Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Gastrointestinal stromal tumours (GISTs) are the most common form of mesenchymal tumour of the gastrointestinal tract. Clinically, they range from small indolent tumours curable with surgery alone to aggressive cancers. Making a distinction between an indolent and a malignant GIST is unreliable with conventional histopathological techniques. The presence of metastases at the time of diagnosis confirms malignancy, but all GISTs should be regarded as having malignant potential. GISTs characteristically express the KIT protein, a transmembrane tyrosine kinase receptor for stem-cell factor. Most GISTs have a mutation in the KIT proto-oncogene that translates into a gain-of-function constitutive activation of the KIT kinase. KIT activation seems to be an early tumour-promoting event in pathogenesis. Commonly, malignant GISTs show high-level primary resistance to conventional chemotherapy. Imatinib mesylate is an orally administered selective inhibitor of certain tyrosine kinases including KIT. Most patients with advanced malignant GISTs achieve clinical benefit and significant antitumour responses with imatinib mesylate. Responses have been durable, and most patients tolerate the drug well at clinically effective doses. Imatinib mesylate is the first effective systemic therapy for advanced GIST.
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PMID:Management of malignant gastrointestinal stromal tumours. 1242 67

Imatinib mesylate (imatinib) is an orally administered competitive inhibitor of the tyrosine kinases associated with the KIT protein (stem cell factor receptor), ABL protein and platelet-derived growth factor receptors. The KIT tyrosine kinase is abnormally expressed in gastrointestinal stromal tumour (GIST), a rare neoplasm for which there has been no effective systemic therapy. In a randomised, nonblind, multicentre study that evaluated imatinib 400 or 600mg once daily in 147 patients with advanced GIST, confirmed partial responses were achieved in 54% of patients overall (median duration of follow-up was 288 days). Stable disease was experienced by 28% of patients and the estimated 1-year survival rate was 88%. Similar response rates were reported in a smaller, dose-escalation study, in which objective tumour response was a secondary endpoint. Although nearly all patients with GIST treated with imatinib experienced adverse events, most events were mild or moderate in nature. Severe or serious adverse events occurred in 21% of patients in the larger study, and included gastrointestinal or tumour haemorrhage. The control of cellular processes, such as cell growth, division and death, involves signal transduction, which commonly involves the transfer of phosphate from adenosine triphosphate (ATP) to tyrosine residues on substrate proteins, by tyrosine kinase enzymes. Activation of oncogenes coding for kinase proteins can lead to the production of kinases that are continually active in the absence of a normal stimulus,leading to increased cell proliferation and/or decreased apoptosis. A major focus of cancer research in recent years has been to identify oncogenic molecules and the signal transduction pathways in which they are involved, in order to develop specifically targeted drugs. One such drug is imatinib mesylate (imatinib, Glivic/Gleevec), an orally administered 2-phenylaminopyrimidine derivative that is a competitive inhibitor of the tyrosine kinases associated with platelet-derived growth factor (PDGF) receptors, the Abelson (ABL) protein and the KIT protein (also known as stem cell factor [SCF] receptor). Imatinib was initially evaluated for the treatment of chronic myeloid leukaemia (CML) [reviewed previously in Drugs]. More recently, imatinib has been approved for the treatment of patients with advanced gastrointestinal stromal tumour (GIST), in which KIT, a tyrosine kinase receptor, is abnormally expressed. GISTs are soft tissue gastrointestinal sarcomas probably arising from mesenchymal cells. They are rare neoplasms, with between 5000 and 10 000 new cases being diagnosed each year in the US. GISTs occur throughout the gastrointestinal tract but the stomach and small intestine are the most common sites. Symptoms depend on the site and size of the tumour, and may include abdominal pain, gastrointestinal bleeding or signs of obstruction; small tumours may be asymptomatic. The diagnosis of GIST is made by immunohistochemical staining for CD117, a cell surface antigen on the extracellular domain of KIT, in conjunction with pathological examination of tissue with light microscopy. All GISTs may have some degree of malignant potential. They are unresponsive to standard chemotherapy and to radiotherapy, and the mainstay of treatment in the past has been surgery. However, recurrence rates are high, and there has been no effective systemic treatment for unresectable GIST or metastatic disease. For patients in whom complete resection is not possible, or in patients with metastatic or recurrent disease, the median duration of survival is 9-12 months, and 10-19 months, respectively. Gain-of-function mutations of the KIT proto-oncogene occur in up to 90% of GISTs, allowing constitutive activation of tyrosine kinase (i.e. auto-phosphorylation of tyrosine residues independent of ligand-receptor binding), leading to aberrant cell division and tumour growth. Imatinib selectively inhibits the tyrosine kinase activity associated with KIT, which forms the rationale for evaluating its effects in GIST. Subsequent to initial evidence of the clinical efficacy of imatinib in a single patient with progressive, metastatic, CD117-positive GIST, formal studies of imatinib in this new indication were initiated. This article summarises the pharmacology, efficacy and tolerability profile of imatinib in the treatment of patients with advanced GIST.
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PMID:Imatinib mesylate: in the treatment of gastrointestinal stromal tumours. 1260 Feb 28

