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)

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

Treatment of gastrointestinal stromal tumor (GIST) is a paradigm for targeted therapy. These mesenchymal tumors are refractory to standard chemotherapy and radiation therapy. Targeted therapy has successfully exploited the oncologic drivers of GIST--the tyrosine kinases, KIT, and the platelet-derived growth factor receptor. Therapy with imatinib has dramatically altered the natural history of patients with advanced GIST. However, patients are developing resistance to imatinib and thus presenting with a major clinical challenge. Alternative approaches to imatinib-refractory disease are needed. Newer approaches using biologic data regarding the mechanisms of resistance are being tested alone or in combination with imatinib and are the focus of this review. Effective novel agents for imatinib-refractory GIST used as single agents or in combination with imatinib will likely become future regimens to be tested in first-line metastatic disease and in the adjuvant setting.
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PMID:Imatinib-refractory gastrointestinal stromal tumors: the clinical problem and therapeutic strategies. 1661 83

Adenoid cystic carcinoma (ACC) accounts for about 1% of all head and neck malignancies. It has a tendency for a prolonged clinical course, with local recurrences and distant metastases sometimes occurring many years after presentation. Standard treatment for salivary gland ACC is surgery and post-operative radiotherapy. The aim of this review was to examine the reported efficacy of various chemotherapy regimens and molecular therapies on recurrent/metastatic salivary gland ACC. One hundred and fourteen publications were reviewed on chemotherapy as well as possible molecular targets of therapy, including KIT, epidermal growth factor receptor (EGFR), human epidermal growth receptor-2 (HER-2), oestrogen and progesterone receptors, proliferating cell nuclear antigen (PCNA), Ki-67 and the p53, bcl-2 and SOX-4 genes. Reported response rates to combination chemotherapy are low and response duration generally short lived. The response to molecular therapies is low also. More research into novel molecular targets is needed.
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PMID:Salivary gland adenoid cystic carcinoma: a review of chemotherapy and molecular therapies. 1675 3

Solid-pseudopapillary neoplasms of the pancreas are uncommon neoplasms of low malignant potential and of uncertain histogenesis. A small percentage of patients develop metastatic disease and some succumb to disease. The management of patients with metastatic disease or unresectable tumor, and patients who are just not good surgical candidates is problematic. Novel therapy targets are needed. Successful treatment of metastatic and unresectable gastrointestinal stromal tumors with KIT kinase inhibitor, imatinib mesylate (Gleevec), makes it intriguing to look at the status of KIT in solid-pseudopapillary neoplasms of the pancreas. In this study, we investigated KIT expression in 50 solid-pseudopapillary neoplasms by immunohistochemical staining. Of the 50 (50%) solid-pseudopapillary neoplasms, 25 showed diffuse expression (in >50% neoplastic cells) of KIT and additional five (10%) cases showed focal staining (in 10-50% neoplastic cells). Expression of KIT was not associated with tumor behavior and prognosis. A subset of 11 cases showing diffuse KIT expression detected by immunohistochemical staining were further evaluated for the presence of activating mutations in KIT exons 9, 11, 13 and 17, and PDGFRA exons 12 and 18 using PCR amplification followed by direct sequencing. However, no KIT or PDGFRA mutations were identified in any of these 11 cases tested, suggesting that the overexpression of KIT is probably not due to activating mutations in KIT or PDGFRA. The exact mechanism of KIT overexpression in solid-pseudopapillary neoplasms remains to be elucidated. One possible mechanism is gene dose effect (increased copies of KIT gene). Experience in gastrointestinal stromal tumors and other tumors have shown that mutation-mediated activation of KIT or PDGFRA is a prerequisite for clinical response with imatinib mesylate. Thus, lack of mutations in KIT or PDGFRA in solid-pseudopapillary neoplasms suggests that imatinib mesylate is less likely to be effective in the treatment for patients with metastatic disease or unresectable tumor, and patients who are just not good surgical candidates.
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PMID:Positive immunohistochemical staining of KIT in solid-pseudopapillary neoplasms of the pancreas is not associated with KIT/PDGFRA mutations. 1677 26

