c-kit基因突变的多细胞克隆有关。舒尼替尼和新近的瑞格非尼均已获美国食品药品监督管理局（FDA）批准分别用于伊马替尼治疗失败的GIST二线和三线治疗,从而拓展了伊马替尼耐药GIST的治疗选择。对于酪氨酸激酶抑制剂治疗基础上出现局部进展的转移GIST,减瘤手术可使病人获益。对于伴发急性肠梗阻、穿孔或出血的晚期GIST,手术可减轻病人症状。     

细胞内伊马替尼浓度在胃肠道间质瘤耐药过程中的作用

目的探讨细胞内伊马替尼浓度与胃肠道间质瘤（GIST）耐药性的关系。 方法随机选择南京医科大学第一附属医院2014年12月至2016年4月伊马替尼耐药和敏感的进展期GIST患者各4例,采用液相色谱-串联质谱法（LC-MS/MS）检测细胞内外、组织内与血浆伊马替尼浓度。苏木精-伊红染色和免疫组织化学法观察细胞的形态特征。 结果伊马替尼耐药患者组织内药物浓度比敏感患者的组织内药物浓度低（P<0.05）。与亲代敏感细胞株相比,伊马替尼耐药GIST细胞株中细胞内伊马替尼浓度显著降低,同时细胞形态也发生了变化。 结论低细胞内药物浓度可能是伊马替尼耐药的重要原因,细胞内伊马替尼浓度可能是治疗GIST过程中的关键要素。     

直肠间质瘤伊马替尼新辅助治疗后经肛门内镜显微手术切除：附13例报告

目的:评价伊马替尼新辅助治疗结合经肛门内镜显微手术(TEM)局部切除治疗直肠间质瘤(GIST)的疗效和安全性。方法:入组13例直肠GIST患者,先予以伊马替尼治疗30~90 d,肿瘤退缩后予以TEM局部切除肿瘤,分析患者术前临床病理资料、新辅助治疗反应性及相关手术指标。结果:接受伊马替尼新辅助治疗3个月内所有患者均出现缓解,肿瘤降期显著。所有患者除1例改行腔镜下经腹直肠局部切除外,均行TEM局部切除,其中9例的患者(70%)在接受伊马替尼治疗2个月内进行手术。平均手术时间45 min,平均术后住院时间6.7 d。11例患者(85%)手术出血少于20 m L,无术后严重出血或感染病例。无治疗相关死亡或其他严重不良事件。12例TEM患者随期无复发或死亡。结论:部分局部进展期直肠GIST,伊马替尼新辅助治疗后结合TEM能够获得理想的手术效果,安全性高,手术创伤小,是一种可选择的治疗方式。     

胃肠道间质瘤的分子靶向治疗

分子靶向药物的出现,改变了胃肠道间质瘤(GIST)的治疗模式.伊马替尼400 mg/d被推荐为转移性GIST的标准一线治疗方案.伊马替尼标准剂量治疗失败后,增加伊马替尼剂量或换用舒尼替尼治疗可进一步延长患者生存时间,同时新的分子靶向药物显示出了治疗GIST的潜在活性.GIST完整切除术后,伊马替尼辅助治疗可改善中高度复发风险患者的无复发生存率.伊马替尼术前治疗可提高手术切除率,但是否使患者生存获益尚未得到最终证实.c-kit和(或)血小板源性生长因子受体α(PDGFRα)基因突变可以预测伊马替尼与舒尼替尼的疗效,同时亦有助于辅助治疗获益人群的筛选.     

