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Purpose: In myelodysplastic syndromes (MDS), severe thrombocytopenia is associated with poor prognosis. This multicenter trial presents the second-part long-term efficacy and safety results of eltrombopag in patients with low-risk MDS and severe thrombocytopenia., Methods: In this single-blind, randomized, placebo-controlled, phase-II trial of adult patients with International Prognostic Scoring System low- or intermediate-1-risk MDS, patients with a stable platelet (PLT) count (<30 × 10 3 /mm 3 ) received eltrombopag or placebo until disease progression. Primary end points were duration of PLT response (PLT-R; calculated from the time of PLT-R to date of loss of PLT-R, defined as bleeding/PLT count <30 × 10 3 /mm 3 or last date in observation) and long-term safety and tolerability. Secondary end points included incidence and severity of bleeding, PLT transfusions, quality of life, leukemia-free survival, progression-free survival, overall survival and pharmacokinetics., Results: From 2011 to 2021, of 325 patients screened, 169 patients were randomly assigned oral eltrombopag (N = 112) or placebo (N = 57) at a starting dose of 50 mg once daily to maximum of 300 mg. PLT-R, with 25-week follow-up (IQR, 14-68) occurred in 47/111 (42.3%) eltrombopag patients versus 6/54 (11.1%) in placebo (odds ratio, 5.9; 95% CI, 2.3 to 14.9; P < .001). In eltrombopag patients, 12/47 (25.5%) lost the PLT-R, with cumulative thrombocytopenia relapse-free survival at 60 months of 63.6% (95% CI, 46.0 to 81.2). Clinically significant bleeding (WHO bleeding score ≥ 2) occurred less frequently in the eltrombopag arm than in the placebo group (incidence rate ratio, 0.54; 95% CI, 0.38 to 0.75; P = .0002). Although no difference in the frequency of grade 1-2 adverse events (AEs) was observed, a higher proportion of eltrombopag patients experienced grade 3-4 AEs (χ 2 = 9.5, P = .002). AML evolution and/or disease progression occurred in 17% (for both) of eltrombopag and placebo patients with no difference in survival times., Conclusion: Eltrombopag was effective and relatively safe in low-risk MDS with severe thrombocytopenia. This trial is registered with ClinicalTrials.gov identifier: NCT02912208 and EU Clinical Trials Register: EudraCT No. 2010-022890-33.

TP53 gene mutations are common in Myelodysplastic Syndromes (MDS) with del5q and have a clinical and prognostic significance. Next Generation Sequencing (NGS) is an accurate, but expensive, technique, and not commonly available. Immunohistochemistry (IHC) for TP53 expression has been recently used as a surrogate to assess TP53 mutations. To compare the concordance between TP53 expression in IHC and TP53 mutations by NGS, 30 cases with MDS harbouring a del5q abnormality were evaluated. Overall, 10/30 patients (33.3%) had TP53 mutations by NGS, while 16/29 (55.1%) had TP53 overexpression in IHC. TP53 expression by IHC had a 70% sensitivity to identify patients with TP53 mutation by NGS, but its specificity was low (52.6%, kappa = 0.198; P = 0.24). In addition, ROC curve analyses showed that the overall diagnostic value (accuracy) of TP53 expression in IHC to identify patients with TP53 mutation by NGS was 68% in the whole study sample and 67% in patients with isolated del5q-. In both cases, the areas under the curves did not attain the statistical significance (P = 0.11 and P = 0.29, respectively). Based on the ROC curve, the cut-off of 2.3% TP53 expression in IHC was shown to be the best cut-off to identify TP53 mutations: using this cut-off, the agreement between TP53 expression and TP53 mutation by NGS reached statistical significance (kappa = 0.42; P = 0.023). In conclusion, the agreement between TP53 expression in IHC and TP53 mutation analysis by NGS is rather unsatisfactory in MDS patients with del5q at the standard cut-off. Thus, the IHC technique cannot be considered a valid alternative to NGS evaluation of TP53 mutational status in these patients., Competing Interests: None., (AJBR Copyright © 2021.)

