UMLS:C1261473 - FACTA Search

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Query: UMLS:C1261473 (sarcoma)
25,952 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Protein phosphorylation on serine/threonine or tyrosine residues represents a significant regulatory mechanism in signal transduction during spermatogenesis, oogenesis, and fertilization. There are several families of tyrosine protein kinases operating during spermatogenesis: the Src family of tyrosine protein kinases; the Fujinami poultry sarcoma/feline sarcoma (Fps/Fes) and Fes-related protein (Fer) subfamily of non-receptor proteins; and c-kit, the transmembrane tyrosine kinase receptor that belongs to the family of the PDGF receptor. A remarkable characteristic is the coexistence of full-length and truncated tyrosine kinases in testis. Most of the truncated forms are present during spermiogenesis. Examples include the truncated forms of Src tyrosine kinase hematopoietic cell kinase (Hck), FerT, and tr-kit. A feature of FerT and tr-kit is the kinase domain that ensures the functional properties of the truncated protein. FerT, a regulator of actin assembly/disassembly mediated by cortactin phosphorylation, is present in the acroplaxome, a cytoskeletal plate containing an F-actin network and linking the acrosome to the spermatid nuclear envelope. This finding suggests that Fer kinase represents one of the tyrosine protein kinases that may contribute to spermatid head shaping. The c-kit ligand, stem cell factor (SCF), which induces c-kit dimerization and autophosphorylation, exists as both membrane-associated and soluble. Although tyrosine protein kinases are prominent in spermatogenesis, a remarkable observation is the paucity of phenotypic alterations in spermatogenic cells in male mice targeted with Fer kinase-inactivating mutation. It is possible that the redundant functions of the tyrosine protein kinase pool present during spermatogenesis may explain the limited phenotypes of single mutant mice. The production of compound and viable mutant mice, lacking the expression of two or more tyrosine kinases, may shed light on this intriguing issue.
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PMID:Tyrosine protein kinases and spermatogenesis: truncation matters. 1643 22

KIT (CD117) is a 145-KD transmembrane glycoprotein that is the product of the kit-gene. As a member of the subclass III family of receptor tyrosine kinases, KIT is closely related to the receptors for platelet derived growth factor alpha and beta (PDGF-A and B), macrophage colony stimulating factor (M-CSF), and FLT3 ligand. The ligand for KIT, stem cell factor (SCF), also known as steel factor or mast cell growth factor promotes the dimerisation and autophosphorylation of KIT receptors. The phosphorylated tyrosine residues provide binding sites for signal molecules that contain SH2 domains. KIT mediated signal transduction is critical for the normal development and survival of haematopoietic progenitor cells, mast cells, interstitial cells of Cajal (intestinal pacemaker cells), melanocytes and germ cells. Upon differentiation, KIT expression is lost with the exception of mast cells, melanocytes and interstitial cells of Cajal. The detection of CD117 expression is of paramount diagnostic relevance in gastrointestinal stromal tumors (GIST). About 95% of all GISTs are immunohistochemically CD117 positive. The vast majority of all other sarcoma, carcinoma and also lymphoma are CD117 negative. Therefore, CD117 expression has a high sensitivity and specificity for the diagnosis of GIST. Moreover, activating mutations of KIT tyrosine kinase play a crucial pathogenetic role in GIST 80 to 85% of all GIST's contain activating mutations, primarily in Exon's 11 and 9 of the kit gene. Since the resulting mutant isoformes are sensitive to inhibition by imatinib (glivec), a specific tyrosine kinase inhibitor, the detection of a specific mutation has also a high predictive value. Besides GIST mastocytoses and seminomas are the neoplasias that most commonly express CD117. In contrast to GIST however, these two neoplasias contain mutations in different exons and are only partly imatinib sensitive. Moreover, CD117 expression is by no means entirely specific for these entities. It can also be detected in adenoid cystic carcinomas, thymic carcinomas and melanomas. Very rarely (< 5%) it can also be observed in other carcinomas and sarcomas. However, in the great majority of these cases with a CD117 protein expression there is no corresponding gene mutation of kit. Importantly, the lack of an activating mutation of KIT tyrosine kinase is good evidence that imatinib will not be effective. In other words, detection of sole CD117 protein expression is no solid basis for targeted therapy. The molecular pathological detection of CD117 expression in combination with the corresponding mutational status in patients with GIST (and other tumors) paradigmatically highlights the importance of modern molecular diagnostics in the era of targeted therapy.
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PMID:[The diagnostic and predictive role of kit (CD117)]. 1668 59

