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Träfflista för sökning "WFRF:(Pavel Marianne) srt2:(2010-2014)"

Sökning: WFRF:(Pavel Marianne) > (2010-2014)

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1.
  • Lascorz, Jesus, et al. (författare)
  • Genome-wide association study for colorectal cancer identifies risk polymorphisms in German familial cases and implicates MAPK signalling pathways in disease susceptibility
  • 2010
  • Ingår i: Carcinogenesis. - : Oxford University Press. - 0143-3334. ; 31:9, s. 1612-1619
  • Tidskriftsartikel (refereegranskat)abstract
    • Genetic susceptibility accounts for similar to 35% of all colorectal cancer (CRC). Ten common low-risk variants contributing to CRC risk have been identified through genome-wide association studies (GWASs). In our GWAS, 610 664 genotyped single-nucleotide polymorphisms (SNPs) passed the quality control filtering in 371 German familial CRC patients and 1263 controls, and replication studies were conducted in four additional case-control sets (4915 cases and 5607 controls). Known risk loci at 8q24.21 and 11q23 were confirmed, and a previously unreported association, rs12701937, located between the genes GLI3 (GLI family zinc finger 3) and INHBA (inhibin, beta A) [P = 1.1 x 10(-3), odds ratio (OR) 1.14, 95% confidence interval (CI) 1.05-1.23, dominant model in the combined cohort], was identified. The association was stronger in familial cases compared with unselected cases (P = 2.0 x 10(-4), OR 1.36, 95% CI 1.16-1.60, dominant model). Two other unreported SNPs, rs6038071, 40 kb upstream of CSNK2A1 (casein kinase 2, alpha 1 polypeptide) and an intronic marker in MYO3A (myosin IIIA), rs11014993, associated with CRC only in the familial CRC cases (P = 2.5 x 10(-3), recessive model, and P = 2.7 x 10(-4), dominant model). Three software tools successfully pointed to the overrepresentation of genes related to the mitogen-activated protein kinase (MAPK) signalling pathways among the 1340 most strongly associated markers from the GWAS (allelic P value < 10(-3)). The risk of CRC increased significantly with an increasing number of risk alleles in seven genes involved in MAPK signalling events (P-trend = 2.2 x 10(-16), ORper allele = 1.34, 95% CI 1.11-1.61).
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  • Modlin, Irvin M., et al. (författare)
  • Chromogranin A : Biological Function and Clinical Utility in Neuro Endocrine Tumor Disease
  • 2010
  • Ingår i: Annals of Surgical Oncology. - 1068-9265 .- 1534-4681. ; 17:9, s. 2427-2443
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Neuroendocrine tumors (NETs) are a form of cancer that differ from other neoplasia in that they synthesize, store, and secrete peptides, e.g., chromogranin A (CgA) and amines. A critical issue is late diagnosis due to failure to identify symptoms or to establish the biochemical diagnosis. We review here the utility of CgA measurement in NETs and describe its biological role and the clinical value of its measurement. METHODS: Literature review and analysis of the utility of plasma/serum CgA measurements in NETs and other diseases. RESULTS: CgA is a member of the chromogranin family; its transcription and peptide processing are well characterized, but its precise function remains unknown. Levels are detectable in the circulation but vary substantially (~25%) depending on which assay is used. Serum and plasma measurements are concordant. CgA is elevated in ~90% of gut NETs and correlates with tumor burden and recurrence. Highest values are noted in ileal NETs and gastrointestinal NETs associated with multiple endocrine neoplasia type 1. Both functioning and nonfunctioning pancreatic NETs have elevated values. CgA is more frequently elevated in well-differentiated tumors compared to poorly differentiated NETs. Effective treatment is often associated with decrease in CgA levels. Proton pump inhibitors falsely increase CgA, but levels normalize with therapy cessation. CONCLUSIONS: CgA is currently the best available biomarker for the diagnosis of NETs. It is critical to establish diagnosis and has some utility in predicting disease recurrence, outcome, and efficacy of therapy. Measurement of plasma CgA is mandatory for the effective diagnosis and management of NET disease.
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3.
  • Pavel, Marianne E, et al. (författare)
  • Everolimus plus octreotide long-acting repeatable for the treatment of advanced neuroendocrine tumours associated with carcinoid syndrome (RADIANT-2) : a randomised, placebo-controlled, phase 3 study
  • 2011
  • Ingår i: The Lancet. - 0140-6736 .- 1474-547X. ; 378:9808, s. 2005-2012
  • Tidskriftsartikel (refereegranskat)abstract
    • Background Everolimus, an oral inhibitor of the mammalian target of rapamycin (mTOR), has shown antitumour activity in patients with advanced pancreatic neuroendocrine tumours. We aimed to assess the combination of everolimus plus octreotide long-acting repeatable (LAR) in patients with low-grade or intermediate-grade neuroendocrine tumours (carcinoid). Methods We did a randomised, double-blind, placebo-controlled, phase 3 study comparing 10 mg per day oral everolimus with placebo, both in conjunction with 30 mg intramuscular octreotide LAR every 28 days. Randomisation was by interactive voice response systems. Participants were aged 18 years or older, with low-grade or intermediate-grade advanced (unresectable locally advanced or distant metastatic) neuroendocrine tumours, and disease progression established by radiological assessment within the past 12 months. Our primary endpoint was progression-free survival. Adjusted for two interim analyses, the prespecified boundary at final analysis was p <= 0.0246. This study is registered at ClinicalTrials.gov, number NCT00412061. Findings 429 individuals were randomly assigned to study groups; 357 participants discontinued study treatment and one was lost to follow-up. Median progression-free survival by central review was 16.4 (95% CI 13.7-21.2) months in the everolimus plus octreotide LAR group and 11.3 (8.4-14.6) months in the placebo plus octreotide LAR group (hazard ratio 0.77, 95% CI 0.59-1.00; one-sided log-rank test p=0.026). Drug-related adverse events (everolimus plus octreotide LAR vs placebo plus octreotide LAR) were mostly grade 1 or 2, and adverse events of all grades included stomatitis (62% vs 14%), rash (37% vs 12%), fatigue (31% vs 23%), and diarrhoea (27% vs 16%). Interpretation Everolimus plus octreotide LAR, compared with placebo plus octreotide LAR, improved progression-free survival in patients with advanced neuroendocrine tumours associated with carcinoid syndrome.
