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

In this study we analyzed the clinicopathologic features of duodenal smooth muscle or stromal tumors, including 156 GISTs, 6 leiomyomas (LMs), and 5 leiomyosarcomas (LMSs) from the files of the Armed Forces Institute of Pathology and the Haartman Institute of the University of Helsinki. GISTs were documented as KIT positive (n = 109); 47 tumors were also included because of their histologic identity to KIT-positive cases. GIST-specific c-kit gene mutations were documented in exon 11 in 9 of 30 cases (30%) and exon 9 in 4 of 30 cases (13%). The GISTs occurred in patients with an age range of 10-88 years (median 56 years); 54% were male. Ten patients had neurofibromatosis type I; six of them had multiple GISTs. The GISTs ranged from small asymptomatic intramural or external nodules to large masses that extended into the retroperitoneum (median size 4.5 cm). They were mostly spindle cell tumors; three malignant GISTs had an epithelioid morphology, and 81 cases had skeinoid fibers. The tumors often coexpressed CD34 and KIT (54%) and were variably positive for smooth muscle actin (39%) and S-100 protein (20%) but never for desmin. A total of 86% of patients with tumors >5 cm with >5 mitoses/50 high power fields (HPF) (n = 21) died of disease, whereas no tumor <2 cm with <5 mitoses/50 HPF (n = 12) recurred or caused death. Long latency was common between primary operation and recurrences or metastases; either one occurred in 49 of 140 patients with follow-up (35%). No formula could accurately predict metastases, which occasionally developed even if mitotic activity was <5/50 HPF and size <5 cm. Metastases were in the abdominal cavity, liver, and rarely in bones and lungs but never in lymph nodes. Four actin- and desmin-positive and KIT-negative benign intramural LMs were similar to those more often seen in the esophagus. There were five LMSs, one of which formed a polypoid intraluminal mass; all were actin positive and KIT negative. The great majority of duodenal mesenchymal tumors are GISTs, which have a spectrum from small indolent tumors to overt sarcomas. LMs and LMSs are rare.
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PMID:Gastrointestinal stromal tumors, intramural leiomyomas, and leiomyosarcomas in the duodenum: a clinicopathologic, immunohistochemical, and molecular genetic study of 167 cases. 1271 47

Melanoma begins with benign nevi and progresses to radial growth phase (RGP) and to vertical growth phase [(VGP), metastatic phenotype]. The molecular changes associated with these transitions are not yet well defined. However, transcriptional regulation of some genes that are critical in melanoma progression is beginning to be elucidated. The first part of this review will focus on our recent studies demonstrating that progression of human melanoma is associated with loss of expression of the transcription factor AP-2. In metastatic melanoma cells, this loss resulted in overexpression of MCAM/MUC18 and MMP-2, and lack of expression of c-KIT. In further investigations, we inactivated AP-2 in SB-2 primary cutaneous melanoma cells by using a dominant-negative AP-2, the AP-2B gene. Expression of AP-2B in SB-2 cells augmented their tumorigenicity in nude mice and upregulated MMP-2 expression and activity. We have also recently demonstrated that loss of AP-2 expression in metastatic melanoma cells resulted in overproduction of the thrombin receptor, PAR-1. Other studies have shown that AP-2 regulates additional genes involved in melanoma development and progression, including E-cadherin, p21/WAF-1, HER2, Bcl-2, FAS/APO-1, IGF-R-1, and VEGF. We propose that loss of AP-2 is crucial in the development of malignant melanoma. Additionally, the transition of melanoma cells from RGP to VGP is associated with overexpression of two transcription factors, CREB and ATF-1, both of which may act as survival factors for human melanoma cells. The second part of the review will briefly discuss the role of other transcription factors, including ATF-2, SNAIL, MITF, and NFkappaB in the progression of human melanoma and will summarize recent knowledge on how changes in the expression of these transcription factors contribute to acquisition of the metastatic phenotype in human melanoma.
Clin Exp Metastasis 2003
PMID:Transcriptional regulation of metastasis-related genes in human melanoma. 1274 83

