212例胃肠间质瘤的临床病理特征及预后分析

目的探讨胃肠间质瘤（GIST）的临床特征和分子病理学特点,分析影响GIST预后的相关因素。方法回顾性分析2004年4月至2011年8月南方医院收治的212例GIST患者的临床病理和随访资料,应用生存分析比较不同因素对预后的影响。对接受甲磺酸伊马替尼治疗的53例患者,采用基质辅助激光解析/电离-飞行时间质谱方法检测KIT和PDGFRa基因相关位点的突变情况。结果单因素生存分析显示肿瘤大小、核分裂数、美国国立卫生研究所（NIH）危险度分级、转移、手术及甲磺酸伊马替尼影响GIST患者的生存率。多因素生存分析提示,NIH危险度分级和甲磺酸伊马替尼是影响预后的独立因素。53例GIST患者中,KIT基因突变39例（73.6%）,其中外显子11突变21例（53.8%）,外显子9突变13例（33.3%）。KIT外显子11突变形式主要为5’端第557-558密码子缺失最常见;外显子9突变均为插入串联重复。未检测到PDGFRa基因突变的病例。结论 NIH危险度分级和甲磺酸伊马替尼治疗与GIST患者的生存密切相关,基因突变检测对指导生物靶向治疗和预测其疗效具有重要意义。     

KIT阴性的胃肠道间质肿瘤

胃肠道间质肿瘤 (gastrointestinalstromaltumor,GIST)是消化道最常见的间叶源性肿瘤 ,显示出类似Cajal间质细胞的形态学特点和免疫表型 ,特征性表达KIT蛋白(CD117)。多数GIST具有KIT癌基因突变 ,从而导致细胞增殖。KIT抑制剂伊马替尼 (商品名格列卫 )治疗GIST显效证实了KIT在GIST发病机制中的重要作用。然而 ,某些肿瘤具有GIST的临床病理特征 ,但KIT阴性。这类肿瘤是否真是GIST以及伊马替尼治疗是否有效尚存争议。作者研究了 2 5例具有GIST临床病理特征但KIT免疫组化阴性的肿瘤。此组患者发病年龄 (2 9～ 79岁 )和肿瘤…     

甲磺酸伊马替尼对胃肠间质瘤患者外周血中Foxp3~+ Treg细胞及其亚群的影响

目的探讨甲磺酸伊马替尼对胃肠间质瘤(GIST)患者外周血中Foxp3~+Treg细胞及其各亚群含量的变化及其意义。方法采集35名靶向治疗前的GIST病例、31名靶向治疗后的GIST病例及31名健康志愿者的外周血,通过流式细胞术检测其中Foxp3~+Treg细胞占总CD4~+T细胞的比例,并基于Foxp3和CD45RA含量将Foxp3~+Treg细胞分为3个亚群:r Treg细胞、aTreg细胞和nonTreg细胞,分别检测各亚群所占比例。结果 2个GIST病例组的外周血中Foxp3~+Treg细胞含量均高于健康对照组,且靶向治疗前组也高于靶向治疗后组,差异有统计学意义(P0.01);病例组aTreg细胞所占比例明显高于健康对照组,且靶向治疗前组也高于靶向治疗后组,差异有统计学意义(P0.01)。Foxp3~+Treg细胞及aTreg细胞亚群在高危GIST患者较中低危者更高,差异有统计学意义(P0.01)。而Foxp3~+Treg细胞及其各亚群含量的变化与年龄、性别和肿瘤位置等因素无关(P0.05)。结论 GIST患者外周血中Foxp3~+Treg细胞较正常人明显升高,其中aTreg细胞亚群与GIST的进展有关;甲磺酸伊马替尼可能通过抑制Foxp3~+Treg细胞及其有功能的亚群增强机体抗肿瘤免疫反应发挥抗肿瘤活性。     

中国胃肠道间质瘤诊断治疗共识

胃肠道间质瘤(gastrointestinal stromal tumors,GIST)是胃肠道最常见的间叶源性肿瘤,免疫组织化学染色大多数呈CD117阳性.传统放疗和化疗对GIST几乎无效.酪氨酸激酶抑制剂甲磺酸伊马替尼的临床应用使GIST的治疗发生了重大的改变,为部分晚期GIST患者带来了延长生存期的疗效.同时由于对GIST基因突变认识的进一步提高,使GIST的诊断率显著提高.     

