Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C1261473 (sarcoma)
 25,952 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Primary sarcomas of the great vessels are very rare neoplasms and only a few cases have been reported. They are divided into the two broad categories of intimal or luminal and mural sarcomas. We analysed eight advanced high-grade sarcomas originating from major vessels (seven intimal and one mural sarcoma) by means of immunohistochemistry and FISH analysis for PDGFRA, PDGFRB, EGFR and KIT receptor tyrosine kinases (RTKs), together with immunoprecipitation/western blotting, sequencing of the corresponding genes, and the search for cognate ligands. The intimal sarcomas showed a wide spectrum of morphologies and immunophenotypes, whereas the mural sarcoma had common leiomyosarcomatous features. Regardless of their category, all of the cases had a PDGFRA-deregulated cytogenetic profile mainly consisting of an amplification cluster; five were also polysomic for PDGFRB, whereas three showed disomy. Six cases had a deregulated EGFR gene, and c-Kit gene status was similar to that of PDGFRA. In one case, biochemical analysis revealed the presence of activated and highly expressed PDGFRA, PDGFRB and EGFR, whereas KIT was expressed at reference level. Sequencing of the corresponding genes revealed no activating mutations in any of the analysed receptors. The cognate ligands were detected in all cases. In predictive terms, the evidence of gene amplification/high polysomy of several RTKs, together with PDGFRA, PDGFRB and EGFR expression and phosphorylation, suggests that these tumours may be sensitive to RTK-inhibiting treatments.
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PMID:Analysis of potential receptor tyrosine kinase targets in intimal and mural sarcomas. 1747 66

Methodologies employed in the rapidly developing field of soft tissue sarcoma molecular testing focus primarily on diagnosis using chromosomal translocations and the resulting fusion transcripts. Molecular prognostic testing holds promise in this complex group of rare mesenchymal malignancies, but results are preliminary and require further confirmation. Analysis of activating KIT mutations in gastrointestinal stromal tumors is currently being used in management of patient therapy.
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PMID:Sarcoma molecular testing: diagnosis and prognosis. 1758 56

Gastrointestinal stromal tumors (GISTs) may be caused by germline mutations of the KIT and platelet-derived growth factor receptor-alpha (PDGFRA) genes and treated by Imatinib mesylate (STI571) or other protein tyrosine kinase inhibitors. However, not all GISTs harbor these genetic defects and several do not respond to STI571 suggesting that other molecular mechanisms may be implicated in GIST pathogenesis. In a subset of patients with GISTs, the lesions are associated with paragangliomas; the condition is familial and transmitted as an autosomal-dominant trait. We investigated 11 patients with the dyad of 'paraganglioma and gastric stromal sarcoma'; in eight (from seven unrelated families), the GISTs were caused by germline mutations of the genes encoding subunits B, C, or D (the SDHB, SDHC and SDHD genes, respectively). In this report, we present the molecular effects of these mutations on these genes and the clinical information on the patients. We conclude that succinate dehydrogenase deficiency may be the cause of a subgroup of GISTs and this offers a therapeutic target for GISTs that may not respond to STI571 and its analogs.
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PMID:Clinical and molecular genetics of patients with the Carney-Stratakis syndrome and germline mutations of the genes coding for the succinate dehydrogenase subunits SDHB, SDHC, and SDHD. 1766 67

Primary and metastatic so-called malignant fibrous histiocytoma/undifferentiated high-grade pleomorphic sarcoma (MFH) is rare in the gastrointestinal (GI) tract with approximately 50 primary and five metastatic cases reported so far. We evaluated two primary gastric and three metastatic intestinal high-grade pleomorphic sarcomas with features of storiform-pleomorphic MFH. Gastric tumours occurred in a 79-year-old man and a 68-year-old woman. One patient died post-operatively, and the other was disease-free at 6 months. Three patients presented with GI metastasis 24, 60 and 0 months after diagnosis of MFH of the heart (n = 1) and the thigh (n = 2). Metastases were located in the small (n = 1) and large bowel (n = 2) and were characteristically pedunculated and polypoid with oedematous haemorrhagic stroma. Concurrent metastases (brain, lung, bone) were present in all three cases. Tumours expressed alpha-smooth muscle actin (four of five), platelet-derived growth factor receptor (PDGFR) alpha (three of three) and PDGFRbeta (two of three) but were negative for CD117, CD34 and other lineage-specific markers. Ultrastructural examination revealed myo/fibroblastic features. Both gastric MFH were wild type for KIT and PDGFRalpha. In conclusion, primary and metastatic MFH of the GI tract commonly express PDGFRalpha and show a myo/fibroblastic phenotype. They should be distinguished from a variety of primary and metastatic pleomorphic neoplasms, in particular high-grade sarcomatous GI stromal tumours (GIST), pleomorphic leiomyosarcoma, sarcomatoid carcinoma and other mimics.
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PMID:Primary and metastatic high-grade pleomorphic sarcoma/malignant fibrous histiocytoma of the gastrointestinal tract: an approach to the differential diagnosis in a series of five cases with emphasis on myofibroblastic differentiation. 1787 30

