Eric M. Liotta

Engineered conformation-dependent VEGF peptide mimics are effective in inhibiting VEGF signaling pathways.

Angiogenesis, or formation of new blood vessels, is crucial to cancer tumor growth. Tumor growth, progression, and metastasis are critically influenced by the production of the pro-angiogenic vascular endothelial growth factor (VEGF). Promising anti-angiogenic drugs are currently available; however, their susceptibilities to drug resistance and long term toxicity are serious impediments to their use, thus requiring the development of new therapeutic approaches for safe and effective angiogenic inhibitors. In this work, peptides were designed to mimic the VEGF-binding site to its receptor VEGFR-2. The VEGF conformational peptide mimic, VEGF-P3(CYC), included two artificial cysteine residues, which upon cyclization constrained the peptide in a loop native-like conformation to better mimic the anti-parallel structure of VEGF. The engineered cyclic VEGF mimic peptide demonstrated the highest affinity to VEGFR-2 by surface plasmon resonance assay. The VEGF peptide mimics were evaluated as inhibitors in several in vitro assays in which VEGF-dependent signaling pathways were observed. All VEGF mimics inhibited VEGFR-2 phosphorylation with VEGF-P3(CYC) showing the highest inhibitory effects when compared with unstructured peptides. Additionally, we show in several angiogenic in vitro assays that all the VEGF mimics inhibited endothelial cell proliferation, migration, and network formation with the conformational VEGF-P3 (CYC) being the best. The VEGF-P3(CYC) also caused a significant delay in tumor development in a transgenic model of VEGF+/−Neu2-5+/−. These results indicate that the structure-based design is important for the development of this peptidomimetic and for its anti-angiogenic effects.

Desmopressin Improves Platelet Activity in Acute Intracerebral Hemorrhage

Background and Purpose— Minimizing hematoma growth in high-risk patients is an attractive strategy to improve outcomes after intracerebral hemorrhage. We tested the hypothesis that desmopressin (DDAVP), which improves hemostasis through the release of von Willebrand factor, improves platelet activity after intracerebral hemorrhage. Methods— Patients with reduced platelet activity on point-of-care testing alone (5), known aspirin use alone (1), or both (8) received desmopressin 0.4 &mgr;g/kg IV. We measured Platelet Function Analyzer-epinephrine (Siemens AG, Germany) and von Willebrand factor antigen from baseline to 1 hour after infusion start and hematoma volume from the diagnostic to a follow-up computed tomographic scan. Results— We enrolled 14 patients with of mean age 66.8±14.6 years, 11 (85%) of whom were white and 8 (57%) were men. Mean Platelet Function Analyzer-epinephrine results shortened from 192±18 seconds pretreatment to 124±15 seconds (P=0.01) 1 hour later, indicating improved plate activity. von Willebrand factor antigen increased from 242±96% to 289±103% activity (P=0.004), indicating the expected increase in von Willebrand factor. Of 7 (50%) patients who received desmopressin within 12 hours of intracerebral hemorrhage symptom onset, changes in hematoma volume were modest, −0.5 (−1.4 to 8.4) mL and only 2 had hematoma growth. One patient had low blood pressure and another had a new fever within 6 hours of desmopressin administration. Conclusions— Intravenous desmopressin was well tolerated and improved platelet activity after acute intracerebral hemorrhage. Larger studies are needed to determine its potential effects on reducing hematoma growth versus platelet transfusion or placebo. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00961532.

