UMLS:C0027627 - FACTA Search

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Query: UMLS:C0027627 (metastases)
103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Patients with poorly differentiated thyroid cancers (PDTC), anaplastic thyroid cancers (ATC), and radioactive iodine-refractory (RAIR) differentiated thyroid cancers have a high mortality, particularly if positive on [(18)F]fluorodeoxyglucose (FDG)-positron emission tomography (PET). To obtain comprehensive genetic information on advanced thyroid cancers, we designed an assay panel for mass spectrometry genotyping encompassing the most significant oncogenes in this disease: 111 mutations in RET, BRAF, NRAS, HRAS, KRAS, PIK3CA, AKT1, and other related genes were surveyed in 31 cell lines, 52 primary tumors (34 PDTC and 18 ATC), and 55 RAIR, FDG-PET-positive recurrences and metastases (nodal and distant) from 42 patients. RAS mutations were more prevalent than BRAF (44 versus 12%; P = 0.002) in primary PDTC, whereas BRAF was more common than RAS (39 versus 13%; P = 0.04) in PET-positive metastatic PDTC. BRAF mutations were highly prevalent in ATC (44%) and in metastatic tumors from RAIR PTC patients (95%). Among patients with multiple metastases, 9 of 10 showed between-sample concordance for BRAF or RAS mutations. By contrast, 5 of 6 patients were discordant for mutations of PIK3CA or AKT1. AKT1_G49A was found in 9 specimens, exclusively in metastases. This is the first documentation of AKT1 mutation in thyroid cancer. Thus, RAIR, FDG-PET-positive metastases are enriched for BRAF mutations. If BRAF is mutated in the primary, it is likely that the metastases will harbor the defect. By contrast, absence of PIK3CA/AKT1 mutations in one specimen may not reflect the status at other sites because these mutations arise during progression, an important consideration for therapies directed at phosphoinositide 3-kinase effectors.
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PMID:Mutational profile of advanced primary and metastatic radioactive iodine-refractory thyroid cancers reveals distinct pathogenetic roles for BRAF, PIK3CA, and AKT1. 1948 99

Rapidly growing insight into the molecular biology of colorectal cancer has led to high hopes for the identification of molecular markers to be used in optimized and tailored treatment regimens. However, many of the published data on gene-specific biomarkers are contradictory in their findings, and no tests are currently used in clinical practice, with the exception of microsatellite instability (MSI) and guanylyl cyclase C (GCC) testing in the adjuvant setting, and in Europe KRAS mutation testing is used in the setting of epidermal growth factor receptor (EGFR)-targeted therapy for metastatic disease. There are many reasons for the failure of the initial marker hypothesis-driven approach. Although supported by a good biologic rationale, single markers such as tumor protein p53 (TP53) gene mutations, when applied to a complex tumor type containing many synchronous alterations, do not perform well in predicting outcome. Many markers also suffer from technical shortcomings, resulting from the lack of quantitative techniques to capture the impact of the molecular alteration. The impact of markers obtained from microarray expression profiling needs to be further investigated in studies based on much larger cohorts, and cross-validation studies will be essential. Recently, mutations in the KRAS gene were shown to be strong negative predictors of response to EGFR inhibitors in metastatic disease. It has also been suggested that BRAF gene mutations may be predictive of EGFR inhibitor resistance, and there are some conflicting data regarding the role of the PIK3CA gene. Further studies are needed to help integrate the latest findings into clinically useful tools for personalized medicine.
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PMID:Clinical biomarkers in oncology: focus on colorectal cancer. 1953 45