Once a poorly understood pathologic entity, gastrointestinal stromal tumor (GIST) has emerged in recent years as a distinct oncologic-molecular paradigm that is now a leading model for kinase-targeted therapies in oncology. Most GISTs are KIT-expressing and KIT signaling-driven mesenchymal tumors, many of which have KIT-activating mutations. A small subset of GIST show activating mutations in PDGFRA, encoding a related member of the type III receptor tyrosine kinase family. The revelation of KIT expression as a diagnostic signature of GIST has not only revolutionized the pathologic criteria in classifying GIST, but also shed light on the histogenesis of these tumors. The similarities in KIT immunoreactivity and ultrastructural appearance between GISTs and the intestinal pacemaker, the interstitial cells of Cajal (ICC), suggested that GISTs derive from or differentiate toward the ICC lineage. KIT plays a significant role in proliferation, survival, and differentiation of hematopoietic stem cells, mast cells, melanocytes, and interstitial cells of Cajal; activating KIT mutations have been identified in tumors affecting most of these cell lineages. This review will include a summary of the biology behind the specific targeted therapies, emphasizing the central role of KIT and PDGFRA oncogenic mutations in GISTs and their clinical and pathologic correlates. The role of KIT immunohistochemistry vs mutation testing will be discussed, with an insight into the indications for KIT/PDGFRA genotyping in GIST. The morphologic and molecular changes that appear with imatinib treatment, such as response and acquired imatinib resistance, are being discussed. The success GIST story based on targeted molecular paradigm may be applied in other imatinib-responsive sarcoma, such as dermatofibrosarcoma protuberans.
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PMID:Targeted therapy of cancer: new roles for pathologists in identifying GISTs and other sarcomas. 1843 71

The common feature of gastrointestinal stromal tumors (GISTs) is the expression of KIT protein or acquisition of activating, constitutive mutations in the KIT or platelet-derived growth factor receptor alpha (PDGFRA) genes that are the early oncogenic events during GIST development. With these discoveries, GIST has emerged as a distinct sarcoma entity, enabling the introduction of targeted therapy using the inhibition of KIT/PDGFRA and their downstream signaling cascade. The introduction of a small-molecule tyrosine kinase inhibitor, imatinib mesylate, to clinical practice has revolutionized the treatment of patients with advanced GISTs and is currently approved as first-line treatment for patients with metastatic and/or inoperable GISTs. Mutation screening is currently a tool in GIST diagnosis, assessment of sensitivity to tyrosine kinase inhibitors, and prediction of achieving response to molecularly targeted therapy. This article discusses the histologic and molecular criteria for distinguishing GISTs from other types of sarcoma, and the molecular diagnostic tools that are currently available or in development to assist in therapy decisions.
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PMID:Gastrointestinal stromal tumors: key to diagnosis and choice of therapy. 1851 Mar 77

A 77-year-old woman presented with hoarseness and hemoptysis. Chest CT scan revealed a mediastinal tumor in the lumen of the left pulmonary artery. A definitive diagnosis could not be made based on mediastinoscopy and thoracotomy. Eight months later, multiple nodular shadows appeared in both lung fields.Video-assisted lung biopsy showed that these nodules were lung metastases of a spindle cell sarcoma. Based on the pathological and radiological findings, a pulmonary artery sarcoma was eventually diagnosed. Interestingly, on immunohistological staining, the tumor cells were diffusely positive for KIT, which is an immunohistochemical marker of gastrointestinal stromal tumors. The patient was treated with imatinib, a KIT tyrosine kinase inhibitor; however, the tumors progressed. The relationship between pulmonary artery sarcoma and KIT requires further study.
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PMID:[Diffuse expression of KIT in a pulmonary artery sarcoma]. 1851 91