Gastrointestinal stromal tumor (GIST) is now defined as a specific, KIT-expressing and KIT-signaling driven mesenchymal tumor of the gastrointestinal (GI) tract. The specific identification of GIST has become more important after the availability of KIT-selective tyrosine kinase inhibitor Imatinib mesylate, STI571, commercially known as Gleevec/Glivec (Novartis Pharma, Basel, Switzerland) in the treatment of unresectable and metastatic tumors. GISTs are the most common mesenchymal neoplasms of the GI tract, and encompass most tumors previously classified as gastric and intestinal smooth muscle tumors. GISTs typically present in adults over 40 years (median age 55-60 years) and only exceptionally in children. They can present anywhere in the GI-tract from the lower esophagus to the anus. A great majority of GISTs occur in the stomach (60-70%) or small intestine (25-35%). Colon, rectum, appendix (together 5%) and esophagus (2-3%) are rare sites. Some GISTs are primary in the omentum, mesentery or retroperitoneum, unrelated to the tubular GI-tract, but most GISTs in these sites are metastases from gastric or intestinal primary. Histologically GISTs vary from cellular spindle cell tumors to epithelioid and pleomorphic ones, and morphology differs somewhat by site. By definition, GISTs are KIT(CD117)-positive. Positivity for nestin (90-100%) and CD34 (70%) are also characteristic but less specific features. Smooth muscle actins (20-30%) and heavy caldesmon (80%) are often expressed, whereas desmin is usually absent. Predictive of malignancy are mitotic rate over 5 per 50 HPF or size over 5 cm. However, mitotically inactive intestinal tumors can metastasize, and gastric tumors are in average less often malignant than the intestinal ones. True smooth muscle tumors, GI-schwannoma and undifferentiated sarcomas are the most important differential diagnoses. KIT activating mutations occur in 70-80% of cases. Their signaling consequences, clinical correlation and response to tyrosine kinase inhibitors, and specific genetic alterations are under intense investigation. Majority of these mutations are in-frame-deletions and missense mutations clustering in the 5'-end of juxtamembrane domain (exon 11). A rare mutation, an Ala502-Tyr503 duplication in exon 9, is specific for intestinal GISTs.
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PMID:Gastrointestinal stromal tumors (GISTs): definition, occurrence, pathology, differential diagnosis and molecular genetics. 1281 76

Gastrointestinal stromal tumours (Gist) are mesenchymal tumour with uncertain prognosis occurring in the gastrointestinal tract wall. For clinicians, these tumours raise two problems: to establish the diagnosis and to determinate the future behaviour for the choice officient therapeutics. For the diagnosis the new marker c-KIT is useful. A new treatment with an inhibitor of c-KIT has given encouraging results. currently there is no consensus on specific cut-points to distinguish as low or high risk (i.e., malignant) Gist. For metastases-free Gist, the prominent histopronostic markers are size, mitotic index and localization of the tumour. The small intestine Gist have the reputation to be more aggressive than in other localization. Skenoid fibers in small intestine Gist could be a marker of good prognostic. The authors reported three cases of small intestine Gist with skenoid fibers. The discussion point out the significance of this particular morphological aspect.
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PMID:[Small intestinal stromal tumors with skenoid fibers. Clinicopathological study of three cases]. 1294 39

