甲磺酸伊马替尼治疗手术无法切除的晚期胃肠间质瘤

目的：探讨甲磺酸伊马替尼用于治疗晚期胃肠间质瘤的疗效及生存获益。方法：收集2004年9 月至2015年6 月天津医科大学肿瘤医院收治的无法手术切除的61例晚期胃肠间质瘤患者的临床资料,接受初始剂量400 mg/d 的口服甲磺酸伊马替尼治疗,定期随访,评价生存获益及药物不良反应。结果：61例患者开始接受治疗1 年后,治疗有效率为57.4%（35/ 61）,疾病控制率为88.5%（54/ 61）,Logic二元回归分析显示性别、年龄和腹盆腔多发病灶是影响治疗有效率的因素（P < 0.05）。 本组患者5 年累积生存率为53% ,Cox 回归模型分析提示腹盆腔的多发病灶是影响患者生存获益的重要因素（P < 0.05）。 除2 例患者出现出血,其余患者不良反应轻微。结论：甲磺酸伊马替尼显著改善晚期胃肠间质瘤的生存获益,可作为无法手术切除的晚期胃肠间质瘤的首选治疗。     

Consensus approaches to best practice management of gastrointestinal stromal tumors

Gastrointestinal stromal tumors are rare mesenchymal tumors of the gastrointestinal tract. Progress in diagnosis has led to increased recognition of this disease, and the availability of effective, molecularly targeted therapy has revolutionised its management. Treatment of metastatic gastrointestinal stromal tumors with imatinib has led to unprecedented improvements in progression free and overall survival and there are ongoing investigations into the optimal pre‐operative and adjuvant use of imatinib. Second‐line sunitinib is now available for patients who develop resistance to imatinib, and third‐ and fourth‐line therapies are being investigated in clinical trials. In this ever‐changing environment, evidence from controlled clinical trials and the authors' experience were used to comprehensively outline current best practice management of patients with gastrointestinal stromal tumors.     

The role of surgery in the multidisciplinary management of patients with localized gastrointestinal stromal tumors

Surgical resection of localized gastrointestinal stromal tumors (GISTs) is associated with recurrence rates of approximately 50% at 5 years of follow-up. The introduction of tyrosine kinase inhibitors, such as imatinib, improved overall survival rates in advanced disease, while in the adjuvant setting, improved recurrence-free survival following resection of high-risk GIST. The demonstration of the clinical benefit of tyrosine kinase inhibitors in both the metastatic and adjuvant settings generated interest in neoadjuvant approaches for patients with operable locally advanced disease, particularly in difficult anatomic locations. The potential impact of tumor downsizing in areas such as the gastroesophageal junction, the duodenum or the rectum, on the extent of surgical resection and morbidity is real. The ongoing research regarding neoadjuvant therapy, the duration of adjuvant therapy and the optimal means by which to risk stratify patients with GIST continues to keep the treatment of this disease at the forefront of personalized cancer care.     

DOG1在胃肠道间质瘤中的表达及其临床意义

目的：探讨 DOG1在胃肠道间质瘤（GIST）中的表达及其临床意义。方法：免疫组化 Envision 法对73例 GIST 和26例非 GIST 间叶源性肿瘤检测 DOG1的表达,分析 DOG1与 GIST 的各项临床病理参数之间的关系。结果：在73例 GIST 中 DOG1、CD117和 CD34的阳性率分别为91．78％、94．52％和91．78％,而在26例非GIST 中阳性率为11．54％、3．85％ 和23．08％,以上指标在两组间的表达有统计学差异（P ＝0．000）;DOG1检测 GIST 灵敏度和特异度分别为91．80％、88．50％,而 DOG1联合 CD117检测 GIST 灵敏度和特异度分别为98．60％和84．60％,灵敏度最高;DOG1的表达与 GIST 的性别、年龄、肿瘤的位置、肿瘤的大小、核分裂象和恶性潜能分级等临床病理因素无相关性（P ＞0．05）,同时 DOG1的表达与 GIST 的预后也无相关性（P ＞0．05）。结论：在 GIST 的诊断中 DOG1与 CD117一样是敏感而特异的指标,尤其是对 CD117阴性的 GIST 的诊断中,能够起很好的补充作用,但不能作为评价 GIST 预后的指标。     