The considerable progress made in radiology, in surgical management with curative intent, and in the identification of molecularly targeted small molecules, such as the tyrosine kinase inhibitor imatinib mesylate, in the treatment of gastrointestinal stromal tumors has greatly influenced the treatment of sarcoma manifestations within the liver. This requires not only the unequivocal pathomorphological differentiation of sarcomas from other tumor entities, e. g. spindle cell dedifferentiated/pleomorphic carcinomas, aggressive non-Hodgkin lymphomas or amelanotic malignant melanomas, but also an accurate subtyping of this complex group of tumors. Additionally to macroscopic and histological findings, the recognition of characteristic immunophenotypic constellations and, at least in some types of sarcoma, the identification of molecular signatures, have greatly expanded the diagnostic tools in pathology.
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PMID:[Primary sarcomas and sarcoma metastases in the liver: morphological and molecular aspects]. 1677 10

Systemic mastocytosis (SM) is characterized by the abnormal growth and accumulation of mast cells (MC) in one or more organs. The interaction between the cytokine stem cell factor (SCF) and its cognate receptor, the c-kit receptor tyrosine kinase (KIT), plays a central role in regulating MC growth and differentiation. Whereas germline and somatically acquired activating mutations of KIT have been identified in SM, the issue as to whether individual KIT mutation(s) are necessary and sufficient to cause MC transformation remains unclear based on currently available data. Activating mutations of platelet-derived growth factor receptor-alpha (FIP1 L1-PDGFRA) are identified in a significant number of SM cases that have associated eosinophilia. To date, as with gastrointestinal stromal tumors, activating mutations of KIT and PDGFRA appear to be alternative and mutually exclusive genetic events in SM. The World Health Organization has specified criteria for classification of SM into six major subtypes: cutaneous mastocytosis, indolent systemic mastocytosis (ISM), systemic mastocytosis with an associated clonal hematological non-mast-cell disorder (SM-AHNMD), aggressive systemic mastocytosis (ASM), mast cell leukemia, and mast cell sarcoma. The ability to molecularly classify individual SM cases based on the presence or absence of specific mutations allows for molecularly targeted therapy in a growing number of cases. Imatinib mesylate therapy might result in complete remission of SM cases with wild-type KIT, certain KIT mutations, such as F522C, or the FIP1L1-PDGFRA fusion gene, but not of D816V-KIT-bearing SM. For the latter, interferon-alpha and 2-CdA are potential first- and second-line therapeutic options. Other drugs under investigation include novel tyrosine kinase inhibitors, as well as NF-kappaB inhibitors, which might display greater selectivity towards D816V-KIT as compared to wild type KIT. The pathogenesis of mastocytosis, its major clinical subtypes, and recent treatment advances are discussed in this chapter.
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PMID:Pathogenesis, clinical features, and treatment advances in mastocytosis. 1678 90

