Imatinib mesylate neoadjuvant treatment for rectal malignant gastrointestinal stromal tumor

Surgical treatments including radical resection and local excision remain the main treatment for primary rectal gastrointestinal stromal tumors （GISTs）. However, since patients with high-grade rectal GISTs have a higher risk of tumor recurrence and a shorter life expectancy, neoadjuvant treatment is necessary. In this case report, the efficacy of imatinib mesylate （IM） as a neoadjuvant therapy was assessed in an old man with malignant rectal GIST. The patient received IM preoperative treatment for a short period of one and a half months; at the end of the IM treatment, computed tomography scanning showed a markedly reduced tumor size and cystic changes of the tissue. At that time, a function sphincter-sparing surgery was performed. The histological examination of the resected specimen detected no tumor cells, but residual blood vessels and scattered inflammatory lymphocytes. After surgery, the patient has been followed up without additional IM treatment and remained disease-free for 57 mo. This case indicates that IM neoadjuvant therapy can dramatically improve the prognosis of rectal malignant GIST.     

Modern treatment of gastric gastrointestinal stromal tumors

Gastrointestinal stromal tumors (GIST) are rare mesenchymal smooth muscle sarcomas that can arise anywhere within the gastrointestinal tract. Sporadic mutations within the tyrosine kinase receptors of the interstitial cells of Cajal have been identified as the key molecular step in GIST carcinogenesis. Although many patients are asymptomatic, the most common associated symptoms include: abdominal pain, dyspepsia, gastric outlet obstruction, and anorexia. Rarely, GIST can perforate causing life-threatening hemoperitoneum. Most are ultimately diagnosed on cross-sectional imaging studies (i.e., computed tomography and/or magnetic resonance imaging in combination with upper endoscopy. Endoscopic ultrasonographic localization of these tumors within the smooth muscle layer and acquisition of neoplastic spindle cells harboring mutations in the c-KIT gene is pathognomonic. Curative treatment requires a complete gross resection of the tumor. Both open and minimally invasive operations have been shown to reduce recurrence rates and improve long-term survival. While there is considerable debate over whether GIST can be benign neoplasms, we believe that all GIST have malignant potential, but vary in their propensity to recur after resection and metastasize to distant organ sites. Prognostic factors include location, size (i.e., > 5 cm), grade (> 5-10 mitoses per 50 high power fields and specific mutational events that are still being defined. Adjuvant therapy with tyrosine kinase inhibitors, such as imatinib mesylate, has been shown to reduce the risk of recurrence after one year of therapy. Treatment of locally-advanced or borderline resectable gastric GIST with neoadjuvant imatinib has been shown to induce regression in a minority of patients and stabilization in the majority of cases. This treatment strategy potentially reduces the need for more extensive surgical resections and increases the number of patients eligible for curative therapy. The modern surgical treatment of gastric GIST combines the novel use of targeted therapy and aggressive minimally invasive surgical procedures to provide effective treatment for this lethal, but rare gastrointestinal malignancy.     

Assessment of gastrointestinal stromal tumors with computed tomography following treatment with imatinib mesylate

AIM： To evaluate and characterize the patterns of disease progression of metastatic or unresectable gastrointestinal stromal tumor （GIST） treated with imatinib mesylate, and to determine the prognostic significance associated with disease progression. METHODS： Clinical data and computed tomography （CT） images were retrospectively reviewed in 17 GIST patients who were treated with imatinib mesylate from October 2002 to October 2006. Apart from using size measurement for evaluation of tumor response [Response Evaluation Criteria in Solid Tumors （RECIST） criteria], patterns of CT changes during treatment were evaluated and correlated with clinical data. RESULTS： There were eight non-responders and nine responders. Five patterns of CT change during treatment were found： focal progression （FP）, generalized progression （GP）, generalized cystic change （GC）, new cystic lesion （NC） and new solid lesion （NS）. At the end of study, all non-responders showed GP, whereas responders showed cystic change （GC and NC） and response according to RECIST criteria. Overall survival was significantly better in patients with cystic change or response within the RECIST criteria compared with GP patients （P = 0.0271）. CONCLUSION： Various patterns of CT change in patients with GIST who responded to imatinib mesylate were demonstrated, and might determine the prognosis of the disease. A combination of RECIST criteria and pattern of CT change are proposed for response evaluation in GIST.     

Molecular basis and management of gastrointestinal stromal tumors

Molecularly targeted agents have dramatically impacted the management of several cancers. Targeting KIT has led to a new treatment paradigm in gastrointestinal stromal tumors (GISTs). KIT is a cell surface receptor with tyrosine kinases that, upon binding of its ligand, stem cell factor, activates various signaling pathways. Imatinib and sunitinib, both tyrosine kinase inhibitors directed to KIT, were approved for firstand secondline treatment of metastatic and unresectable GISTs. In this article, we will r...     

