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

We performed immunohistochemical analysis for KIT in 365 soft tissue sarcomas. Most tumors evaluated were completely negative for KIT, including all cases of leiomyosarcoma, rhabdomyosarcoma, myxofibrosarcoma, liposarcoma, solitary fibrous tumor, synovial sarcoma, dermatofibrosarcoma protuberans, schwannoma, malignant peripheral nerve sheath tumor, clear cell sarcoma, low-grade endometrial stromal sarcoma, and follicular dendritic cell sarcoma. Tumors showing occasional immunoreactivity for KIT included extraskeletal myxoid chondrosarcoma (2/20), Ewing sarcoma/malignant primitive peripheral neuroectodermal tumor (4/20), melanotic schwannoma (3/5), metastatic melanoma (4/20), and angiosarcoma (5/20). In most cases, staining for KIT was focal. Rare tumor cells showing KIT positivity were identified in a small number of other tumors. This study demonstrates very limited expression of KIT in soft tissue tumors other than gastrointestinal stromal tumors and underscores the discriminatory value of KIT immunohistochemical analysis for differential diagnosis. As some of these findings differ markedly from previous reports, it is evident again that variations in immunohistochemical technique can lead to major discrepancies in positive staining. Since treatment eligibility for selective tyrosine kinase inhibitors such as STI571 hinges on positive immunostaining, standardization and reproducibility of meaningful results are critically important.
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PMID:Immunohistochemical staining for KIT (CD117) in soft tissue sarcomas is very limited in distribution. 1221 91

Gastrointestinal stromal tumors (GIST) are rare tumors occuring at all levels of the gastrointestinal tract, whose estimated incidence may be close to 2 new cases per 100 000 persons per year. GIST derive from the interstital cells of Cajal (ICC) responsible for the motility of the GI tract, or from a common precursor of ICC and of the smooth muscle cells of the digestive tract. GIST cells express the c-kit protoconcogene under an activated form, either mutated or constitutively activated, as well as the CD34 Ag. Mutations of the KIT gene is an early event in the process of transformation in these tumors. Until recently, GIST were not recognized as a distinct entity among soft tissue sarcoma. It is now clear that conventional chemotherapy is generally inactive in this tumor, surgery being the only efficient therapeutic modality even in patients with advanced disease. Rapidly accruing phase I, II and III trials in the USA and Europe (EORTC) have demonstrated since 2000 that imatinib mesylate (STI571) is an active agent in GIST with an initial response rate of 70 % and 10 % only of primary refractory tumors, yelding an improved overall survival as compared to historical series. Resistance are now being observed however. GIST has become the first model of a solid tumor treated efficiently by a treatment targetting the initial genetic alteration of the disease. Numerous question regarding the integration of this treatment with surgery and the long term outcome of these patients still remain to be answered however.
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PMID:[Gastro-intestinal stromal tumors: news and comments]. 1260 7

Immunohistochemical staining for KIT (CD117) was performed on 144 cases of soft tissue sarcoma and 11 cases of gastrointestinal stromal tumor (GIST). Diffuse global staining in almost all neoplastic cells was a consistent feature of GIST but was also seen in some types of soft tissue sarcoma that resemble GISTs morphologically, such as synovial sarcoma and leiomyosarcoma. This finding is of diagnostic importance because some of these sarcoma types may involve the intestinal wall and simulate primary GIST. Most other positive cases showed focal staining. Although focal positivity may not be a problem in resected specimens, it has the potential to be misleading in biopsy material. Our results are concordant with some reports of CD117 expression in soft tissue tumors, but they differ from those reported by other laboratories. This discrepancy in the literature may be the result of variation in antibodies used or variation in immunohistochemical staining protocol. Regardless of the technical or scientific explanation, an understanding of the difficulties with KIT immunostaining is critical. Not only is KIT positivity used as a prerequisite for the diagnosis of GISTs, but treatment eligibility for STI571 in patients with GIST, and increasingly with other tumors, relies on positive KIT immunostaining.
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PMID:The problem with KIT: clinical implications and practical difficulties with CD117 immunostaining. 1261 Mar 58