Cytogenetic discoveries of balanced translocations in soft tissue tumors have opened the way to molecular genetic definition of these translocations as gene fusions from the late 1980s. Many sarcomas are known to have such fusions, and the demonstration of the fusion transcripts in tumor tissue is of great value in specific diagnosis of synovial sarcoma (SYT-SSX), Ewing sarcoma (EWS-Fli1), clear cell sarcoma (EWS-ATF1), myxoid liposarcoma (FUS-CHOP), and other sarcomas. These translocations are believed to be disease-specific and pathogenetic forces, despite occasional observations to the contrary. Demonstration of SYT-SSX and EWS-ATF1 fusion assists in the diagnosis of synovial and clear cell sarcomas in unusual locations, such as the gastrointestinal tract, where these tumors occur with low frequency. Demonstration of sarcoma translocations and their fusion by different assays is well established; use of in situ hybridization is limited by availability of specific probes. In two exceptional instances, the same translocation and gene fusion occurs in two unrelated diseases: ETV6-NTRK fusion in infantile fibrosarcoma and secretory carcinoma of the breast, and ALK-TPM3 fusion in inflammatory myofibroblastic tumor and large cell anaplastic lymphoma. Thus, the target cell of the genetic change is an important factor to define the resulting disease. Activating mutations in two related receptor tyrosine kinases (RTKs), KIT, and platelet-derived growth factor receptor alpha (PDGFRA) is central to the pathogenesis of gastrointestinal stromal tumors (GISTs), and countering the mutational activation by specific tyrosine kinase inhibitors, such as Imatinib mesylate, is now standard treatment for metastatic GISTs. KIT exon 11 mutations (in frame deletions, point mutations, and duplications) occur in GISTs of all locations, whereas a characteristic exon 9 insertion-duplication AY502-503 is nearly specific for intestinal vs gastric tumors. In contrast, PDGFRA mutations are nearly specific for gastric GISTs, especially those with epithelioid morphology. Mutation type influences therapy responsiveness, but fortunately very few GISTs carry primarily Imatinib-resistant mutations. Secondary drug resistance acquired during Imatinib treatment based on new, Imatinib-resistant mutations is a major problem limiting treatment success. Loss of NF2 tumor suppressor gene in a biallelic fashion is believed to be central in the pathogenesis of neurofibromatosis 2 (NF2) associated and sporadic schwannomas and meningiomas. The mechanism includes nonsense or missense mutation in NF2 gene, and loss of the other NF2 allele as a part of losses in chromosome 22q. Schwannoma types may differ in their pathogenesis: gastrointestinal schwannomas lack NF2 changes suggesting a different pathogenesis. Intraneural and sclerosing perineuriomas display similar NF2 gene alterations as seen in meningioma, indicating a similar pathogenesis and molecular homology. Specific viral sequences of human herpesvirus 8 (HHV8) are diagnostic markers for Kaposi sarcoma (KS), and are absent in angiosarcoma. Despite discovery on simian virus SV40 sequences in mesothelioma as a possible pathogenetic factor, recent studies suggest that the presence of these sequences may be artifactual and based on common presence of some SV40 sequences as PCR contaminants.
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PMID:From morphological to molecular diagnosis of soft tissue tumors. 1716 60

