Resection of residual disease in patients with metastatic gastrointestinal stromal tumors responding to treatment with imatinib

Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors of the gastrointestinal tract. Long-term survival of patients with metastatic disease has only been observed in patients with completely resected disease. Recently, the tyrosine kinase inhibitor imatinib has been found to yield responses in the majority of patients with metastatic GIST suggesting improved resectability in responding patients. Combined treatment approaches including resective surgery after imatinib treatment in patients with advanced metastatic disease have rarely been explored. We report a series of 90 patients with metastatic GIST in whom treatment with imatinib enabled 12 patients with mostly recurrent and extensive disease to be considered for resection of residual disease. In 11 of these patients, complete resection could be achieved. Viable tumor cells were found in all but one resected specimens suggesting that despite favorable radiological or clinical responses, imatinib is unlikely to induce pathological complete responses. Until more mature data from prospective trials are available, these data suggest that an early aggressive surgical approach should be considered for all patients with metastatic GIST. Further trials investigating a combined surgical and pre/postoperative treatment with imatinib in patients with advanced metastatic GIST are warranted.     

Imatinib mesylate: a molecularly targeted therapy for gastrointestinal stromal tumors

Although their overall incidence is uncommon, gastrointestinal stromal tumors (GIST) are the most frequently encountered mesenchymal tumors of the GI tract. Their pathology has been recently defined by the presence of KIT (transmembrane receptor tyrosine kinase). The majority of GISTs have c-kit gain-of-function mutations mainly in exon 11 (highly conserved juxtamembrane region) that eventuates in constitutive activation of KIT, promoting proliferation and antiapoptotic signaling. Imatinib mesylate (Gleevec) is a specific inhibitor of KIT kinase activation, and in phase II clinical trials has proven to be remarkably efficacious in heavily pretreated GIST patients with advanced disease. The molecular and genomic determinants of response/resistance patterns are the subject of ongoing studies, and adjuvant studies are also under way. The initial evaluations of imatinib provide proof of concept for the hypothesis-driven design of selective molecularly targeted therapies for solid tumor malignancies.     

胃肠间质瘤的治疗进展

作为胃肠道最常见的一类间叶源性肿瘤,胃肠间质瘤（GIST）越来越受到关注。近10年来,随着对GIST分子机制研究的深入,以伊马替尼为代表的分子靶向药物的出现,改变了GIST的传统治疗理念,形成了外科手术联合分子靶向药物的治疗模式。靶向药物在GIST的术前、术后辅助治疗及晚期GIST中的应用显著改善了患者的预后,延长了生存时间。但是,针对不同期别的GIST,应该如何合理应用这些靶向药物,临床还有很多问题亟待解决。本文就GIST的围手术期治疗及晚期GIST治疗的最新进展作一综述。     

胃肠间质瘤的基因分型及相关研究进展

胃肠间质瘤（gastrointestinal stromal tumors,GISTs）是最常见的胃肠道间质肿瘤,常规化疗无效,主要的治疗方式是手术切除和靶向治疗。分子检测作为推荐的诊断标准化流程,还可以预示疾病的临床表现、治疗、预后甚至发生附加肿瘤的风险。本文对其基因型分型以及相关研究进展进行综述。     

A decade of tyrosine kinase inhibitor therapy: Historical and current perspectives on targeted therapy for GIST

The introduction of molecularly targeted therapies has ushered in a considerable transformation in the management of gastrointestinal stromal tumors (GIST) that currently defines the paradigm of targeted therapy for solid tumors. Indeed, in the past decade the management of GIST has evolved from a disease only effectively treatable by surgery to the archetype of a tumor treatable with a molecularly targeted therapy. Better understanding of the molecular and genetic characteristics that underlie the aberrant behavior of GIST has increased the accuracy of its diagnosis and allowed for the identification of distinct genetic hallmarks, prognostic groups, and treatment strategies. Collectively, this has resulted in the development of the targeted tyrosine kinase inhibitors (TKIs) imatinib and sunitinib, and continues to prompt studies of novel agents in this disease. Since approval in 2002, imatinib has been shown to provide a high level of clinical efficacy in patients with advanced GIST, including a median progression-free survival (PFS) of 2 years and median overall survival approaching 5 years, with some patients progression-free after 10 years of treatment. Imatinib is now also approved in adult patients following resection of KIT-positive GIST. In 2006, sunitinib was approved for the treatment of advanced GIST after failure of imatinib. Sunitinib provides significant benefit in this setting, with a median PFS close to 6 months after imatinib failure. Following progression on these agents, patients have limited treatment options. This critical unmet need is being addressed by the development of new TKIs and the use of novel regimens with approved agents.     