Background: In myelodysplastic syndromes, thrombocytopenia is associated with mortality, but treatments in this setting are scarce. We tested whether eltrombopag, a thrombopoietin receptor agonist, might be effective in improving thrombocytopenia in lower-risk myelodysplastic syndromes and severe thrombocytopenia., Methods: EQoL-MDS was a single-blind, randomised, controlled, phase 2 superiority trial of adult patients with low-risk or International Prognostic Scoring System intermediate-1-risk myelodysplastic syndromes and severe thrombocytopenia. Patients with a stable platelet count of lower than 30 × 10 9 platelets per L, aged at least 18 years, with refractoriness, ineligibility to receive treatment with alternative medications, or relapse while receiving treatment with alternative medications were included in this trial. Patients were randomly assigned (2:1) to receive eltrombopag (50 mg to 300 mg) or placebo for at least 24 weeks and until disease progression and were masked to treatment allocation. Here, we report the results in the intention-to-treat population of the first phase of the trial, for which the primary endpoints were the proportion of patients achieving a platelet response within 24 weeks and safety. The interim analysis presented here was protocol-specified and used a two-sided significance level of 0·001 and a p value at or below this limit for both primary endpoints to indicate the need for early trial termination. Duration of platelet transfusion independence, duration of response, overall survival, leukaemia-free survival, and pharmacokinetics will be reported at the end of the phase 2 portion of the trial. This trial is registered with EudraCT, number 2010-022890-33., Findings: Between June 13, 2011, and June 17, 2016, we enrolled 90 participants for the first phase of the trial. The median follow-up time to assess platelet responses was 11 weeks (IQR 4-24). Platelet responses occurred in 28 (47%) of 59 patients in the eltrombopag group versus one (3%) of 31 patients in the placebo group (odds ratio 27·1 [95% CI 3·5-211·9], p=0·0017). During the follow-up, 21 patients had at least one severe bleeding event (WHO bleeding score ≥2). There were a higher number of bleeders in the placebo (13 [42%] of 31 patients) than in the eltrombopag arm (eight [14%] of 59 patients; p=0·0025). 52 grade 3-4 adverse events occurred in 27 (46%) of 59 patients in the eltrombopag group versus nine events in five (16%) of 31 patients in the placebo group (χ 2 =7·8, p=0·0053, stopping rule not reached). The outcome acute myeloid leukaemia evolution or disease progression occurred in seven (12%) of 59 patients in the eltrombopag group versus five (16%) of 31 patients in the placebo group (χ 2 =0·06, p=0·81)., Interpretation: Eltrombopag is well-tolerated in patients with lower-risk myelodysplastic syndromes and severe thrombocytopenia and is clinically effective in raising platelet counts and reducing bleeding events. The assessment of long-term safety and efficacy of eltrombopag and its effect on survival (phase 2 part of study) is still ongoing., Funding: Associazione QOL-ONE., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background and Purpose: White matter changes (WMCs), or leukoaraiosis (LA), are associated with increased age, hypertension, diabetes mellitus, and history of stroke. Although several lines of evidence suggest a role of atherosclerosis in atherothrombotic vascular events, their involvement in LA remains to be determined. Our study examines this association in ischemic stroke patients., Methods: One hundred and seventy consecutive ischemic stroke or transient ischemic attack (TIA) patients were included. All patients underwent brain computed tomography (CT) with assessment of the extension and severity of WMCs, carotid arteries duplex scan with measurements of intima-media thickness (IMT) and plaques., Results: Seventy-two patients (42.4%) were found to have white matter lesions, of whom 28.8% had advanced LA. Mean IMT was significantly higher in patients with LA and with advanced LA (P = 0.002, P = 0.003, resp.). In addition, LA and LA severity were associated with existence of carotid plaque (P = 0.007, P = 0.004, resp.). In multivariate logistic regression analysis, including all vascular risk factors, LA was found to be associated with age and IMT., Conclusion: This study reinforces the tight association between LA and carotid atherosclerosis in ischemic stroke patients. We conclude that a chronic atherosclerotic disease underlies the pathophysiology of leukoaraiosis and its progression.

