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1.
BACKGROUND & AIMS: Activating mutations in platelet-derived growth factor receptor alpha (PDGFRA) have been reported in a subset of gastrointestinal stromal tumor (GIST) patients who do not express the mutant stem cell factor receptor c-kit. The responsiveness of mutant PDGFRA-positive GIST to imatinib depends on the location of the PDGFRA mutation; for example, the V561D juxtamembrane domain mutation is more sensitive to imatinib than the D842V kinase domain mutation. In this study, we compare the effects of 3 tyrosine kinase inhibitors, PKC412 and nilotinib, and imatinib, on 2 GIST-related PDGFRA mutants, V561D and D842V, which possess differential sensitivity to imatinib. METHODS: The effects of PKC412, nilotinib, and imatinib, alone and in combination, were evaluated via in vitro proliferation studies performed with V561D- or D842V-PDGFRA mutants. The effects of nilotinib and PKC412, alone and combined, were investigated in vivo. RESULTS: PKC412 potently inhibited the V561D-PDGFRA mutant in vitro and the D842V-PDGFRA mutant in vitro and in vivo. Both imatinib and nilotinib displayed potent activity in vitro against the V561D-PDGFRA mutant but were significantly less efficacious against D842V-PDGFRA. However, when combined with either imatinib or PKC412, nilotinib showed no evidence for antagonism and acted in a cooperative fashion against D842V-PDGFRA. CONCLUSIONS: Our findings support the clinical testing of PKC412 for treatment of mutant PDGFRA-GIST. The data also support the use of nilotinib as a treatment option for V561D-PDGFRA-associated GIST, although the reduced sensitivity of D842V-PDGFRA probably limits the potential of nilotinib monotherapy for D842V-PDGFRA-associated GIST. 相似文献
2.
Gastrointestinal stromal tumors (GISTs) are often associated with activating KIT mutations, affecting regulatory domains of the KIT tyrosine kinase. Sporadic mastocytosis in adults is usually also caused by KIT mutations that, however, activate KIT by affecting the intracellular enzymatic site of the molecule. Most GISTs respond to KIT inhibitors that bind to the enzymatic site; in most cases of mastocytosis, however, the modified enzymatic site is not affected by these drugs. We present a kindred with both familial GISTs and mastocytosis that express a novel germline KIT mutation in exon 8, resulting in deletion of codon 419 and affecting the extracellular domain of KIT. This mutation activates KIT, and the mutant KIT is inhibited by the tyrosine kinase inhibitor imatinib mesylate. Our studies identify a new regulatory region in the KIT molecule and strongly suggest that patients with extracellular KIT mutations respond to tyrosine kinase inhibitors. 相似文献
3.
BACKGROUND & AIMS: Imatinib, a tyrosine kinase inhibitor of BCR-ABL, KIT, and platelet-derived growth factor receptor, is used in patients with chronic myelogenous leukemia (CML) and gastrointestinal stromal tumors (GIST). Primary and acquired resistance to the drug can occur in both diseases. Molecular mechanisms have been reported in CML and GIST for primary resistance, whereas extensive studies on the mechanisms responsible for secondary resistance have been almost exclusively reported for CML. METHODS: In a patient with advanced GIST undergoing imatinib therapy, an isolated progressing peritoneal mass was excised, along with 2 still-responding lesions. Complementary DNA and genomic DNA were analyzed by sequencing for c-Kit gene mutations. KIT receptor expression and phosphorylation status were assessed by immunoprecipitation and Western blot. Transient-transfection experiments were performed with mutagenized KIT constructs, and their activation status was assessed. RESULTS: In addition to an exon 11 mutation, shared among all of the analyzed lesions, a novel point mutation in c-Kit exon 14 resulting in T670I substitution was found only in the progressing lesion, which harbored a phosphorylated receptor, as opposed to the finding of an inactive receptor in responding lesions. Functional analyses showed that KIT/T670I is insensitive to imatinib and that T670I mutation, introduced in a receptor responding to imatinib, subverted its sensitivity to the drug. CONCLUSIONS: This new mutation was confined to the progressing lesion; the resulting amino acidic substitution, T670I, affecting the ATP/imatinib pocket of KIT, makes it insensitive to the drug. Interestingly, this substitution is a homologue to the T315I mutation already reported in CML, where it is responsible for acquired resistance to imatinib. 相似文献
4.
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. 相似文献
5.