Warfarin-associated Intracerebral Hemorrhage is Increasing in Prevalence in the United States

BACKGROUND Warfarin-associated intracerebral hemorrhage (WAICH) is expected to increase in prevalence as the population ages. We sought to evaluate national trends, characteristics, and in-hospital outcomes among intracerebral hemorrhage (ICH) patients taking warfarin at baseline. METHODS We reviewed the Nationwide Inpatient Sample to identify all admissions with primary diagnosis of ICH by International Classification of Diseases, Ninth Revision code (431) from 2005 to 2008. We identified premorbid warfarin use by the V code (V58.93) and calculated the proportion of WAICH among all ICH patients in each year. We employed univariate statistics and generalized estimating equation regression models to assess whether warfarin use independently increased the risk of in-hospital mortality after adjusting for relevant covariates. P value less than .05 was considered significant. RESULTS There were 52,993 patients (mean age 68.8 years; 49.7% male) coded for ICH between 2005 and 2008. The proportion with WAICH increased each year (2005, 5.8%; 2006, 6.5%; 2007, 6.9%; 2008, 7.3%; P < .001). While in-hospital mortality declined each year for non-WAICH (29.0%-25.4%, P < .001), it remained unchanged for WAICH (42.1%-40.0%, P = .346). In multivariable analysis, warfarin use (adjusted odds ratio 1.35; 95% confidence interval 1.24-1.47) remained an independent predictor of in-hospital mortality. CONCLUSIONS WAICH is increasing in prevalence in the United States and is associated with a 35% higher mortality than non-WAICH. While mortality has declined over time for non-WAICH, mortality after WAICH is unchanged. Specific strategies to decrease the mortality of WAICH such as rapid reversal of anticoagulation are warranted.

Surveillance neuroimaging and neurologic examinations affect care for intracerebral hemorrhage

Objective: We tested the hypothesis that surveillance neuroimaging and neurologic examinations identified changes requiring emergent surgical interventions in patients with intracerebral hemorrhage (ICH). Methods: Patients with primary ICH were enrolled into a prospective registry between December 2006 and July 2012. Patients were managed in a neuroscience intensive care unit with a protocol that included serial neuroimaging at 6, 24, and 48 hours, and hourly neurologic examinations using the Glasgow Coma Scale and NIH Stroke Scale. We evaluated all cases of craniotomy and ventriculostomy to determine whether the procedure was part of the initial management plan or occurred subsequently. For those that occurred subsequently, we determined whether worsening on neurologic examination or worsened neuroimaging findings initiated the process leading to intervention. Results: There were 88 surgical interventions in 84 (35%) of the 239 patients studied, including ventriculostomy in 52 (59%), craniotomy in 21 (24%), and both in 11 (13%). Of the 88 interventions, 24 (27%) occurred subsequently and distinctly from initial management, a median of 15.9 hours (8.9–27.0 hours) after symptom onset. Thirteen (54%) were instigated by findings on neurologic examination and 11 (46%) by neuroimaging. Demographics, severity of hemorrhage, and hemorrhage location were not associated with delayed intervention. Conclusions: More than 25% of surgical interventions performed after ICH were prompted by delayed imaging or clinical findings. Serial neurologic examinations and neuroimaging are important and effective surveillance techniques for monitoring patients with ICH.

Warfarin-Associated Intracerebral Hemorrhage Is Inadequately Treated at Community Emergency Departments

Background and Purpose— The purpose of this study was to investigate time delays, adherence to guidelines, and their impact on outcomes in patients with warfarin-associated intracerebral hemorrhage transferred from community emergency departments to a comprehensive stroke center. Methods— We collected demographic, clinical, transfer time, treatment, and outcome data for patients transferred to our institution with warfarin-associated intracerebral hemorrhage from community emergency departments. Results— Among 928 patients with intracerebral hemorrhage, 56 (6%) with warfarin-associated intracerebral hemorrhage (median international normalized ratio, 2.55) were transferred to the comprehensive stroke center. Twenty patients received no acute reversal therapy before transfer, only 4 of whom had international normalized ratios ⩽1.4 in the community emergency department. Median time of emergency department stay was 3.66 hours and median time to initiation of acute reversal therapy was 4.48 hours. Those who received ≥3 U of fresh–frozen plasma or recombinant activated Factor VIIa (11 patients) before transfer had lower repeat international normalized ratios and better discharge dispositions than those treated less aggressively. Conclusions— Treatment of warfarin-associated intracerebral hemorrhage in community emergency departments is often suboptimal and does not adhere to published guidelines. Treating coagulopathy aggressively before interhospital transfer may improve outcomes and warrants further investigation.