We have pursued an approach of complete resection for patients with gastrointestinal stromal tumors (GISTs), including multivisceral resection, for patients with disease involving adjacent organs. We have also extended the limits of resection to include patients with metastatic disease who were treated with imatinib mesylate. The aim of this study is to report the outcomes and prognostic factors associated with this clinical approach. Study subjects were identified using the pathology database at our institution; for inclusion in the study group, patients must have undergone surgical resection for a KIT-positive gastrointestinal stromal tumor between January 1992 and March 2004. We calculated survival by using the Kaplan-Meier method. Univariate and multivariate analysis was performed using log-rank analysis and the Cox proportional hazards model. Thirty-four patients met the study criteria. Fifty-nine percent of patients had GISTs of gastric origin, 20.6% had duodenal GISTs, and the remainder was comprised of a variety of other sites. Twenty-two (64.7%) patients underwent single-organ resection, and 12 patients (35.3%) underwent multivisceral resection. Estimated actuarial survival at 5 years was 65.2%. Seven patients (five patients with metastases, one patient with locally advanced disease, and one patient with organ-confined disease) received imatinib mesylate. Independent predictors of poor survival included incomplete resection, metastatic disease at presentation, and high mitotic index. Mitotic index and the presence of metastases remain the primary predictors of postoperative survival. Complete surgical resection, even if multivisceral resection is required, is associated with improved survival.
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PMID:Outcome following surgical therapy for gastrointestinal stromal tumors. 1696 28

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 tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. Clinicians previously classified GISTs as "benign" or "malignant," but now place resected tumors in risk categories that are based on size and mitotic rate. Historically, GIST patients were managed with surgery alone, as chemotherapy and radiotherapy have minimal activity in this disease. In the pre-imatinib era, patients with recurrent or metastatic disease generally did very poorly. GIST therapy was revolutionized following the discovery of oncogenic mutations in the c-kit gene, as well as in the platelet-derived growth factor receptor. Subsequently, it has been confirmed that the KIT receptor tyrosine kinase is both a diagnostic marker and a useful therapeutic target in GIST. Imatinib, a potent inhibitor of KIT activity, is now standard front-line therapy for advanced GIST. With the introduction of imatinib, there have been dramatic improvements in response rates, time to progression, and survival. Imatinib is now being investigated and shows promise in the neoadjuvant and adjuvant settings. Unfortunately, many patients eventually recur or progress during imatinib therapy. For these patients, imatinib dose escalation and/or surgical evaluation are appropriate. Additionally, a novel tyrosine kinase inhibitor such as SU11248 (sunitinib) is a reasonable option for progressive, imatinib-resistant disease. With the identification of other downstream pathways, several other promising therapies are under current investigation either alone or in combination with imatinib and surgery.
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PMID:Gastrointestinal stromal tumors: imatinib and beyond. 1703 55

Cancer of unknown primary site (CUP) ranks as the fourth most common cause of cancer deaths. Regression of the primary, early development of systemic metastases and resistance to therapy are hallmarks of this heterogeneous clinical entity. Targeted therapy offers promise for improvement of outcome of such patients, but it is currently hindered by lack of known molecular targets on which tumours are dependent for growth. In this review, we present the gene and protein profiling studies done on expression of oncogenes, tumour-suppressor genes and angiogenesis effectors and discuss the therapeutic potential of developed targeted agents. Existing data show occasional overexpression of Ras, BCL2 oncoproteins, absence of active EGFR/c-KIT/PDGFR signalling, uncommon presence of tumour-suppressor gene mutations and highly active angiogenesis in CUP. High-throughput multi-gene, multi-protein platforms offer promise for unravelling the complex molecular pathophysiology of CUP, for identification of targets suitable for modulation and ultimately hope for abrogation of its aggressive natural history.
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PMID:Perspectives for targeted therapies in cancer of unknown primary site. 1704 64

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

Neuroendocrine tumors are very heterogeneous, develop from a variety of tissues, and can be difficult to diagnose. Without the clinical manifestation of metastases, it is often difficult to characterize them as malignant. Even so-called completely (R0) resected tumors can spread clinically visible metastases within a few months after initial surgery. Treatment options for neuroendocrine tumors including pheochromocytoma are limited. Molecular targeted therapies using tyrosine kinase inhibitors might prove to be helpful in patients with these tumors. In an immunohistochemical study, we examined KIT in 26 pheochromocytomas, 8 of which were malignant (3 adrenal pheochromocytomas, 5 paragangliomas). KIT expression was found in one of these 8 malignant tumors. This 2.5-cm-large adrenal pheochromocytoma originated from a woman with neurofibromatosis type 1 and spread into spine, skull, and lung. KIT expression could be demonstrated in 5% of tumor cells. On the basis of KIT expression immunohistochemically, we treated patients with neuroendocrine (i.e., medullary thyroid cancer) and other tumors with imatinib 400 mg per day, but without efficacy after 2 months of therapy. Similar results were shown by other investigators. Therefore, monotherapy with imatinib may not be efficacious in patients with neuroendocrine tumors that express KIT. Tyrosine kinase inhibitors such as sorafenib that targets several receptors in addition to KIT may be more efficacious in treating patients with neuroendocrine tumors.
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PMID:Does the expression of c-kit (CD117) in neuroendocrine tumors represent a target for therapy? 1710 20


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