To date there is no diagnostic biomarker for mild stroke, although elevation of inflammatory biomarkers has been reported at early stages. Previous studies implicated acetylcholinesterase (AChE) involvement in stroke, and circulating AChE activity reflects inflammatory response, since acetylcholine suppresses inflammation. Therefore, carriers of polymorphisms that modify cholinergic activity should be particularly susceptible to inflammatory damage. Our study sought diagnostic values of AChE and Cholinergic Status (CS, the total capacity for acetylcholine hydrolysis) in suspected stroke patients. For this purpose, serum cholinesterase activities, butyrylcholinesterase-K genotype and inflammatory biomarkers were determined in 264 ischemic stroke patients and matched controls during the acute phase. AChE activities were lower (P<0.001), and butyrylcholinesterase activities were higher in patients than in controls (P=0.004). When normalized to sampling time from stroke occurrence, both cholinergic parameters were correlated with multiple inflammatory biomarkers, including fibrinogen, interleukin-6 and C-reactive protein (r=0.713, r=0.607; r=0.421, r=0.341; r=0.276, r=0.255; respectively; all P values<0.001). Furthermore, very low AChE activities predicted subsequent nonsurvival (P=0.036). Also, carriers of the unstable butyrylcholinesterase-K variant were more abundant among patients than controls, and showed reduced activity (P<0.001). Importantly, a cholinergic score combining the two cholinesterase activities discriminated between 94.3% matched pairs of patients and controls, compared with only 75% for inflammatory measures. Our findings present the power of circulation cholinesterase measurements as useful early diagnostic tools for the occurrence of stroke. Importantly, these were considerably more distinctive than the inflammatory biomarkers, albeit closely associated with them, which may open new venues for stroke diagnosis and treatment.

Background: Early biomarkers for survival in an acute ischaemic stroke/transient ischaemic attack might serve as a useful tool for the clinician. Several studies have highlighted the role of inflammatory biomarkers as an early signal for acute ischaemic stroke prognosis., Aims: This study examines the potential advantage of using high-sensitivity interleukin-6 as a possible biomarker at the early stages of acute stroke for identifying patients at a high risk for 12-month mortality., Methods: Inflammatory biomarkers and neurological scores were determined in 250 patients following mild to moderate acute ischaemic stroke within 24 h of hospital admission. Outcome data on mortality were collected after 12 months. The signal detection methodology was used to identify subgroups that were at a high risk for 12-month mortality., Results: Twelve months following the event, 234 of the 250 stroke patients survived. Signal detection identified predictors that distinguished individuals likely to die from those with a better recovery prediction. Plasma interleukin-6 concentration emerged as the optimal predictor, with a cut point of 6.47 pg/ml, chi(2) (l, N=250)=20.5, P<0.001. Interleukin-6 above 6.47 pg/ml during the acute phase predicted subsequent non-survival (P=0.006, odds ratio 8.0)., Conclusions: This study demonstrates the clinical potential of using high-sensitivity interleukin-6 as an early signal for acute ischaemic stroke survival and suggests a clear cut point for patients at a high risk who might benefit from closer clinical surveillance and/or administration of therapeutic interventions.

Introduction: C-reactive protein (CRP) is an inflammatory protein that may play a role in the pathogenesis of atherosclerosis. CRP gene single nucleotide polymorphisms (SNPs) have been shown to be associated with CRP concentration; however, their independent effect on atherosclerosis has not been yet established. We aimed to determine whether the 5'-flanking -757T>C CRP gene polymorphism is associated with CRP concentration and carotid atherosclerosis., Methods: We genotyped the -757T>C CRP gene SNP and determined the concentration of serum CRP, the intima-media thickness (IMT) of the common carotid artery and the existence of plaque/s in 612 apparently healthy men and women aged 66+/-10 years., Results: Carriers of the CRP -757C allele presented with higher IMT and higher CRP concentrations (p=0.002, p=0.042, respectively). After adjustment for vascular risk factors, linear regression analysis showed an independent effect of CRP -757C allele on carotid IMT, beyond serum CRP concentrations. This SNP was also associated with carotid plaque occurrence (O.R. 1.74, 95% CI 1.1-2.77, p=0.002)., Conclusions: The present study provides evidence that a genetic variant of CRP gene is associated with carotid atherosclerosis, independently of traditional vascular risk factors. Further large-scale genomic studies are required, which may identify the genetic vulnerable subjects to develop atherosclerosis.