胃肠间质瘤个体化治疗策略的探讨

胃肠间质瘤（GIST）是最常见的胃肠道间叶源性肿瘤,多见于胃和小肠,GIST多具有恶性潜能,生物学行为可以从良性到高度恶性不等。GIST的预后与肿瘤的发病部位、瘤体大小、核分裂数以及肿瘤是否破裂密切相关,伊马替尼辅助治疗明显延长了GIST患者的生存时间。近年对于GIST患者实施个体化治疗的理念也得到了越来越多的重视,本文就GIST个体化治疗的策略研究进行阐述。     

伊马替尼治疗不能切除和（或）转移性胃肠道间质瘤的系统评价

目的系统评价伊马替尼治疗不能切除和（或）转移性胃肠道问质瘤的有效性和安全性。方法计算机检索PubMed（1989～2009．4）、EMbase（1989～2009．4）、Cochrane图书馆（2009年第3期）、CBM（1989～2009．4）、CNKI（1989～2009．4）、VIP（1989～2009．4）。同时手工检索其引文,以便发现新的可纳入文献。按Cochrane协作网推荐的方法进行系统评价。结果共纳入5个RCT,包括1845例患者。meta分析结果显示：与标准剂量组（400mg／d）相比,高剂量组（600mg／d或800rag／d）依马替尼虽然增加2年无疾病进展生存率[RR=1．15,95％CI=1．01～1．30,P=0．03],但在2年总生存率（RR=1．00,95％CI=0．92—1．08,P=0．93）、完全肿瘤反应率（RR=1．02,95％CI=0．66～1．59,P=0．93）、部分肿瘤反应率（RR=1．06,95％CI=0．96～1．17,P=0．28）方面两组相似。在安全性方面,高剂量组依马替尼增加了血液毒性反应（RR=1．08,95％CI=1．03—1,14,P=0．003）和各种非血液毒性反应（RR：1．18～2．07,95％CI=1．06～3．32,P均〈0．05）,特别是增加了3级以上毒性反应（RR=1．48,95％CI=1．33～1．65,P〈0．00001）。依马替尼间断治疗的患者出现疾病进展的风险明显增高（RR=0．27,95％CI=0．13～0．58,P〈0．05）,而生存质量未见改善（MD=3．50,95％CI=-11．17～18．17,P〉0．05）。结论对不能切除和（或）转移性的胃肠道间质瘤患者,增加剂量,病人未见明显临床获益;依马替尼治疗胃肠道间质瘤取得疗效后,应持续服药,以免引起疾病进展的风险增加。     

直肠胃肠间质瘤的临床病理特征和治疗

直肠是胃肠间质瘤的第三常见部位,其临床病理学特征、生物学行为和解剖部位使其诊治具有特殊性。好发于直肠中下段且术后局部复发率偏高,都是直肠GIST治疗的难点。伊马替尼的围手术期治疗增加了手术切除率并降低了复发率,5 cm以下的直肠GIST靶向治疗联合手术切除治疗效果较好。目前,国内外尚缺少直肠GIST的诊疗规范,未来还需要更多的前瞻性多中心研究进一步探讨并得出结论。     

Cooperative laparoscopic endoscopic and hybrid laparoscopic surgery for upper gastrointestinal tumors: Current status

AIM: To investigate the cooperative laparoscopic and endoscopic techniques used for the resection of upper gastrointestinal tumors.METHODS: A systematic research of the literature was performed in PubMed for English and French language articles about laparoscopic and endoscopic cooperative, combined, hybrid and rendezvous techniques. Only original studies using these techniques for the resection of early gastric cancer, benign tumors and gastrointestinal stromal tumors of the stomach and the duodenum were included. By excluding case series of less than 10 patients, 25 studies were identified. The study design, number of cases, tumor pathology size and location, the operative technique name, the endoscopy team and surgical team role, operative time, type of closure of visceral wall defect, blood loss, complications and length of hospital stay of these studies were evaluated. Additionally all cooperative techniques found were classified and are presented in a systematic approach.RESULTS: The studies identified were case series and retrospective cohort studies. A total of 706 patients were operated on with a cooperative technique. The tumors resected were only gastrointestinal stromal tumors (GIST) in 4 studies, GIST and various benign submucosal tumors in 22 studies, early gastric cancer (pT1a and pT1b) in 6 studies and early duodenal cancer in 1 study. There was important heterogeneity between the studies. The operative techniques identified were: laparoscopic assisted endoscopic resection, endoscopic assisted wedge resection, endoscopic assisted transgastric and intragastric surgery, laparoscopic endoscopic cooperative surgery (LECS), laparoscopic assisted endoscopic full thickness resection (LAEFR), clean non exposure technique and non-exposed endoscopic wall-inversion surgery (NEWS). Each technique is illustrated with the roles of the endoscopic and laparoscopic teams; the indications, characteristics and short term results are described.CONCLUSION: Along with the traditional cooperative techniques, new procedures like LECS, LAEFR and NEWS hold great promise for the future of minimally invasive oncologic procedures.     

