BACKGROUND Patients with anemia and lower-risk myelodysplastic syndromes in whom erythropoiesis-stimulating agent therapy is not effective generally become dependent on red-cell transfusions. Luspatercept, a recombinant fusion protein that binds transforming growth factor β superfamily ligands to reduce SMAD2 and SMAD3 signaling, showed promising results in a phase 2 study. METHODS In a double-blind, placebo-controlled, phase 3 trial, we randomly assigned patients with very-low-risk, low-risk, or intermediate-risk myelodysplastic syndromes (defined according to the Revised International Prognostic Scoring System) with ring sideroblasts who had been receiving regular red-cell transfusions to receive either luspatercept (at a dose of 1.0 up to 1.75 mg per kilogram of body weight) or placebo, administered subcutaneously every 3 weeks. The primary end point was transfusion independence for 8 weeks or longer during weeks 1 through 24, and the key secondary end point was transfusion independence for 12 weeks or longer, assessed during both weeks 1 through 24 and weeks 1 through 48. RESULTS Of the 229 patients enrolled, 153 were randomly assigned to receive luspatercept and 76 to receive placebo; the baseline characteristics of the patients were balanced. Transfusion independence for 8 weeks or longer was observed in 38% of the patients in the luspatercept group, as compared with 13% of those in the placebo group (P<0.001). A higher percentage of patients in the luspatercept group than in the placebo group met the key secondary end point (28% vs. 8% for weeks 1 through 24, and 33% vs. 12% for weeks 1 through 48; P<0.001 for both comparisons). The most common luspaterceptassociated adverse events (of any grade) included fatigue, diarrhea, asthenia, nausea, and dizziness. The incidence of adverse events decreased over time. CONCLUSIONS Luspatercept reduced the severity of anemia in patients with lower-risk myelodysplastic syndromes with ring sideroblasts who had been receiving regular red-cell transfusions and who had disease that was refractory to or unlikely to respond to erythropoiesisstimulating agents or who had discontinued such agents owing to an adverse event. (Funded by Celgene and Acceleron Pharma; MEDALIST ClinicalTrials.gov number, NCT02631070; EudraCT number, 2015-003454-41.)

Subtle cognitive decline following CEA occurs and persists for at least several weeks after surgery. This decline was absent in a control group.

Background: Between 9% and 23% of patients undergoing otherwise uncomplicated carotid endarterectomy (CEA) develop subtle cognitive decline 1 month postoperatively. The APOE-ε4 allele has been associated with worse outcome following stroke. Objective: To investigate the ability

OBJECTIVE-Carotid endarterectomy (CEA) is an effective means of stroke prevention among appropriately selected patients; however, neuropsychometric testing has revealed subtle cognitive injuries in the early postoperative period. The purpose of this study was to establish whether serum levels of two biochemical markers of cerebral injury were correlated with postoperative declines in neuropsychometric test performance after CEA. METHODS-Fifty-five consecutive patients underwent a battery of neuropsychometric tests 24hours before and 24 hours after elective CEA. Two patients were excluded because of postoperative strokes. The pre-and postoperative serum levels of S100B protein and neuronspecific enolase for injured patients, defined as those who exhibited significant declines in neuropsychometric test performance (n = 12), were compared with the levels for uninjured patients (n = 41).RESULTS-There were no significant differences in the baseline S100B levels for the two groups. Injured patients exhibited significantly higher S100B levels, compared with uninjured patients, at 24, 48, and 72 hours after surgery (P < 0.05). There were no significant differences in neuron-specific enolase levels for injured and uninjured patients at any time point.CONCLUSION-These data suggest that subtle cerebral injuries after CEA, even in the absence of overt strokes, are associated with significant increases in serum S100B but not neuron-specific enolase levels. Analyses of earlier time points in future studies of subtle cognitive injuries and biochemical markers of cerebral injury after CEA may be revealing. KeywordsCarotid endarterectomy; Cerebral ischemia; Neuron-specific enolase; Neuropsychological tests; S100B Carotid endarterectomy (CEA) is an effective means to prevent stroke among patients at high risk. Although the risk of major stroke after CEA is relatively low, the incidence of subtle cognitive injuries, as revealed by neuropsychometric tests (NPMTs), is quite high (4,6,11). NPMTs are sensitive measures of subtle neurological dysfunctions that are not revealed in routine neurological examinations. We recently demonstrated that as many as A variety of biochemical markers of severe neurological injury have been described. Neuron-specific enolase (NSE) is a glycolytic enzyme found in neurons and neuroendocrine cells (19). The calcium-binding protein S100B is an important participant in neuronal and glial cell-cell communication and intracellular signal transduction and exhibits its highest levels of expression in the nervous system (33). These molecules have been demonstrated to be markers of cerebral injury in animal models of stroke (1,9) and among human stroke patients (3,5,21,23,27).Among patients with cerebral infarctions, high S100B levels were correlated with mildly poorer performance on NPMTs, but these results did not reach significance (32). Another study demonstrated no correlation between increased NSE and S100B levels and a decline in performance on NPMTs after CEA (25). In that study, however, the au...

