An internal tandem duplication in the fms-like tyrosine kinase 3 gene (FLT3/ITD) is associated with poor prognosis in acute myeloid leukemia (AML), but the impact of mutant level, size, and interaction with nucleophosmin 1 (NPM1) mutations remains controversial. We evaluated these characteristics in a large cohort of young adult AML patients. There was a highly significant trend for worsening in relapse risk (RR) and overall survival (OS) with increasing FLT3/ITD mutant level (P < .001 for both), and even in the low level mutant group (1%-24% of total FLT3 alleles), RR was significantly worse than in the FLT3 wild-type (WT) group (P < .001). In multivariate analysis, mutant level was the most powerful prognostic factor for RR. Mutant size and number had no significant impact on outcome. The beneficial impact of an NPM1 mutation on RR and OS was seen in FLT3/ITD(+) as well as FLT3/WT patients; both markers were highly significant independent predictors of outcome (P < .001). Stratification using both markers identified 3 prognostic groups: good (FLT3/ITD(-)NPM1(+)), intermediate (FLT3/ITD(-)NPM1(-) or FLT3/ITD(+)NPM1(+)), and poor (FLT3/ITD(+)NPM1(-)). Patients with high FLT3/ITD mutant level (greater than 50%) or FLT3/ITD(+) in the absence of an NPM1 mutation may be good candidates for more experimental therapeutic approaches.

We have investigated the prognostic significance of isocitrate dehydrogenase 2 (IDH2) mutations in 1473 younger adult acute myeloid leukemia patients treated in 2 United Kingdom Medical Research Council trials. An IDH2 mutation was present in 148 cases (10%), 80% at R140 and 20% at R172. Patient characteristics and outcome differed markedly between the 2 mutations. IDH2 R140 significantly correlated with nucleophosmin mutations (NPM1 MUT ), whereas IDH2 R172 cases generally lacked other molecular mutations. An IDH2 R140 mutation was an independent favorable prognostic factor for relapse (P ‫؍‬ .004) and overall survival (P ‫؍‬ .008), and there was no significant heterogeneity with regard to NPM1 or FLT3 internal tandem duplication (FLT3/ITD) genotype. Relapse in FLT3/ITD WT NPM1 MUT IDH2 R140 patients was lower than in favorable-risk cytogenetics patients in the same cohort (20% and 38% at 5 years, respectively). IntroductionRecurrent mutations in the genes coding for isocitrate dehydrogenase isoforms 1 and 2 (IDH1 and IDH2) have recently been described in acute myeloid leukemia (AML) patients. 1-3 Both enzymes convert isocitrate to ␣-ketoglutarate in an NAD phosphate ϩ -dependent manner, but they have different subcellular locations: IDH1 in the cytoplasm and IDH2 in mitochondria. Heterozygous mutations at IDH1 R132 , the functionally equivalent IDH2 R172 , and also IDH2 R140 were found to cause loss of normal enzymatic function and accumulation of 2-hydroxyglutarate (2-HG) through neomorphic enzyme activity, with a substrate switch from isocitrate to ␣-ketoglutarate, which is then converted to 2-HG. 4 IDH2 mutations have been reported in 9% to 19% of AML cases, predominantly IDH2 R140 rather than IDH2 R172 alterations. [5][6][7][8] However, the prognostic significance of these mutations remains unclear with either no impact on outcome, [5][6][7] or an adverse effect when IDH1 and IDH2 mutant patients are analyzed together in the subgroup of normal karyotype patients with a nucleophosmin 1 mutation (NPM1 MUT ) but not an internal tandem duplication in the fms-like tyrosine kinase gene (FLT3/ITD WT ). 8 In addition, there is some evidence that IDH2 R172 mutations confer an extremely poor prognosis, although this is based on very small numbers of patients, many of them elderly. 5,9 We recently demonstrated that the prognostic impact of an IDH1 mutation is dependent on FLT3/ITD genotype. 10 To determine whether IDH2 mutations have a similar effect on outcome and to investigate whether IDH2 R140 and IDH2 R172 mutations differ in their impact, we analyzed IDH2 mutant status and clinical outcome in 1473 adult nonacute promyelocytic leukemia AML patients, mostly 60 years of age or younger, treated on the United Kingdom Medical Research Council AML10 and 12 trials. MethodsDetails of the study cohort and samples, patient therapy, clinical end points, and statistical methods are in supplemental Methods (available on the Blood Web site; see the Supplemental Materials link at the top of the online article). Amplicons of I...