伊马替尼治疗胃肠间质瘤并瘢痕疙瘩增生一例

甲磺酸伊马替尼是一种选择性酪氨酸激酶抑制剂,能在细胞水平上抑制bcr-abl、PDGF受体、SCF、c-Kit等受体的酪氨酸激酶,抑制细胞增殖、诱导细胞凋亡,是治疗胃肠道间质瘤一线药物。最常见的不良反应有水肿、皮疹、疲劳、恶心、中性粒细胞减少,但其促进患者瘢痕疙瘩增生尚未有报道,现报道如下。     

Retrospective analysis of extra-gastrointestinal stromal tumors

AIM:To investigate the clinicopathologic features of patients with extra-gastrointestinal stromal tumors(EGISTs)in South Korea.METHODS:A total of 51 patients with an EGIST were identified.The clinicopathologic features,including sex,age,location,tumor size,histology,mitotic rate,immunohistochemical features,genetic status and survival data,were analyzed.RESULTS:The median age was 55 years(range:29-80years),and male:female ratio was 1:1.04.The most common site was in the mesentery(n=15)followed by the retroperitoneum(n=13)and omentum(n=8).The median tumor size was 9.0 cm(range:2.6-30.0cm)and the median mitotic rate was 5.0/50HPF.(1/50-185/50).KIT was analyzed in 16,which revealed 10cases with wild-type KIT and 6 cases with an exon 11mutation.Among 51 patients,31 patients had undergone surgery,and 10 had unresectable disease and had taken palliative imatinib,which resulted in 22.7 mo of progression-free survival.Of the patients who had undergone surgery,18 did not take adjuvant imatinib,and 8 of these were categorized ashigh riskaccording to the risk criteria.However,the relapse-free survival was not different(P=0.157)between two groups.CONCLUSION:Because the biologic behaviors of GISTs differ according to the location of the tumor,a more stratified strategy is required for managing EGISTs including incorporation of molecular features.     

胃肠道间质瘤的诊断治疗

胃肠道间质瘤(gastrointestinal stromal tumors,GIST)是消化系最常见的间叶组织源性肿瘤,是一种潜在恶性的肿瘤.其临床表现缺乏特异性,术前诊断上存在较大困难.近几年其发病机制已经逐渐被人们所认识,诊断及治疗水平上也有了很大的提高.原癌基因kit突变是其主要发病机制之一.以CD117为代表的免疫织化学染色在其诊断中作为一个重要的决定性因素.治疗上目前注重于综合治疗,手术完整切除仍然是其首选治疗,包括新辅助治疗及术后辅助治疗在内的分子靶向治疗的出现成为GIST治疗上的一次巨大进步,甲磺酸伊马替尼等选择性酪氨酸激酶抑制剂制剂的出现,给GIST患者的治疗带来了新的希望.     

Synchronous incidental gastrointestinal stromal and epithelial malignant tumors

AIM： To investigate the incidence of incidental gastrointestinal stromal tumor （GIST） and its etiopathogenesis. METHODS： From January 1, 2000 to December 31, 2007, 13804 cases of gastrointestinal epithelial malignant tumor （EMT） and 521 cases of pancreatic adenocarcinoma （PAC） were successfully treated with surgery at the Department of General Surgery and the Department of Thoracic Surgery, West China Hospital, Sichuan University, China. The clinical and pathologic data of 311 cases of primary GIST, including 257 cases with clinical GIST and 54 cases of incidental GIST were analyzed. RESULTS： Of the 311 patients, 54 had incidental GIST, accounting for 17.4%. Of these tumors, 27 were found in 1.13% patients with esophageal squamous cell carcinoma （ESCC）, 22 in 0.53% patients with gastric adenocarcinoma （GAC）, 2 in 0.38% patients with PAC, 2 in 0.03% patients with colorectal adenocarcinoma, and 1 in one patient with GAC accompanying ESCC, respectively. Patients with incidental GIST presented symptoms indistinguishable from those with EMT. All incidental GIST lesions were small in size, and the majority had a low mitotic activity while only 1.9% （5/257） of clinical GIST lesions had a high risk.CONCLUSION： Incidental GIST may occur synchronously with other tumors and has a high prevalence in males. Surgery is its best treatment modality.     