OBJECTIVE-Neurocognitive dysfunction has been shown to occur in roughly 25% of patients undergoing carotid endarterectomy (CEA). Despite this, little is known about the mechanism of this injury. Recently, several groups have shown that new diffusion weighted imaging (DWI)-positive lesions are seen in 20% of patients undergoing CEA. We investigated to what degree neurocognitive dysfunction was associated with new DWI lesions.METHODS-Thirty-four consecutive patients undergoing CEA were subjected to preand postoperative cognitive evaluation with a battery of neuropsychological tests. Postoperative magnetic resonance imaging was performed in all patients within 24 hours of surgery. Lesions that showed high signal on DWI and restricted diffusion on apparent diffusion coefficient maps but no abnormal high signal on the fluid-attenuated inversion recovery images were considered hyperacute. RESULTS-Cognitive dysfunction was seen in eight (24%) patients. New hyperacute DWI lesions were seen in three (9%). Only one (13%) of the patients with cognitive dysfunction had a new DWI lesion. Two thirds of the new DWI lesions occurred in the absence of cognitive deterioration. Patients with cognitive dysfunction had significantly longer carotid cross-clamp times.CONCLUSION-Neurocognitive dysfunction after CEA does not seem to be associated with new DWI positive lesions.Correspondence to: Eric J. Heyer. Carotid endarterectomy (CEA) is an effective means of preventing future stroke (1,6,11,14). The low occurrence of perioperative complications such as stroke makes this a very safe procedure. However, subtle cognitive decline occurs in 28% of patients undergoing CEA when they are evaluated by a battery of neuropsychometric (NP) tests 1 day after surgery (5). This functional change in performance reflects a significant alteration in the brain because patients who have cognitive dysfunction also have a statistically significant increase in S100B, a glial protein serum marker of brain injury, at 24 and 48 hours after surgery (2).Cognitive dysfunction may arise because of multiple reasons. The two most evident relate to ischemic events caused by emboli or global hypoperfusion. Gaunt et al. (4) have shown that the majority of patients having CEA have an average of five emboli per procedure. Furthermore, these emboli, at least when generated during preclamp dissection, may lead to diffusion weighted imaging (DWI) or T1-weighted contrast-enhanced magnetic resonance imaging (MRI) lesions of cerebral infarct (17). On the other hand, upon clamping the carotid artery, there may be a decrease in cerebral blood flow determined by xenon, transcranial Doppler ultrasonography, and electroencephalography (EEG). In fact, there can be as much as a 50% decline in cerebral blood flow before significant changes become evident on the electroencephalogram (15).Therefore, we wanted to determine whether patients having CEA and neurocognitive changes also have acute ischemic lesions on MRI associated with the surgical procedure. To identify these les...