This is a report of a patient who manifests all of the features of Carney's syndrome, including gastrointestinal stromal tumors (GISTs), extra-adrenal paragangliomas, and pulmonary chondromas. The patient underwent surgical resection of a gastric GIST; a retroperitoneal, nonfunctional paraganglioma; and a mediastinal, catecholamine-secreting paraganglioma (pheochromocytoma). Recently, new gastric GISTs were diagnosed by endoscopic, ultrasound-guided, fine-needle aspiration (EUS-FNA) biopsy and were resected. Recurrence of stromal tumors following complete resection is common in Carney's syndrome and presents considerable management challenges. This case illustrates several important points: (1) Carney's syndrome, although rare, should be considered in patients with foregut GISTs; (2) GISTs associated with Carney's syndrome, like sporadic gastric GISTs, may have a more indolent clinical course; and (3) EUS-FNA may be useful for the diagnosis and management of GISTs in this syndrome. 相似文献
6.
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors. The molecular etiology is the result of mutations in the c- Kit gene. The mutant c-Kit proteins, which are activated without a stem cell factor, contribute to the tumor development. STI571 selectively inhibits c-Kit, BCR-ABL, and PDGFR tyrosine kinases. Based on this potential to inhibit critical c-Kit function in GISTs, case studies have reported effective outcomes following treatment with STI571. This case report describes a highly effective use of STI571 in a 54-year-old woman with multiple liver metastases from a GIST originating in the duodenum. 相似文献
7.
BACKGROUND & AIMS: Most gastrointestinal stromal tumors (GISTs) have gain-of-function mutations of c-kit receptor tyrosine kinase (KIT) gene, but some GISTs do not. We investigated the cause of GISTs without KIT mutations. Because GISTs apparently expressed platelet-derived growth factor receptor (PDGFR) alpha, we examined whether GISTs without KIT mutations had a mutation of PDGFR alpha. METHODS: Whole coding region of PDGFR alpha complementary DNA (cDNA) was sequenced in GISTs with or without KIT mutations. Mutant PDGFR alpha cDNA was transfected into 293T human embryonic kidney cells, and autophosphorylation of PDGFR alpha was examined. Proliferation of Ba/F3 murine lymphoid cells stably transfected with mutant PDGFR alpha cDNA was estimated by tritium thymidine incorporation. Wild-type KIT cDNA was cotransfected with mutant PDGFR alpha cDNA, and immunoprecipitation by anti-KIT antibody was performed. Inhibitory effect of Imatinib mesylate on activated PDGFR alpha was examined. RESULTS: We found 2 types of constitutively activated mutations of PDGFR alpha, Val-561 to Asp or Asp-842 to Val, in 5 of 8 GISTs without KIT mutations but not in 10 GISTs with KIT mutations. Stable transfection of each mutation induced autonomous proliferation of Ba/F3 cells. Constitutively activated mutant PDGFR alpha bound and activated the cotransfected wild-type KIT. The constitutive activation of PDGFR alpha with Val-561 to Asp was inhibited effectively by Imatinib mesylate but that of PDGFR alpha with Asp-842 to Val was inhibited only weakly, even at the concentration of 10 micromol/L. CONCLUSIONS: The gain-of-function mutations of PDGFR alpha appear to play an important role in development of GISTs without KIT mutations. 相似文献
8.
We report herein a rare case of gastrointestinal stromal tumor (GIST) type, arising from the greater omentum. A 65-year-old man who had a large abdominal tumor was referred to our hospital. Ultrasonography (US) and computed tomography (CT) scans showed a mass occupying almost the entire abdomen anterior to the bowel loops. Abdominal angiography showed that the main feeding artery of the tumor was the right gastroepiploic artery. The preoperative diagnosis was suspected gastric leiomyosarcoma. Laparotomy revealed a large mass arising from the greater omentum, and the tumor seemed to be completely excised. Histopathological and immunohistochemical studies indicated the tumor had the same characteristics as GIST. Twelve months after the operation, the tumor recurred in the peritoneal cavity at the site of the stomach, and was associated with multiple liver metastases. The patient died of hypovolemic shock. Necropsy revealed that rupture of one of the metastatic liver tumors had resulted in a massive intraperitoneal hemorrhage. 相似文献
9.
Background: We aimed to investigate the role of intracellular imatinib concentration in drug resistance and the expression of candidate drug transporters in gastrointestinal stromal tumor (GIST) cell lines. Method: The imatinib concentrations were measured by the liquid chromatography-tandem mass spectrometry (LC-MS/MS). The expression of candida te drug transporters was detected by qRT-PCR. Results: The tissue imatinib concentrations in imatinib resistant patients were significantly lower than that of sensitive patients (p?<?.05). Compared with parental cell lines, the intracellular imatinib concentration was notably lower in imatinib resistant GIST cell lines. For candidate transporters, MRP1 and BCRP were overexpressed in resistant GIST cell lines. Conclusion: The intracellular imatinib concentration may play a crucial role in imatinib resistance and the intracellular differences of imatinib concentration may be induced by the upregulation of efflux transporters. Our study highlights the importance of intracellular imatinib concentration and the potential of using imatinib transporters as therapeutic targets for patients with GIST. 相似文献
11.