Predictive factors for long-term effects of imatinib therapy in patients with inoperable/metastatic CD117(+) gastrointestinal stromal tumors (GISTs)

The purpose To analyze the outcomes of treatment and factors predicting effects of imatinib (IM) therapy in inoperable/metastatic gastrointestinal stromal tumors (GIST) CD117(+) patients. Materials and methods We identified 232 patients in a prospectively collected Clinical GIST Registry with advanced inoperable/metastatic GIST treated with IM 400-800 mg daily (129 males and 103 females and median age 56 years). Median follow-up time was 26 months. Results The estimated 3-year progression-free survival (PFS; calculated from the date of the start of IM) was 54% and median PFS was 40.5 months. The following factors significantly and negatively influenced PFS in univariate analysis: poor baseline World Health Organization (WHO) performance status ≥2 (P < 0.00001), tumor genotype indicating other than KIT exon 11 isoform (P = 0.005), baseline high neutrophils count (P < 0.00001), age <45 years at the diagnosis (P = 0.04), mitotic index >10/50 high-power fields (HPF) (P = 0.001), GIST histological type other than spindle-cell (P = 0.03), baseline low albumin level (P = 0.0005), low baseline hemoglobin level (P < 0.00001), and primary overtly malignant tumors (unresectable and/or metastatic lesions at presentation) (P = 0.05). We identified four factors negatively affecting PFS, statistically significant (P < 0.05) in multivariate analysis: baseline poor WHO performance status ≥2, high baseline neutrophils count (>5 × 10⁹/l), tumor genotype indicating the presence of non-exon 11 KIT mutant and mitotic index >10/50 HPF. Conclusions We confirmed that many advanced GIST patients benefit from IM therapy for a prolonged time, although resistance to therapy is observed. We identified four independent biological factors influencing the PFS during long-term IM therapy.     

胃肠道间质瘤的药物治疗现状与未来

胃肠道间质瘤（GIST）是胃肠道最常见的间质肿瘤。其分子机制的研究极大促进了治疗的发展,特别是药物靶向治疗。格列卫可以抑制kit、PDGFRα和PDGFRβ等蛋白酪氨酸激酶受体,主要用于手术不能切除、转移的GIST。然而,一部分病人却存在对格列卫的耐药现象。另一种靶向治疗药物索坦是一个多靶点酪氨酸激酶抑制剂,可抑制kit、PDGFR、FLT3和VEGFR等,主要用于对格列卫耐药和不能耐受的病人。同时,还有一些新的酪氨酸激酶抑制药物单独或与格列卫合用,正在进行基础和临床研究。     

Thy-1 as a potential novel diagnostic marker for gastrointestinal stromal tumors

Purpose Only few immunohistochemical markers besides c-kit exist for gastrointestinal stromal tumors (GISTs). Thy-1, a cell-surface glycoprotein, is a marker for several types of stem cells and particularly for neuronal precursor cells. The aim of this study was to determine Thy-1 expression in GISTs. Materials and methods Fifty-seven surgically resected and paraffin-embedded GIST samples were analyzed by immunohistochemistry with peroxidase method for Thy-1 molecule. Results Thy-1 was detected in the majority of 57 GIST samples (54 out of 57 patients, 95%). All samples were c-kit positive and 90% were CD34 positive. All three Thy-1 negative samples were CD34 positive, had a low proliferative index (Ki-67 ≤ 10%) and were located in the upper gastrointestinal tract (one in esophagus and two in the stomach). As a tendency, Thy-1 negative patients had a better prognosis, although not reaching level of significance due to low numbers. Conclusions Thy-1 is expressed in the majority of GISTs, suggesting a novel, additional standard marker for identifying GIST. Future studies should focus on the role of Thy-1 in the pathogenesis of GIST and subsequently on its potential to act as a molecular target for adjuvant therapy with new molecular antitumor agents. Financial support for this study was provided by research grants from the Hamburger Krebsgesellschaft e. V. (J.T.K., E.F.Y., J.R.I.).     