Increased fibrinogen concentration is a well known phenomenon following acute ischemic stroke. However, the natural course of this hyperfibrinogenemia is uncertain. We aimed to clarify whether it is of a transient or more persistent nature in patients who harbor an underlying morbid biology of atherothrombo-inflammation. Venous blood for fibrinogen measurements was obtained from the control group participants and from stroke patients within 24 hours of admission, as well as 12 months following the acute event. In order to perform a time course analysis, we divided our cohort into tiles of time from symptoms' onset and compared the fibrinogen concentrations using ANOVA. Elevated fibrinogen concentrations were found in stroke patients on admission compared with matched controls (p < 0.001). Analysis of variance in the different tertiles of time from symptoms' onset identified that fibrinogen concentrations were already relatively high during the initial phase of the event and did not differ significantly between the tiles (p = 0.268). Moreover, when we calculated the absolute differences between the patients' fibrinogen concentrations and that of the matched controls there was clearly a minor increment during the time course from symptoms' onset in the stroke patients group. In conclusion, persistent hyperfibrinogenemia is present in patients with acute ischemic cerebral events and it might be present during the earlier stages of the disease as presently shown. Prompt and long-term, rather than short term, interventions to reduce the concentrations of this protein might therefore be of relevance.

Background: Atherosclerosis is a chronic inflammatory disease., Design: We have evaluated the degree of erythrocyte aggregation (EA) as a microinflammatory biomarker in a cohort of hospital-based, neurologically asymptomatic outpatients., Methods: The degree of EA and carotid artery stenosis was evaluated in 510 individuals by using a simple slide test and image analysis., Results: Four hundred and sixteen individuals had minimal carotid stenosis (< 30%); 47 had mild to moderate stenosis (30-69%) and 47 had severe stenosis (> 70%). A significant correlation was noted between the degree of carotid stenosis and the erythrocyte sedimentation rate (ESR), white blood cell count (WBCC) and fibrinogen (r=0.160, p=0.005; r=0.191, p=0.001 and r=0.126, p=0.026, respectively). The significant correlation was noted between the degree of carotid stenosis and EA (r=0.209, p< 0.001). The subjects with severe stenosis differed significantly from the other groups in their ESR, WBCC and EA. High sensitivity C-reactive protein (hs-CRP) concentrations did not discriminate between the presence and absence of significant carotid atherosclerotic disease., Conclusions: Inflammatory biomarkers such as ESR and the EA test are more sensitive than hs-CRP to the presence of a significant atherosclerotic carotid burden. These biomarkers might aid in the detection and quantification of microinflammation in individuals with carotid atherosclerosis.

Introduction: Several studies have highlighted the role of interleukin-6 (IL-6) as an early signal of the inflammatory response following acute ischemic stroke. This study examines the potential advantage of employing high-sensitivity (hs)-IL-6 as a possible biomarker at the early stages of acute stroke for identifying an acute phase response and its potential rheological and clinical implications., Methods: Venous blood was obtained from 186 stroke patients within 24 h of hospital admission and 3-5 days thereafter in order to characterize an inflammatory and hemorheological profile (including erythrocyte aggregation). Neurological state was assessed by the National Institutes of Health Stroke Scale (NIHSS) and the modified Rankin scale (mRs)., Results: While most biomarkers displayed elevated concentrations with time, serum concentrations of hs-IL-6 declined 3-5 days following acute stroke. Initially elevated levels of hs-IL-6 at presentation further correlated with unfavorable clinical outcomes (by NIHSS and mRs) at both time points. Analysis of variance in the different quartiles identified an hs-IL-6 gradient-dependent correlation at both time points, such that the higher the initial hs-IL-6 concentration, the higher the elevation in inflammatory biomarkers and the poorer the neurological state at both time points (p<0.001 for NIHSS and p=0.001 for mRs, for trend across quartiles)., Conclusions: This study demonstrates the potential of employing hs-IL-6 as an early stage biomarker for the prognosis of acute ischemic stroke. Such an advance would provide the means to identify at an early stage the patients who would require closer clinical surveillance and/or administration of therapeutic interventions.