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  • Yao, James C, et al. (författare)
  • Chromogranin A and Neuron-Specific Enolase as Prognostic Markers in Patients with Advanced pNET Treated with Everolimus
  • 2011
  • Ingår i: Journal of Clinical Endocrinology and Metabolism. - 0021-972X .- 1945-7197. ; 96:12, s. 3741-3749
  • Tidskriftsartikel (refereegranskat)abstract
    • Context:Everolimus, an oral inhibitor of mammalian target of rapamycin, significantly prolongs progression-free survival (PFS) in patients with advanced pancreatic neuroendocrine tumors (pNET). Chromogranin A (CgA) and neuron-specific enolase (NSE) are considered general biomarkers of these tumors. Objective:The objective of the study was to evaluate the prognostic value of CgA and NSE in patients with pNET treated with everolimus. Patients and Methods:Patients with low- to intermediate-grade advanced pNET enrolled in two phase 2 studies [RAD001 in Advanced Neuroendocrine Tumors (RADIANT-1) and single institution phase II study at The University of Texas M. D. Anderson Cancer Center] received everolimus. Blood samples were collected and analyzed by a central laboratory at baseline and monthly thereafter. PFS and overall survival (OS) were evaluated in patients with elevated and nonelevated baseline CgA/NSE levels. Results:In RADIANT-1, elevated vs. nonelevated baseline CgA was associated with shorter median PFS (8.34 vs. 15.64 months; P = 0.03) and OS (16.95 months vs. not reached; P < 0.001). Elevated vs. nonelevated baseline NSE resulted in shorter median PFS (7.75 vs. 12.29 months; P = 0.01) and OS (13.96 vs. 24.90 months; P = 0.005). Median PFS was prolonged in patients with early CgA or NSE response (11.0 vs. 5.0 months) compared with those without early biomarker response. More patients with CgA (87 vs. 50%) or NSE (81 vs. 14%) response experienced tumor shrinkage compared with those without response. CgA response data from the single-institution phase II study at The University of Texas M. D. Anderson Cancer Center study are consistent with data from the RADIANT-1 study. Conclusions:Elevated baseline CgA/NSE provided prognostic information on PFS and survival; early CgA/NSE responses are potential prognostic markers for treatment outcomes in patients with advanced pNET.
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  • Yao, James C., et al. (författare)
  • Everolimus for advanced pancreatic neuroendocrine tumors
  • 2011
  • Ingår i: New England Journal of Medicine. - 0028-4793 .- 1533-4406. ; 364:6, s. 514-523
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Everolimus, an oral inhibitor of mammalian target of rapamycin (mTOR), has shown antitumor activity in patients with advanced pancreatic neuroendocrine tumors, in two phase 2 studies. We evaluated the agent in a prospective, randomized, phase 3 study. METHODS: We randomly assigned 410 patients who had advanced, low-grade or intermediate-grade pancreatic neuroendocrine tumors with radiologic progression within the previous 12 months to receive everolimus, at a dose of 10 mg once daily (207 patients), or placebo (203 patients), both in conjunction with best supportive care. The primary end point was progression-free survival in an intention-to-treat analysis. In the case of patients in whom radiologic progression occurred during the study, the treatment assignments could be revealed, and patients who had been randomly assigned to placebo were offered open-label everolimus. RESULTS: The median progression-free survival was 11.0 months with everolimus as compared with 4.6 months with placebo (hazard ratio for disease progression or death from any cause with everolimus, 0.35; 95% confidence interval [CI], 0.27 to 0.45; P<0.001), representing a 65% reduction in the estimated risk of progression or death. Estimates of the proportion of patients who were alive and progression-free at 18 months were 34% (95% CI, 26 to 43) with everolimus as compared with 9% (95% CI, 4 to 16) with placebo. Drug-related adverse events were mostly grade 1 or 2 and included stomatitis (in 64% of patients in the everolimus group vs. 17% in the placebo group), rash (49% vs. 10%), diarrhea (34% vs. 10%), fatigue (31% vs. 14%), and infections (23% vs. 6%), which were primarily upper respiratory. Grade 3 or 4 events that were more frequent with everolimus than with placebo included anemia (6% vs. 0%) and hyperglycemia (5% vs. 2%). The median exposure to everolimus was longer than exposure to placebo by a factor of 2.3 (38 weeks vs. 16 weeks). CONCLUSIONS: Everolimus, as compared with placebo, significantly prolonged progression-free survival among patients with progressive advanced pancreatic neuroendocrine tumors and was associated with a low rate of severe adverse events. (Funded by Novartis Oncology; RADIANT-3 ClinicalTrials.gov number, NCT00510068.).
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