对复发转移性胃肠间质瘤手术还是不手术

复发转移性胃肠间质瘤（GIST）的处理是目前临床治疗的一大难题。国际上一些大型临床试验显示．伊马替尼治疗可显著改善复发转移GIST患者的生存期。而手术联合伊马替尼已成为转移GIST的理想治疗方法。然而．两者如何联合应用尚存在争议。伊马替尼可能影响凝血机制．因此,建议术前1周停药。细胞减灭术在复发转移性GIST中有一定的临床疗效,可与靶向药物联合应用。而复发转移GIST的临床试验尚需进一步评价。     

晚期胃肠道间质瘤靶向治疗后的外科治疗

目的探讨手术对于伊马替尼治疗后晚期胃肠道间质瘤（GIST）患者的临床疗效。方法回顾性分析13例术前予以伊马替尼治疗,然后接受手术切除的晚期GIST患者的临床资料。结果13例伊马替尼治疗后手术切除的患者中,有3例为局部晚期原发肿瘤,10例为复发或转移患者。治疗有效（RD组）的5例中有4例、疾病进展（PD组）的8例中有1例共计5例（38．5％）患者肿瘤获得完全切除。RD组无疾病进展生存（PFS）为24．8个月,PD组的PFS为2．8个月,两组比较,差异有统计学意义（P〈0．01）。RD组和PD组患者的总生存率比较,差异无统计学意义（P〉0．05）。结论在对伊马替尼治疗有效的晚期GIST患者中,伊马替尼治疗后再行外科手术切除是可行的。     

胃肠间质瘤的外科及靶向治疗策略

众所周知,伊马替尼等靶向药物改变了胃肠间质瘤（GIST）病人的治疗策略。但目前伊马替尼等的应用已从单纯药物治疗模式向与外科治疗联合应用的模式转变。PET?CT显像结果与临床症状缓解相一致,可早期评价GIST病人的疗效。动态增强超声造影已成为GIST靶向药物治疗疗效评价新的功能成像方法。对于高危的GIST病人,术后应采用伊马替尼辅助治疗1~2年。新辅助治疗在GIST中的应用已被广泛接受。目前认为对于伊马替尼耐药的病例,应用舒尼替尼治疗是安全可接受的。     

A Randomized, Phase II Study of Preoperative plus Postoperative Imatinib in GIST: Evidence of Rapid Radiographic Response and Temporal Induction of Tumor Cell Apoptosis

Gastrointestinal stromal tumor (GIST) is the most common sarcoma arising in the gastrointestinal (GI) tract. Imatinib mesylate (imatinib) is efficacious in treating advanced and metastatic GIST. Patients undergoing resection of GIST realize a highly variable median disease-free survival (DFS). In the absence of prospective data, we conducted a randomized, phase II study to assess the safety and efficacy of preoperative and postoperative imatinib for the treatment of GIST. Nineteen GIST patients undergoing surgical resection were randomized to receive 3, 5, or 7 days of preoperative imatinib (600 mg daily). Patients received postoperative imatinib for 2 years. Perioperative adverse events were compared with those in an imatinib-naïve historical control. The efficacy of imatinib was assessed by ¹⁸fluorodeoxyglucose positron emission tomography (¹⁸FDG-PET), dynamic computed tomography (dCT), terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, and DFS. Imatinib did not affect surgical morbidity as compared with an imatinib-naïve cohort (p ≥ 0.1). Most patients responded to preoperative imatinib by ¹⁸FDG-PET and dCT (69% and 71%, respectively). Tumor cell apoptosis increased by an average of 12% (range 0–33%) and correlated with the duration of preoperative imatinib (p = 0.04). Median DFS of patients treated with surgery and imatinib was 46 months (range 10–46 months). Tumor size was a predictor of recurrence after postoperative imatinib (p = 0.02). Imatinib appears to be safe and may be considered for patients undergoing surgical resection of their GIST. Radiographic response and tumor cell apoptosis occur within the first week of imatinib therapy.     

