Abstract
Objective
Evaluate neurocognitive change after single low-dose targeted intra-arterial (IA) bevacizumab in patients with brain radiation necrosis.
Methods
Phase II, single-arm, prospective ...trial. 10 adults underwent targeted 2.5 mg/kg IA bevacizumab. Neurocognitive indices (Neuropsychological Assessment Battery® and Wechsler Test of Adult Reading) were measured at baseline and 12-months to document performance in 5 domains: Attention, Language, Learning and Memory, Visuospatial, and Executive Function. Clinical indices also quantified. Data (mean ± SD, 95% confidence interval CI, Cohen’s d) were analyzed using paired t tests. Null hypothesis rejected for p < 0.05.
Results
At baseline, Numbers-&-Letters Speed T-score (38.2 ± 10.7) indicated decreased processing speed consistent with sub-cortical pattern of illness. All other baseline neurocognitive indices were within normalized means (image). 12-months post-treatment, Numbers-&-Letters Errors T-score increased by 6.0 ± 4.9 95%CI 1.9,10.1 (t = 3.464, d = 1.225, p = 0.010). List-Learning List-Long-Delayed-Recall T-score increased by 9.0 ± 5.6 95% CI 4.3,13.7 (t = 4.520, d = 1.598, p = 0.003) and Design-Construction T-score increased by 3.5 ± 4.1 95%CI 0.04,7.0 (t = 2.391, d = 0.845, p = 0.048). Volume of radiation necrosis decreased by 74.4 ± 14.7% (t = −3.308, d = 1.169, p = 0.013). Headache decreased by 84.4 ± 18.2% (t = −3.495, d = 1.236, p = 0.010). 0/10 died or exhibited AEs attributed to bevacizumab. 2/10 patients experienced radiation necrosis recurrence at months 10 and 11, respectively.
Conclusions
Single low-dose intra-arterial targeted bevacizumab led to durable neuropsychological performance increase in memory retrieval and visuospatial ability consistent with improvement in sub-cortical function. To our knowledge this is the first prospective report of this novel approach in adults. Clinical improvements mirrored neuropsychologic improvements. Randomized trials are needed comparing targeted low-dose IA bevacizumab to multi-cycle IV bevacizumab at higher doses to determine which is best alternative in brain radiation necrosis.
In this study, we propose a fast, simple method to biofunctionalise microfluidic systems for cellomic investigations based on micro‐fluidic protocols. Many available processes either require ...expensive and time‐consuming protocols or are incompatible with the fabrication of microfluidic systems. Our method differs from the existing since it is applicable to an assembled system, uses few microlitres of reagents and it is based on the use of microbeads. The microbeads have specific surface moieties to link the biomolecules and couple cell receptors. Furthermore, the microbeads serve as arm spacer and offer the benefit of the multi‐valent interaction. Microfluidics was adapted together with topology and biochemistry surface modifications to offer the microenvironment for cellomic studies. Based on this principle, we exploit the streptavidin–biotin interaction to couple antibodies to the biofunctionalised microfluidic environment within 5 h using 200 μL of reagents and biomolecules. We selected the antibodies able to form complexes with the MHC class I (MHC‐I) molecules present on the cell membrane and involved in the immune surveillance. To test the microfluidic system, tumour cell lines (RMA) were rolled across the coupled antibodies to recognise and strip MHC‐I molecules. As result, we show that cell rolling performed inside a microfluidic chamber functionalised with beads and the opportune antibody facilitate the removal of MHC class I molecules. We showed that the level of median fluorescent intensity of the MHC‐I molecules is 300 for cells treated in a not biofunctionalised surface. It decreased to 275 for cells treated in a flat biofunctionalised surface and to 250 for cells treated on a surface where biofunctionalised microbeads were immobilised. The cells with reduced expression of MHC‐I molecules showed, after cytotoxicity tests, susceptibility 3.5 times higher than normal cells.
Background
The prognostic value of the change in heart rate from the supine to upright position (∆HR) in patients with chronic heart failure (HF) is unknown.
Methods and Results
∆HR was measured in ...patients enrolled in the Trial of Intensified Medical Therapy in Elderly Patients with Congestive Heart Failure (TIME‐CHF) who were in sinus rhythm and had no pacemaker throughout the trial (n=321). The impact of ∆HR on 18‐month outcome (HF hospitalization‐free survival) was assessed. In addition, the prognostic effect of changes in ∆HR between baseline and month 6 on outcomes in the following 12 months was determined. A lower ∆HR was associated with a higher risk of death or HF hospitalization (hazard ratio 1.79 95% confidence interval {95% CI} 1.19‐2.75 if ∆HR ≤3 beats/min bpm, P=0.004). In the multivariate analysis, lower ∆HR remained an independent predictor of death or HF hospitalization (hazard ratio 1.75 95% CI, 1.18‐2.61 if ∆HR ≤3 bpm, P=0.004) along with ischemic HF etiology, lower estimated glomerular filtration rate, presence and extent of rales, and no baseline β‐blocker use. In patients without event during the first 6 months, the change in ∆HR from baseline to month 6 predicted death or HF hospitalization during the following 12 months (hazard ratio=2.13 95% CI 1.12–5.00 if rise in ∆HR <2 bpm; P=0.027).
Conclusions
∆HR as a simple bedside test is an independent prognostic predictor in patients with chronic HF. ∆HR is modifiable, and changes in ∆HR also provide prognostic information, which raises the possibility that ∆HR may help to guide treatment.
Clinical Trial Registration Information
URL: www.isrctn.org. Unique identifier: ISRCTN43596477.