小肠胃肠道间质瘤的诊断与治疗

目的探讨小肠胃肠道间质瘤（GIST）的诊断、综合治疗疗效及预后。方法回顾性分析GIST25例临床资料。结果恶性GIST23例（92.0%）,交界性恶性GIST2例（8.0%）。临床常见的症状为腹痛、腹部肿块、消化道出血。肿瘤完全切除23例（92.0%）,姑息性切除2例。免疫组织化学检测CD117,CD34阳性率分别为94.4%（17/18）和50.0%（10/20）。本组无手术死亡病例。平均随访时间8年,复发和转移18例。全部病例术后口服伊玛替尼（格列卫）,中位无瘤生存期短期服药组（15±3）月,长期服药组（52±3）月。全组无瘤生存期（35±13）月,转移、复发后中位生存期未治疗组（6±0.3）月,单纯服药组（23±10）月;服药加手术组（51±11）月,平均生存期（12±13）月。短期服药组与长期服药组1、3、5年无瘤生存率分别为57.0%、21.0%、21.0%和100.0%、82.0%、36.0%。肿瘤转移、复发后未治疗组,单纯服药组与服药手术组0.5、1、3、5年肿瘤复发后生存率分别为14.0%、0.0%、0.0%、0.0%,64.0%、51.0%、0.0%、0.0%和88.0%、83.0%、76.0%、21.0%。结论小肠GIST临床症状缺乏特异性,确诊依靠临床及病理,免疫组织化学染色CD117、CD34阳性的联合诊断。肿瘤的完整切除和分子靶向综合治疗是小肠GIST的主要手段。肿瘤复发转移后的积极治疗是获得良好预后的重要途径。     

十二指肠间质瘤的临床病理学特点和外科治疗进展

十二指肠胃肠道间质瘤（gastrointestinal stromal tumors,GISTs）是起源于消化道卡哈尔间质细胞（interstitial cells of Cajal,ICCs）一种少见的亚群。虽然影像学、内镜技术和病理免疫组织化学已经取得显著的进步,但术前仍很难达到完全确诊。内镜超声下细针穿刺活检被认为是诊断的金标准,具有很高的敏感性和特异性,GISTs诊断率高达80%。对于非转移性原发的十二指肠GISTs,获得显微镜下阴性切缘的手术切除仍是潜在治愈性治疗手段,但由于胰十二指肠区域的复杂解剖,最佳治疗策略仍具有挑战性。复发风险和无瘤生存时间取决于肿瘤大小、核分裂数和美国国立卫生研究院（national institutes of health,NIH）复发风险分层,而不是手术方式。伊马替尼作为新辅助治疗,对治疗复发和转移性GISTs起到重要作用。对十二指肠GISTs的病理生理和治疗方式的全面深入研究将有利于发现更新且更有效的治疗方式。      