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??Analysis of the effectiveness of imatinib preoperative adjuvant therapy in 23 patients with locally advanced gastrointestinal stromal tumor CHEN Si-le, SONG Wu, PENG Jian-jun, et al. The First Affiliated Hospital, SUN Yat-sen University, Guangzhou 510080, China
Corresponding author: ZHANG Xin-hua??E-mail: zhangxh_sysu@163.com
Abstract Objective To investigate the efficacy and safety of preoperative adjuvant therapy with imatinib for locally advanced gastrointestinal stromal tumor (GIST). Methods The clinicopathological data of 23 patients diagnosed with locally advanced GISTs who received imatinib as preoperative adjuvant therapy in the First Affiliated Hospital, SUN Yat-sen University from January 2008 to December 2013 were analyzed retrospectively. Results Preoperative imatinib was given for 6??1-18??months, 22 patients with 400 mg/day, and 1 with 600 mg/day, with continuous oral administration. Image study for response assessment was achieved in 22 cases, of which 19 cases(86.4%) gained partial response [18 cases (81.8%) with pathologically partial response , 1 cases providing pathologically complete response (4.5%) after operation], 3 cases(13.6%)with stable disease . The tumor size was reduced 4??0-9??cm after preoperative treatment. The mean time from imatinib withdrawal to operation was 7??5-14??days. During the preoperative treatment of imatinib, the incidence of adverse event of grade 3 or above was 26.1??6/23??, including 2 cases of neutropenia(grade 3), 1 case of rash(grade 4), and 3 cases of gastrointestinal bleeding(1 case death). Complete resection was performed in 22 cases. Postoperative complications at grade 3 or above occurred to 2 patients (9.1%), both of whom were of delayed gastric emptying and resolved with conservative therapy. There were 18 cases (81.8%) with KIT exon 11 mutation, 3 cases(13.6%) with KIT exon 9 mutation and 1 case(4.5%) with KIT and PDGFRA wild-type. Twenty out of 22 patients received adjuvant therapy after operation, and the median time of adjuvant therapy was 25(4—74) months. The median time of follow-up was 50 (39—105) months, 5-year disease-free survival rate and overall survival rate were estimated to be 65.6% and 80.5%, respectively. But univariate and multivariate Cox regression analysis showed no significant difference in progression free survival and overall survival time. Conclusion Preoperative imatinib therapy for locally advanced GISTs is generally well tolerated, and is helpful to narrow the scope of surgery. Though the incidence of serious adverse event is low, the side effects of the treatment should be observed and treated reasonably during the preoperative imatinib therapy. Whether or not imatinib preoperative adjuvant therapy can improve the total survival of patients with GIST needs to be further studied in large samples.     

接受伊马替尼治疗的156例胃肠间质瘤临床分析

目的探讨胃肠间质瘤（GIST）不同危险程度、不同部位以及不同方案治疗患者的预后。方法回顾性总结2006年1月至2010年12月间在天津医科大学附属肿瘤医院接受伊马替尼治疗的156例成人GIST患者的临床资料。依据改良的NIH危险度分级,30例患者纳入中危组：126例患者纳人高危组,其中67例为晚期GIST（复发转移或病情进展）。肿瘤原发于胃78例,非胃（小肠、结直肠、肠系膜及腹膜后）78例。全组均接受口服伊马替尼400mg／d的治疗,其中根治术后口服伊马替尼89例（根治术后辅助治疗组）;另67例为晚期GIST（复发转移或病情进展）患者中,根治术后肿瘤进展后口服伊马替尼26例（根治术后进展治疗组）,姑息术后口服伊马替尼27例,未手术而单纯服用伊马替尼14例。比较原发肿瘤不同危险程度、不同部位以及不同治疗方法患者的生存情况。结果全组156例患者对伊马替尼治疗的总体耐受性良好。全组均获得随访,随访时间9～56（中位时间27）月,1、2、3年总体生存率（OS）分别为96％、81％和71％。高危组1、2、3年0s分别为95％、77％和65％,中危组均为100％,两组差异有统计学意义（P=0．001）。肿瘤原发于胃组患者1、2、3年0s分别为97％、90％和84％;肿瘤原发非胃组患者1、2、3年OS分别为95％、69％和52％,两组差异有统计学意义（P=0．000）。根治术后辅助治疗组患者1、2、3年OS分别为98％、95％和90％。晚期GIST患者1、2、3年OS分别为91％、58％和43％;其中根治术后进展治疗组分别为92％、74％和56％,姑息术后治疗组分别为92％、51％和21％,未手术治疗组分别为77％、27％和0;前组的预后明显优于后两组（P=0．000）。结论高危GIST和肿瘤位于非胃以及晚期患者的预后不佳。根治性手术及应用伊马替尼能够改善晚期GIST患者的预后。     

