Luspatercept in Patients with Lower-Risk Myelodysplastic Syndromes.

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 ß 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 luspatercept-associated 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 erythropoiesis-stimulating 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.).

Neuropsychological dysfunction in the absence of structural evidence for cerebral ischemia after uncomplicated carotid endarterectomy.

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 pre- and 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.

High dose magnesium infusions are not associated with increased pressor requirements after carotid endarterectomy.

INTRODUCTION: Although magnesium provides cerebral protection in animal stroke models, magnesium therapy has significant side effects in humans. Therefore, we sought to examine the incidence of alpha-agonist treated hypotension in our ongoing, prospective, randomized, double-blind, placebo-controlled Phase I/IIa dose escalation study of magnesium therapy in patients undergoing carotid endarterectomy. METHODS: Eighty patients undergoing elective carotid endarterectomy were randomly assigned to a placebo control group (n = 38) or to one of the three intravenous magnesium groups. Magnesium levels were obtained before induction, and then 15 minutes, 1 hour, 2 hours, 6 hours, 12 hours, and 24 hours after a loading dose and infusion. After surgery, a target systolic blood pressure range was chosen, and the amount and duration of phenylephrine needed to maintain that pressure was compared across treatment groups. RESULTS: All treatment groups achieved levels significantly different from baseline at 12 and 24 hours (P < 0.01). Magnesium treatment did not significantly increase the proportion of patients requiring pressure support. For those requiring pressure support, the amount and average duration of phenylephrine required was not different between control patients and those receiving magnesium, even when the individual minimum systolic blood pressures required were subdivided on the basis of dose of magnesium administered. CONCLUSION: There were no significant differences detected in the 1) percentage of patients requiring pressor support, 2) the duration of postoperative pressor support, or 3) the amount of phenylephrine support needed between controls and magnesium treated patients. The percentage of patients requiring pressure support depended on the minimum systolic blood pressure ordered after surgery.

Failure of intraoperative jugular bulb S-100B and neuron-specific enolase sampling to predict cognitive injury after carotid endarterectomy.

OBJECTIVE: Cognitive decline occurs in 25% of patients after carotid endarterectomy (CEA). Elevated serum concentrations of S-100B and neuron-specific enolase (NSE) occur after stroke, and serum S-100B levels at 24 hours are associated with clinical outcome after both stroke and CEA. We hypothesized that we could detect acute elevations in serum levels of these markers obtained intraoperatively from the jugular bulb (JB) and that these elevations would predict cognitive dysfunction postoperatively as measured by neuropsychometric test performance. METHODS: Forty-three patients scheduled for elective CEA were assessed with a battery of neuropsychometric tests before and 1 day after surgery. Before the carotid artery was clamped, a 6-French Fogarty catheter was inserted into the facial vein and threaded 6 cm rostrally into the JB. Serum samples were withdrawn from this catheter and simultaneously from a radial arterial catheter (A-line) at three time points: before clamping, 15 minutes into clamping, and after unclamping the carotid artery. Concentrations between groups were compared by analysis of variance and paired t tests. RESULTS: Total deficit scores were significantly worse in 13 (30%) of the 43 patients 1 day after surgery. There was a trend toward elevations in JB concentrations of S-100B relative to A-line levels 15 minutes after cross-clamping (11% elevation, P = 0.079, paired t test). In addition, 15 minutes after clamping of the carotid artery, levels of S-100B from the JB were significantly elevated compared with levels at baseline (P = 0.040, one-way analysis of variance). No significant changes were found between any time point in levels of S-100B from the A-line blood or of NSE from either the JB or the A-line. Subtle cognitive decline after CEA was not correlated with intraoperative levels of S-100B or NSE, but there was a weak, statistically nonsignificant, association between a rise in 15-minute S-100B levels and cognitive injury that was not seen with JB samples. CONCLUSION: Although intraoperative levels of S-100B and NSE from the JB failed to predict cognitive injury, carotid cross-clamping, independent of injury, seems to be associated with early elevations in S-100B.

Cerebral injury predicted by transcranial Doppler ultrasonography but not electroencephalography during carotid endarterectomy.

When shunts are selectively used during carotid endarterectomy, the adequacy of collateral cerebral blood flow (CBF) after the carotid artery is clamped is determined by monitors based on different physiologic measurements. In this series of three patients, we used electroencephalography (EEG) to measure neuronal electrical activity and transcranial Doppler ultrasonography (TCD) to measure CBF velocity. In each of our cases, the EEG was unchanged from preclamp values, while TCD CBF velocity was dramatically reduced. All three patients had transient neuropsychometric or neurologic changes after surgery, which resolved.

A controlled prospective study of neuropsychological dysfunction following carotid endarterectomy.

BACKGROUND: Although subtle cognitive injury as revealed by neuropsychological testing occurs in a substantial number of patients following carotid endarterectomy (CEA), there is controversy about whether this finding is a result of the surgery or the anesthesia. OBJECTIVES: To examine the changes in neuropsychological test performance in patients following CEA vs a control group of patients older than 60 years following spine surgery, so as to determine whether neuropsychological dysfunction after CEA is a result of surgery or anesthesia. METHODS: Patients undergoing CEA (n = 80) and lumbar spine surgery (n = 25) were assessed with a battery of neuropsychological tests preoperatively and on postoperative days 1 and 30. The neuropsychological performance of patients in the control group was used to normalize performance for patients in the CEA group, by calculating z scores using the mean and SD of the change scores in the control group. Significant cognitive dysfunction was defined as performance that exceeded 2 SDs above the mean performance of patients in the control group. RESULTS: Postoperative days 1 and 30 total deficit scores were significantly worse in the CEA group compared with the controls. When individual test results were examined, the CEA group performed significantly worse than the controls on the Rey Complex Figure test and Halstead-Reitan Trails B on day 1, and on the Rey Complex Figure on day 30. Overall, cognitive dysfunction was seen in 22 patients (28%) in the CEA group on day 1 and in 11 (23%) of 48 patients on day 30. CONCLUSIONS: Subtle cognitive decline following CEA occurs and persists for at least several weeks after surgery. This decline was absent in a control group.