Female adnexal tumors of probable wolffian origin (FATWO) are rare neoplasms believed to originate from mesonephric (wolffian) remnants. Rarity and variable location of FATWO make the diagnosis difficult. Although most cases follow a benign clinical course, approximately 10% of them either recur or metastasize and are thought to be resistant to chemoradiation therapy. In 2004, imatinib therapy, a tyrosine kinase inhibitor known to be effective against gastrointestinal stromal tumors, was reported to be effective also in a case of KIT-positive FATWO. However, c-kit gene mutations in FATWO have never been studied. Herein is reported the case of a 50-year-old Japanese woman with FATWO arising in the right paratubal site. The tumor had typical characteristics of FATWO in both morphology and immunohistochemistry. KIT protein was diffusely and weakly expressed, but DNA analysis revealed no mutational change in exon 9 or 11 of the c-kit gene. It is believed that accumulation of such genetic data of FATWO are essential from a therapeutic standpoint, although the present case had no mutation. In addition, the cytological features of this rare tumor are presented, which have not been described previously.
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PMID:Female adnexal tumor of probable wolffian origin: morphological, immunohistochemical, and ultrastructural study with c-kit gene analysis. 1644 22

Gastrointestinal stromal tumors (GISTs) may be defined as morphologically spindle cell, epithelioid, or occasionally pleomorphic mesenchymal tumours of the gastrointestinal tract that usually express the KIT protein and harbour mutation of a gene that encodes for a type III receptor tyrosine kinase (either KIT or PDGFRA). In Caucasian populations their annual incidence is 10 to 15 cases per million. Approximately 80% of GISTs have mutated KIT and 5% mutated PDGFRA. Most KIT mutations occur in untreated GISTs in the juxtamembrane exon 11 and only rarely in the kinase domain, whereas in imatinib-treated patients secondary mutations are frequent in exons encoding for the ATP/imatinib binding pocket or the kinase activation loop. Surgery is the standard treatment of local GIST. Tyrosine kinase inhibitor imatinib is the standard treatment for metastatic disease with few exceptions. A majority (80-90%) of patients with metastatic disease respond to imatinib or achieve durable tumour growth stabilisation with continuous therapy using a daily dose of 400 mg to 600 mg. Treatment with imatinib increases survival of patients with advanced disease with a few years and is associated with only moderate toxicity. Imatinib is being evaluated as adjuvant treatment following surgery, and other tyrosine kinase inhibitors as treatments of advanced GIST.
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PMID:Gastrointestinal stromal tumor (GIST). 1701 39

