Factors associated with disease progression in patients with gastrointestinal stromal tumors in the pre-imatinib era.
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The aim of this study was to determine the predictors of survival in 38 patients with curatively resected gastrointestinal stromal tumors (GISTs). The tumor was located in the stomach in 23 cases, the small bowel in 13, and the colon in 2. In 23 patients (61%), a mutation in exon 11 of the kit gene was detected. In 7 cases, all small gastric tumors, a mutation in the platelet-derived growth factor receptor a (PDGFRA) gene was detected. The overall 5-year survival rate was 70%. In 9 patients, GISTs relapsed, leading to an actuarial 5-year disease-free survival of 78%. By multivariate analysis, the presence of distant metastases, the proliferative (MIB-1) index, and deletional mutation in codons 557 and/or 558 of kit exon 11 correlated significantly with poor outcome. None of the PDGFRA mutant GISTs relapsed. These findings suggest a strong relationship between various tyrosine kinase receptor mutations and survival outcome in patients with GISTs. (+info)
Spurt bleeding from a calcificated gastrointestinal stromal tumor in the stomach.
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Calcifications within primary gastrointestinal tumors are rare. Gastrointestinal stromal tumor (GIST) is an unusual nonepithelial tumor that develops in the gastrointestinal tract. In this paper we describe a case of spurt bleeding from a calcificated GIST in the stomach successfully treated by partial gastric resection. A 77-year-old man was admitted for chest discomfort and loss of consciousness. Endoscopic examination revealed spurt bleeding from the top of the submucosal tumor. No other lesions or points of bleeding were found in the stomach. Emergency partial gastrectomy was performed, and the stomach was closed. The cut surface of the tumor had a firm, solid, whitish-gray parenchyma with patchy calcification. Microscopic observation revealed a profusion of spindle-shaped tumor cells with calcification growing from the gastric muscular propria to the submucosa. The cells exhibited low mitotic activity and no prominent signs of nuclear atypia. Immunohistochemical staining of the tumor demonstrated positive reactivity for CD34, KIT, and vimentin, but negative reactivity for alpha-smooth muscle actin, desmin, and S-100 protein. Tumor cells positive for Mib-1 were rare. The diagnosis of the tumor was established as GIST. (+info)
GISTs with PDGFRA exon 14 mutations represent subset of clinically favorable gastric tumors with epithelioid morphology.
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Gastrointestinal stromal tumors (GISTs) are common mesenchymal tumors of the gastrointestinal tract. Activating KIT or PDGFRA (platelet-derived growth factor receptor alpha) mutations have been shown to be a major force in GIST pathogenesis. Recently, a previously undescribed N659K PDGFRA exon 14 mutation has been reported in GISTs. The purpose of this study was to evaluate the frequency of GISTs with PDGFRA exon 14 mutations and define the clinicopathologic profile of such tumors. In all, 200 GISTs negative for mutations in KIT exons 9, 11, 13 and 17 and PDGFRA exons 12 and 18 were evaluated for PDGFRA exon 14 mutations by PCR amplification and direct sequencing. Mutations were found in 11 of 119 (9%) gastric GISTs. None of the 81 GISTs from other than gastric location had such a PDGFRA mutation. A majority of these mutations (eight cases) represented simple 2125C>A or C>G missense mutations, leading to substitution of the lysine for asparagine (N659K). However, in two cases, 2123A>T missense mutations leading to substitution of the tyrosine for asparagine (N659Y) was found instead. Of 11 PDGFRA N659-mutant GISTs, 10 had pure epithelioid morphology. One tumor had mixed, predominantly spindle and focally epithelioid cell morphology. Frequency of PDGFRA N659-mutant GISTs among pure epithelioid GISTs was almost 19%. Immunohistochemically, the majority (64%) of these tumors lacked KIT expression or showed only focal scattered KIT positivity. Tumor size ranged from 2.5 to 16 cm (average 7.1 cm). Low mitotic activity, 5 cm tumors. Based on mitotic activity and tumor size, six tumors were classified as probably benign with very low malignant potential. Low to moderate malignant potential and high malignant potential was suggested in three and two tumors, respectively. In four cases with moderate or high malignant potential GISTs, a long-term follow-up (average 235.5 months) showed favorable course of disease. (+info)
An in vivo tumor model exploiting metabolic response as a biomarker for targeted drug development.
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In vivo models that recapitulate oncogene-dependent tumorigenesis will greatly facilitate development of molecularly targeted anticancer therapies. We have developed a model based on activating mutations in c-KIT in gastrointestinal stromal tumors (GISTs). This model comprises murine tumors of FDC-P1 cell lines expressing c-KIT mutations that render the tumors either responsive (V560G) or resistant (D816V) to the small-molecule c-KIT inhibitor, imatinib. Clinically, GIST response to imatinib is associated with rapid reduction in fluorodeoxyglucose (FDG) uptake on positron emission tomography (PET), preceding changes in conventional response criteria by several weeks. Using the FDC-P1 model in small animal PET, FDG uptake into tumors expressing the c-KIT V560G mutation was significantly reduced as early as 4 hours after imatinib treatment. In contrast, no change in FDG uptake was observed in resistant c-KIT D816V-expressing tumors after 48 hours of imatinib treatment. Consistent with the PET results, expression of the glucose transporter, GLUT1, was significantly reduced in V560G tumors at 4 hours, preceding changes in markers of proliferation by several hours. In vitro, imatinib treatment of V560G cells resulted in a reduction of glucose transporter numbers at the cell surface and decreased glucose uptake well before changes in cell viability. Notably, decreased ambient glucose concentrations enhanced the cytotoxic effect of imatinib. Taken together, these data account for the rapidity and significance of the PET response to imatinib and suggest that metabolic effects may contribute to imatinib cytotoxicity. Further, the FDC-P1 model represents a very useful paradigm for molecularly targeted drug development. (+info)
Gastric duplication cyst in an adult: case report.