Cetuximab, an anti-EGFR human/mouse chimeric antibody, has just been approved in Japan for patients with EGFR positive unresectable or recurrent colorectal cancer, as monotherapy or in combination with irinotecan. We reported two cases of unresectable or recurrent colorectal cancer effectively treated by cetuximab after the progression of the prior chemotherapy. Case 1: A51-year-old male suffered from sigmoid colon cancer with synchronous liver metastases. He received cetuximab plus irinotecan combination therapy in the third-line setting. Amonth after the initiation of the chemotherapy, abdominal CT showed tumor shrinkage of liver metastases. Case 2: A57-year-old female suffered from sigmoid colon cancer with metachronous liver, ovarian metastases, ascites and pleural effusion. Her performance status(PS)according to ECOG performance scale was 1, and she complained of dyspnea on exertion. She received cetuximab monotherapy in the fourth-line setting. Five weeks after initiation of chemotherapy, her chest, abdominal and pelvic CT showed tumor shrinkage of the liver metastases and the reduction of both ascites and pleural effusion, together with resolution of her dyspnea on exertion. Before cetuximab administration, we investigated KRAS status on cancer tissue previously resected in the above 2 cases, which showed KRAS wild-type. Cetuximab could be effective for KRAS wild-type colorectal cancer, as well as the previous reports from Western countries.
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PMID:[Two cases of KRAS wild-type unresectable or recurrent colorectal cancer effectively treated by cetuximab after progression of prior chemotherapy]. 1954 25

Contrast-enhanced multislice computer tomography (MSCT) has established itself as the standard tomographic imaging method both for diagnosis and for treatment monitoring of hepatic lesions. To clarify local conditions before partial liver resection, diffusion-weighted magnetic resonance tomography (DWI-MRT) can also provide important additional information. In order to meet the criteria for a R0 resection, a margin of 0.5 mm seems to be sufficient. Neoadjuvant chemotherapy aiming to reduce tumour size can be given in parallel with portal artery embolisation without adversely affecting perioperative morbidity and mortality. As far as the management of primary resectable liver metastases is concerned, there is an urgent need for more studies. Despite the relatively limited evidence, adjuvant chemotherapy is currently more widely favoured in Germany than perioperative chemotherapy. There is also considerable need for studies concerning preoperative therapy in patients with liver metastases that are not (yet) resectable. In KRAS wild-type tumours, high response rates (in terms of a reduction in the size of metastases) are achieved with a cetuximab/chemotherapy combination. Bevacizumab/chemotherapy combinations lead to high rates of pathohistological complete and partial remissions. What the best parameter for judging the success of preoperative therapy is remains unknown, and so comparison studies using survival as a 'hard' endpoint must be carried out.
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PMID:[Diagnosis and treatment of liver metastases from primary colorectal tumour]. 1954 96

In the US, colorectal cancer is the third leading cause of cancer-related death. Approximately 20% of patients present with metastatic disease, and an additional 30% to 40% develop metastasis during the course of their disease. Patients with metastatic colon cancer have a 5-year survival rate of only 11%. Although surgery is the mainstay of treatment for early stage colon cancer, adjuvant treatment is usually used in patients advanced stage disease. In particular, epidermal growth factor receptor (EGFR) inhibitor therapies have emerged as effective treatments in a subset of patients with metastatic colorectal carcinoma. Two anti-EGFR biologics, cetuximab and panitumumab, have been approved by the Food and Drug Administrations for the treatment of refractory metastatic colorectal carcinoma. Mounting evidence has shown that these therapies are ineffective in tumors with mutations of codons 12 and 13 of exon 2 of the KRAS gene. Because of this compelling data, the National Comprehensive Cancer Network and the American Society of Clinical Oncology have recommended determination of KRAS mutation status in all patients with metastatic colorectal cancer who are candidates for anti-EGFR therapy. Anatomic pathologists play an integral role in coordinating the testing for KRAS mutations, as this assay is performed on tissue samples selected by the pathologist. Herein, the authors present an up-to-date review of the biologic, clinical, and laboratory aspects of KRAS mutation testing in colorectal cancer.
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PMID:KRAS mutation testing in colorectal cancer. 1954 8