Purpose. To study the evolution of concepts concerning gastrointestinal stromal tumours (GISTs) over 30 years.Discussion. GISTs have been, for more than 30 years, the subject of considerable controversy regarding their line of differentiation as well as the prediction of their behaviour. Furthermore, once they spread within the peritoneal cavity, they are extremely hard to control. The recent findings of c-Kit mutations and the immunohistochemical detection of the product of this gene, KIT or CD117, in the mainly non-myogenic subset of this family of tumours, has led to a reappraisal of this group of lesions, which, with some exceptions, is now thought to be derived from the interstitial cells of Cajal, and this has facilitated a clearer definition of their pathological spectrum. In this article, we review chronologically the evolution of the concept of GIST with the gradual application of electron microscopy, immunohistochemistry, DNA ploidy analysis. We discuss the impact of these techniques on the pathological assessment and clinical management of GISTs.
Sarcoma 1998
PMID:Gastrointestinal stromal tumours: an update. 1852 Dec 45

Ewing Sarcoma (ES) shows several deregulated autocrine loops mediating cell survival and proliferation. Therefore, their blockade is a promising therapeutic approach. We previously reported the in vitro effect of insulin-like growth factor 1 receptor (IGF1R)/KIT pathway blockade on ES cell lines, and we now extend our observations to changes induced by this treatment in interacting proteins/networks. A proteomic analysis revealed that Heat Shock Protein (HSP)90 was differentially expressed between ES cell lines sensitive and resistant to specific IGF1R/KIT inhibitors. We therefore inhibited HSP90 with 17-allylamino-17-demethoxygeldanamycin (17-AAG) and siRNA, and observed that ES cell line growth and survival were reduced, especially in the resistant cell lines. Conversely, HSP90 induced-expression conferred resistance to anti-IGF1R/KIT treatment in the sensitive cell lines. 17-AAG treatment induced HSP90 client protein degradation, including AKT, KIT, or IGF1R, by inhibiting their physical interaction with HSP90. Xenograft models developed with A673 ES cell line confirmed that HSP90 inhibition, alone or combined with IGF1R inhibition, significantly reduced tumor growth and expression of client proteins. Remarkably, using two independent clinical sample sets, we have found that nearly half of IGF1R-positive tumors also show HSP90 overexpression. This delineates a subset of patients that could benefit from combination of anti-HSP90 agents when considering IGF1R-targeting therapies. Importantly, sensitivity to drugs such as ADW/IMA depends not only on the levels of expression and basal activation of IGF1R/KIT, but also, and for the first time reported in ES, on the development of the stress response mechanism. Accordingly, HSP90 expression could be a predictive factor of response to IGF1R-targeting therapies.
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PMID:A pivotal role for heat shock protein 90 in Ewing sarcoma resistance to anti-insulin-like growth factor 1 receptor treatment: in vitro and in vivo study. 1867 50

Gastrointestinal stromal tumors (GISTs) are a rare and heterogeneous group of spindle cell neoplasms that have also been reported outside of gastrointestinal (GI) tract. These tumors are characterized by somatic mutations of c-KIT (CD117), a proto-oncogene that encodes a receptor tyrosine kinase normally expressed in the interstitial cell of Cajal that control the GI smooth muscle peristalsis, and an exquisite sensitivity to the action of the tyrokinase inhibitor imatinib mesylate (STI571; Gleevec). We report two cases of gastrointestinal stromal tumor identified on prostatic biopsies, where a primary prostatic sarcoma was considered in the differential diagnosis. In one of the cases, there was extensive local disease involving prostate, rectum, and pelvic wall, as well as metastatic disease that quickly lead to the patient's death despite aggressive treatment with imatinib mesylate and conventional chemotherapy. In the other case, the tumor was mostly confined to the rectum but also focally extended into the prostate capsule. The patient underwent resection and was alive without disease 18 months after surgery. In both cases, tissue samples from prostate and the rectum showed a malignant spindle cell neoplasm, which was positive for CD117 (c-kit). Given their unique clinical management, gastrointestinal stromal tumors should be considered in the differential diagnosis of spindle cell lesions on prostatic needle biopsies and CD117 should be added to the immunohistochemical panel in the work-up of such lesions to avoid misinterpreting them as primary prostatic neoplasms.
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PMID:Gastrointestinal stromal tumors presenting as a prostatic mass. 1922 92


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