软组织肉瘤分子靶向治疗研究进展

软组织肉瘤(soft tissue sarcoma,STS) 是一组起源于间叶组织的恶性肿瘤,约占成人恶性肿瘤的 1%,恶性程度较高和亚类繁多是其主要特点。目前主要治疗手段包括手术、放疗及化疗等。与胃肠间质瘤对伊马替尼的良好反应不同,其他 STS 的治疗面临着更多困难,不同亚型间遗传性和临床特点异质性强,生存时间差异较大。近年来,分子靶向药物的应用进展迅速,在个体化治疗和提高患者生存质量等方面优势明显,为不宜手术和不能接受常规化疗的患者提供了新的治疗手段。本文就近年来 STS 的靶向治疗药物和相关通路进行简要阐述。      

Critical issues in response evaluation on computed tomography: Lessons from the gastrointestinal stromal tumor model

Imaging technology plays a major role in treatment response assessment in solid tumors and in surveillance for recurrence or progression. Currently available response evaluation criteria, Response Evaluation Criteria in Solid Tumors (RECIST), are based on unidimensional tumor size. Recently, however, these strictly size-based criteria for evaluating responses have been criticized because they do not reflect the biologic changes of solid tumors induced by targeted therapies and thus may be misleading. This problem is evident in response evaluation in advanced gastrointestinal stromal tumor (GIST) treated with a new molecularly targeted agent, imatinib. GISTs can increase in size despite good response to imatinib, and focal progression within a responding GIST can be overlooked with current size-based imaging criteria. Modified objective criteria using a combination of tumor size and density on CT are promising in early response evaluation and in predicting long-term prognosis in patients with advanced GIST treated with imatinib. These criteria may have broad applicability as additional targeted therapies become available to treat solid tumors.     

Surgical therapy of liver metastases

The liver is the most common site of metastatic disease from both gastrointestinal and extra-intestinal malignancies. Historically, only a minority of patients with colorectal liver metastases were candidates for resection. However, over the past several decades, liver resection has evolved as a safe and potentially curative treatment for hepatic colorectal metastases. The development of active chemotherapy and molecular targeted therapies, together with newer modalities like radiofrequency ablation, have expanded the indications for hepatic resection and improved survival. Selected patients with isolated liver metastases from neuroendocrine tumors, germ cell cancers, ocular melanoma, gastrointestinal stromal tumors (GIST), and breast cancer also may be considered for hepatic surgery.     

72例胃肠道间质瘤治疗的回顾性研究

背景与目的:胃肠道间质瘤(gastrointestinal stromal tumor,GIST)是一组起源于胃肠道肌层的间叶性肿瘤,以往外科手术是唯一治疗手段,随着CD117和CD34在肿瘤中表达的发现及分子靶向药物的出现,GIST的诊治有了重大进展.本研究回顾性分析72例手术治疗的GIST患者的临床资料,探讨GIST的诊断和治疗方法.方法:回顾性分析72例手术治疗的GIST患者的临床资料.术前采用消化内镜、B超及CT等影像学方法,所有患者予手术治疗,对其术后病理、临床诊断和治疗方法进行分析.结果:本组患者平均发病年龄为54.3岁.本病临床表现无特异性,常以腹部肿物和消化道出血为首发症状.消化内镜、B超及CT等检查可发现肿瘤,免疫标记物CD117、CD34在GIST中有较高表达,通过病理组织学及免疫组化检查可明确诊断.术后发生胃瘫5例,吻合口瘘2例,胰瘘1例,均经保守治疗后治愈或好转,平均随访时间为36个月.31例恶性间质瘤患者中有16例术后采用甲磺酸伊马替尼治疗(400 mg/d),其中4例复发,15例未作治疗的患者中有8例复发,差异有统计学意义(P<0.01).结论:CD117和CD34联合使用可协助鉴别诊断GIST.手术完整切除肿瘤仍然是首选治疗方法,分子靶向药物在新辅助治疗和术后辅助治疗中前景乐观.     

