Location and type of isocitrate dehydrogenase mutations influence clinical characteristics and disease outcome of acute myeloid leukemia

Background: Mutations of isocitrate dehydrogenase 1 and 2 are novel common genetic alterations identified in acute myeloid leukemia. Aims: To investigate the frequency, clinical associations and prognostic effect of isocitrate dehydrogenase 1 and 2 mutations together, followed by a detailed investigation of particular mutations. Methods: A consecutive cohort of 376 patients diagnosed with acute myeloid leukemia were enrolled to compare clinical characteristics. Prognostic impact was analyzed for 314 patients younger than 60 years treated with curative intention. Isocitrate dehydrogenase 1 and 2 mutations were screened using allele-specific PCR and high resolution melting, followed by a confirmatory sequencing. Results: Isocitrate dehydrogenase (IDH) 1 and 2 mutations were mutually exclusive, detected in 8.5% and 7.5% of the cases respectively. Presence of mutations was associated with older age (p=0.001), higher platelet count (p=0.001), intermediate risk karyotype (p<0.0001), nucleophosmin1 mutation (p=0.022), and with lower mRNA expression level of ABCG2 gene (p=0.006), as compared to mutation negative cases. Remission, relapse rates and overall survival were not different in IDH-mutation positive patients. Interestingly, particular mutations differred in association with nucleophosmin1 mutation: co-occurrence was observed in 14.3% of R132C vs. 70% of R132H carriers (p=0.02); and in 47.4% of R140Q vs. 0% R172K carriers (p=0.02) of IDH1 and IDH2 genes, respectively. R132H negatively influenced overall survival compared to isocitrate dehidrogenase 1 and 2 negative (p=0.02) or to R132C (p=0.019) patients. Conclusions: IDH mutations are frequent recurrent mutations in acute myeloid leukemia. Although a general common pathogenetic role is proposed, our results indicate that differences in clinical characteristics and treatment outcome may exist among disctinct mutations of both genes

Impaired eye region search accuracy in children with autistic spectrum disorders.

To explore mechanisms underlying reduced fixation of eyes in autism, children with autistic spectrum disorders (ASD) and typically developing children were tested in five visual search experiments: simple color feature; color-shape conjunction; face in non-face objects; mouth region; and eye region. No group differences were found for reaction time profile shapes in any of the five experiments, suggesting intact basic search mechanics in children with ASD. Contrary to early reports in the literature, but consistent with other more recent findings, we observed no superiority for conjunction search in children with ASD. Importantly, children with ASD did show reduced accuracy for eye region search (p = .005), suggesting that eyes contribute less to high-level face representations in ASD or that there is an eye region-specific disruption to attentional processes engaged by search in ASD

Color-shape conjunction search.

<p><i>A:</i> ASD children were <i>not</i> more accurate at conjunction search. <i>B:</i> RTs increased with array size for target-present and target-absent searches in both groups. ASD children were <i>not</i> faster at conjunction search. <i>C:</i> ASD children trended for poorer fixation.</p

Additional Clinical Information for ASD Participants for Conjunction.

<p>Additional Clinical Information for ASD Participants for Conjunction.</p

Eyes-absent search.

<p><i>A:</i> Eye region search accuracy was significantly worse in ASD. <i>B:</i> However, both groups showed similar, shallow target-present/steep target-absent RT functions. <i>C:</i> Fixation was marginally better and not different across groups.</p

Face in non-face-object search.

<p><i>A:</i> Contrary to our prediction, both groups accurately searched for faces in arrays of non-face objects. <i>B:</i> Both groups showed shallow target-present/steep target-absent RT profiles. ASD children were not slower than typical children. <i>C:</i> Both groups evidenced poor central fixation.</p

Clinical Information for Conjunction.

<p>(Age, WISC, SRS, N = 55; SWAN, CBCL, N = 54).</p>*<p>Positive SWAN scores indicate superior attention and negative scores reflect ADHD symptoms.</p

Example stimulus arrays.

<p><i>A.</i> Five-item, target-present, color search trial display. <i>B.</i> Four-item, target-absent, color search array. <i>C.</i> Nine-item, target-present, color-shape conjunction trial. The target is the left-most circle. <i>D.</i> Target-present face search. <i>E.</i> Mouth-absent experiment target-present search. <i>F.</i> Eyes-absent experiment target-present array.</p

Mouth-absent search.

<p>There was no ASD advantage for mouth region search, as measured by <i>A:</i> Accuracy. <i>B:</i> RT. Both groups showed shallow target-present/steep target-absent RT profiles. <i>C:</i> Fixation was poor, with a trend for worse fixation in ASD.</p

Color search.

<p><i>A:</i> Accuracy (% correct) versus array size. <i>B:</i> RT versus array size; Color search was accurate and efficient for both groups. <i>C:</i> Percent of trials fixated, measured with horizontal EOG. ASD children trended for poorer fixation. All plotted Standard Error of the Means (SEMs) are adjusted for repeated measures (error bar = 1 adjusted SEM).</p