We report on a patient with mental and growth retardation, bilateral cleft lip and palate, hypertelorism, ptosis, hearing loss and mild epispadias, suggestive of Malpuech syndrome. High-resolution karyotype and microarray-CGH using an oligonucleotide array with 75Kb oligo's were normal, excluding Wolf-Hirschhorn syndrome. Long-term follow-up revealed psychiatric manifestations starting at young age.

C-reactive protein (CRP) increases following an acute stroke/transient ischemic attack (TIA), but the increment level varies among patients. We analyzed CRP concentrations during an acute stroke/TIA in relation to the CRP gene -717A>G polymorphism. Six months following an acute ischemic stroke/TIA, basal concentrations of CRP were measured in 507 controls and 219 patients and were found to be unassociated with the CRP -717A>G polymorphism. However, during the acute phase of stroke/TIA, individuals with the AG/GG genotype had significantly elevated CRP concentrations as opposed to those with the AA genotype (2.02 +/- 1.59 vs. 1.73 +/- 1.69 mg/l, P = 0.027). In addition, significant 3.22-fold increments in CRP concentrations was noted in individuals carrying the -717G allele when comparing the acute phase with the basal state of each patient and averaging the results. CRP -717A>G polymorphism is associated with triggered CRP concentrations during acute stroke/TIA. These findings might shed more light on the mechanisms of CRP elevation in acute ischemic stroke/TIA.

Objective: To compare the recently introduced wide-range C-reactive protein (wr-CRP) with the widely used high-sensitivity Behring Dade method (hs-CRP) in acute stroke/transient ischemic attack (TIA) patients., Materials and Methods: A total of 119 consecutive patients admitted to a tertiary medical center with acute ischemic stroke/TIA were included in the study. Venous blood was obtained for both assays during the first 24 h, 3-5 days, as well as 3-6 months thereafter., Results: A highly significant correlation (r=0.994, P<0.0001) was found between the two methods even when analyzed at three different time points. In addition, a similar correlation was noted between these two assays and other commonly used biomarkers, including white blood cell count, Westergren's sedimentation rate and quantitative fibrinogen., Conclusion: Real-time, on-line and low-cost wr-CRP assay is a reasonable alternative to the Behring Dade hs-CRP method in acute stroke/TIA patients.

An increased erythrocyte aggregation (EA) is associated with capillary slow flow, tissue hypoxemia and endothelial dysfunction. Fibrinogen is a major determinant in the formation of aggregated red blood cells. It has been suggested that the B beta-fibrinogen -455 G/A polymorphism is associated with erythrocyte hyperaggregability in men with coronary artery disease. The purpose of this study was to investigate the influence of the beta-fibrinogen -455 G/A polymorphism on erythrocyte aggregation in apparently healthy individuals. Plasma fibrinogen, red blood cell count, serum lipids, erythrocyte sedimentation rate, and the genotype of the B beta-fibrinogen -455 G/A polymorphism were examined in a cohort of 545 apparently healthy individuals and those with atherothrombotic risk factors. A whole blood erythrocyte aggregation test was performed by using a simple slide test and image analysis. In men, EA levels and plasma fibrinogen levels were significantly higher in subjects carrying the -455 A allele compared to subjects with the -455 GG genotype. This association did not exist in women carrying the fibrinogen -455 A allele. The -455 GA/AA men presented significantly higher correlation between the plasma fibrinogen concentrations and EA. This observation raises the prospect of possible change in the functional properties of the -455 GA/AA fibrinogen, enhancing its ability to induce EH. This study suggests that the B beta-fibrinogen -455 A allele is related to EH in men only. Putative mechanism could be hyperfibrinogenemia and a functional change in the fibrinogen molecule that alters its ability to interact with red blood cells and supports the aggregability of these cells.