Availability of KIT tyrosine kinase inhibitors for specific treatment of GISTs has magnified the importance of accurate differential diagnosis of GIST from other tumors occurring in the GI tract and abdomen. The general problems in this distinction include histological mimicry of other mesenchymal tumors with GIST, occasional KIT-negativity of GIST, and KIT-positivity of non-GISTs. Up to 5% to 10% gastric GISTs and <2% of intestinal GISTs can be KIT-negative. The identification of these tumors as GISTs is based on knowledge of the spectrum of GIST morphology, and can be supported by molecular diagnosis of KIT and PDGFRA mutations (the latter pertain to gastric tumors). True smooth muscle tumors (rare in GI tract except in esophagus and colon) can be separated from GISTs by the eosinophilic tinctorial quality of tumor cells, positivity for smooth muscle markers, and negativity for KIT. Desmoids can form large GIST-like masses, but are composed of spindled or stellate-shaped cells in a densely collagenous stroma. Negativity for KIT and nuclear positivity for beta-catenin are differentiating features. GI schwannomas, melanoma, and rare primary clear cell sarcoma are S100-positive, usually with characteristic histology. The latter two can be KIT-positive. KIT-positive non-GISTs include some sarcomas, especially angiosarcoma and Ewing sarcoma, extramedullary myeloid tumor, seminoma, and a few carcinomas, notably small cell carcinoma of lung. Spurious KIT-positivity, seen with some polyclonal KIT antibodies, has been a source of confusion leading to probable false-positive results in fibroblastic tumors and occasional other sarcomas, such as leiomyosarcomas. Integration of histological features with carefully standardized immunohistochemistry, supported by KIT and PDGFRA mutation analysis, is the cornerstone of state-of-the art differential diagnosis of GIST. To comprehensively capture all GISTs, KIT immunostains should be performed on all unclassified epithelioid and mesenchymal tumors of the abdomen. This is a US government work. There are no restrictions on its use.
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PMID:Gastrointestinal stromal tumors: differential diagnosis. 1719 24

Soft tissue sarcomas are rare cancers of mesenchymal origin. Recent progress in the understanding of the biology of these rare tumours has enabled the identification of distinct molecular and pathological entities within this heterogenous group of neoplasms, and has paved the way for the development of targeted therapeutics directed against activated kinases. One of the most clear examples is the identification of KIT and platelet-derived growth factor receptor-alpha kinase mutations in gastrointestinal stromal tumours, a subset of sarcomas arising from precursors of the interstitial cells of Cajal in the digestive tract, which led to the development of imatinib, sunitinib and other tyrosine kinase inhibitors for the treatment of solid tumours. This model has become the paradigm of a targeted treatment of solid tumours designed to inhibit the causal alteration in the oncogenesis of these tumours. This review summarises treatment strategies in the context of advanced disease and discusses new compounds being developed for patients with soft tissue sarcomas.
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PMID:Emerging drugs for the treatment of soft tissue sarcomas. 1735 19

Sarcomas are rare malignant mesenchymal tumors for which there are limited treatment options. One potential molecular target for sarcoma treatment is the Src tyrosine kinase. Dasatinib (BMS-354825), a small-molecule inhibitor of Src kinase activity, is a promising cancer therapeutic agent with p.o. bioavailability. Dasatinib exhibits antitumor effects in cultured human cell lines derived from epithelial tumors, including prostate and lung carcinomas. However, the action of dasatinib in mesenchymally derived tumors has yet to be shown. Based on our previous findings of Src activation in human sarcomas, we evaluated the effects of dasatinib in 12 cultured human sarcoma cell lines derived from bone and soft tissue sarcomas. Dasatinib inhibited Src kinase activity at nanomolar concentrations in these sarcoma cell lines. Downstream components of Src signaling, including focal adhesion kinase and Crk-associated substrate (p130(CAS)), were also inhibited at similar concentrations. This inhibition of Src signaling was accompanied by blockade of cell migration and invasion. Moreover, apoptosis was induced in the osteosarcoma and Ewing's subset of bone sarcomas at nanomolar concentrations of dasatinib. Inhibition of Src protein expression by small interfering RNA also induced apoptosis, indicating that these bone sarcoma cell lines are dependent on Src activity for survival. These results show that dasatinib inhibits migration and invasion of diverse sarcoma cell types and selectively blocks the survival of bone sarcoma cells. Therefore, dasatinib may provide therapeutic benefit by preventing the growth and metastasis of sarcomas in patients.
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PMID:Dasatinib inhibits migration and invasion in diverse human sarcoma cell lines and induces apoptosis in bone sarcoma cells dependent on SRC kinase for survival. 1736 2

