Outcome of Core Binding Factor Acute Myeloid Leukemia by Receptor Tyrosine Kinase Mutation

BackgroundCore binding factor acute myeloid leukemia (CBF-AML) encodes 2 recurrent cytogenetic abnormalities, t(8;21) and inv(16), which carries an overall good prognosis. However, some patients will develop a relapse. We sought define the unfavorable group of CBF-AML by analysis of (c-KIT and FLT3-ITD) and to correlate them with treatment outcome.Patients and MethodsWe performed a prospective study of 70 patients with CBF-AML diagnosed and managed at the medical oncology department of the (National Cancer Institute), Cairo University, with analysis of c-KIT and FLT3 mutations. All patients had received “3 + 7” induction, followed by 3 to 4 courses of high-dose cytarabine consolidation. The institutional review board approved the present study.ResultsThe median patient age was 31 years (range, 18-60 years), with a male/female ratio of 4:3. Of the 70 patients, 42 (60%) had t(8;21) and 28 had inv(16) (40%). c-KIT mutations (exons 8 and 17) were detected in 10 of 52 tested patients, and FLT3-ITD was detected in 3 of 70 patients. Patients with inv(16) experienced more lymphadenopathy and splenomegaly, had a higher median initial leukocyte count. Hepatitis C antibody positivity (8 of 42) was exclusively present in patients with t(8;21). The median overall survival (OS) was 19.5 months, and the median disease-free survival (DFS) was not reached. Patients with inv(16) had near-significant (P = .07) better DFS than patients with t(8;21). c-KIT mutations had no significant effect on OS or DFS. However, reverse tyrosine kinase mutations had a negative effect on DFS but not OS (P = .04).ConclusionCBF-AML with reverse tyrosine kinase mutation conveys a worse prognosis. Hepatitis C virus antibody positivity might be associated with t(8;21) AML and inv(16) with more extramedullary disease.     

Bayesian inference of hemodynamic changes in functional arterial spin labeling data.

The study of brain function using MRI relies on acquisition techniques that are sensitive to different aspects of the hemodynamic response contiguous to areas of neuronal activity. For this purpose different contrasts such as arterial spin labeling (ASL) and blood oxygenation level dependent (BOLD) functional MRI techniques have been developed to investigate cerebral blood flow (CBF) and blood oxygenation, respectively. Analysis of such data typically proceeds by separate, linear modeling of the appropriate CBF or BOLD time courses. In this work an approach is developed that provides simultaneous inference on hemodynamic changes via a nonlinear physiological model of ASL data acquired at multiple echo times. Importantly, this includes a significant contribution by changes in the static magnetization, M, to the ASL signal. Inference is carried out in a Bayesian framework. This is able to extract, from dual-echo ASL data, probabilistic estimates of percentage changes of CBF, R(2) (*), and the static magnetization, M. This approach provides increased sensitivity in inferring CBF changes and reduced contamination in inferring BOLD changes when compared with general linear model approaches on single-echo ASL data. We also consider how the static magnetization, M, might be related to changes in CBV by assuming the same mechanism for water exchange as in vascular space occupancy.     

Functional MRI Studies of Animal Models in Epilepsy

Summary:  Functional magnetic resonance imaging (fMRI) has become a widely used imaging modality in the past decade in both human studies and animal models. Epilepsy presents unique challenges for neuroimaging due to subject movement during seizures, and the need to correlate the timing of often unpredictable seizure events with fMRI data acquisition. These challenges can readily be overcome in animal models of epilepsy. Animal models also provide an opportunity to investigate the fundamental relationships between fMRI signals and brain electrical activity through invasive studies not possible in humans. fMRI studies in animal models of epilepsy can enable us to correctly interpret fMRI signal increases and decreases in human studies, ultimately elucidating specific networks that will be targeted for improved treatment of epilepsy.     

Distinct microRNA expression profiles in acute myeloid leukemia with common translocations

MicroRNAs (miRNAs) are postulated to be important regulators in cancers. Here, we report a genome-wide miRNA expression analysis in 52 acute myeloid leukemia (AML) samples with common translocations, including t(8;21)/AML1(RUNX1)-ETO(RUNX1T1), inv(16)/CBFB-MYH11, t(15;17)/PML-RARA, and MLL rearrangements. Distinct miRNA expression patterns were observed for t(15;17), MLL rearrangements, and core-binding factor (CBF) AMLs including both t(8;21) and inv(16) samples. Expression signatures of a minimum of two (i.e., miR-126/126*), three (i.e., miR-224, miR-368, and miR-382), and seven (miR-17-5p and miR-20a, plus the aforementioned five) miRNAs could accurately discriminate CBF, t(15;17), and MLL-rearrangement AMLs, respectively, from each other. We further showed that the elevated expression of miR-126/126* in CBF AMLs was associated with promoter demethylation but not with amplification or mutation of the genomic locus. Our gain- and loss-of-function experiments showed that miR-126/126* inhibited apoptosis and increased the viability of AML cells and enhanced the colony-forming ability of mouse normal bone marrow progenitor cells alone and particularly, in cooperation with AML1-ETO, likely through targeting Polo-like kinase 2 (PLK2), a tumor suppressor. Our results demonstrate that specific alterations in miRNA expression distinguish AMLs with common translocations and imply that the deregulation of specific miRNAs may play a role in the development of leukemia with these associated genetic rearrangements.     

