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)

Dermatofibrosarcoma protuberans (DFSP) is a rare, cutaneous tumor characterized by aggressive local invasion. Local recurrence after excision is common, especially when negative margins are not achieved. DFSP frequently exhibits translocation of chromosomes 17 and 22, t(17;22). This rearrangement fuses the collagen type Ialpha1 (COL1A1) gene to the platelet-derived growth factor B-chain (PDGFB) gene. The resultant chimeric gene causes unregulated expression of platelet-derived growth factor leading to abnormal activation of the platelet-derived growth factor receptor (PDGFR) beta tyrosine kinase through an autocrine loop. This is believed to be the critical event in DFSP tumorigenesis. Imatinib mesylate is a potent inhibitor of several protein tyrosine kinases, including the PDGFRs. Clinical evidence suggests that imatinib mesylate is a safe and effective treatment in DFSP, especially in cases of recurrent or metastatic disease. Three phase II, multicenter clinical trials are open to further investigate the role of imatinib mesylate in DFSP.
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PMID:Targeted therapy for dermatofibrosarcoma protuberans. 1725 29

Gastro-intestinal stromal tumors (GIST), an abdominal sarcoma entity are characterized by a gain-of-function mutation in c-kit proto-oncogen (CD117). Initial treatment should aim at complete removal of the primary tumor (R0 resection) which almost never develops lymphatic metastases. Distant metastatic spread involves mainly the peritoneal cavity and the liver. In patients with metastatic disease, treatment with tyrosinkinase inhibitor imatinib mesylate (Glivec) is indicated and very effective. Systemic chemotherapy and external beam radiation must be considered ineffective. Patients requiring multivisceral resection to remove their primary tumor rapidly develop tumor recurrence and could potentially benefit from preoperative treatment with imatinib. Primary tumors are classified into four risk categories according to their size and mitotic activity. Whether there is an advantage of adjuvant treatment is currently under investigation within international randomized trials. Patients who develop an extensive remission of metastatic disease should be evaluated individually for resection of the tumor remnants. Even resection of single progressive lesions (with newly developed mutations) should be considered in carefully selected patients, if the remaining tumor can be controlled by continued imatinib treatment.
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PMID:[Gastrointestinal stromal tumors]. 1725 58

c-KIT is a tyrosine kinase receptor found to be overexpressed in several tumours, namely, GISTs, breast, lung, prostate, ovarian and colorectal carcinomas (CRC). We aimed at determining the frequency of c-KIT expression and mutations in a series of 109 CRC cases (73 primary tumours and 36 lymph node metastases) characterised for KRAS and BRAF mutations. We also aimed at analysing the cellular effects of STI571/Gleevec in CRC-derived cell lines displaying c-KIT expression and KRAS or BRAF mutations. By immunohistochemistry, we found c-KIT overexpression in 15% (11/73) of primary tumours and in 14% (5/36) of metastasis; however, cases showing overexpression did not show c-kit mutations in hotspot regions. The majority (64%) of primary tumours with c-KIT overexpression had mutations at KRAS-BRAF genes. The same was true for 60% of the metastases. We treated CRC cell lines with STI571/Gleevec and verified that it inhibits proliferation and induces apoptosis in all cell lines. In conclusion, overexpression of c-KIT is observed in a subset of primary and CRC metastases in the absence of c-kit mutations. STI571/Gleevec increases apoptosis in CRC cell lines independently of its genetic profile, suggesting that STI571/Gleevec is likely to be an alternative drug for the clinical trials of CRC.
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PMID:A subset of colorectal carcinomas express c-KIT protein independently of BRAF and/or KRAS activation. 1748 4

Lymph node metastasis from gastrointestinal stromal tumor (GIST) is quite rare. We report two cases of gastric GIST with nodal metastases and results of their mutation analyses. In the first case (78-year-old male), a mass 4.0 cm in size was located at the gastric cardia. Proximal gastrectomy was performed. In the other case (40-year-old female), the gastric tumor was 2.5 cm in size. Computed tomography scan revealed a hepatic metastasis. Imatinib mesylate was administered as primary treatment, at the patient's preference, but the tumors exhibited no response. Wedge resection of the stomach and partial hepatectomy were performed. In both cases, histological examination revealed that the tumors consisted of spindle cells. In the former case, there was an isolated lymph node metastasis at the right cardia. In the latter, three of 5 sampled nodes adjacent to the tumor were positive. In both cases, immunohistochemical analyses showed that primary and metastatic tumors were diffusely positive for CD117 and CD34 and negative for desmin and S100-protein. In the former case, there was a deletion mutation in CD117 exon 11, the most common genotype in GIST. In the latter, there were no detectable mutations in CD117 or platelet-derived growth factor receptor alpha.
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PMID:Two cases of gastrointestinal stromal tumor of the stomach with lymph node metastasis. 1762 38