胰岛素样生长因子系统在胃肠道间质瘤靶向治疗中的意义及研究进展

胃肠道间质瘤(gastrointestinal stromal tumor,GIST)是胃肠道最常见的间叶组织肿瘤,针对其突变基因的靶向治疗药物伊马替尼的应用,对控制转移和复发的GIST取得显著效果,但仍有部分病人耐药.胰岛素样生长因子(insulin-like growth factor,IGF)系统在多种恶性肿瘤的发生中起重要作用.近年来,有人对其在GIST中的表达进行研究,并提出IGF系统可能作为一个新的治疗靶点,用于GIST患者,尤其是对耐药患者的治疗.本文主要对IGF系统在GIST中的表达情况及其意义进行综述.     

胃肠间质瘤患者中Imatinib血药浓度与治疗疗效的相关性

目的 检测中国晚期胃肠间质瘤(GIST)患者中伊马替尼(Imatinib)血药浓度,并分析血药浓度与治疗疗效的相关性.方法 收集112例接受Imatinib治疗超过28 d的GIST患者的117份血浆样本,用HPLC-MS/MS法检测血浆中Imatinib浓度.分析Imatinib血药浓度与治疗疗效的相关性.结果 高剂量组(600 ms/d)患者的血药浓度较低剂量组(400 mg/d)明显升高(P<0.001).服药时间为1～2年患者的血药浓度(平均值1 268 ng/mL)较服药时间小于1年的患者(平均值1 845 ng/mL)明显降低(P<0.05).随着血药浓度的增加有效率也随之增加,血药浓度低、中及高水平组的有效率分别为50%、67.5%及66.7%.结论 Imatinib血药浓度与服药剂量及服药时间明显相关;Imatinib治疗有效率随着血药浓度的增高呈增加趋势.     

甲磺酸伊马替尼对真性红细胞增多症患者红细胞生成的作用

<正>目的:真性红细胞增多症(PV)患者的骨髓中同时存在良性造血祖细胞和恶性造血祖细胞。恶性红细胞克隆可以在体外无外源性促红细胞生成素()存在的情况下,形成红细胞集落形成单位()。本实验观察甲磺酸伊马替尼对PV患者自发性红细胞生成的抑制作用。方法:15例PV患者(PV组),其中14例采集外周血2ml,1例采集骨髓2ml,另选10例无血液病的健康人(对照组),采集外周血2ml,所有样本均以EDTA-K2抗凝。用密度梯度法分离对照组和PV组外周血和骨髓的单个核细胞(PBMCs),将PBMCs浓度调整为1×105个/ml,分别在有甲磺酸伊马替尼(10μM)的半固体培养基和无甲磺酸伊马替尼的半固体培养基中进行培养。     

实时荧光定量PCR监测治疗前后BCR-ABL水平的变化

目的探讨实时荧光定量PCR(Quantitative Real-time PCR,RQ-PCR)方法在监测慢性粒细胞白血病(chronic myeloid leukemia,CML)患者治疗效果和预后判断的应用价值。方法应用实时荧光定量PCR方法分别检测CML患者采用异基因造血干细胞移植或伊马替尼治疗前、治疗3个月、治疗6个月、治疗1年时BCR-ABL融合基因的表达水平。结果治疗前,CML患者的BCR-ABL水平分布在164%~469%,造血干细胞移植组的患者的BCR-ABL水平降至0.1%~0.2%,伊马替尼组患者随着治疗BCR-ABL水平逐渐下降,在治疗一年后降至0.1%~0.3%。治疗前后患者的BCR-ABL水平差异有统计学意义(P0.05),造血干细胞移植组与伊马替尼组患者的BCR-ABL水平差异不显著(P0.05)。结论使用RQ-PCR方法监测BCR-ABL水平可以作为CML患者评价治疗效果和判断预后的指标。     