Background: It is uncertain whether deterioration after acute ischemic stroke is neurological and/or systemic (somatic) in origin., Methods: 442 consecutive patients admitted with first-ever ischemic stroke (FIS) were assessed by the Unified Neurological Stroke Scale (UNSS) at admission, on hospitalization days 1, 2 and 3 and before discharge., Results: Among 71/442 (16.1%) patients deteriorated during hospitalization, the worsening from stroke onset was early (

Background and Purpose: The alanine/valine (A/V) polymorphism at codon 677 of the 5,10 methylenetetrahydrofolate reductase (MTHFR) gene correlates with elevated levels of plasma homocysteine and with an increased risk of atherosclerotic cardiovascular disease. Our study was designed to assess the frequency of the A and V alleles in patients with asymptomatic severe carotid artery stenosis (CAS) assessed by extracranial duplex examination in comparison with age- and sex-matched subjects without carotid atherosclerosis., Methods: Consecutive patients (n=48; 28 men, mean+/-SD age 67.1+/-11. 4 years) with asymptomatic severe (>75%) CAS were compared with subjects without CAS (n=26; 15 men, aged 61.2+/-11.5). The MTHFR genotype was analyzed by polymerase chain reaction followed by HinfI digestion. The chi(2) analysis and t test were used to compare the groups., Results: The frequency of V alleles was significantly higher in the CAS group (0.47) compared with control subjects (0.27, chi(2) test; OR 2.4 [95% CI 1.1 to 5.3]; P<0.02)., Conclusions: Our results indicate that the MTHFR A677V allele is significantly associated with severe CAS.

Background and Purpose: Identification of the subgroup of asymptomatic patients with severe internal carotid artery stenosis and high risk of stroke has important clinical implications. Cerebral vasomotor reactivity provides information regarding intracranial hemodynamic features and might have a prognostic value in predicting cerebrovascular ischemic events, especially in patients with carotid stenosis. The aim of our study was to assess the cerebral vasomotor reactivity in asymptomatic patients with carotid stenosis and evaluate its role in stroke occurrence., Methods: Cerebral vasomotor reactivity was assessed using transcranial Doppler ultrasonology and the Diamox test (intravenous administration of 1.0 g acetazolamide) in 44 asymptomatic patients with severe (> 70%) internal carotid artery stenosis. Patients were followed up prospectively (mean, 2 years)., Results: Cerebral vasomotor reactivity was estimated as good (> 40% increase of blood flow velocity in the middle cerebral artery ipsilateral to the carotid stenosis after undergoing the Diamox test) in 23 patients; it was impaired in the other 21. During the follow-up period, the overall annual rate for ipsilateral stokes was 2.3%; it was 7.9% for all ischemic cerebral events. No strokes or transient ischemic attacks occurred in the former group, but there were 7 cerebral ischemic events (2 strokes [1 fatal] and 5 transient ischemic attacks) in the latter group. There was a statistically significant correlation between cerebral ischemic events and impaired cerebral vasomotor reactivity (P = .009)., Conclusions: The data of this preliminary study suggest an important role of impaired cerebral vasomotor reactivity in predicting ischemic cerebral events. Preventive vascular surgery might be considered in this high-risk subgroup of asymptomatic patients with severe carotid stenosis.

Background and Purpose: Prior studies have demonstrated that infections might precipitate ischemic strokes (IS), but the role of infection as a risk factor remains unclear. We conducted a case-control study to investigate this issue., Methods: Consecutive patients (n = 182) with acute IS were examined within 48 hours after admission to our center. A history of acute infections within 2 months before the IS was assessed by means of a specially designed questionnaire that was also given to a control group consisting of 194 consecutive patients who were seen in our outpatient clinic and had suffered IS at least 6 months previously., Results: The prevalence of acute infection in the study group was significantly higher (44/182 = 24.2%) than in the control group (19/194 = 9.7%; odds ratio, 2.93; 95% confidence interval, 1.64 to 5.26; P = .0002) and infection occurred mostly within 1 week before the IS (41/44). Neither the severity of the IS nor the type of the infection was significantly different in patients and control subjects., Conclusions: Acute infections of different types constitute a risk factor for IS, particularly within 1 week of the event. However, the severity of the stroke is not related to this factor.

A treatment modality of a new original design was used in 87 survivors of ischemic stroke. Apart from the standard remedies, the authors administered drugs affecting the syndrome of disseminated intravascular coagulation, such as dipyridamole, glutamic acid and phytin, with heparin and freshly frozen plasma containing antithrombin III employed in grave cases. Hemostatic parameters in the study patients were observed to normalize more rapidly compared with the control group.