胃肠道内外间质瘤影像表现与病理危险级别相关分析

目的:探讨胃肠道内外间质瘤CT、MR表现及临床病理特点,及两者相关性。方法:回顾性分析我院27例经手术病理证实的胃肠道内、外间质瘤影像表现及其临床病理资料,对照分析影像表现与免疫组化、病理危险级别相关性。结果:27例病例均为单发病灶。病变位于胃11例,小肠5例,直肠2例,十二指肠1例,胃肠道外肠系膜及腹膜后8例。10例病灶呈圆形,其中6例位于胃,4例呈椭圆形,13例呈分叶形。直径＞5.0cm 17例,直径＜5.0cm 10例。其中19例病灶密度不均,18例病灶内见局部液化坏死,3例出现溃疡、3例出现瘘道,8例病灶密度均匀。增强扫描动脉期23例病灶边缘索条状或血管样强化,实质期全部病灶实性成分均表现进一步强化。其中4例出现肝脏转移,4例出现周围侵犯,均未出现区域淋巴结转移。病理结果:CD117（+）、CD34（+）23例,CD117（+）、CD34（-）3例,CD117（-）、CD34（+）1例;病理危险级别分组:极低危险组1例、低危险组5例、中危险组3例、高危险组18例。结论:胃肠道间质瘤影像表现具有一定特征性,病灶直径大于5.0cm,形态不规则,密度不均和/或伴液化坏死、瘘道形成,增强出现索条或血管样强化,出现周围侵犯及转移等影像表现常提示病理危险级别为中、高危险组,即恶性表现,预后不良。     

Mutational characteristics of gastrointestinal stromal tumors: A single-center analysis of 302 patients

Gastrointestinal stromal tumors (GISTs) represent a spectrum of tumors characterized by variable behaviors and activating mutations in KIT proto-oncogene, receptor tyrosine kinase (KIT) or platelet derived growth factor receptor α (PDGFRA) genes. However, whether genotype analysis should be regarded as a prognostic indicator remains unclear. In the present study, clinicopathological data and the mutation phenotypes of KIT and PDGFRA genes were assessed in a series of 302 patients with GISTs at a single center. Univariate and multivariate Cox regression analyses were performed to identify the clinicopathological and mutational factors associated with relapse-free survival (RFS) in patients who had undergone complete primary GIST resection. KIT and PDGFRA mutations were identified in 233 (77.2%) and 30 (9.9%) cases, respectively. The following clinicopathological parameters were significantly associated with a shorter RFS: Male, non-gastric tumor origin, larger tumor size (>5 cm), high mitotic activity (>5/50 high-power fields), necrosis and epithelioid morphology. Tumors at non-gastric sites, with high National Institutes of Health risk classification, high World Health Organization (WHO) grade and KIT deletion involving codons 557/558/559 exhibited a significantly higher risk of progression. In the Cox regression model, KIT deletion involving codons 557/558/559, non-gastric origin and high WHO grade were independent indicators of RFS. The adverse prognosis associated with KIT deletions involving codons 557/558/559 was also observed for gastric GISTs. Conversely, spindle morphology, KIT exon 11 substitution and PDGFRA exon 18 mutation were associated with a longer RFS and lower rate of relapse. Furthermore, the coexistence of KIT exon 11 deletion and exon 13 duplication was observed in one tumor, with adverse prognostic features. Heterogeneity affecting morphology, immunostaining and genotype was identified in 4 cases. In addition, the presence of succinate dehydrogenase-deficient GIST was found in 5 cases (3.6%). In conclusion, the tumor genotype with regard to KIT and PDGFRA mutations exhibited prognostic significance for the risk of GIST progression and may be helpful for the optimization of tailored adjuvant therapy.     

胃肠间质瘤47例临床分析

目的总结胃肠间质瘤的临床病理和免疫组织化学（免疫组化）特征,探讨其诊断和治疗,并评价预后。方法对2002年1月-2007年3月5年期间收治的47例胃肠间质瘤病人的临床资料进行回顾性分析,并完成随访。结果47例病人中CD117阳性40例（85．1％）,CD34阳性39例（83．0％）,S-100阳性10例（21．3％）,平滑肌肌动蛋白SMA阳性3例（6．4％）,结蛋白desmin全部阴性。结论CT结合内镜检查可提高诊断率,最终确诊主要依靠病理及免疫组化,CD117是诊断GIST的重要标记物,手术完整切除肿瘤效果满意．恶性GIST宜行较大范围的切除术,必要时须行联合脏器切除。     

Adherence to imatinib therapy in patients with gastrointestinal stromal tumors

Imatinib mesylate, an oral tyrosine kinase inhibitor, is indicated for first-line treatment of patients with unresectable and/or metastatic gastrointestinal stromal tumors (GIST). Imatinib also is approved as adjuvant therapy for patients following resection of primary GIST. Despite the efficacy of imatinib for the treatment of patients with GIST, adherence to treatment can prove difficult.     