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

The purpose of this study was to analyze the clinical features of the group of c-KIT positive GIST patients with liver metastases evaluated and treated in two referral institutions as well as to attempt to define the role of surgery in the management of GIST given the emergence to imatinib as an important part of treatment strategy in GIST patients. Between August 2001 and December 2002, 90 patients with c-KIT positive GIST were referred to our institutions. In 50 patients metastatic disease were disclosed. Of these, 35 patients (35/50; 70%) were rendered to have liver metastases and therefore offered imatinib or surgical therapy depend on CT assessment. The median follow-up of these 35 patients calculated from the time of first operation was 23 months (range 3-246 months). Male patients comprised the majority of patients (70%) with liver metastases. In 14 patients (40%) the metastases were confined only to the liver, in the others 21 patients (60%) the liver metastases were accompanied by intraperitoneal dissemination (17; 48.6%) or local recurrences (4; 11.4%). The period of time between the diagnosis of primary lesion and occurring liver metastases ranged from 0 to 164 months (median time of liver metastases presentation was 16 months for patients undergone primary curative surgery). The liver metastases were estimated as resectable in 3 cases (8.6%) and hepatic resection of all gross lesions was possible. Group of 32 patients with unresectable liver involvement was considered to treatment with imatinib. The median time of imatinib treatment for survivors is 7.5 months (range: 3.5-18.5 months). Twelve patients (37.5%) demonstrated partial response (PR) and 16 patients (50%) stable disease (SD) according to RECIST criteria. We did not observe any complete response (CR). At median follow-up 7 months, 32 of 35 patients (91.4%) were alive, 3 patients (8.6%)remained free of disease and 28 patients (87.5%) remained on imatinib treatment and have maintained disease although with partial response or stabilization only. Radical surgical resection remains the only possibility of cure for GIST patients because the complete response after imatinib therapy is restricted to a few patients only. However, despite the advanced metastatic disease, approximately 90% of patients are alive and continue imatinib treatment with median follow-up time more than 7 months. Surgery in combination with adjuvant imatinib treatment may result in improved survival with patients with advanced GIST.
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PMID:The clinical characteristics and the role of surgery and imatinib treatment in patients with liver metastases from c-Kit positive gastrointestinal stromal tumors (GIST). 1468 66

Gastrointestinal stromal tumor (GIST) is a neoplasm of the gastrointestinal tract, mesentery, or omentum that expresses the protein-tyrosine kinase KIT (CD117) and is the most common mesenchymal tumor arising at these sites. Surgical resection is the first-line intervention for operable GISTs, particularly localized primary tumors, and it was historically the only effective treatment. However, more than half of all GIST patients present with locally advanced, recurrent, or metastatic disease. The 5-year survival rate ranges from 50% to 65% after complete resection of a localized primary GIST and decreases to approximately 35% for patients with advanced disease who undergo complete surgical resection. A total of 40% to 90% of all GIST surgical patients subsequently have postoperative recurrence or metastasis. Imatinib is a potent, specific inhibitor of KIT that has demonstrated significant activity and tolerability in the treatment of malignant unresectable or metastatic GIST, inducing tumor shrinkage of 50% or more or stabilizing disease in most patients. A key strategy for prolonging the survival of patients with GIST is to improve the outcome of surgery. It is possible that the adjuvant and neoadjuvant use of imatinib (e.g., rendering initially inoperable tumors resectable) in the overall management approach to advanced GIST may contribute to surgeons' success in attaining this objective.
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PMID:Surgery and imatinib in the management of GIST: emerging approaches to adjuvant and neoadjuvant therapy. 1512 59

Intertubular growth in seminoma is characterized by seminoma cells, either singly or in small clusters, between preserved seminiferous tubules. It is a common, although focal, pattern in many seminomas where it is admixed with the usual sheet-like and nested arrangements and does not pose any diagnostic problems in such cases. We describe, in contrast, the clinicopathologic features of 12 cases with exclusively intertubular growth and which were typically diagnostically problematic. The 12 patients lacked overt clinical signs of a primary testicular mass. Three presented with infertility, 2 with cryptorchidism, 2 with metastases, 1 with pain and testicular atrophy, and the presentation was unknown in 4. On gross examination, no mass was apparent in 9 cases with available data, but ill-defined firm areas or foci of whitish-brown discoloration were occasionally noted. Microscopically, the process was characterized by individual, dispersed tumor cells or small clusters of cells growing between the seminiferous tubules. The tumor cells were often obscured by a lymphocytic infiltrate or, less commonly, nodules of hyperplastic Leydig cells. Common associated findings were tubular atrophy with sclerosis and thickening of tubular basement membranes and intratubular germ cell neoplasia, unclassified type. Immunostains against placental-like alkaline phosphatase and c-KIT (CD117) highlighted the seminoma cells in all cases examined. In pure form, intertubular seminoma is both clinically and pathologically inconspicuous and may be misdiagnosed as atrophy, scar, or orchitis.
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PMID:Seminomas with exclusive intertubular growth: a report of 12 clinically and grossly inconspicuous tumors. 1531 15