Mast cell sarcoma is an extremely rare and aggressive type of mast cell disease. Only a few cases have been described so far, and little is known about the biology and phenotype of afflicted cells. We describe morphologic and immunophenotypic properties of neoplastic mast cells in a case of an intracranial mast cell sarcoma. In Wright-Giemsa-stained cytospin preparations, the morphology of dispersed cells appeared to be highly atypical with a considerable percentage of metachromatic blasts and mast cells with bilobed or multilobed nuclei. Combined toluidine blue/immunofluorescence staining revealed expression of CD13, CD45, CD88, CD116, and CD117 (c-KIT) on neoplastic mast cells. As assessed by immunohistochemistry, mast cells were immunoreactive for tryptase and CD68R, In contrast, the CD2 antigen that is expressed in mast cells in patients with indolent systemic mastocytosis was not detectable. Mast cells also failed to display the c-KIT mutation Asp-816-Val, which is typically found in systemic mast cell disorders. Together, neoplastic mast cells in a case of mast cell sarcoma were found to exhibit unique morphologic, phenotypical, and molecular features when compared with mast cells in indolent mastocytosis or normal tissue mast cells.
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PMID:Morphologic and immunophenotypic properties of neoplastic cells in a case of mast cell sarcoma. 1282 96

Scientific knowledge on gastrointestinal stromal tumors (GIST) has dramatically progressed over the last 10 years. During this period, this distinct disease entity was identified under various acronyms (GIST remaining the most commonly used), the molecular basis of disease transformation (i.e. activating c-KIT mutations) was identified in sporadic and familial cases, and finally GIST was identified as the sarcoma subtype most resistant to chemotherapy in both retrospective and prospective studies. Until 2000, surgery was the only reported efficient treatment modality in this disease, both in the localized and metastatic phase. In 2000, the first GIST patient received Glivec, and in the last 3 years, more than 2,000 patients were included in prospective trials evaluating this compound in advanced phases. Disease control is initially achieved in 80-90% of patients, with only 10-15% of patients dying in the first year following the occurrence of metastases, while the median overall survival was less than 12 months with previous treatment options. However, there still remain several questions regarding long-term outcome, tolerance, cure, dose of Glivec, and alternative treatment upon relapse of GIST in patients receiving Glivec. Additional follow-up is necessary. Glivec treatment of GIST is the first example of an efficient targeted treatment in a solid tumor.
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PMID:Gastrointestinal stromal tumors: biology and treatment. 1465 91

Soft tissue sarcomas represent a heterogeneous group of tumors and include over 50 histotypes. Some of these tumor types are characterized by specific chromosomal translocations, whereas other types show complex genetic aberrations. The recent developments within gene expression technologies have now been applied to studies of soft tissue sarcomas (STS) and the first results indicate that genetic signatures are useful for classification and diagnosis. Distinctive expression profiles have been found in e.g. gastrointestinal stromal tumors (GISTs), synovial sarcomas, malignant peripheral nerve sheath tumors (MPNSTs), and in subsets of liposarcomas. The more pleomorphic tumor types, such as high-grade variants of leiomyosarcomas, malignant fibrous histiocytomas (MFHs), fibrosarcomas, and subtypes of liposarcomas, show a greater variability among the expression profiles, but interestingly subsets with distinctive expression profiles can be identified also among these tumors. The data available place many of the genes hypothesized to be involved in the development of a certain type of STS, such as the KIT gene in GIST development, among the top discriminating genes. Thereby expression profiling provides novel insights into the pathogenesis of STS. Although much work remains to be done to validate the data and to define optimal discriminating gene lists, the current lessons from gene expression studies in STS are encouraging and imply that genetic signatures may serve as diagnostic and prognostic markers and may help identify novel therapeutic strategies.
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PMID:Lessons from genetic profiling in soft tissue sarcomas. 1518 64

KIT expression is a key diagnostic feature of gastrointestinal stromal tumors (GISTs), and virtually all of the GISTs express oncogenic forms of the KIT or PDGFRA receptor tyrosine kinase proteins, which serve as therapeutic targets of imatinib mesylate (Gleevec; Novartis, Basel, Switzerland). However, KIT expression can be low in PDGFRA-mutant GISTs, increasing the likelihood of misdiagnosis as other types of sarcoma. We report that the signaling intermediate protein kinase C theta (PKCtheta) is a diagnostic marker in GISTs, including those that lack KIT expression and/or contain PDGFRA mutations. PKCtheta is strongly activated in most GISTs and hence may serve, along with KIT/PDGFRA, as a novel therapeutic target.
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PMID:Protein Kinase C theta (PKCtheta) expression and constitutive activation in gastrointestinal stromal tumors (GISTs). 1528 15