Multifocal sporadic gastrointestinal stromal tumours (GISTs) may be misinterpreted as recurrent or metastatic disease, leading to inappropriate treatment. As molecular analysis is generally not available in routine practise, histological criteria that would facilitate diagnosis of multiple primary GISTs in routine slides are needed. We studied 14 GISTs (mean size, 2.7 cm) from six men and one woman (mean age, 70 years) applying morphological features and direct sequencing of KIT, PDGFRA, BRAF, and KRAS. Diagnosis was synchronous in five and metachronous in two patients. Paired tumours originated in stomach/small bowel (n = 5), duodenum/jejunum (n = 1), and stomach/oesophagus (n = 1) and revealed spindle (n = 10) and mixed spindle and epithelioid (n = 4) phenotype. Tumours were well circumscribed and have involved the muscularis propria in a pattern typical of primary GISTs. Different somatic KIT mutations were found in tumours from four patients. One patient had a KIT-mutated and a BRAF-mutated (V600E) tumour. Two patients had wild-type tumours. No PDGFRA or KRAS mutations were detected. Our results underscore the molecular heterogeneity of sporadic multifocal GISTs. The characteristic involvement of the muscularis propria and the site-typical morphology and immunophenotype facilitated the diagnosis of primary GISTs in all cases and correlated with molecular findings, emphasising the value of conventional histology in recognising independent primary GISTs.
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PMID:Multiple sporadic gastrointestinal stromal tumours arising at different gastrointestinal sites: pattern of involvement of the muscularis propria as a clue to independent primary GISTs. 1957 46

Mutation analysis of the KRAS oncogene is now established as a predictive biomarker in colorectal cancer (CRC). Large prospective clinical trials have shown that only CRCs with wild-type KRAS respond to anti-epidermal growth factor receptor (EGFR) treatment. Therefore, mutation analysis is mandatory before treatment, and reliable benchmarks for the frequency and types of KRAS mutations have to be established for routinely testing large numbers of metastatic CRCs. A thousand and eighteen cases (879 primary tumors and 139 metastases) of metastatic colorectal cancer were analyzed for the KRAS mutational status of codons 12 and 13 of the KRAS gene by genomic sequencing in a routine setting. Results were analyzed separately for specimens derived from primary tumors and metastases. KRAS mutations in codons 12 and 13 were present in 39.3% of all analyzed CRCs. The most frequent types of mutations were glycine to aspartate on codon 12 (p.G12D, 36.0%), glycine to valine on codon 12 (pG12V, 21.8%), and glycine to aspartate on codon 13 (p.G13D, 18.8%). They account for 76.6% of all mutations and prevail in primary tumors and distant metastases, indicating a robustness of the KRAS mutational status during neoplastic dissemination. The frequency of KRAS mutations and the preponderance of three types of mutations in codons 12 and 13 in a large, unselected cohort of metastatic CRC confirm the previous data of small and selected CRC samples. Thus, a mutation frequency of 40% and a cluster of three mutation types (p.G12D, pG12V, and p.G13D) in primaries and metastases can be defined as benchmarks for routine KRAS analyses.
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PMID:Frequency and type of KRAS mutations in routine diagnostic analysis of metastatic colorectal cancer. 1967

The CRYSTAL study demonstrated an advantage in terms of objective response and progression-free survival for the FOLFIRI-cetuximab combination compared with first-line FOLFIRI for patients with metastatic colorectal cancer. The results of an ancillary biological study with screening for a KRAS gene mutation in 540 patients were reported at the 2008 American Society of Clinical Oncology congress. The analysis confirmed the value of adding cetuximab only in the absence of KRAS mutation. These results led to recommend restriction of the use of cetuximab in Europe to patients with a tumour bearing wild-type KRAS. How should this apparent simplification be integrated into clinical practice? The FOLFIRI-cetuximab combination is certainly a useful supplementary first-line option although its place in relation to other high-dose regimens (high-dose FOLFIRI, FOLFOXIRI or FOLFOX-7), conventional chemotherapy plus bevacizumab, or even a fluoropyrimidine alone in the case of unresectable metastases, has yet to be specified. For subsequent lines, no study has prospectively assessed the value of the chemotherapy--anti-epidermal growth factor receptor combination as a function of KRAS status. Should the absence of objective response constantly observed in retrospective analyses in patients with a tumour presenting a KRAS mutation definitively exclude these patients while stable disease (and potentially a slight gain in survival) may be obtained?
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PMID:KRAS mutational status assessment in patients with metastatic colorectal cancer: are the clinical implications so clear? 1970 96

