Low and high PTCH1 expression groups (measured by RT-qPCR) had a 5 year rates of IFFS of 18% vs 94% (p<0.001), CCyR of 46.1% vs 100% (p=0.005) and OS CML 74% vs 100% (p=0.017). PTCH1 was successfully validated, and there was good correlation (r=0.823, p<0.001) between both techniques however, the RT-qPCR results for XIAP did not recapitulate the TLDA data. In order to corroborate our results, RT-qPCR using a different set of primers and probes (designed in-house) was performed on a subset of 37 patient diagnostic samples from the initial cohort and a further 20 samples taken on treatment, once patients had achieved CCyR, were also analysed for comparison. Using a consistent PTCH1 expression threshold, significant differences in IFFS, CCyR and CML OS were seen, while XIAP predicted only for IFFS and CCyR. Of the 29 genes, only PTCH1 (inhibitor of Smoothed ( SMO), member of the Hedgehog (Hh) signalling pathway and tumour suppressor gene involved in different cancers) and XIAP (X-linked inhibitor of apoptosis) were significant across multiple endpoints across both cohorts. Results were validated in an independent cohort composed of 56 patients enrolled in the SPIRIT-1 trial.
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Imatinib failure free survival (IFFS), cumulative incidence of CCyR and overall survival related to CML (CML OS) were analyzed by Kaplan-Meier and log-rank test for each gene. Imatinib failure (IF) was defined as loss of complete hematologic response (CHR) or of complete cytogenetic response (CCyR), progression to advanced phase disease, death or change in treatment from imatinib due to lack of efficacy. ROC curves were plotted in order to find the optimal thresholds for each gene to divide patients into low and high expression groups in the case of a low area under curve, the median expression value was used. RNA was extracted from archived white cell lysates from the peripheral blood of 73 patients (with appropriate ethical approval), converted to cDNA via first-strand synthesis and these were then analyzed as the learning cohort. TaqMan Low Density Array (TLDA) technology was used to measure the expression of 29 genes that have been previously implicated in CML pathogenesis, normalized against 3 control genes ( GUSB, B2M and 18S). We sought to identify a biomarker, or biomarkers that could be used to predict at diagnosis which patients will respond to first line treatment using routinely accessible material. However, around 23–32% of patients discontinue this therapy due to lack of efficacy, so there is scope to further improve the management of CML patients. Imatinib treatment has radically changed the prognosis of patients with chronic myeloid leukaemia (CML).
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