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.     

Robust arterial transit time and cerebral blood flow estimation using combined acquisition of Hadamard‐encoded multi‐delay and long‐labeled long‐delay pseudo‐continuous arterial spin labeling: a simulation and in vivo study

Arterial transit time (ATT) prolongation causes an error of cerebral blood flow (CBF) measurement during arterial spin labeling (ASL). To improve the accuracy of ATT and CBF in patients with prolonged ATT, we propose a robust ATT and CBF estimation method for clinical practice. The proposed method consists of a three‐delay Hadamard‐encoded pseudo‐continuous ASL (H‐pCASL) with an additional‐encoding and single‐delay with long‐labeled long‐delay (1dLLLD) acquisition. The additional‐encoding allows for the reconstruction of a single‐delay image with long‐labeled short‐delay (1dLLSD) in addition to the normal Hadamard sub‐bolus images. Five different images (normal Hadamard 3 delay, 1dLLSD, 1dLLLD) were reconstructed to calculate ATT and CBF. A Monte Carlo simulation and an in vivo study were performed to access the accuracy of the proposed method in comparison to normal 7‐delay (7d) H‐pCASL with equally divided sub‐bolus labeling duration (LD). The simulation showed that the accuracy of CBF is strongly affected by ATT. It was also demonstrated that underestimation of ATT and CBF by 7d H‐pCASL was higher with longer ATT than with the proposed method. Consistent with the simulation, the 7d H‐pCASL significantly underestimated the ATT compared to that of the proposed method. This underestimation was evident in the distal anterior cerebral artery (ACA; P = 0.0394) and the distal posterior cerebral artery (PCA; 2 P = 0.0255). Similar to the ATT, the CBF was underestimated with 7d H‐pCASL in the distal ACA (P = 0.0099), distal middle cerebral artery (P = 0.0109), and distal PCA (P = 0.0319) compared to the proposed method. Improving the SNR of each delay image (even though the number of delays is small) is crucial for ATT estimation. This is opposed to acquiring many delays with short LD. The proposed method confers accurate ATT and CBF estimation within a practical acquisition time in a clinical setting.     

转录调控因子CBF1（RBP—Jκ）对Cbfal和Ose2元件启动子活性的影响

目的：探讨Notch信号转录调控因子CBF1(RBP—Jκ)对核心结合因子Cbfal基因启动子和骨钙素基因启动子区域Ose2元件启动子活性的影响。方法：构建CBF1真核表达载体pCMV—Tag4／CBF1；将梯度浓度pCMV—Tag4／CBF1和荧光素酶报告质粒共转染两成骨前体细胞系Kusa—A1和Kusa-O，用双荧光素酶报告基因方法检测Cbfa1和Ose2元件启动子活性。结果：随CBF1浓度增加，Kusa—A1和Kusa-O细胞中Cbfa1和Ose2元件启动子活性均逐渐提高。统计分析表明：Kusa—A1细胞中1／40μg／μL实验组两启动子活性均与对照组差异显著；Kusa-0细胞中1／40μg／μL实验组Ose2元件启动子活性与对照组差异显著。结论：转录调控因子CBF1可以促进Cbfa1和Ose2元件启动子活性，从而可能对细胞的成骨性分化有正调节作用。     

Evoked-cerebral blood oxygenation changes in false-negative activations in BOLD contrast functional MRI of patients with brain tumors

Blood oxygenation level dependent contrast functional MRI (BOLD-fMRI) has been used to define the functional cortices of the brain in preoperative planning for tumor removal. However, some studies have demonstrated false-negative activations in such patients. We compared the evoked-cerebral blood oxygenation (CBO) changes measured by near-infrared spectroscopy (NIRS) and activation mapping of BOLD-fMRI in 12 patients with brain tumors who had no paresis of the upper extremities. On the nonlesion side, NIRS demonstrated a decrease in deoxyhemoglobin (Deoxy-Hb) with increases in oxyhemoglobin (Oxy-Hb) and total hemoglobin (Total-Hb) during a contralateral hand grasping task in the primary sensorimotor cortex (PSMC) of all patients. On the lesion side, NIRS revealed a decrease in Deoxy-Hb in five patients (Deoxy-decrease group), and an increase in Deoxy-Hb in seven patients (Deoxy-increase group); the Oxy-Hb and Total-Hb were increased during activation in both groups, indicating the occurrence of rCBF increases in response to neuronal activation. BOLD-fMRI demonstrated clear activation areas in the PSMC on the nonlesion side of all patients and on the lesion side of the Deoxy-decrease group. However, in the Deoxy-increase group, BOLD-fMRI revealed only a small activation area or no activation on the lesion side. Intraoperative brain mapping identified the PSMC on the lesion side that was not demonstrated by BOLD-fMRI. The false-negative activations might have been caused by the atypical evoked-CBO changes (i.e. increases in Deoxy-Hb) and the software employed to calculate the activation maps, which does not regard an increase of Deoxy-Hb (i.e., a decrease in BOLD-fMRI signal) as neuronal activation.     