局限进展期胃肠间质瘤行伊马替尼术前辅助治疗23例疗效分析

目的 探讨局限进展期胃肠间质瘤（GIST）行伊马替尼术前辅助治疗的有效性和安全性。方法 回顾性分析中山大学附属第一医院2008年1月至2013年12月确诊为局限进展期GIST并接受伊马替尼术前辅助治疗的23例病人的临床病理资料。结果 术前伊马替尼治疗中位时间为6（1～18）个月,22例400 mg/d,1例600 mg/d持续口服。22例获得有效的影像学评价,其中,19例（86.4%）影像学评价为部分缓解［1例术后证实病理学完全缓解（4.5%）;实际部分缓解18例（81.8%）］;疾病稳定3例（13.6%）。无原发耐药进展的病人。经过术前治疗,肿瘤缩小中位数为4（0～9）cm。伊马替尼术前停药时间为7（5～14）d。伊马替尼术前治疗期间,3级或以上不良反应发生率26.1%（6/23）,其中3级粒细胞减少2例,4级药疹1例,消化道出血3例（1例死亡）。手术完整切除22例。术后发生3级以上手术相关并发症2例（9.1%）,均为术后延迟性胃排空,均经保守治疗后治愈。22例病人中,KIT基因外显子11突变18例（81.8%）,KIT基因外显子9突变3例（13.6%）,KIT和PDGFRA野生型1例（4.5%）。20例病人术后接受辅助治疗,辅助治疗中位时间25（4～74）个月。随访中位时间为50（39～105）个月。预计术后5年无病存活率和总存活率分别为65.6%和80.5%。但单因素及多因素Cox回归分析显示,术后无进展生存及总生存时间与各种因素无相关性。结论 伊马替尼术前辅助治疗局限进展期GIST总体耐受良好,有助于缩小手术范围,严重不良反应发生率低,治疗期间应注意观察和合理处理药物副反应。伊马替尼术前辅助治疗能否改善GIST病人总生存期尚待进一步大样本研究。     

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??Application of preoperative target therapy and the timing of surgery for gastrointestinal stromal tumor LI Zi-yu, LI Shuang-xi, JI Jia-fu.Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education)??Department of Gastrointestinal Surgery, Peking University Cancer Hospital & Institute, Beijing 100142, China
Corresponding author: LI Zi-yu, E-mail: ziyu_li@hsc.pku.edu.cn
Abstract With the progression in pathogenesis and drug developments, the emergence of small molecule tyrosine kinase inhibitor (imatinib) changed the treatment modality of gastrointestinal stromal tumors (GIST), which centered on surgery mainly in the past. For the locally advanced or metastatic disease, the preoperative treatment could increase resection rate, preserve organ function, decrease recurrence, and even bring survival benefits. However, preoperative treatment of GIST still lacks large sample prospective randomized study data. Various studies have significant differences in patients' enroll standard, dosage, time, evaluation and adjuvant therapy. There are still many controversies about the duration of the preoperative treatment of GIST and timing of surgery.     

靶向治疗高危胃肠道间质瘤的临床疗效

目的:探讨应用伊马替尼治疗高危胃肠道间质瘤(GIST)的临床疗效。方法:回顾性分析2010年1月—2015年6月收治的56例接受伊马替尼靶向治疗的高危GIST患者临床资料,并对疗效进行分析。结果:19例无手术切除机会的患者经伊马替尼(400 mg/d)治疗6~8个月后,无完全缓解(CR)者,部分缓解(PR)14例,疾病稳定(SD)4例,疾病进展(PD)1例;7例(36.8%)PR患者获得手术切除机会。35例行手术切除后服用伊马替尼(400 mg/d)1年,随访3例复发,1年复发率8.6%;2例终断服药,无法评估疗效。结论:伊马替尼治疗GIST疗效肯定,对于高危GIST患者,术前新辅助化疗能让无法手术切除的肿瘤获得手术机会,术后辅助化疗可能提高无瘤生存率,不良反应较轻能够耐受。     