酪氨酸激酶抑制剂甲磺酸伊马替尼对PTEN介导的K562细胞侵袭的影响

目的:研究酪氨酸激酶抑制剂甲磺酸伊马替尼对K562细胞PTEN信号转导的调控,以及对细胞侵袭功能的影响.方法:不同浓度甲磺酸伊马替尼作用K562细胞不同时间后,通过荧光定量PCR检测BCR/ABL、PTEN、FAK水平变化及相互关系,免疫细胞化学染色检测FAK蛋白水平,Transwell小室检测K562细胞侵袭功能.结果:2μg/mL甲磺酸伊马替尼作用K562细胞在36 h内,随着BCR/ABL融合基因表达减低,PTEN mRNA表达上调,FAK mRNA及蛋白表达下调,K562细胞侵袭功能明显减弱.作用48 h后,随着BCR/ABL融合基因的抑制减弱,PrEN表达进而减低,而FAK表达升高.BCR/ABL mRNA与PTEN mRNA呈负相关趋势,与FAK mRNA呈正相关趋势.结论:甲磺酸伊马替尼通过抑制BCR/ABL融合基因调控PTEN/FAK信号转导通路,参与抑制白血病K562细胞侵袭作用.     

与神经纤维瘤病Ⅰ型伴发的胃肠道间质瘤临床病理学和分子遗传学研究进展

大多数散发性胃肠道间质瘤(gastrointestinal stromaltumors,GIST)具有c-kit基因或血小板衍生的生长因子受体A(PDGFRA)的突变,最常发生于胃,其次是小肠、肛门直肠等。通常单发,偶见多发。部分多发性GIST与Ⅰ型神经纤维瘤病(NF1)有关。NF1可伴发多种病变,GIST被认为是最常见的与NF1相关的胃肠道肿瘤,NF1患者发生GIST的危险性明显提高,多项研究证实:NF1伴发的GIST与散发性GIST在临床病理、c-kit和PDGFRA基因突变状态等方面均有不同,是一种独特的肿瘤,表现为多中心发生、好发于小肠,瘤细胞呈梭形,缺乏KIT及PDGFRA突变,不对甲磺酸伊马替尼的治疗产生应答,大多数临床经过良好。     

GIST under imatinib therapy

The prognosis of patients with a GIST improved significantly since the introduction of imatinib mesylate treatment, leading to disease control in 70% to 85% of patients. The response depends on the presence/ absence and type of mutations in the KIT or Platelet derived growth factor receptor. Unfortunately, we are increasingly faced with the problem of resistance to imatinib treatment, mainly secondary resistance, which by definition occurs after at least 6 months of initial response to the drug. The effects of imatinib on a GIST are still in full exploration and this review focuses upon the available data on the phenotype and genotype of a GIST treated with imatinib. Two settings are elaborated separately, a responding/stable GIST, and a resistant GIST. In addition, the attention will be drawn to remarkable (immuno)phenotypic changes that can occur in a GIST under imatinib treatment.     

Imatinib Plasma Monitoring-Guided Dose Modification for Managing Imatinib-Related Toxicities in Gastrointestinal Stromal Tumor Patients

Imatinib, the first-line treatment in patients with advanced gastrointestinal stromal tumors (GIST), is generally well tolerated, although some patients have difficulty tolerating the standard dose of 400 mg/day. Adjusting imatinib dosage by plasma level monitoring may facilitate management of patients who experience intolerable toxicities due to overexposure to the drug. We present two cases of advanced GIST patients in whom we managed imatinib-related toxicities through dose modifications guided by imatinib plasma level monitoring. Imatinib blood level testing may be a promising approach for fine-tuning imatinib dosage for better tolerability and optimal clinical outcomes in patients with advanced GIST.     

Dedifferentiated gastrointestinal stromal tumor arising de novo from the small intestine

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract and usually display monotonous cytologic features and immunoactivity for CD117. Anaplastic GIST, with pleomorphic cells and loss of CD117, until recently have only been reported in patients with chronic imatinib mesylate treatment. Dedifferentiated GISTs arising de novo is a newly identified entity that may prove to be difficult to diagnose. We present the case of a 52-year-old female found to have a dedifferentiated GIST without prior imatinib mesylate therapy. This case is the first reported dedifferentiated GIST arising de novo from the small bowel, and at 30 cm in greatest diameter, the largest reported to date. Additionally, we demonstrate for the first time the loss of DOG1 in the anaplastic component of the tumor. De novo dedifferentiated GIST is a rare and diagnostically challenging tumor that may be mischaracterized unless considered in the differential diagnosis.     