Gastrointestinal stromal tumor (GIST) has become a well-recognized pathologic entity defined by expression of the KIT protein and often associated with gain of function mutations of the c-KIT oncogene. Imatinib, a specific inhibitor of the aberrant KIT protein, is an approved, well-tolerated oral drug for the management of metastatic or inoperable GIST. Traditional radical surgery resection for locally advanced, recurrent, or metastatic GIST is associated with a poor outcome. The rationale for combining imatinib with surgery for GIST, either as an adjuvant agent in the situation of primary resection for patients at high risk or in the neoadjuvant setting for patients with locally advanced, recurrent, or metastatic disease, is compelling in the continuous effort to improve disease-free and overall survival. Several clinical trials are addressing these issues as well as timing of surgery, assessment of drug response, and the addition of surgical resection in the situation of focal progressive disease on imatinib. The results of these studies will be meaningful in future standard therapy consideration.
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PMID:Combining imatinib with surgery in gastrointestinal stromal tumors: rationale and ongoing trials. 1710 Oct 65

Recent studies showed KIT gene aberrations in a substantial number of melanomas on acral skin and mucosa, suggesting the therapeutic benefit of tyrosine kinase inhibitors, such as imatinib. We therefore examined the expression and mutations of KIT in 4 primary and 24 metastatic acral and mucosal melanomas. Immunohistochemistry revealed moderate or strong KIT protein expression in 13 (48%) tumors. Sequence analysis revealed K642E and D820Y mutations in two metastases. Amplification of KIT was identified by real-time PCR in 4 tumors, including one that had K642E. Western blot analysis showed phosphorylation of the KIT receptor in 8 (62%) of 13 cryopreserved samples, indicating the frequent pathological activation of the receptor in vivo. Phosphorylation of KIT protein was detected in 2 tumors harboring KIT mutations, as well as in one tumor with KIT gene amplification. Furthermore, 5 tumors without detectable KIT gene aberrations showed phosphorylation of the KIT receptor. Expression of stem cell factor (SCF) in melanoma cells as well as stromal cells suggests SCF/KIT autocrine and paracrine activation in these tumors. Finally, we found significant growth suppressive effects of sunitinib in two acral melanoma cell lines; one harboring the D820Y mutation and one showing SCF-dependent KIT activation. These results show pathological activation of KIT in a substantial number of metastatic tumors of acral and mucosal melanomas, and suggest a potential therapeutic benefit of sunitinib for these melanomas.
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PMID:Pathological activation of KIT in metastatic tumors of acral and mucosal melanomas. 1903 43

Gastrointestinal stromal tumors (GISTs) are the most common non-epithelial mesenchymal tumors of the gastrointestinal tract. GISTs represent a specific group of mesenchymal tumors with uncertain biological behaviors. These tumors are assumed to originate from progenitor cells, usually unable to self-regenerate, which differentiate towards Cajal cells. Apart from common GISTs that occur predominantly in adulthood, a heterogeneous group of tumors has been described that are morphologically identical with GIST, but have a specific clinical presentation and biological properties. Approximately 30% of newly diagnosed GISTs are malignant or have a high potential for malignancy. Currently, GISTs are routinely identified with histological, immunohistochemical, and molecular genetic assays. However, clinical diagnoses, particularly of small or intramural GISTs, might be difficult. The most useful techniques for imaging and monitoring disease progression are endoscopic examinations and fused PET/CT imaging. Surgical treatment is the first-line treatment and the only method that might lead to full remission in patients with a primary GIST. There is currently no consensus on the issues of whether to perform resections in patients with positive margins or resections of metastases. Endoscopic resection could represent a relatively simple and less aggressive alternative as compared to traditional surgery in the treatment of small sized GISTs. Biological therapy with imatinib mesylate is recommended for patients with newly diagnosed, locally advanced, inoperable, or metastasizing gastrointestinal GISTs that express the c-KIT protein. Treatment may reduce a primary tumor to a size small enough for surgical excision. Current research is focusing on the development of new therapies for the treatment of advanced disease and/or disease prophylaxis.
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PMID:Gastrointestinal stromal tumors: review on morphology, molecular pathology, diagnostics, prognosis and treatment options. 2108 37