Aims
Heart failure (HF) represents a clinical syndrome resulting from different aetiologies and degrees of heart diseases. Among these, a key role is played by primary heart muscle disease ...(cardiomyopathies), which are the combination of multifactorial environmental insults in the presence or absence of a known genetic predisposition. The aim of the Maastricht Cardiomyopathy registry (mCMP‐registry; NCT04976348) is to improve (early) diagnosis, risk stratification, and management of cardiomyopathy phenotypes beyond the limits of left ventricular ejection fraction (LVEF).
Methods and results
The mCMP‐registry is an investigator‐initiated prospective registry including patient characteristics, diagnostic measurements performed as part of routine clinical care, treatment information, sequential biobanking, quality of life and economic impact assessment, and regular follow‐up. All subjects aged ≥16 years referred to the cardiology department of the Maastricht University Medical Center (MUMC+) for HF‐like symptoms or cardiac screening for cardiomyopathies are eligible for inclusion, irrespective of phenotype or underlying causes. Informed consented subjects will be followed up for 15 years. Two central approaches will be used to answer the research questions related to the aims of this registry: (i) a data‐driven approach to predict clinical outcome and response to therapy and to identify clusters of patients who share underlying pathophysiological processes; and (ii) a hypothesis‐driven approach in which clinical parameters are tested for their (incremental) diagnostic, prognostic, or therapeutic value. The study allows other centres to easily join this initiative, which will further boost research within this field.
Conclusions
The broad inclusion criteria, systematic routine clinical care data‐collection, extensive study‐related data‐collection, sequential biobanking, and multi‐disciplinary approach gives the mCMP‐registry a unique opportunity to improve diagnosis, risk stratification, and management of HF and (early) cardiomyopathy phenotypes beyond the LVEF limits.
Heart failure (HF), a global pandemic affecting millions of individuals, calls for adequate predictive guidance for improved therapy. Congestion, a key factor in HF-related hospitalizations, further ...underscores the need for timely interventions. Proactive monitoring of intracardiac pressures, guided by pulmonary artery (PA) pressure, offers opportunities for efficient early-stage intervention, since haemodynamic congestion precedes clinical symptoms.
The BioMEMS study, a substudy of the MONITOR-HF trial, proposes a multifaceted approach integrating blood biobank data with traditional and novel HF parameters. Two additional blood samples from 340 active participants in the MONITOR-HF trial were collected at baseline, 3-, 6-, and 12-month visits and stored for the BioMEMS biobank. The main aims are to identify the relationship between temporal biomarker patterns and PA pressures derived from the CardioMEMS-HF system, and to identify the biomarker profile(s) associated with the risk of HF events and cardiovascular death.
Since the prognostic value of single baseline measurements of biomarkers like N-terminal pro-B-type natriuretic peptide is limited, with the BioMEMS study we advocate a dynamic, serial approach to better capture HF progression. We will substantiate this by relating repeated biomarker measurements to PA pressures. This design rationale presents a comprehensive review on cardiac biomarkers in HF, and aims to contribute valuable insights into personalized HF therapy and patient risk assessment, advancing our ability to address the evolving nature of HF effectively.
The identification of miRNA targets by Ago2 crosslinking-immunoprecipitation (CLIP) methods has provided major insights into the biology of this important class of non-coding RNAs. However, these ...methods are technically challenging and not easily applicable to an
in vivo
setting.
To overcome these limitations and facilitate the investigation of miRNA functions
in vivo
, we have developed a method based on a genetically engineered mouse harboring a conditional Halo-Ago2 allele expressed from the endogenous Ago2 locus. By using a resin conjugated to the HaloTag ligand, Ago2-miRNA-mRNA complexes can be purified from cells and tissues expressing the endogenous Halo-Ago2 allele. We demonstrate the reproducibility and sensitivity of this method in mouse embryonic stem cells, developing embryos, adult tissues, and autochthonous mouse models of human brain and lung cancers.
This method and the datasets we have generated will facilitate the characterization of miRNA-mRNA networks
in vivo
under physiological and pathological conditions.
Li, Pritykin, Concepcion et al. report the development of Halo-enhanced Ago2 pulldown (HEAP), a method that streamlines the experimental identification of Ago2-miRNA-mRNA interaction sites in murine cells and tissues.
The use of aspirin for the prevention of thrombotic complications in polycythemia vera is controversial.
We enrolled 518 patients with polycythemia vera, no clear indication for aspirin treatment, ...and no contraindication to such treatment in a double-blind, placebo-controlled, randomized trial to assess the safety and efficacy of prophylaxis with low-dose aspirin (100 mg daily). The two primary end points were the cumulative rate of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes and the cumulative rate of nonfatal myocardial infarction, nonfatal stroke, pulmonary embolism, major venous thrombosis, or death from cardiovascular causes. The mean duration of follow-up was about three years.
Treatment with aspirin, as compared with placebo, reduced the risk of the combined end point of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes (relative risk, 0.41; 95 percent confidence interval, 0.15 to 1.15; P=0.09) and the risk of the combined end point of nonfatal myocardial infarction, nonfatal stroke, pulmonary embolism, major venous thrombosis, or death from cardiovascular causes (relative risk, 0.40; 95 percent confidence interval, 0.18 to 0.91; P=0.03). Overall mortality and cardiovascular mortality were not reduced significantly. The incidence of major bleeding episodes was not significantly increased in the aspirin group (relative risk, 1.62; 95 percent confidence interval, 0.27 to 9.71).
Low-dose aspirin can safely prevent thrombotic complications in patients with polycythemia vera who have no contraindications to such treatment.
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