Incidence and prognosis of c-KIT and FLT3 mutations in core binding factor (CBF) acute myeloid leukaemias

DNA from 110 adult de novo acute myeloid leukaemia (AML) patients exhibiting either inv(16) (n = 63) or t(8;21) (n = 47) was screened for mutations in the c-KIT (exon 8 and Asp816) and FLT3 (ITD and Asp835) genes. c-KIT exon 8 mutations were found in 15/63 (23.8%) inv(16) patients and 1/47 (2.1%) t(8;21) patients. c-KIT Asp816 mutations were present in 5/63 (7.9%) inv(16) AML and 5/47 (10.6%) t(8;21) AML. FLT3 mutations were identified in five patients (7.9%) with inv(16) and three patients (5.6%) with t(8;21) AML. All mutations were mutually exclusive; 40% of inv(16) AML patients possessed either a c-KIT or FLT3 mutation. c-KIT exon 8 mutations were shown to be a significant factor adversely affecting relapse rate.     

The impact of individual electrical fields and anatomical factors on the neurophysiological outcomes of tDCS: A TMS-MEP and MRI study

BackgroundTranscranial direct current stimulation (tDCS), a neuromodulatory non-invasive brain stimulation technique, has shown promising results in basic and clinical studies. The known interindividual variability of the effects, however, limits the efficacy of the technique. Recently we reported neurophysiological effects of tDCS applied over the primary motor cortex at the group level, based on data from twenty-nine participants who received 15min of either sham, 0.5, 1.0, 1.5 or 2.0 mA anodal, or cathodal tDCS. The neurophysiological effects were evaluated via changes in: 1) transcranial magnetic stimulation (TMS)-induced motor evoked potentials (MEP), and 2) cerebral blood flow (CBF) measured by functional magnetic resonance imaging (MRI) via arterial spin labeling (ASL). At the group level, dose-dependent effects of the intervention were obtained, which however displayed interindividual variability.MethodIn the present study, we investigated the cause of the observed inter-individual variability. To this end, for each participant, a MRI-based realistic head model was designed to 1) calculate anatomical factors and 2) simulate the tDCS- and TMS-induced electrical fields (EFs). We first investigated at the regional level which individual anatomical factors explained the simulated EFs (magnitude and normal component). Then, we explored which specific anatomical and/or EF factors predicted the neurophysiological outcomes of tDCS.ResultsThe results highlight a significant negative correlation between regional electrode-to-cortex distance (rECD) as well as regional CSF (rCSF) thickness, and the individual EF characteristics. In addition, while both rCSF thickness and rECD anticorrelated with tDCS-induced physiological changes, EFs positively correlated with the effects.ConclusionThese results provide novel insights into the dependency of the neuromodulatory effects of tDCS on individual physical factors.     

伴CBFβ/MYH11阳性初诊AML患儿的预后影响因素分析

目的:分析伴CBFβ/MYH11阳性初诊急性髓系白血病(AML)患儿的预后影响因素。方法:选取2012年5月至2018年6月本院收治的原发性初治伴inv(16)/CBFβ-MYH11阳性AML患儿28例,对其临床资料及治疗效果等进行分析和评估。结果:所有患儿5年总生存(OS)率76.8%,5年无事件生存(EFS)率64.0%。单因素分析结果显示,WBC<60.0×10⁹/L的患儿OS率为86.5%,显著性高于WBC≥60.0×10⁹/L的患儿的50.0%(χ²=3.891,P<0.05)。WBC<60.0×10⁹/L的患儿EFS率为76.0%,显著性高于WBC≥60.0×10⁹/L的患儿的37.5%(χ²=4.588,P<0.05)。XRCC-Thr241Met野生型患儿EFS率为77.9%,显著性高于XRCC-Thr241Met变异型患儿的43.6%(χ²=3.960,P<0.05)。Cox多因素生存分析显示,初诊WBC水平为影响该类患儿OS率的危险因素,初诊WBC水平及XRCC-Thr241Met是否野生型为影响该类患儿EFS率的危险因素。结论:初诊WBC水平及XRCC-Thr241Met基因型为影响伴CBFβ/MYH11阳性初诊AML患儿预后的主要因素。