Gastrointestinal stromal tumors: from a surgical to a molecular approach

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the digestive tract. These tumors span a wide clinical spectrum from benign to malignant and have long been recognized for their nearly absolute resistance to chemotherapy and radiation treatment. We reviewed the worldwide experience on GIST diagnosis, prognosis and treatment and describe our own series. PubMed was searched for references using the terms gastrointestinal stromal tumor, GIST and gastrointestinal sarcoma. Recent reports were given emphasis because GIST is a novel clinical entity and older published work on gastrointestinal sarcomas might be contaminated with other histologic tumor types. At present, surgery is the standard treatment for primary resectable GIST. To increase the activity of conventional chemotherapeutic agents, locoregional therapies are being implemented in the clinical setting. A major breakthrough is the development of a new class of anticancer agents targeting tumor-specific molecular abnormalities. Preliminary results on administration of imatinib mesylate, a signal transduction inhibitor, are particularly encouraging, showing potent activity of this drug against metastatic GIST. Molecular targeting of the critical pathogenetic mechanism underlying GIST might not only revolutionize the strategy to treat locally advanced and metastatic GIST but also improve disease control after macroscopically radical surgery.     

A case of small intestinal GIST maintained as a long stable disease by imatinib mesylate 400 mg/day, alternate-day administration for 2 weeks followed by a 2 week interval

Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors of the gastrointestinal tract. The recent molecular-targeted therapies (imatinib and sunitinib) have improved the treatment of GIST remarkably. However, it would be ideal if the amount of these drugs could be adjusted according to each patient because they have various side effects and are very expensive. We experienced a case of non-curative resectable GIST maintained as a long, stable disease after operation, despite tapering down the dose of imatinib mesylate for personal reasons. Case: A woman aged 50. She had received surgery for a lower abdominal tumor, and had been diagnosed with GIST of the small intestine and disseminations. When she suspended taking imatinib (400 mg/day) after her operation, these tumors regrew. After restarting imatinib at 400 mg/day in an alternate-day administration lasting 2 weeks followed by a 2 week interval, the disseminated tumors were in significant for 60 months after the operation.     

Gastrointestinal stromal tumors: a spectrum of disease

The majority of gastrointestinal stromal tumors (GIST) express c-kit, a growth factor receptor with tyrosine kinase activity. Mutations in the c-kit proto-oncogene may lead to constitutive ligand-independent activation of c-kit and subsequent neoplastic transformation. Selective tyrosine kinase inhibitors target this property of GIST and have become the standard chemotherapy for metastatic or unresectable tumors. The mainstay of treatment, however, continues to be complete surgical resection. Tyrosine kinase inhibitors may prove expedient for adjuvant therapy, and are currently the focus of clinical trials conducted by the ACOSOG, RTOG, and ACRIN. It is important to distinguish GISTs from other mesenchymal tumors of the GI tract because of differences in natural history, as well as the efficacy of treatments targeting the GIST tyrosine kinase.     

