49 Background: Gastrointestinal stromal tumours (GISTs) contain oncogenic KIT or PDGFRA tyrosine kinase (TK) mutations leading to disturbance of downstream signaling pathways that contribute to GIST pathogenesis. Additional genetic aberrations were found in GISTs, demonstrating the involvement of other genes important in tumor progression. The aim of the study was to evaluate the prognostic relevance of different TK mutations in GISTs and to analyze the additional genetic aberrations in GISTs according to mutational status. Methods: 180 GIST patients were examined for KIT (9, 11, 13, 17 exons) and PDGFRA mutations (12, 14, 18 exons) by direct sequencing of DNA obtained from microdissected tumor sections. Tumor tissue DNA from 44 GISTs patients was screened for loss of heterozygosity (LOH) at 11 microsatellite loci on 1p, 9p, 14q, 15q and 22q arms. Results: KIT and PDGFRA mutations were identified in 76.1% and 10% of GISTs, respectively. 13.9% GISTs had no mutations (wild type). Most of KIT mutations were located in exon 11 (65%) and exon 9 (9.4%). Prognostic significance of TK mutations was evaluated. There was a trend of better survival for patients with PDGFRA mutation then with KIT mutation or wild type GISTs. The higher overall survival prior to target therapy was shown for patients with duplication or point mutation in KIT exon 11 in comparison to exon 11 deletion. Analysis of LOH revealed allelic deletions in 85% of GISTs, more frequently at 14q arm. There was a different LOH pattern in subgroups of GISTs. GISTs with PDGFRA mutation and with KIT exon 11 point mutation had LOH at 14q, while GISTs with KIT exon 11 deletions revealed high LOH frequency also on 22q, 15q and 1p arms. LOH in wild type GISTs occurred on all chromosomes with low frequency. LOH on 9p was found exclusively in metastatic and recurrent GISTs. Specific gene loci of frequent LOH were identified on 9p, 15q and 22q that may be contributed to GIST progression. Conclusions: Specific mutations are associated with GISTs prognosis. Tumors with point mutations and duplications in KIT exon 11 are associated with a better survival then GISTs with other KIT mutations. Specific pattern of allelic deletions was identified in subgroups of GISTs according to type of mutation and tumor progression. No significant financial relationships to disclose.
Currently, reperfusion therapy is the main method of treating patients with ischemic stroke (IS). The safety and efficacy of systemic thrombolytic therapy with a recombinant tissue plasminogen activator in patients with IS within 3 hours, and then 4.5 hours after the onset of symptoms of the disease was demonstrated in the NINDS (1995) and ECASS III (2008) studies. In 2018, based on the results of five studies, clear indications were formulated for performing thrombectomy (TE) in patients with IS, which involve the detection of thrombosis of a large stroke-associated artery. Given the continuous growth in the number of the adult population, which constitutes the bulk of patients with IS, information on the prevalence of patients with thrombotic occlusion of cerebral arteries, who are potential candidates for TE, may be important for regional vascular centers.Aim of study. To describe IS patients admitted within the 6-hour “therapeutic window”.Materials and methods. The study included 145 patients with cerebral IS who were admitted within the first 6 hours after the onset of symptoms of the disease. All patients underwent computed tomographic (CT) angiography in order to verify the occlusion of the cerebral artery.Results. In our study, a correlation was established between the NIHSS severity of IS and the likelihood of verification of stroke-related artery thrombosis by CT angiography, but in 32.6% of patients with severe stroke (NIHSS at least score 14), no thrombotic occlusion was detected, and in 13% of patients with a clinic of mild acute cerebrovascular accident (NIHSS no more than 6), on the contrary, thrombotic occlusion was detected. Mortality in patients with verified thrombotic occlusion of the cerebral artery was higher than in patients without it (38% versus 10.5%, p<0.001). Such a significant difference in the mortality rate was due to the initially more severe stroke (NIHSS at admission 17 [10; 23] versus 5 [2; 10], p><0.001) in patients with thrombotic occlusion of a stroke-related artery, as well as a higher incidence of severe swallowing disorders (30% versus 9.5%, p ><0.002), which are a risk factor for pneumonia, as well as a higher frequency of such a comorbid background as chronic kidney disease and atrial fibrillation (30% versus 13.7%, p=0.018% and 58% versus 29.5%, p=0.001, respectively). CONCLUSION 1. Thrombosis of the cerebral stroke-associated artery was detected in 34.5% of patients with ischemic stroke who were admitted within the first 6 hours from the onset of the disease. 2. The main reason for the failure to perform thrombectomy in patients with ischemic stroke admitted within the 6-hour therapeutic window is the lack of verification of stroke-related artery thrombosis using computed tomographic angiography. Due to thrombosis at a different location (other than thrombosis of the internal carotid artery and / or M1 segment of the middle cerebral artery), 10% of patients with verified thrombosis did not meet the currently existing selection criteria for thrombectomy. Keywords: ischemic stroke, reperfusion therapy, cerebral artery thrombosis, cryptogenic stroke>˂0.001). Such a significant difference in the mortality rate was due to the initially more severe stroke (NIHSS at admission 17 [10; 23] versus 5 [2; 10], p˂0.001) in patients with thrombotic occlusion of a stroke-related artery, as well as a higher incidence of severe swallowing disorders (30% versus 9.5%, p˂0.002), which are a risk factor for pneumonia, as well as a higher frequency of such a comorbid background as chronic kidney disease and atrial fibrillation (30% versus 13.7%, p=0.018% and 58% versus 29.5%, p=0.001, respectively).Conclusion. 1. Thrombosis of the cerebral stroke-associated artery was detected in 34.5% of patients with ischemic stroke who were admitted within the first 6 hours from the onset of the disease. 2. The main reason for the failure to perform thrombectomy in patients with ischemic stroke admitted within the 6-hour therapeutic window is the lack of verification of stroke-related artery thrombosis using computed tomographic angiography. Due to thrombosis at a different location (other than thrombosis of the internal carotid artery and / or M1 segment of the middle cerebral artery), 10% of patients with verified thrombosis did not meet the currently existing selection criteria for thrombectomy.
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