Quantitative perfusion computed tomography measurements of cerebral hemodynamics: correlation with digital subtraction angiography identified primary and secondary cerebral collaterals in internal carotid artery occlusive disease

Background

The aim of the present study was to assess hemodynamic variations in symptomatic unilateral internal carotid artery occlusion (ICAO) patients with primary collateral flow via circle of Willis or secondary collateral flow via ophthalmic artery and/or leptomeningeal collaterals.

Methods

Thirty-eight patients with a symptomatic unilateral ICAO were enrolled in the study. Based on digital subtraction angiography (DSA) findings, patients were classified into 2 groups: primary collateral (n = 14) and secondary collateral (n = 24) groups. Collateral flow hemodynamics were investigated with perfusion computed tomography (PCT) by measuring the cerebral blood flow (CBF), cerebral blood volume (CBV) and time to peak (TTP) in the hemispheres ipsilateral and contralateral to ICAO. Based on the measurements, the ipsilateral to contralateral ratio for each parameter was calculated and compared.

Results

Irrespective of the collateral patterns, ipsilateral CBF was not significantly different from that of the contralateral hemisphere (P = 0.285); ipsilateral CBV and TTP was significantly increased compared with those of the contralateral hemisphere (P = 0.000 and P = 0.000 for CBV and TTP, respectively). Furthermore, patients with secondary collaterals had significantly larger ipsilateral-to-contralateral ratios for both CBV (rCBV, P = 0.0197) and TTP (rTTP, P = 0.000) than those of patients with only primary collaterals. These two groups showed no difference in ipsilateral-to-contralateral ratio for CBF (rCBF, P = 0.312).

Conclusion

Patients with symptomatic unilateral ICAO in our study were in an autoregulatory vasodilatation status. Moreover, secondary collaterals in ICAO patients were correlated with ipsilateral CBV and delayed TTP that suggested severe hemodynamic impairment, presumably increasing the risk of ischemic events.     

Age-related autoregulatory dysfunction and cerebromicrovascular injury in mice with angiotensin II-induced hypertension

Hypertension in the elderly substantially contributes to cerebromicrovascular damage and promotes the development of vascular cognitive impairment. Despite the importance of the myogenic mechanism in cerebromicrovascular protection, it is not well understood how aging affects the functional adaptation of cerebral arteries to high blood pressure. Hypertension was induced in young (3 months) and aged (24 months) C57/BL6 mice by chronic infusion of angiotensin II (AngII). In young hypertensive mice, the range of cerebral blood flow autoregulation was extended to higher pressure values, and the pressure-induced tone of middle cerebral artery (MCA) was increased. In aged hypertensive mice, autoregulation was markedly disrupted, and MCAs did not show adaptive increases in myogenic tone. In young mice, the mechanism of adaptation to hypertension involved upregulation of the 20-HETE (20-hydroxy-5,8,11,14-eicosatetraenoic acid)/transient receptor potential cation channel, subfamily C (TRPC6) pathway and this mechanism was impaired in aged hypertensive mice. Downstream consequences of cerebrovascular autoregulatory dysfunction in aged AngII-induced hypertensive mice included exacerbated disruption of the blood–brain barrier and neuroinflammation (microglia activation and upregulation of proinflammatory cytokines and chemokines), which were associated with impaired hippocampal dependent cognitive function. Collectively, aging impairs autoregulatory protection in the brain of mice with AngII-induced hypertension, potentially exacerbating cerebromicrovascular injury and neuroinflammation.