Gastrointestinal stromal tumors (GISTs) are rare mesenchymal tumors of the gastrointestinal tract characterized by the expression of a receptor that activates tyrosine kinase called c-kit. Since malignant GISTs are resistant to conventional radiation therapy and chemotherapy, recurrent or malignant GIST has an extremely poor prognosis even after surgical resection. The development of a tyrosine kinase inhibitor, STI571 (imatinib mesylate, Glivec, Gleevec), which inhibits the BCR-ABL, PDGF-R alpha and c-kit receptors, has changed the management of unresectable malignant GIST and has improved the survival of patients with metastatic disease. We report a patient with GIST and diffused peritoneal metastases, whose tumor initially responded to STI571 and eventually became resistant. A 45-year-old woman underwent partial jejunostomy on September 3, 1998, under a diagnosis of submucosal tumor of the jejunum. Pathological examination of the primary tumor revealed a strong c-kit expression and GIST was diagnosed. The patient underwent an excision of peritoneal recurrences on October 31, 2000; April 17, 2001; and August 28, 2001. A treatment with STI571 (400 mg/day) was initiated on October 15, 2001, and she was free from peritoneal masses for 8 months after the fourth operation. However, the patient herself suspended the STI571 therapy for one month and multiple peritoneal metastases developed. Although the treatment with STI571 was restarted at 400 mg/day, the peritoneal masses did not respond this time. She died of liver, lung, and peritoneal metastases after the seventh cytoreductive operation on February 11, 2004. Several mechanisms of the resistance to STI571 have been identified. Amplification or an overexpression of KIT has been proposed to be involved in the resistance development. Several mutations of KIT were also correlated with the clinical outcome. Her tumors showed mutations in exons 9 or 11 of KIT, which had longer event-free and overall survival times than those tumors that had mutations of exons 13 or 17. In this case, an exon 11 mutation of KIT was initially noted. After the interruption of the treatment, an additional point mutation arose in exon 13 that caused a resistance to STI571. Currently STI571 is the first-line therapy for non-resectable GISTs, but a single-agent therapy often leads to tumor resistance. It is our hope that we will be able to design an alternative treatment to overcome such resistance.
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PMID:[A case of metastatic gastrointestinal stromal tumor developing a resistance to STI571 (imatinib mesylate)]. 1555 17

Merkel cell carcinoma (MCC) is an aggressive neuroendocrine tumor of the skin that is associated with a high incidence of recurrence and metastasis. The therapeutic arsenal for this malignancy is limited and once it spreads, there is no effective treatment. c-kit expression has been demonstrated previously in primary MCCs thus raising the possibility of treating MCCs with imatinib mesylate, the tyrosine kinase inhibitor that has shown promise in the management of c-kit expressing tumors. In this study we examine 25 additional primary MCCs and also 6 of their lymph node metastases. Formalin-fixed, paraffin-embedded tissues were stained immunohistochemically with an antibody directed against the KIT receptor. Percentage and intensity of staining were analyzed semiquantitatively using a three-tiered system. Twenty-one of the 25 (84%) primary tumors stained positively for KIT, of which 14 (67%) showed widespread positivity. Five of the 6 lymph nodes (83%) were similarly positive. High mitotic rate and vascular invasion in the primary tumors tended to be associated with prominent staining in the lymph node metastases. No association was found between c-kit expression and outcome. We confirm that the majority of primary MCCs express c-kit and further find that metastases are positive for the KIT receptor as well. Thus, c-kit expression may be an early event in the transformation of MCC, but not a marker for tumor progression.
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PMID:c-kit expression in primary and metastatic merkel cell carcinoma. 1561 26


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