Preoperative imatinib for patients with primary unresectable or metastatic/recurrent gastrointestinal stromal tumor

OBJECTIVES:

Despite its rising popularity, reports on the use of preoperative imatinib mesylate (IM) in patients with advanced gastrointestinal stromal tumor (GIST) are limited. This study aims to explore the clinical efficacy of preoperative IM in patients with primarily unresectable or metastatic/recurrent GIST.

METHODS:

Between September 2009 and February 2014, patients with primarily unresectable or metastatic/recurrent GIST treated by a single medical team were recruited and considered for preoperative IM therapy. Re-examination was conducted regularly and abdominal enhanced CT data, blood biochemistry and responses to IM were recorded.

RESULTS:

A total of 18 patients were enrolled, including 13 with a primary tumor (7 stomach, 3 small bowel, 2 rectal and 1 pelvic tumor) and 5 with recurrent or metastatic GIST (2 with liver metastasis, 2 with anastomotic recurrence and 1 with pelvic GIST). The median follow-up time was 9.5 months (range of 3-63). The median tumor sizes before and after initiation of IM treatment were 9.1 cm and 6.0 cm (p = 0.003) based on the CT findings, respectively. All patients showed a decrease in tumor burden and the median tumor size reduction was 35%. Sixteen of the 18 patients showed a partial response to IM and two possessed stable disease. Nine of the 18 patients (50%) underwent surgical resection of primary or metastatic/recurrent tumors, with a median of 7 months of IM therapy. One case each of multivisceral resection and tumor recurrence were noted.

CONCLUSIONS:

IM as a preoperative therapy is feasible and safe for unresectable or metastatic/recurrent GIST that can effectively decrease tumor size, facilitating resection.     

KIT and PDGFRA mutations in gastrointestinal stromal tumors (GISTs)

Mutually exclusive KIT and PDGFRA mutations are central events in GIST pathogenesis, and their understanding is becoming increasingly important, because specific treatment targeting oncogenic KIT and PDGFRA activation (especially imatinib mesylate) has become available. KIT mutations in GIST are clustered in four exons. Most common are exon 11 (juxtamembrane domain) mutations that include deletions, point mutations (affecting a few codons), and duplications (mostly in the 3' region). The latter mutations most often occur in gastric GISTs. Among gastric GISTs, tumors with deletions are more aggressive than those with point mutations; this does not seem to hold true in small intestinal GISTs. Exon 9 mutations (5-10%) usually are 2-codon 502-503 duplications, and these occur predominantly in intestinal versus gastric GISTs. Lesser imatinib sensitivity of these tumors has been noted. Kinase domain mutations are very rare; GISTs with such mutations are variably sensitive to imatinib. PDGFRA mutations usually occur in gastric GISTs, especially in the epithelioid variants; their overall frequency is approximately 30% to 40% of KIT mutation negative GISTs. Most common is exon 18 mutation leading Asp842Val at the protein level. This mutation causes imatinib resistance. Exon 12 and 14 mutations are rare. Most mutations are somatic (in tumor tissue only), but patients with familial GIST syndrome have consitutitonal KIT/PDGFRA mutations; >10 families have been reported worldwide with mutations generally similar to those in sporadic GISTs. GISTs in neurofibromatosis 1 patients, children, and Carney triad seem to lack GIST-specific KIT and PDGFRA mutations and may have a different disease mechanism. Secondary mutations usually occur in KIT kinase domains in patients after imatinib treatment resulting in resistance to this drug. Mutation genotyping is a tool in GIST diagnosis and in assessment of sensitivity to kinase inhibitors. This is a US government work. There are no restrictions on its use.     