Background Gastrointestinal stromal tumor (GIST) is the most common type of nonepithelial tumor in the gastrointestinal tract. The gastrointestinal stromal tumor is defined immunohistologically as a c-Kit-positive tumor. For those GISTs that are malignant, the only effective treatment modality has been surgical. Early clinical reports have shown that imatinib mesylate (STI571) produces substantial anticancer activity in patients with metastatic or unresectable GIST.Methods Nine Japanese patients who were found clinically and immunohistochemically to have inoperable GISTs were entered into this study. These patients were given 400mg STI571 orally once daily. We then evaluated the tumor response and the safety of the drug.Results Five of the nine patients achieved partial responses, two had stable disease, and two had progressive disease. The main side effects were skin rash, edema, periorbital edema, diarrhea, nausea, and vomiting. Mild anemia, leukocytopenia, and neutropenia were also noted. No patients required dose reduction or cessation because of adverse events.Conclusions This study demonstrates that STI571 might be an active agent against malignant GIST in Japanese patients with manageable toxicities. 相似文献
12.
Gastrointestinal stromal tumors (GISTs) and leiomyomas of the gastrointestinal tract both may present as intramural smooth
muscle cell tumors. Immunohistochemically, these tumors demonstrate different spectrums of protein expression, which helps
in differential diagnosis. Leiomyomas of the uterine type are similar by the spectrum of protein expression to gastrointestinal
leiomyomas, but they express in addition both estrogen (ER) and progesterone (PR) receptors, which makes hormonal therapy
possible for these tumors. In the current study, we investigated expression of ER and PR in GISTs and intramural gastrointestinal
leiomyomas. Our data demonstrate that none of the 22 cases of gastrointestinal leiomyomas nor 19 cases of GIST were positive
for either ER or PR expression. In contrast, leiomyomas of the uterine type were strongly positive for both ER and PR. Our
data demonstrate that GIST and gastrointestinal leiomyomas differ from leiomyomas of the uterine type by the expression of
ER and PR. Immunostaining for ER and PR may be a useful tool to distinguish these tumors and more precisely to plan further
clinical interventions. 相似文献
15.
Gastrointestinal stromal tumor (GIST) in the distal third of the rectum was detected in a 57-year-old man who underwent an
abdominoperineal resection of the rectum. Because the tumor expressed CD34 and c- kit gene product, but did not express smooth muscle actin or S-100 protein, it was diagnosed as an uncommitted type of GIST.
Moreover, a specific mutation in the sequence coding the juxtamembrane domain in exon 11 of the c- kit proto-oncogene was revealed by a polymerase chain reaction-single-strand conformation polymorphism method. One year after
resection, the patient developed multiple liver metastases. It is suggested that a specific mutation in exon 11 of the c- kit proto-oncogene may have played an essential role in the development of the liver metastases.
Received: October 27, 1999 / Accepted: January 28, 2000 相似文献
16.
We report a case of somatostatinoma of the papilla of Vater with multiple gastrointestinal stromal tumors in a patient with
von Recklinghausen's disease (VRD). A 64-year-old woman who had had recurrent attacks of acute pancreatitis and cholangitis
was found, on gastroduodenal endoscopy, to have a tumor of the papilla of Vater and multiple submucosal tumors of the stomach
and duodenum. Numerous submucosal tumors were observed in the stomach, duodenum, and jejunum, and total excision of the papilla
of Vater and resection of the duodenal and jejunal submucosal tumors was performed. The tumor of the papilla of Vater showed
the histologic appearance of a dense proliferation of tumor cells in acinar form, from the duodenal mucosa to the muscle layer,
and psammoma bodies were revealed within the tumor. Immunohistologically, the tumor cells were intensely positive for somatostatin.
The submucosal tumors of the duodenum and jejunum were negative for smooth muscle actin, s-100, and neuron-specific enolase
(NSE), and positive for CD34 and c-kit, and they were diagnosed as gastrointestinal stromal tumors (GISTs) according to the
strict definition. The only 25 cases of papilla of Vater somatostatinoma associated with VRD to have been reported in the
English-language literature since 1982 are reviewed, as well as our own case.
Received: January 22, 2001 / Accepted: August 10, 2001
Reprint requests to: M. Usui 相似文献
17.
