This article has an accompanying continuing medical education activity, also eligible for MOC credit, on page e19. Learning Objective: Upon completion of this CME activity successful learners will be able to (1) evaluate the probability of a venous thromboembolism (VTE) in patients with newly diagnosed pancreatic ductal adenocarcinoma (PDAC); (2) identify the risk factors for VTE in patients with PDAC; and (3) assess the impact of VTE on survival in patients with PDAC. Venous Thromboembolism and Pancreatic CancerThe BACAP-VTE Study : pancreatic cancer patients prospectively followed-up from time of enrollment until last visit or death 152 patients (20.79%) developed a VTE during a median follow-up of 19.3 months Patients developing VTE during follow-up had lower PFS (HR 1.74, 95%CI 1.19-2.54, P=.004) Patients developing VTE during follow-up had lower OS (HR 2.02, 95%CI 1.57-2.60, P<.001).
Purpose: Gastrointestinal stromal tumors (GIST) are frequently associated with gain-of-function mutations of KIT, which can be inhibited by imatinib both in vitro and in vivo. The survival of patients with GIST, following imatinib therapy, has been correlated with the nature of mutations but not with KITexpression. Experimental Design: Subcellular localization, activation, and trafficking of the mature and the immature forms of KIT were investigated in GIST samples and in NIH3T3 cells infected with two different GIST-type exon 11^mutated human KIT cDNA. Results: Paranuclear dot expression of KIT was more frequent in GISTs with homozygous KIT mutations than in those with heterozygous (P = 0.01) or no mutations (P < 0.01). Activation of the immature 125 kDa form of KITwas detected in most GISTs with KIT mutations but not in GISTs without KIT mutations. In NIH3T3 cells, mutant KIT was mainly retained within endoplasmic reticulum and Golgi compartments in an immature constitutively phosphorylated form, whereas the wild-type KIT was expressed at the plasma membrane, in a mature nonphosphorylated form. Imatinib-induced inhibition of the phosphorylation of immature and mature mutant KIT proteins resulted in the restoration of KITexpression at the cell surface. Conclusions: These results show that GIST-type KIT mutations induce an activation-dependent alteration of normal maturation and trafficking, resulting in the intracellular retention of the activated kinase within the cell. These observations likely account for the absence of correlation between response to imatinib and KIT expression using immunohistochemistry and may deserve to be investigated in other tyrosine kinase^activated tumors.
BACKGROUND: KIT exon 11 mutations are observed in 60% of gastrointestinal stromal tumours (GIST). Exon 11 codes for residues Tyr568 and Tyr570, which play a major role in signal transduction and degradation of KIT. Our aim was to compare the outcome of patients with deletion of both Tyr568 -570 (delTyr) and the most frequent deletion delWK557 -558 (delWK). METHODS: Pathology and clinical characteristics of 68 patients with delTyr (n ¼ 26) or delWK (n ¼ 42) were reviewed and compared. RESULTS: GISTs with delTyr were more frequently extragastric than those with delWK (69 vs 26%, Po0.0005). After curative surgery, median relapse-free survival were 10.8 and 11.1 months for patients with delTyr (n ¼ 14) and delWK (n ¼ 29), respectively (P ¼ 0.92). All patients treated with imatinib for a non-resectable or metastatic GIST had an objective response (n ¼ 15) or a stable disease (n ¼ 21) as best response, regardless of mutation. Median progression-free survival with imatinib were 21.9 and 18.9 months for patients with GIST with delTyr (n ¼ 14) and delWK (n ¼ 22), respectively (P ¼ 0.43). CONCLUSION: In this large retrospective series, the type of KIT exon 11 mutation was correlated with the origin of GIST, but not with prognosis or response to imatinib.
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