Tailored management of primary gastrointestinal stromal tumors

Gastrointestinal stromal tumors (GISTs) are the most common human sarcoma and can form along the entire gastrointestinal tract. Over the last 20 years, considerable advances have been made in our understanding of the biology of GISTs. The advent of tyrosine kinase inhibitors has provided effective medical therapy for the first time. In fact, given that GIST typically is driven by either a KIT or PDGFRA gene mutation, it has become a paradigm of targeted molecular therapy. In addition, diagnostic and surgical techniques have been refined. Here, the critical aspects of primary GISTs and how they are now managed with an integrated approach are summarized. Treatment plans are developed based on specific pathologic and molecular features of the tumor. The authors outline the general principles of therapy and highlight some of the nuances. Particular focus is given to diagnosis, surgical considerations, and the use of preoperative and postoperative tyrosine kinase inhibitors.     

Perspective on updated treatment guidelines for patients with gastrointestinal stromal tumors

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract and present predominantly in middle‐aged and older individuals. Historically, the outlook for patients with GISTs was very poor because of the general lack of efficacy of conventional chemotherapy and the often limited surgical options. However, the recognition of the role of mutations of the v‐kit Hardy/Zuckerman 4 feline sarcoma viral oncogene homolog KIT and the platelet derived growth factor receptor alpha gene PDGFRα in the development of GISTs led to the evaluation of potential antitumor effects of the tyrosine kinase inhibitors imatinib and, more recently, sunitinib. Consequently, these molecularly targeted therapies were introduced into clinical practice, and the outcome for patients with GISTs improved considerably. In the last few years, the European Society of Medical Oncology, the National Comprehensive Cancer Network, and the Canadian Advisory Committee on GIST each published a major set of guidelines or practice recommendations for the management of patients with GIST. In the current review, the latest recommendations from each organization are summarized in terms of diagnosis and risk assessment, tumor staging, surgical and/or drug treatment of primary resectable and recurrent metastatic disease, and patient follow‐up and assessment. In addition, areas of consensus and points of divergence among the guidelines are highlighted along with any unresolved issues. Cancer 2010. © 2010 American Cancer Society     

甲磺酸伊马替尼治疗不能切除和/或转移的胃肠道间质瘤的临床分析

目的：评价甲磺酸伊马替尼(ST1571)治疗不能手术切除和／或转移的胃肠道间质瘤疗效和毒性。方法：口服甲磺酸伊马替尼400mg/日治疗10例不能手术切除和／或转移的胃肠道间质瘤患者。结果：9例可评价疗效，4例部分缓解，4例稳定。10例评价不良反应，非血液学毒性有水肿(主要是眼眶周围水肿)、腹痛、腹泻、恶心呕吐、乏力、腹腔肿瘤出血、间歇性肌肉痉挛和结膜炎，大多为I～Ⅱ度。血液学毒性少见。结论：酪氨酸激酶抑制剂甲磺酸伊马替尼治疗不能手术切除和／或转移的胃肠道间质瘤有一定疗效，且毒性可耐受。     

DOG1在胃肠间质瘤中表达的临床病理意义

目的：探讨DOG1、CD117等在胃肠间质瘤（GIST）中表达及其临床病理意义。方法：应用免疫组化检测40例GIST中DOG1、CD117、CD34、SMA、S-100的表达情况。结果：40例GIST中DOG1、CD117、CD34阳性率为97.5%、92.5%、80%。SMA,S-100阳性率分别为7.5%和5%。结论：DOG1和CD117的联合应用在GIST的诊断中可以提高敏感性,但是DOG1和CD117表达与GIST的危险程度无关。DOG1蛋白是一种较为敏感和特异的GIST辅助诊断抗体,对指导伊马替尼和舒尼替尼等靶向药物的应用有重要意义。     