GASTROINTESTINAL STROMAL TUMORS OF THE ANORECTUM——A SPECIAL ENTITY： GISTs OF THE ANORECTUM

Objective： Until recently gastrointestinal stromal tumor （GIST） has been separated from other mesenchymal neoplasms and categorized as a special entity. Morphology of tumor cells and immunohistochemical findings with CD117 are crucial in the pathological diagnosis of GISTs. Newly developed drug imatinib mesylate （formerly called STI571） has been proved effective for GISTs. The distinction of GISTs and other mesenchymal tumors has great clinical significance, especially for lesions located in the anorectum. Methods： The authors searched the database of Peking University, School of Ontology for patients with anorectal neoplasms treated from January 1995 to June 2002. Information of 12 patients with anorectal mesenchymal tumors was collected. The patients were reevaluated and discussed according to current criteria of GISTs with clinical data and immunohistochemical findings. Results： Six patients （including 3 males） were finally diagnosed as anorectal GISTs. The median age of those patients was 59.5 years （27～69）. The symptoms were not specific. Three cases with original diagnosis of leiomyoma or leiomyosarcoma were actually GISTs. A total of six anorectal GISTs was found comprising about 1.06% of patients with anorectal neoplasmas in the same period. Besides CD117, CD34 and vimentin were also expressed in majority of these patients. Five of the six patients underwent surgical resection one of which received neoadjuvant chemotherapy before resection Conclusion： Anorectal GISTs should be considered as a special entity using current diagnostic criteria. Surgical resection remains the primary therapeutic strategy. Neoadjuvant imatinib mesylate may be helpful in sphincter-sparing operations and improvement of the quality of life for these patients.     

Gastrointestinal stromal tumors (GISTs), 10-year experience: Patterns of failure and prognostic factors for survival of 127 patients

BackgroundGastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract (GIT) and are believed to originate from the interstitial cell of Cajal. Management of GIST has evolved very rapidly in the last decade.AimTo report our surgical experience in the treatment of GIST patients, to evaluate the prognostic factors and to discuss some controversial issues about the role of target therapy.Patients and methodsOne hundred and twenty seven consecutive patients who underwent surgical resection for GISTs at Nasser Institute (98 patients) and NCI, Cairo University (29 patients) from January 2000 to December 2009 were reviewed retrospectively. The clinical and pathological features of patients were collected. Also data about treatment variables, patterns of failure and factors that predict survival were collected and analyzed.ResultsOf the 127 patients, 81 (64%) had primary disease without metastasis, 11 (9%) had metastatic lesions at presentation, and 35 (27%) presented with recurrence (isolated, metastasis or both). Patients with primary disease underwent complete resection of gross disease. The 5-year overall survival was 53.4% and disease free survival (DFS) was 46.5%. The median DFS was 43.0 months (95% CI: 21.2–64.9). On multivariate analysis, survival was affected by mode of presentation, gastric origin and tumor size. Failures after resection were predominantly intra-abdominal (original site, peritoneal, and liver), and rarely lungs.ConclusionSurgical resection is the mainstay of treatment of GIST. Tumor size and gastric origin were the predicators for DFS in patients presenting with primary disease.     

Gastrointestinal stromal tumors: evolving role of the multidisciplinary team approach in management

Gastrointestinal stromal tumors (GISTs) are rare tumors of the GI tract arising from mesenchymal cells. Treatment options include surgical resection and medical therapy with imatinib. A summary of National Comprehensive Cancer Network and European Society of Medical Oncology clinical practice guidelines relating to GIST management are presented here. A multidisciplinary team of physicians is essential to the successful treatment of GIST. Evidence supports multidisciplinary team management with a gastroenterologist, surgeon, medical oncologist, pathologist and radiologist. Consultations between them are recommended to ensure optimal care of patients with GIST. The role for individual core team workers is highlighted. The benefits of multidisciplinary disease management of patients include reducing recurrent disease, optimizing timing of surgery and organ preservation, prolonging survival for the patient and enhancing response to targeted therapies.     

Gastrointestinal stromal tumor: 5 years later

There is now considerable interest in gastrointestinal stromal tumor (GIST) because it can be treated effectively with a targeted molecular agent. The majority of GISTs contain an activating mutation in the KIT protooncogene or, occasionally, in the platelet-derived growth factor-alpha (PDGFRA) gene. Five years ago, imatinib mesylate, a specific molecular inhibitor of the protein products of these 2 genes, was applied to metastatic GIST. Approximately 80% of patients with metastatic GIST benefit from imatinib, although acquired resistance to the agent may develop. For patients with primary GIST, surgery remains the treatment of choice, and whether outcome is improved by adjuvant imatinib is currently under broad investigation. A combination of imatinib therapy and surgery also may be effective in a subset of patients with metastatic or unresectable primary GIST. In this review, the authors summarize the new multimodality approach to GIST. The integration of surgery and molecular therapy in GIST will serve as a prototype for the management of other solid tumors for which targeted agents become available.     