The number of effective cytotoxic agents for the treatment of patients with metastatic adult soft tissue sarcoma is limited, especially when patients have failed anthracycline- and ifosfamide-based chemotherapy. For the subgroup of patients with inoperable gastrointestinal stromal tumour (GIST), progress has been made via the rapid development and approval of the targeted therapy imatinib. Small round cell tumours (SRCTs), such as Ewing's sarcoma/primitive neuroectodermal tumour, desmoplastic SRCT and rhabdomyosarcoma, are chemotherapy-sensitive and potentially curable malignancies, which are treated with multimodality, dose-intensive, neoadjuvant protocols regardless of size or overt metastatic disease. Most other high-grade (grading >I), so-called 'adult type', soft tissue sarcomas such as fibrosarcoma, liposarcoma, pleomorphic and synovial sarcomas are treated with an anthracycline-based regimen with or without ifosfamide as front-line therapy. In relapsed 'adult type' soft tissue sarcomas, trofosfamide, gemcitabine and trabectedin (ecteinascidin 743) appear to be drugs associated with some activity and an acceptable toxicity profile. A high activity has been reported for the taxanes, in particular for paclitaxel, in vascular sarcomas located in the scalp or face and in Kaposi's sarcoma. It is interesting to note that the different drugs have particular effects in distinct subtypes of soft tissue sarcoma; however, it should be taken into account that the number of patients included in the phase II trials is limited. The role of the newer agents (e.g. epothilones, brostallicin) is currently undefinable. Targeted therapy inhibiting vascular endothelial growth factor receptor, epidermal growth factor receptor, RAF kinase, c-KIT or platelet-derived growth factor receptors will continue to be tested in GIST patients refractory to imatinib and in other sarcoma histologies.
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PMID:Recent developments in salvage chemotherapy for patients with metastatic soft tissue sarcoma. 1563 40

Gastrointestinal stromal tumor (GIST), a form of soft-tissue sarcoma, is the most common noncarcinomatous tumor of the gastrointestinal tract. Despite its high incidence of recurrence, the malignant potential of GIST has been under-recognized. Advances in diagnostic technology since 2000 have led to increased diagnoses of GIST, suggesting that GIST is more common than previously suspected. Historically, the only treatment for GIST was surgical resection, but recent advances in the understanding of the pathogenesis of the disease have led to the development of a new treatment. A key factor in the growth and survival of cancerous GIST cells is the uncontrolled activation of a signaling enzyme known as KIT, a receptor tyrosine kinase, which becomes locked in an activated state. The abnormal signaling from the overactive KIT enzyme causes GIST cells to survive and proliferate uncontrollably. Imatinib mesylate is an oral drug designed to inhibit the kinase enzyme activity of KIT. Imatinib has been proven in several clinical trials to be effective against GIST and is currently the firstline medical therapy for malignant metastatic or recurrent GIST. Imatinib is administered as an outpatient oral drug and warrants nursing management with particular attention to potential side effects, significant drug interactions, monitoring, and patient education. This article--based on published trials and clinical experience--summarizes the nursing implications, clinical efficacy, and safety of imatinib as an effective and rationally targeted treatment for GIST.
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PMID:Nursing implications of imatinib as molecularly targeted therapy for gastrointestinal stromal tumors. 1585 60

Sarcomas are a heterogeneous group of tumors, requiring different chemotherapeutic approaches. Recently, several regimens for metastatic tumors were evaluated with respect to the different responses to conventional chemotherapy of the various histologic subtypes of sarcomas. The impact of pharmacogenetics in the progress of chemotherapy appears to be crucial in defining the clinical response to many drugs, such as anthracycline or alkylating agents, that are widely used in treatment regimens for soft tissue sarcomas (STS) or sarcomas of the bone. Polymorphisms of metabolizing enzymes (e.g., cytochrome P450 and glutathione-S-transferase), transporter proteins (reduced folate carrier and P-glycoprotein) or target proteins (thymidylate synthase, methylenetetrahydrofolate reductase, dihydrofolate reductase, and c-KIT) may be responsible for an altered clinical outcome, in terms of both response and toxicity. The administration of new chemotherapeutic agents, such as imatinib for gastrointestinal tumors (GIST), requires the study of genetic polymorphisms possibly affecting the integrity of the target (c-KIT), which may provide valid information regarding possible developments of therapy. For STS and sarcoma of the bone, the genetic markers, which could be unambiguously predictive of the phenotypic profile of patients, are as yet undetermined.
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PMID:Sarcomas and pharmacogenetics. 1614 99


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