胃肠道间质瘤37例诊治体会

目的：探讨胃肠道间质瘤的诊断与治疗。方法：回顾分析2000年-2005年收治的37例胃肠道间质瘤（GIST）的临床资料。结果：本组患者平均年龄52．3岁，男女比为1．6：1。免疫组化表型CD117、CD34阳性率均为84％，SMA阳性率38％，S-100蛋白阳性率2％。病理诊断GIST良性9例，交界性10例，恶性18例。其中36例行根治性手术或局部切除。结论：GIST的诊断有赖于内镜及影像学与免疫组化的结合，手术切除是最有效的治疗手段。     

伊马替尼治疗晚期胃肠道间质瘤

背景与目的:胃肠道间质瘤(gastrointestinal stromal tumors,GISTs)是胃肠道最常见的间叶源性肿瘤,对传统的化疗耐药.本研究评价选择性的酪氨酸激酶抑制剂伊马替尼治疗晚期胃肠道间质瘤的效果.方法:入组60例患者,男性43例,女性17例,95.0%的患者体能状况评分(ECOG)0～2分.中位年龄53岁(23～80岁).所有患者口服伊马替尼400 mg/d,评价抗肿瘤疗效和安全性,主要的入选标准是晚期胃肠道间质瘤,有可测量病灶.结果:1例无法评价疗效,无CR,PR 35例(59.3%,35/59),SD持续6个月以上者13例(22.0%,13/59),6个月内PD 11例(18.6%,11/59).不良反应较轻,最常见的Ⅲ～Ⅳ度毒性有出血(6.7%,4/60)、贫血 (5.0%,3/60)、水肿(3.3%,2/60)、腹痛 (3.3%,2/60)、腹泻 (3.3%,2/60)和恶心(3.3%,2/60).结论:酪氨酸激酶抑制剂伊马替尼治疗晚期胃肠道间质瘤有一定疗效,且毒性可耐受.     

Gastrointestinal stromal tumors: experience in 49 patients

Introduction Gastrointestinal stromal tumours (GIST) are mesenchymal tumours of the digestive tract originated in the interstitial cells of Cajal. They express the tyrosine kinase c-kit (CD117) activity receptor. Mutations in this receptor cause neoplastic development. Curative treatment continues to be radical resection of the tumour and is resistant to commonly employed chemotherapy regimens. Imatinib mesilate is a drug that inhibits c-kit activity expressed by GIST and its activity in these tumours has been demonstrated. Material and methods Retrospective study of all cases of leiomyoma, leiomyosarcoma, schwannoma, and stromal or mesenchymal tumors from 1989 to July 2004. C-kit and CD34 proteins were detected at immunohistochemical study in addition to the usual markers for mesenchymal tumours. Results 49 GISTs were diagnosed, 26 males and 23 females (mean age 64.1). symptoms were digestivetract bleeding (n=13), abdominal pain (n=13), intestinal occlusion (n=4) and others. The lesion was located in small bowel (n=22), stomach (n=19), rectum (n=3), peritoneum (n=2), esophagus (n=1), omentum (n=1), and retroperitoneum (n=1). Forty-three of the 49 patients underwent surgery; radical resection was performed in 37 (75.5%) and palliative surgery in the other six (16.2%). Two of the patients that did not undergo surgery received chemotherapy. At the time of study, 28 (57.14%) patients remained alive, 23 (46.9%) of whom were disease-free and five (10.2%) were not. Nineteen (38.7%) patients died. Conclusions The results of our series are similar to the others published. Before the year 2001, surgery was the only successful option for the GIST. Surgical resection continues being the best treatment to definitively cure this disease. Imatinib is used to treat not only resectable tumours, but even to allow the possibility to make a subsequent rescue surgery. On the other hand, Imatinib is used in the treatment of the metastatic disease.