Gastrointestinal stromal tumors: evolving role of the multidisciplinary team approach in management

Gastrointestinal stromal tumors (GISTs) are rare tumors of the GI tract arising from mesenchymal cells. Treatment options include surgical resection and medical therapy with imatinib. A summary of National Comprehensive Cancer Network and European Society of Medical Oncology clinical practice guidelines relating to GIST management are presented here. A multidisciplinary team of physicians is essential to the successful treatment of GIST. Evidence supports multidisciplinary team management with a gastroenterologist, surgeon, medical oncologist, pathologist and radiologist. Consultations between them are recommended to ensure optimal care of patients with GIST. The role for individual core team workers is highlighted. The benefits of multidisciplinary disease management of patients include reducing recurrent disease, optimizing timing of surgery and organ preservation, prolonging survival for the patient and enhancing response to targeted therapies.     

Practical Aspects of Risk Assessment in Gastrointestinal Stromal Tumors

Introduction

Gastrointestinal stromal tumors (GISTs) are mesenchymal tumors of the gastrointestinal tract, which are characterized in the majority of cases by activating mutations in KIT and platelet-derived growth factor receptor alpha (PDGFRA). The introduction of tyrosine kinase inhibitors has revolutionized the management of patients with metastatic GIST. However, complete surgical resection remains the mainstay of management for those with localized disease. Recently, three large trials have confirmed the benefit of adjuvant imatinib therapy in patients who were at high risk of recurrence following complete resection. In this setting, it is critical that oncologists understand the various GIST risk assessment criteria and be able to apply these methods to accurately assess the risk of recurrence and the need for adjuvant imatinib therapy.

Purpose

The aim of this review is to outline the risk stratification systems currently available to oncologists who are treating patients with GIST, so they can be optimally applied for clinical decision-making.     

Extragastrointestinal stromal tumor originating from the vulva

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. They have gain-of-function mutations of the c-kit receptor tyrosine kinase gene and have been suggested to originate from the interstitial cells of Cajal. A small percentage of GISTs form extragastrointestinal masses. We report a rare case of a GIST originating from the vulva. A 55-year-old woman presented with a vulvar tumor. The tumor was initially diagnosed as a leiomyosarcoma following the first resection. Following a second recurrence the patient was administered chemotherapy. A third recurrence occurred and the patient underwent a third resection. Histology revealed that a bundle of fibrous tumor cells had invaded the connected tissue and muscular coat, and some spindle-shaped and blunt-ended nuclei were detected. Furthermore, immunohistochemical evaluation revealed that the tumor cells exhibited strong and diffuse staining for c-kit and CD34. The recurrent tumor was diagnosed as a GIST and a reevaluation of the original specimens also revealed a GIST. The patient was treated with imatinib, and is currently healthy with no evidence of recurrence at 20 months after the last surgery.     

Gastrointestinal stromal tumors (GIST): C-kit mutations,CD117 expression,differential diagnosis and targeted cancer therapy with imatinib

Gastrointestinal stromal tumors (GISTs) have been recognised as a biologically distinctive tumor type, different from smooth muscle and neural tumors of the gastrointestinal tract. They constitute the majority of gastrointestinal mesenchymal tumors. They are defined and diagnosed by the expression of a protooncogene protein called CD117 detected by immunohistochemistry. It is now believed that GISTs originate from gastrointestinal pacemaker cells known as interstitial cells of Cajal, that control gut motility or from a precursor of these cells. The identification of mutations mostly in exon 11 and to a lesser extent in exons 9 and 13 of the c-kit protooncogene coding for c-kit (CD117) in many GISTs, has resulted in a better understanding of their oncogenic mechanisms.The finding of remarkable antitumor effects of the molecular inhibitor, imatinib (Glivec trade mark ) in metastatic and inoperable GISTs, has necessitated accurate diagnosis of GISTs and their distinction from other gastrointestinal mesenchymal tumors. To achieve this, pathologists need to be familiar with the spectrum of histological appearances shown by GISTs and have a high index of suspicion for these tumors. This review summarises recent advances in knowledge regarding the histogenesis, pathology, molecular biology, genetics and differential diagnosis of GISTs and the basis for the novel targeted cancer therapy with imatinib.