Gastrointestinal stromal tumors have until recently had a uniformly poor prognosis with lack of effective drug therapies. These tumors usually have activating mutations in either KIT or PDGFR-alpha tyrosine kinase receptors. Over the past decade, imatinib (Gleevec), a selective tyrosine kinase inhibitor has become the standard of care for the first-line treatment of patients with unresectable and metastatic disease. For patients with imatinib-resistant disease or intolerant to the side effects of imatinib, sunitinib (Sutent), a multitargeted tyrosine kinase inhibitor was recently approved. For earlier-stage disease, status post-complete surgical excision, preliminary data seem encouraging for the role of adjuvant imatinib in prolonging patients' disease-free interval. The impact of neoadjuvant drug therapy needs to be further classified and explored. With additional evaluation of other tyrosine kinase inhibitors and novel therapies against other molecular markers, the treatment paradigm for this malignancy should continue to evolve.
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PMID:New therapeutic options in gastrointestinal stromal tumors. 1840 63

Gastrointestinal stromal tumors (GISTs) are the most common gastrointestinal mesenchymal tumors. Computed tomography (CT) often shows exophytic gastrointestinal masses with cystic changes, necrosis or fistula formation, and heterogeneous enhancement. After Gleevec therapy, the primary tumor, its metastases, and its recurrences can develop cystic changes and decrease in size, these findings can be satisfactorily monitored by CT. We report on 42 patients with proven GISTs, five presenting with metastases and nine patients with recurrence or development of metastases after surgery and chemotherapy.
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PMID:Value of CT in the diagnosis and follow-up of gastrointestinal stromal tumors. 1850 43

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

During cancer therapy with DNA-damaging drug-agents, the development of secondary resistance to apoptosis can be observed. In the search for novel therapeutic approaches that can be used in these cases, we monitored chemotherapy-induced apoptosis resistance in a syngenic mouse tumor model. For this, syngenic murine colorectal carcinoma cells, which stably expressed a FRET-based caspase-3 activity sensor, were introduced into animals to induce peritoneal carcinomatosis or disseminated hepatic metastases. This syngenic system allowed in vitro, in vivo and ex vivo analysis of chemotherapy induced apoptosis induction by optically monitoring the caspase-3 sensor state in the tumor cells. Tumor tissue analysis of 5-FU treated mice showed the selection of 5-FU-induced apoptosis resistant tumor cells. These and chemo-naive fluorescent tumor cells could be re-isolated from treated and untreated mice and propagated in cell culture. Re-exposure to 5-FU and second line treatment modalities in this ex-vivo setting showed that 5-FU induced apoptosis resistance could be alleviated by imatinib mesylate (Gleevec). We thus show that syngenic mouse systems that stably express a FRET-based caspase-3 sensor can be employed to analyse the therapeutic efficiency of apoptosis inducing chemotherapy.
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PMID:Fluorescence lifetime imaging microscopy of chemotherapy-induced apoptosis resistance in a syngenic mouse tumor model. 1958 98

A young woman was referred to our institution for the appearance of a single pulmonary nodule at a routine follow-up computed tomographic scan of the thorax. She had been operated on 4 years earlier for a parachordoma of the iliopsoas muscle. Wedge resections were accessed through a mini-thoracotomy, and the pathologic examination confirmed the diagnosis of parachordoma lung metastases. Adjuvant chemotherapy (Glivec, 400 mg/daily [imatinib; Novartis, Basel, Switzerland]) was indicated and was administered for 10 months. At the time this case report was written, the patient was alive with no sign of tumor recurrence. We believe that metastatic parachordoma to the lung has been previously reported only once in the English literature. Our case adds evidence that parachordoma, despite its generally indolent behavior, can metastasize to the lung.
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PMID:Pulmonary metastases from parachordoma. 1963 72

Dermatofibrosarcoma protuberans (DFSP) is a soft tissue tumor with tendency to recur locally and only rarely metastasizes to vital organs. Surgery with wide margins remains the standard treatment. DFSP is characterized by specific chromosomal abnormalities involving the platelet derived growth factor B locus (PDGFB). In the majority of cases a supernumerary ring chromosome containing amplified t(17; 22) translocation or a linear unbalanced t(17; 22) containing the COL1A1 -PDGFB fusion gene is present. This molecular event causes aberrant expression of a functional PDGFB leading to activation of PDGFR. Imatinib mesylate is a tyrosine kinase inhibitor with activity against activated PDGFR, and has significant activity against DFSP. Clinical evidence suggests that it has a role in locally advanced and metastatic disease and clinical trials are ongoing examining its role in this rare but potentially fatal sarcoma.
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PMID:Imatinib in the treatment of dermatofibrosarcoma protuberans. 1970 5


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