Recently, a number of medications approved for nondermatologic use have proved useful against dermatologic diseases. This article reviews the dermatologic uses and effects of deferasirox, bortezomib, dasatinib, and cyclosporine eye drops. Deferasirox--an oral iron chelator--could be an effective treatment against porphyria cutanea tarda, hemochromatosis, and pathogens such as mucor that thrive in iron rich environments. Bortezomib, a proteasome inhibitor and multiple myeloma treatment, may be effective against nodular amyloid and has been effectively used against squamous cell carcinoma; although trials demonstrate it is ineffective against metastatic melanoma. Bortezomib has many cutaneous side effects including erythematous plaques or nodules, a generalized morbilliform erythema with ulcerations and fever, purpuric eruptions, leukocytoclastic vasculitis, Sweet's syndrome, and folliculitis. Dasatinib is a multi-targeted tyrosine kinase inhibitor active in vitro against most cell lines containing BCR-ABL mutations that confer resistance to imatinib. Dasatinib is likely to be effective against dermatofibroma sarcoma protuberans and cutaneous acute lymphoblastic leukemia, and has caused panniculitis. Cyclosporine 0.05% ocular emulsion (eye drops) are approved to treat dry eyes including dry eyes caused by collagen vascular disease. Cyclosporine eye drops might also have utility in treating eye pathology of ocular rosacea, atopic keratoconjunctivitis, graft versus host disease, herpes keratitis, chronic sarcoidosis of the conjunctiva, conjunctival manifestations of actinic prurigo, keratitis of keratitis-ichthyosis deafness (KID) syndrome, and lichen planus-related kerato-conjunctivitis. This article speculates that cyclosporine eye drops would also be useful for any disease causing ectropion or eclabion of the eye as well as toxic epidermal necrolysis-related eye pathology (in particular corneal scarring).
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PMID:A review of deferasirox, bortezomib, dasatinib, and cyclosporine eye drops: possible uses and known side effects in cutaneous medicine. 1737 1

Sarcomas are a heterogeneous group of malignant mesenchymal tumors of difficult classification. There is considerable variability in both histological appearance and responsiveness to therapy. Their overall poor clinical prognosis is reflected by the fact that >65% of patients suffering retroperitoneal soft tissue sarcoma die within 5 years [Heslin MJ, et al. Prognostic factors associated with long-term survival for retroperitoneal sarcoma: implications for management. J Clin Oncol 1997;15(8):2832-9]. A greater understanding of the biology of sarcomas is needed in order to increase the potential for identifying new therapeutic targets and strategies. Microarray analysis permits a global approach to gene expression analysis of thousands of genes at the same time and has proven to be useful for further molecular characterization of tumor tissue and cell lines. This article provides a comprehensive review of possible new biomarkers identified in gene expression studies of sarcomas. These markers give new insight into the pathogenesis of sarcomas, such as malignant fibrous histiocytoma [Lee YF, et al. Molecular classification of synovial sarcomas, leiomyosarcomas and malignant fibrous histiocytomas by gene expression profiling. Br J Cancer 2003;88(4):510-5], allow a further subclassifcation of tumors like calponin-positive and calponin-negative leiomyosarcoma, or may help to predict treatment responsiveness and prognosis in patients based on an individual gene expression pattern. In some studies candidate targets for possible new treatment strategies were identified. For instance newly identified markers such as ERBB2 [Allander SV, et al. Expression profiling of synovial sarcoma by cDNA microarrays: association of ERBB2, IGFBP2, and ELF3 with epithelial differentiation. Am J Pathol 2002;161(5):1587-95] and EGFR [Nielsen TO, et al. Molecular characterization of soft tissue tumours: a gene expression study. Lancet 2002;359(9314):1301-7] might lead to the possible therapeutic use of Trastuzumab, Gefitinib or Cetuximab in synovial sarcoma, comparable to the use of tyrosine kinase inhibitor STI (Gleevec) that is the standard treatment today of CD117-positive gastrointestinal stromal tumors.
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PMID:Gene expression profiling in sarcomas. 1755 81

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