In metastatic colorectal cancers (CRC), progress of chemotherapies in 40 years greatly increased their median survival from 6 to 8 months to 20 months. The first step of this development has been: the discovery of 5-fluorouracil, its optimisation by folinic acid and continuous perfusions. In the years 1990 to 2000, oxaliplatin and irinotecan opened the era of polychemotherapies. Their use in fisrt line treatment is not mandatory for all patients for whom chemotherapy may only have a palliative role without need for high response rates as for patients with symptomatic metastases or metastases hardly resectable. Targeted therapies have increased the life expectancy of the metastatic CRC and for some of them to facilitate secondary resections. Bevacizumab, an anti-VEGF antibody, in combination with an irinotecan based regimen increased dramatically the life expectancy with an acceptable toxicity, at least in patients of less than 70 years old. Efficacy of bevacizumab has also been demonstrated in combination with oxaliplatin based regimen (XELOX and FOLFOX) in first and second line, and in combination with 5-fluorouracil alone. Presently, bevacizumab is the most used targeted therapies in first line chemotherapy in combination with FOLFIRI, FOLFOX or XELOX. Cetuximab and panitumumab have first demonstrated their efficacy in the population of fully resistant patients to chemotherapies with a progression free survival gain of about 4 months as single treatment (cetuximab and panitumumab) or combined to irinotecan (cetuximab). Two studies have demonstrated that the adjonction of cetuximab in the first line treatment to FOLFIRI or FOLFOX increased the response rates. The presence of epithelial growth factor receptors (EGFR) at the cell'surface in immunohistochemistry is not a prerequisite for responses to cetuximab and panitumumab, and only patients with tumors without mutation of oncogene KRAS (60% of patients) are able to respond to anti-EGFR. This activity for the KRAS non mutated population has also been demonstrated in patients resistant to chemotherapy, compared to best supportive cases with panitumumab and with cetuximab. Thus, utilisation of anti-EGFR is only authorized in non mutated KRAS tumors and for the first time in metastatic CRC, we have the possibility to enrich the population in selecting non mutated KRAS population and to treat only patients having increased chance of response and of secondary resections of initially non resectable metastases. The cost of these targeted therapies is elevated and we need to find factors which will allow a personalized medicine with the dual selection of the good drug for the right patients.
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PMID:[Targeted biotherapy: a revolution in the management of patients with colorectal cancer?]. 1971 58

Epidermal growth factor receptor (EGFR) and v-Ki-ras 2 (KRAS; viral Kirsten rat sacoma 2 oncogene homolog) oncogenes are predictors of response to EGFR-targeted therapy in lung carcinomas. Morphologic heterogeneity of lung carcinomas is reflected at the molecular level and may confound interpretation of immunohistochemistry, fluorescence in situ hybridization, and mutational assays, which are all used for analysis of KRAS and EGFR genes. Furthermore, molecular characteristics may differ between the primary tumor and corresponding metastases. The aim of this study was to determine if the KRAS and/or EGFR status of primary and metastatic lung carcinoma differs. Three hundred thirty-six cases of primary lung carcinomas were tested for EGFR and KRAS, and 85 cases had a metastasis (25%). Of the 40 cases (47%) with sufficient material for EGFR and KRAS mutational analysis, there were 11 (27.5%) primary tumors and 4 (10%) metastases identified with a KRAS mutation. Of the cases with EGFR fluorescence in situ hybridization results, there were 3 (8%) primary tumors and 8 (24%) metastases that were fluorescence in situ hybridization positive. Overall, there were 9 cases (22.5%) with discordant KRAS status and 11 cases (32.5%) with discordant EGFR fluorescence in situ hybridization status. Our results suggest that the EGFR and KRAS status of primary lung carcinomas may not predict the status in the corresponding metastases. This observation may have important implications for molecular testing for targeted therapies.
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PMID:A comparison of EGFR and KRAS status in primary lung carcinoma and matched metastases. 1974 May 13

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