Pathology of gastrointestinal stromal tumors

Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors in the gastrointestinal tract. It was found that most GIST expressed KIT, a receptor tyrosine kinase encoded by protooncogene c-kit. In normal gastrointestinal wall, KIT is expressed by interstitial cells of Cajal (ICC), which are a pacemaker for autonomous gastrointestinal movement. Because both GIST and ICC are double-positive for KIT and CD34, and because familial and multiple GIST appear to develop from diffuse hyperplasia of ICC, GIST are considered to originate from ICC or their precursor cells. It was also found that approximately 90% of the sporadic GIST have somatic gain-of-function mutations of the c-kit gene, and that the patients with familial and multiple GIST have germline gain-of-function mutations of the c-kit gene. These facts strongly suggest that the c-kit gene mutations are a cause of GIST. Approximately half of the sporadic GIST without c-kit gene mutations were demonstrated to have gain-of-function mutations in platelet-derived growth factor receptor-alpha (PDGFRA) gene that encodes another receptor tyrosine kinase. Because KIT is immunohistochemically negative in a minority of GIST, especially in PDGFRA gene mutation-harboring GIST, mutational analyses of c-kit and PDGFRA genes may be required to diagnose such GIST definitely. Imatinib mesylate was developed as a selective tyrosine kinase inhibitor. It inhibits constitutive activation of mutated KIT and PDGFRA, and is now being used for KIT-positive metastatic or unresectable GIST as a molecular target drug. Confirmation of KIT expression by immunohistochemistry is necessary for application of the drug. The effect of imatinib mesylate is different in various types of c-kit and PDGFRA gene mutations, and the secondary resistance against imatinib mesylate is often acquired by the second mutation of the identical genes. Mutational analyses of c-kit and PDGFRA genes are also significant for prediction of effectiveness of drugs including newly developed agents.     

Hypopigmentation in an African patient treated with imatinib mesylate: a case report

Imatinib mesylate (STI 571, Gleevec) is a potent bcr-abl tyrosine kinase inhibitor. It also inhibits c-kit tyrosine kinase. Imatinib mesylate is active in the treatment of cronic myeloid leukemia (CML) and gastrointestinal stromal tumors (GIST). It is considered by some authorities to be the standard of care in newly diagnosed CML as well as patients in chronic phase who do not have a related match. C-kit and its ligand stem-cell factor regulate melanocyte development and survival. Hypopigmentation in patients receiving imatinib mesylate for CML has been reported recently. In this article, we report a black Nigerian male with GIST, who developed hypopigmentation of distal parts of digits, as well as generalized lightening of skin on the body three months after receiving imatinib mesylate. We believe that this is the first case of hypopigmentation reported in a black patient with GIST.     

Current and emerging tests for the laboratory monitoring of chronic myeloid leukaemia and related disorders

Chronic myeloid leukaemia (CML) is a molecularly defined disease. The BCR-ABL fusion occurs in all cases of classical CML and leukaemic cells express a constitutively activated BCR-ABL tyrosine kinase. Other fusion oncogenes involving tyrosine kinases, including ABL and PDGFRA/B, have been identified, and are associated with leukaemic syndromes that may resemble CML. The discovery and treatment of these related disorders has been facilitated by our detailed understanding of CML. Imatinib mesylate has significantly improved the outcome of patients with CML, but there remains a significant minority of chronic phase CML patients for whom the response to treatment with standard dose imatinib is suboptimal. Cytogenetic and molecular monitoring of the response to treatment provides important prognostic information. Achievement of a major molecular response (MMR) in chronic phase patients treated de novo with imatinib confers near 100% freedom from progression to advanced phase, and MMR is now an important goal of therapy. Standardisation of BCR-ABL molecular monitoring is under way and should enable the accurate and reproducible identification of MMR in laboratories around the world. Point mutations in the kinase domain of BCR-ABL are the most common cause of acquired resistance to imatinib treatment. The susceptibility of a mutation to imatinib, nilotinib, or dasatinib may help to guide changes in therapy in a patient with resistance. In addition to these established methods of monitoring, there are new tests in development that may assist in determining prognosis and optimising therapy. Among patients receiving the same dose of imatinib, the plasma level of imatinib shows considerable inter-patient variation, and there is emerging evidence that higher levels may be associated with improved response to treatment. The intracellular concentration of imatinib also shows considerable variation, most likely related to differences in influx and efflux transport mechanisms. We discuss how these established and emerging assays might be used to optimise the treatment of CML patients.