Predictors of 30-day readmission after intracerebral hemorrhage: a single-center approach for identifying potentially modifiable associations with readmission.

Objective:To determine whether patient’s demographics or severity of illness predict hospital readmission within 30 days following spontaneous intracerebral hemorrhage, to identify readmission associations that may be modifiable at the single-center level, and to determine the impact of readmission on outcomes. Design:We collected demographic, clinical, and hospital course data for consecutive patients with spontaneous intracerebral hemorrhage enrolled in an observational study. Readmission within 30 days was determined retrospectively by an automated query with manual confirmation. We identified the reason for readmission and tested for associations between readmission and functional outcomes using modified Rankin Scale (a validated functional outcome measure from 0, no symptoms, to 6, death) scores before intracerebral hemorrhage and at 14 days, 28 days, and 3 months after intracerebral hemorrhage. Setting:Neurologic ICU of a tertiary care hospital. Patients:Critically ill patients with spontaneous intracerebral hemorrhage. Interventions:Patients received standard critical care management for intracerebral hemorrhage. Measurements and Main Results:Of 246 patients (mean age, 65 yr; 51% female), 193 patients (78%) survived to discharge. Of these, 22 patients (11%) were readmitted at a median of 9 days (interquartile range, 4–15 d). The most common readmission diagnoses were infections after discharge (n = 10) and vascular events (n = 6). Age, history of stroke and hypertension, severity of neurologic deficit at admission, Acute Physiology and Chronic Health Evaluation score, ICU and hospital length of stay, ventilator-free days, days febrile, and surgical procedures were not predictors of readmission. History of coronary artery disease was associated with readmission (p = 0.03). Readmitted patients had similar modified Rankin Scale and severity of neurologic deficit at 14 days but higher (worse) modified Rankin Scale scores at 3 months (median [interquartile range], 5 [3–6] vs 3 [1–4]; p = 0.01). Conclusions:Severity of illness and hospital complications were not associated with 30-day readmission. The most common indication for readmission was infection after discharge, and readmission was associated with worse functional outcomes at 3 months. Preventing readmission after intracerebral hemorrhage may depend primarily on optimizing care after discharge and may improve functional outcomes at 3 months.

Do efforts to decrease door-to-needle time risk increasing stroke mimic treatment rates?

SummaryAn unintended consequence of rapid thrombolysis may be more frequent treatment of stroke mimics, nonvascular conditions that simulate stroke. We explored the relationship between door-to-needle (DTN) times and thrombolysis of stroke mimics at a single academic center by analyzing consecutive quartiles of patients who were treated with IV tissue plasminogen activator for suspected stroke from January 1, 2010 to February 28, 2014. An increase in the proportion of stroke mimic patients (6.7% in each of the 1st and 2nd, 12.9% in the 3rd, and 30% in the last consecutive case quartile; p = 0.03) and a decrease in median DTN time from 89 to 56 minutes (p < 0.01) was found. As more centers reduce DTN times, the rates of stroke mimic treatment should be carefully monitored.

Reversal of the novel oral anticoagulants dabigatran, rivoraxaban, and apixaban.

Purpose of reviewWe summarize the available data related to reversing the anticoagulant effect of the oral direct thrombin and factor Xa inhibitors and provide our opinion on treating patients presenting with severe and life-threatening hemorrhage related to these agents. Recent findingsNo specific antidotes are currently available for the oral direct thrombin and factor Xa inhibitors but two promising agents are under investigation in phase 3 trials. No data are available on reversing these agents in bleeding patients. Activated charcoal may be effective in reducing factor Xa inhibitor absorption up to 6 h after ingestion. Animal models suggest that unactivated 4-factor prothrombin complex concentrate may be an effective reversal agent. Recent data in warfarin-treated patients suggest that 4-factor prothrombin complex concentrate may provide more rapid and effective hemostasis than fresh frozen plasma. SummaryIn the absence of evidence in bleeding patients, animal models and ex-vivo studies suggest administration of coagulant factors in the form of hemostatic agents may be of benefit in reversing the effect of direct thrombin and factor Xa inhibitors. Specific reversal agents and clinical data in patients with hemorrhage remain an unmet need.