We investigated the benefit of adding all-trans retinoic acid (ATRA) to chemotherapy for younger patients with nonacute promyelocytic acute myeloid leukemia and high-risk myelodysplastic syndrome, and considered interactions between treatment and molecular markers. Overall, 1075 patients less than 60 years of age were randomized to receive or not receive ATRA in addition to daunorubicin/Ara-C/thioguanine chemotherapy with Ara-C at standard or double standard dose. There were data on FLT3 internal tandem duplications and NPM1 mutations (n ‫؍‬ 592), CEBPA mutations (n ‫؍‬ 423), and MN1 expression (n ‫؍‬ 195). The complete remission rate was 68% with complete remission with incomplete count recovery in an additional 16%; 8-year overall survival was 32%. There was no significant treatment effect for any outcome, with no significant interactions between treatment and demographics, or cytarabine randomization. Importantly, there were no interactions by FLT3/ internal tandem duplications, NPM1, or CEBPA mutation. There was a suggestion that ATRA reduced relapse in patients with lower MN1 levels, but no significant effect on overall survival. Results were consistent when restricted to patients with normal karyotype. ATRA has no overall effect on treatment outcomes in this group of patients. The study did not identify any subgroup of patients likely to derive a significant survival benefit from the addition of ATRA to chemotherapy. This study is registered at http://www. controlled-trials.com under ISRCTN17833622. (Blood. 2010;115:948-956)

Highlights First study of both serum and DNAm CRP associations with depression/neuroimaging. Serum CRP is associated with somatic symptoms and reduced entorhinal cortex thickness. DNAm CRP is associated with widespread reductions in white matter integrity. Evidence for central effects of peripheral inflammation from serum and DNAm markers.

A goal of genomics is to understand the relationships between biological processes. Pathways contribute to functional interplay within biological processes through complex but poorly understood interactions. However, limited functional references for global pathway relationships exist. Pathways from databases such as KEGG and Reactome provide discrete annotations of biological processes. Their relationships are currently either inferred from gene set enrichment within specific experiments, or by simple overlap, linking pathway annotations that have genes in common. Here, we provide a unifying interpretation of functional interaction between pathways by systematically quantifying coexpression between 1,330 canonical pathways from the Molecular Signatures Database (MSigDB) to establish the Pathway Coexpression Network (PCxN). We estimated the correlation between canonical pathways valid in a broad context using a curated collection of 3,207 microarrays from 72 normal human tissues. PCxN accounts for shared genes between annotations to estimate significant correlations between pathways with related functions rather than with similar annotations. We demonstrate that PCxN provides novel insight into mechanisms of complex diseases using an Alzheimer’s Disease (AD) case study. PCxN retrieved pathways significantly correlated with an expert curated AD gene list. These pathways have known associations with AD and were significantly enriched for genes independently associated with AD. As a further step, we show how PCxN complements the results of gene set enrichment methods by revealing relationships between enriched pathways, and by identifying additional highly correlated pathways. PCxN revealed that correlated pathways from an AD expression profiling study include functional clusters involved in cell adhesion and oxidative stress. PCxN provides expanded connections to pathways from the extracellular matrix. PCxN provides a powerful new framework for interrogation of global pathway relationships. Comprehensive exploration of PCxN can be performed at http://pcxn.org/.

Background: Telephone-based cognitive assessments may be preferable to in-person testing in terms of test burden, economic and opportunity cost. Objective: We sought to determine the accuracy of telephone-based screening for the identification of dementia or mild cognitive impairment (MCI). Methods: Five multidisciplinary databases were searched. Two researchers independently screened articles and extracted data. Eligible studies compared any multi-domain telephone-based assessment of cognition to the face-to-face diagnostic evaluation. Where data allowed, we pooled test accuracy metrics using the bivariate approach. Results: From 11,732 titles, 34 papers were included, describing 15 different tests. There was variation in test scoring and quality of included studies. Pooled analyses of accuracy for dementia: Telephone Interview for Cognitive Status (TICS) (<31/41) sensitivity:0.92, specificity:0.66 (6 studies); TICS-modified (<28/50) sensitivity:0.91, specificity:0.91 (3 studies). For MCI: TICS-modified (<33/50) sensitivity:0.82, specificity:0.87 (3 studies); Telephone-Montreal Cognitive Assessment (<18/22) sensitivity:0.98, specificity:0.69 (2 studies). Conclusion: There is limited diagnostic accuracy evidence for the many telephonic cognitive screens that exist. The TICS and TICS-m have the greatest supporting evidence; their test accuracy profiles make them suitable as initial cognitive screens where face to face assessment is not possible.

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Mechanistic disease stratification will be crucial to develop a precision medicine approach for future disease modifying therapy in sporadic Parkinson's disease (sPD). Mitochondrial and lysosomal dysfunction are key mechanisms in the pathogenesis of sPD and therefore promising targets for therapeutic intervention. We investigated mitochondrial and lysosomal function in skin fibroblasts of 100 sPD patients and 50 age-matched controls. A combination of cellular assays, RNA-seq based pathway analysis and genotyping was applied. Distinct subgroups with mitochondrial (mito-sPD) or lysosomal (lyso-sPD) dysfunction were identified. Mitochondrial dysfunction correlated with reduction in complex I and IV protein levels. RNA-seq based pathway analysis revealed marked activation of the lysosomal pathway with enrichment for lysosomal disease gene variants in lyso-sPD. Conversion of fibroblasts to induced neuronal progenitor cells and subsequent differentiation into tyrosine hydroxylase positive neurons confirmed and further enhanced both mitochondrial and lysosomal abnormalities. Treatment with ursodeoxycholic acid improved mitochondrial membrane potential and intracellular ATP levels even in sPD patient fibroblast lines with comparatively mild mitochondrial dysfunction. The results of our study suggest that in-depth phenotyping and focussed assessment of putative neuroprotective compounds in peripheral tissue are a promising approach towards disease stratification and precision medicine in sPD.