BACKGROUND AND AIM: To evaluate the clinical implications of C-kit gene mutation in patients with gastrointestinal stromal tumors (GIST) greater than 10 cm in size. METHODS: All cases of pathologically diagnosed GIST with positive CD117 immunostaining from one hospital were retrospectively reviewed. Tissue from the 25 patients with tumors greater than 10 cm in diameter were collected and DNA was extracted. Exons 9, 11, and 13 of the C-kit gene were analyzed and the mutations compared with the clinical and pathological characteristics of the corresponding tumors. RESULTS: Of the 25 tumors studied, 16 had C-kit gene mutations and nine did not. Of the 16 with mutations, there were four with exon 9 mutations, 12 with exon 11 mutations, and none with exon 13 mutations. Gene mutations were more frequent in male than female patients (12/13, 92% vs 4/12, 33%). There were no significant differences in age, resectability, recurrence rate, tumor characteristics (ulceration, necrosis, hemorrhage and mitotic counts), or survival in patients with or without gene mutations. CONCLUSIONS: C-kit gene mutations were frequently found in patients with large GIST, more commonly in men than in women. However, the presence of a mutation was not predictive of prognosis in patients with large GIST. 相似文献
18.
目的总结胃肠道间质瘤(gastrointestinal stromal tumor,GIST)的生物学特性,进一步指导临床诊治。方法回顾性分析2004年1月~2008年12月经病理证实的73例GIST的临床资料,包括好发部位、恶性程度、临床表现、组织学特点、治疗及预后,阐述其生物学特性。结果本组GIST好发于胃(74%)及小肠(14%),特别是胃底(44%)及胃体(39%)。恶性程度较低的间质瘤容易出现腹痛,胃底间质瘤较易发生呕血。外科手术是根治GIST的主要方式,内镜下切除有望成为新的重要治疗方式。结论对GIST生物学特性的分析有利于更好地指导临床。 相似文献
19.
There is no practical predictive model for the diagnosis of gastrointestinal stromal tumors (GISTs). To establish a practical predictive model for the diagnosis of subepithelial lesions in the stomach, we reviewed patients with GISTs (n = 89), schwannomas (n = 7), and leiomyomas (n = 28).The tumor was more frequently found along the gastric cardia in the leiomyoma group (57.1%) than in the GIST/schwannoma group (2.1%, P < .01). Contrast enhancement (57.3% vs 0%, P < .01) and intra-tumoral necrosis (34.4% vs 0.0%, P < .01) were more frequently observed in the GIST/schwannoma group than in the leiomyoma group. On endoscopic ultrasonography, 58.3% of GISTs/schwannomas showed uneven echogenicity, whereas the echogenicity was uneven in 21.4% of leiomyomas ( P < .01). There were no differences between the tumor color and the presence or absence of ulcer formation, tumor bleeding, irregularity of the tumor margin, cystic spaces, and hyperechoic spots between the 2 groups. Based on these results, we developed a 2-step diagnostic algorithm for GISTs/schwannomas. The first step comprises 1 endoscopic feature: a cardiac or non-cardiac location. Tumors with a cardiac location were judged as leiomyomas and those with a non-cardiac location were judged as GISTs/schwannomas, with 96.9% sensitivity and 57.1% specificity for GIST/schwannoma diagnosis. The second step comprises a combination of endoscopic (non-cardiac location), radiologic (positive contrast enhancement and intra-tumoral necrosis), and endosonographic (uneven echogenicity) features for a total of 4 points. We assigned 1 point to each feature. Tumors with scores of 2 to 4 were judged as GISTs/schwannomas, with 81.3% sensitivity and 92.9% specificity for GIST/schwannoma diagnosis.Our predictive model will be a practical guide for the management of gastric subepithelial lesions. 相似文献
20.
[目的]分析并讨论胃肠间质瘤的MRI诊断价值和病理组织学的特点。[方法]选取2011年7月~2013年1月期间我院胃肠科收治的患有胃肠道间质瘤患者98例,按照系统分组法将98例患者分为使用MRI方法检查的观察组和使用超声检查的对照组。2组患者在上述检查之后均进行病理组织学分析。[结果]两种检查方法均能检测出胃肠道间质瘤,MRI检测的准确率为95.92%,而超声检查的准确率为67.35%,前者比后者准确率高约28.57%(P〈0.05)。其中通过检查发现,病灶发生于胃部者比肠部和回盲部多约32.56%(P〈O.05)。[结论]MRI对胃肠道间质瘤的诊断准确性高,诊断相对精准。虽然MRI检查的费用较其他影像方法高,但是还是值得在临床上广泛推广。 相似文献
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