Dichotomous “Good Outcome” Indicates Mobility More Than Cognitive or Social Quality of Life

Objective:Worthwhile interventions for intracerebral hemorrhage or subarachnoid hemorrhage generally hinge on whether they improve the odds of good outcome. Although good outcome is correlated with mobility, correlations with other domains of health-related quality of life, such as cognitive function and social functioning, are not well described. We tested the hypothesis that good outcome is more closely associated with mobility than other domains. Design:We defined “good outcome” as 0 through 3 (independent ambulation or better) versus 4 through 5 (dependent) on the modified Rankin Scale at 1, 3, and 12 months. We simultaneously assessed the modified Rankin Scale and health-related quality of life using web-based computer adaptive testing in the domains of mobility, cognitive function (executive function and general concerns), and satisfaction with social roles and activities. We compared the area under the curve between different health-related quality of life domains. Setting:Neurologic ICU with web-based follow-up. Patients:One hundred fourteen patients with subarachnoid hemorrhage or intracerebral hemorrhage. Interventions:None. Measurement and Main Results:We longitudinally followed 114 survivors with data at 1 month, 62 patients at 3 months, and 58 patients at 12 months. At 1 month, area under the curve was highest for mobility (0.957; 95% CI, 0.904–0.98), higher than cognitive function–general concerns (0.819; 95% CI, 0.715–0.888; p = 0.003 compared with mobility), satisfaction with social roles and activities (0.85; 95% CI, 0.753–0.911; p = 0.01 compared with mobility), and cognitive function–executive function (0.879; 95% CI, 0.782–0.935; p = 0.058 compared with mobility). Optimal specificity and sensitivity for receiver operating characteristic analysis were approximately 1.5 SD below the U.S. population mean. Conclusions:Health-related quality of life assessments reliably distinguished between good and poor outcomes as determined by the modified Rankin Scale. Good outcome indicated health-related quality of life about 1.5 SD below the U.S. population mean. Associations were weaker for cognitive function and social function than mobility.

Subarachnoid Extension of Primary Intracerebral Hemorrhage is Associated With Poor Outcomes

Background and Purpose— Extension of hemorrhage into the subarachnoid space is observed in primary intracerebral hemorrhage (ICH), yet the phenomenon has undergone limited study and is of unknown significance. The objective of this study is to evaluate the incidence, characteristics, and clinical consequences of subarachnoid hemorrhage extension (SAHE) in ICH on functional outcomes. Methods— Patients with primary ICH were enrolled into a prospective registry between December 2006 and June 2012. Patients were managed and serial neuroimaging was obtained per a structured protocol. Presence of any subarachnoid blood on imaging was identified as SAHE by expert reviewers blinded to outcomes. Regression models were developed to test whether the occurrence of SAHE was an independent predictor of functional outcomes as measured with the modified Rankin Scale. Results— Of 234 patients with ICH, 93 (39.7%) had SAHE. Interrater agreement for SAHE was excellent (kappa=0.991). SAHE was associated with lobar hemorrhage location (65% of SAHE vs 19% of non-SAHE cases; P<0.001) and larger hematoma volumes (median 23.8 vs 6.7; P<0.001). Fever (69.9% vs 51.1%; P=0.005) and seizures (8.6% vs 2.8%; P=0.07) were more common in patients with SAHE. SAHE was a predictor of death by day 14 (odds ratio, 4.45; 95% confidence interval, 1.88–10.53; P=0.001) and of higher (worse) modified Rankin Scale scores at 28 days (odds ratio, 1.76 per mRS point; 95% confidence interval, 1.01–3.05; P=0.012) after adjustment for ICH score. Conclusions— SAHE is associated with worse modified Rankin Scale independent of traditional ICH severity measures. Underlying mechanisms and potential treatments of SAHE require further study.