Indikationen zur prä- und postoperativen Therapie mit Imatinib bei gastrointestinalen Stromatumoren

Imatinib is a tyrosine kinase inhibitor directed against the KIT and the PDGF-alpha receptors. Imatinib has proven efficacy in the treatment of metastatic GIST with a response rate achieving 70%, but treatment with imatinib alone is not curative. The median progression-free survival is about 2 years. In locally advanced GIST, primary treatment with imatinib proved to be safe and feasible in several cohort studies. The goal of any curatively intended surgical treatment for GIST is R0 resection. Therefore, neoadjuvant treatment with imatinib can be recommended if tumor-free margin resection is doubtful. After R0 resection of GISTs with intermediate or high risk of relapse, preliminary data indicate that imatinib administered for at least 1 year reduces the risk of relapse and may improve the prognosis. However, no mature survival data from randomized studies have been published thus far. Therefore adjuvant treatment with imatinib is not yet approved nor is it a standard of care at this stage. The inclusion of patients with intermediate- and high-risk resected GIST into clinical studies is strongly recommended.     

Surgical Resection of Gastrointestinal Stromal Tumors After Treatment with Imatinib

Background Surgical resection of gastrointestinal stromal tumors (GISTs) has been the most effective therapy for these rare tumors. Imatinib has been introduced as systemic therapy for locally advanced and metastatic GIST. In this study, the surgical resection rates and long-term outcomes of patients treated with preoperative imatinib for locally advanced primary, recurrent, or metastatic GISTs were evaluated. Methods Patients were retrospectively assessed for completeness of surgical resection and for disease-free and overall survival after resection. Results Forty-six patients underwent surgery after treatment with imatinib. Eleven were treated for locally advanced primary GISTs for a median of 11.9 months, followed by complete surgical resection. All eleven were alive at a median of 19.5 months, and ten were free of disease. Thirty-five patients were treated for recurrent or metastatic GIST. Of these, eleven underwent complete resection. Six of the eleven patients had recurrent disease at a median of 15.1 months. All eleven patients were alive at a median of 30.7 months. Patients with a partial radiographic tumor response to imatinib had significantly higher complete resection rates than patients with progressive disease (91% vs. 4%; P < .001). Of the 24 patients with incomplete resection, 18 initially responded to imatinib but were unable to undergo complete resection after they progressed before surgery. Conclusions Preoperative imatinib can decrease tumor volume and is associated with complete surgical resection in locally advanced primary GISTs. Early surgical intervention should be considered for imatinib-responsive recurrent or metastatic GIST, since complete resection is rarely achieved once tumor progression occurs. Presented in part at the Annual Meeting of the Society of Surgical Oncology, Atlanta, GA, March 2005.     

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目的探讨对伊马替尼继发耐药的复发和转移的晚期胃肠道间质瘤(gastrointestinal stromal tumors,GIST)的治疗策略。方法回顾性分析复旦大学附属中山医院2000—2009年对伊马替尼继发耐药的复发和转移的晚期8例GIST病人的临床资料。结果所有病人均行手术治疗,完整切除原发肿瘤后,肿瘤复发和(或)转移,口服伊马替尼治疗产生继发耐药,采取手术切除复发和转移灶(特别是耐药病灶)联合伊马替尼等靶向治疗为主的综合治疗模式,均获得较好的治疗效果。1例死亡,存活96个月;其余7例仍存活,目前存活时间65～145个月,平均98.6个月。结论伊马替尼继发耐药的复发和转移的晚期GIST,选择手术联合酪氨酸激酶抑制剂靶向治疗为主的多学科综合治疗模式,参考肿瘤的基因状态,采取个体化治疗,可取得较好的疗效。