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Duplication cysts of the stomach are uncommon findings in adult patients and diagnosis is often overlooked. Presenting symptoms are often non-specific, but complications, including chronic infections, ruptures or carcinoma arising in the cyst, are rare. We report a case of a non-communicating cyst of the stomach in a 67-year-old man. (+info)
Activating mutations in c-KIT and PDGFRalpha are exclusively found in gastrointestinal stromal tumors and not in other tumors overexpressing these imatinib mesylate target genes.
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Previous studies have shown that Imatinib mesylate (Gleevec), a selective tyrosine kinase inhibitor of c-KIT and platelet-derived growth factor receptors (PDGFR), is highly effective in c-KIT/CD117-positive gastrointestinal stromal tumors (GIST), especially in those having activating mutations in c-kit exon 11. In addition, gain-of-function mutations in the juxtamembrane domain (exon 12) and the kinase activation loop (exon 18) of PDGFRalpha were found in GISTs. Importantly, the presence and type of these mutually exclusive c-KIT or PDGFRalpha mutations were found to be associated with the response to imatinib. Here, we examined the prevalence of c-kit exon 11 and PDGFRalpha exons 12 and 18 mutations in other tumor types known to express these tyrosine kinase receptors in order to explore which other cancer types may potentially benefit from imatinib treatment. We determined the mutational status of these commonly mutated exons by direct sequencing in 11 different tumor types (in total: 215 unrelated cases), including GIST, chordoma, and various distinct tumors of lung, brain and its coverings, and skin cancer. Of the 579 exons examined (211 c-kit exon 11, 192 PDGFRalpha exon 12, 142 PDGFRalpha exon18, 17 PDGFRbeta exon 12 and 17 PDGFRbeta exon 18), only 12 (all GIST) harbored mutations (10 c-kit exon 11 and 2 PDGFRalpha exon18). From these data we conclude that activating c-KIT and PDGFR mutations are sporadic in human cancers known to overexpress these tyrosine kinase receptor genes and suggest that, except in GIST, this overexpression is not correlated with activating mutations. The latter may imply that these wild-type c-KIT and PDGFR tumor types will probably not benefit from imatinib treatment. (+info)
Cytogenetic confirmation of a gastrointestinal stromal tumor and ewing sarcoma/primitive neuroectodermal tumor in a single patient.
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We report a rare case in which two tumor entities, a gastrointestinal stromal tumor (GIST) and Ewing sarcoma/primitive neuroectodermal tumor (ES/PNET), with distinct cytogenetic features occurred in a single patient. The patient was a 72-year-old woman. The first tumor was a submucosal gastric tumor and was diagnosed as a low-risk group GIST based on morphological characteristics and the results of an immunohistochemical analysis for c-kit and CD34. Further cytogenetic analysis revealed that this tumor had a point mutation (D842V substitution) in exon 18 of the platelet-derived growth factor receptor alpha gene. The second tumor was found more than 4 years after the appearance of the first tumor. ES/PNET was highly suspected both morphologically and immunohistochemically, and the diagnosis was confirmed by the detection of an EWS rearrangement using a fluorescence in situ hybridization technique. Although the cytogenetic correlations of these two tumors are unclear, accurate histologic recognition is of clinical importance because the treatments for these two tumors differ. (+info)
Very early detection of response to imatinib mesylate therapy of gastrointestinal stromal tumours using 18fluoro-deoxyglucose-positron emission tomography.
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AIM: To investigate whether 18F-FDG-PET allows early assessment of response to imatinib mesylate in GIST patients. PATIENTS AND METHODS: Five gastrointestinal stromal tumour (GIST) patients and one patient with a KIT-positive small cell cancer were studied. Treatment consisted of 400 mg imatinib mesylate daily. 18F-deoxyglucose-positron emission tomography (18F-FDG-PET) scans were done before and one week after starting imatinib mesylate therapy. RESULTS: Metabolic responses were detected after only one week of therapy in all GIST patients (four partial and one complete response). The mean decrease of the standardised uptake value was 60% (range 43 to 77%). In contrast, the tumour of the non-GIST patient was metabolically stable. Four of the 5 GIST patients achieved a partial response on CT after a mean duration of 23 weeks (range 6 to 48 weeks). CONCLUSION: 18F-FDG-PET is a valuable method for the detection of response to imatinib mesylate in patients with KIT-positive tumours as early as one week after starting therapy. (+info)