Laparoscopic resection of gastric gastrointestinal stromal tumors presenting as left adrenal tumors

Gastrointestinal stromal tumors (GISTs) are rare gastrointestinal malignancies. They are rarely seen near the urinary tract. In a literature review, only one case of GIST presenting as a left adrenal tumor was reported. We report two documented cases of gastric GISTs mimicking left adrenal tumors which were successfully treated with pure laparoscopic adrenalectomy and wedge resection of the stomach by excising the tumor from the stomach with serial firing of endoscopic gastrointestinal staplers. The surgical margins were clear, and the patients recovered smoothly. No adjuvant therapy with imatinib was prescribed. During the surveillance for 9 mo and 44 mo respectively, no tumor recurrence and metastasis were documented. Laparoscopic tumor excision, when adhering to the principles of surgical oncology, seems feasible and the prognosis is favorable for such tumors.     

Current update on molecular cytogenetics,diagnosis and management of gastrointestinal stromal tumors

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal (GI) tract and are thought to arise from precursors of the interstitial cells of Cajal. GISTs can arise anywhere in the GI tract, but most commonly originate from the stomach and small intestine. The majority of GISTs occur as a result of activating mutations in two receptor protein tyrosine kinases: KIT and/or platelet-derived growth factor receptor-α. Mutational analyses allow for predicting patient prognosis and treatment response. Clinical presentations can vary from no symptoms, typical in the case of small incidentally found tumors, to GI bleeding, abdominal discomfort, and ulcer-related symptoms when the tumor is enlarged. Imaging plays a critical role in the diagnosis and management of these tumors with multiphasic computed tomography serving as the imaging modality of choice. Magnetic resonance imaging and positron emission tomography-computed tomography can serve as imaging adjuncts in lesion characterization, especially with liver metastases, and subsequent staging and assessment for treatment response or recurrence. Surgical resection is the preferred management for small GISTs, while tyrosine kinase inhibitors − imatinib mesylate and sunitinib malate − serve as crucial molecular-targeted therapies for locally advanced and metastatic GISTs. This review article highlights the clinical presentation, pathology and molecular cytogenetics, imaging features, and current management of GISTs.     

New-style laparoscopic and endoscopic cooperative surgery for gastric stromal tumors

AIM: To evaluate the feasibility and safety of a new style of laparoscopic and endoscopic cooperative surgery (LECS), an improved method of laparoscopic intragastric surgery (LIGS) for the treatment of gastric stromal tumors (GSTs). METHODS: Six patients were treated with the newstyle LECS. Surgery was performed according to the following procedures: (1) Exposing and confirming the location of the tumor with gastroscopy; (2) A laparoscopy light was placed in the cavity using the trocar at the navel, and the other two trocars penetrated both the abdominal and stomach walls; (3) With gastroscopy monitoring, the operation was carried out in the gastric lumen using laparoscopic instruments and the tumor was resected; and (4) The tumor tissue was removed orally using a gastroscopy basket, and puncture holes and perforations were sutured using titanium clips. RESULTS: Tumor size ranged from 2.0 to 4.5 cm (average 3.50 ± 0.84 cm). The operative time ranged from 60 to 130 min (average 83.33 ± 26.58 min). Blood loss was less than 20 mL and hospital stay ranged from 6 to 8 d (average 6.67 ± 0.82 d). The patients were allowed out of bed 12 h later. A stomach tube was inserted for 72 h after surgery, and a liquid diet was then taken. All cases had single tumors which were completely resected using the new-style LECS. No postoperative complications occurred. Pathology of all resected specimens showed GST: no cases of implantation or metastasis were found.CONCLUSION: New-style LECS for GSTs is a quick, optimized, fast recovery, safe and effective therapy.     

Efficacy of imatinib dose escalation in Chinese gastrointestinal stromal tumor patients

AIM: To investigate the efficacy and safety of imatinib dose escalation in Chinese patients with advanced gastrointestinal stromal tumor (GIST).METHODS: Advanced GIST patients previously failing 400 mg imatinib treatment were enrolled in this study. Patients received imatinib with dose escalation to 600 mg/d, and further dose escalation to 800 mg/d if imatinib 600 mg/d failed. Progression-free survival, overall survival, clinical efficacy, c-kit/PDGFRA genotype and safety were evaluated.RESULTS: 52 patients were enrolled in this study. For the 47 evaluable patients receiving imatinib (600 mg/d), the disease control rate was 40.4%, and the median progression-free survival for all patients was 17 wk (95% CI: 3.9-30.1). The median overall survival after dose escalation was 81 wk (95% CI: 36.2-125.8). Adverse events, mainly edema, fatigue, granulocytopenia and skin rash were tolerable. However, further dose escalation (800 mg/d) in 14 cases was ineffective, with disease progression and severe adverse events. Among 30 cases examined for gene mutations, patients with exon 9 mutations experienced a better progression-free survival of 47 wk.CONCLUSION: Imatinib dose escalation to 600 mg/d is more appropriate for Chinese patients and may achieve further survival benefit.