Gastrointestinal cancer treatment is being based more and more on pathology that yields integrated information leading to targeted therapy, i.e. morphological identification of the histological type of the tumor and its context, staging of the tumor, and identification of various targets. This provides a realistic appraisal of the tumor and allows surgeons and oncologists to choose the best treatment from an increased range of drug options. An accurate diagnosis remains the major determinant of treatment, but new drugs and new insights into molecular pathways acting in carcinogenesis enhance molecular diagnosis in cancer. In most adenocarcinomas, therapy is only organ orientated and staging dependent, and not patient targeted. Currently, the identification and validation of new targets as well as molecular classification of the tumors are inducing the incorporation of new tests into the daily practice of surgical pathology. These new tests require appropriate tissue preservation and selection of the tissue to be analyzed and harmonized to morphological criteria. In colorectal adenocarcinoma, which is the second most common malignant tumor in both genders, the biomarkers that are relevant at the present time are the genetic instability status of the tumor, the KRAS mutation status as a negative predictive marker for the overall rate of response to anti-EGFR treatment in patients with metastatic cancer, and BRAF mutation as an unfavorable prognostic marker. In gastric adenocarcinoma, HER2 overexpression is correlated with poor outcomes and more aggressive disease in a subset of cases with clinical response to trastuzumab. Met mutations have also been evidenced. Hepatocellular carcinoma is a highly chemoresistant tumor with several genetic alterations. Pancreatic adenocarcinoma is a leading cause of cancer death with frequent KRAS mutations. No biomarker has been clearly identified in either of these tumors. Gastrointestinal stromal tumors that constitute less than 3% of all gastrointestinal malignancies have been individualized since 1988. They express the KIT protein, a membrane receptor, and respond to imatinib which is a tyrosine kinase receptor inhibitor, depending on the mutational status of the tumor.
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PMID:Changing pathology with changing drugs: tumors of the gastrointestinal tract. 2167 71

Gastrointestinal stromal tumor (GIST) account for 1% of all gastrointestinal neoplasms and are the most common mesenchymal tumor of gastrointestinal tract. There are considered to originate fom the intestinal cell of Cajal, an intestinal pacemaker cell, characterized usually express the KIT protein on immunohistochemistry. The stomach (40-60%) and small intestine (30-40%) are the most common locations. Diagnosis of these tumors is difficult to establish, because symptoms are vague and traditional diagnostic tests are not specific. GISTs shows a wide variety of clinical behaviours ranging fom benign to frankly malignant, making the outcome totally unpredictable. Surgery is the standard treatment of local GIST while Imatinib (tyrosine kinasi inhibitor) is considered as the standard treatment of metastatic disease. Resistence to Imatinib is also becoming a major clinical problem but new tirosyne kinase inibitor are being studied to improve the treatment and survival. The present paper is a review of the salient features of epidemiology, pathophysiology, diagnosis, therapy and prognostic factors of GIST
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PMID:[Gastrointestinal stromal tumors]. 2222 44

KIT, a transmembrane receptor tyrosine kinase, is one of the specific targets for anti-cancer therapy. In humans, its expression and mutations have been identified in malignant melanomas and therapies using molecular-targeted agents have been promising in these tumours. As human malignant melanoma, canine malignant melanoma is a fatal disease with metastases and the poor response has been observed with all standard protocols. In our study, KIT expression and exon 11 mutations in dogs with histologically confirmed malignant oral melanomas were evaluated. Although 20 of 39 cases were positive for KIT protein, there was no significant difference between KIT expression and overall survival. Moreover, polymerase chain reaction amplification and sequencing of KIT exon 11 in 17 samples did not detect any mutations and proved disappointing. For several reasons, however, KIT expression and mutations of various exons including exon 11 should be investigated in more cases.
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PMID:Analysis of KIT expression and KIT exon 11 mutations in canine oral malignant melanomas. 2184 24


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