Anti-angiogenesis in cancer therapeutics: the magic bullet

Background: Angiogenesis is the formation of new vascular networks from preexisting ones through the migration and proliferation of differentiated endothelial cells. Available evidence suggests that while antiangiogenic therapy could inhibit tumour growth, the response to these agents is not sustained. The aim of this paper was to review the evidence for anti-angiogenic therapy in cancer therapeutics and the mechanisms and management of tumour resistance to antiangiogenic agents. We also explored the latest advances and challenges in this field. Main body of the abstract: MEDLINE and EMBASE databases were searched for publications on antiangiogenic therapy in cancer therapeutics from 1990 to 2020. Vascular endothelial growth factor (VEGF) is the master effector of the angiogenic response in cancers. Anti-angiogenic agents targeting the VEGF and HIF-α pathways include monoclonal antibodies to VEGF (e.g. bevacizumab), small-molecule tyrosine kinase inhibitors (TKIs) e.g. sorafenib, decoy receptor or VEGF trap e.g. aflibercept and VEGFR2 inhibitors (e.g. ramucirumab). These classes of drugs are vascular targeting which in many ways are advantageous over tumour cell targeting drugs. Their use leads to a reduction in the tumour blood supply and growth of the tumour blood vessels. Tumour resistance and cardiovascular toxicity are important challenges which limit the efficacy and long-term use of anti-angiogenic agents in cancer therapeutics. Tumour resistance can be overcome by dual anti-angiogenic therapy or combination with conventional chemotherapy and immunotherapy. Emerging nanoparticle-based therapy which can silence the expression of HIF-α gene expression by antisense oligonucleotides or miRNAs has been developed. Effective delivery platforms are required for such therapy. Short conclusion: Clinical surveillance is important for the early detection of tumour resistance and treatment failure using reliable biomarkers. It is hoped that the recent interest in mesenchymal cell-based and exosome-based nanoparticle delivery platforms will improve the cellular delivery of newer anti-angiogenics in cancer therapeutics

Endovascular treatment for ischemic stroke patients with and without atrial fibrillation, and the effects of adjunctive pharmacotherapy:a narrative review

Introduction: Endovascular thrombectomy (EVT) is associated with good clinical outcomes in patients with ischemic stroke, but the impact of EVT on clinical outcomes in patients with ischemic stroke with and without atrial fibrillation (AF), and the effect of adjunctive pharmacological therapies with EVT, remains unclear. Areas covered: The goal of this narrative review is to provide an overview of studies which have examined: 1) associations between EVT and outcomes for patients following ischemic stroke, 2) associations between EVT and outcomes for patients following ischemic stroke with and without AF, including function, reperfusion, hemorrhage, and mortality, 3) the effect of adjunctive pharmacological therapies peri- and post-thrombectomy, and 4) integration of prehospital care on endovascular treatment outcomes. Expert opinion: There is little evidence from randomized controlled trials on the effect of AF on stroke outcomes following EVT and the safety and efficacy of AF treatment in the peri-EVT such as tirofiban or Intravenous thrombolysis with Non-vitamin K Antagonist Oral Anticoagulant. The available evidence from observational studies on AF and EVT outcomes is inconsistent, but factors such as procedural EVT devices, the center volume, clinician experience, stroke recognition, and inclusion criteria of studies have all been associated with poorer clinical outcomes. Enhancing the clinical network among prehospital and hospitals will facilitate direct transfer to EVT centers, reducing stroke onset to EVT time and optimizing stroke outcomes.</p

The Liverpool Heart And bRain Project (L-HARP): Protocol for an Observational Cohort Study of Cardiovascular Risk and Outcomes Following Stroke.

Further research is needed to refine risk prediction models for adverse cardiovascular outcomes following stroke in contemporary clinical practice, such as incident atrial fibrillation (AF), recurrent stroke, and cognitive impairment and dementia. The aims of this study are to prospectively investigate cardiovascular outcomes and risk factors for incident cardiovascular disease in a post-stroke cohort, and to externally validate, refine and expand current risk prediction models for cardiovascular and cardiovascular-related outcomes. The study sample size was based on the development of post-stroke risk prediction models for AF and was calculated as 1222 participants. The study design is a multicentre, prospective, observational cohort study. Participants will be adult patients admitted for ischaemic stroke confirmed by stroke physician or transient ischaemic attack (TIA) confirmed by MRI. Routinely collected data will be used in addition to the completion of simple validated questionnaires by the participants. Follow-up will be undertaken 12-months from the date of admission to hospital, in addition to linkage to routinely collected follow-up hospitalisation and mortality data. The primary outcomes are cardiovascular outcomes (including incident AF, stroke, TIA and myocardial infarction) at 12-month follow-up, all-cause mortality and mortality from cardiovascular causes, and incident cognitive impairment and dementia. Secondary outcomes include changes in function, depression, anxiety, fatigue and quality of life. The study has received approval from the Health Research Authority Research Ethics Committee (21/WA/0209), and is registered on https://www.clinicaltrials.gov/ (Identifier NCT05132465). Recruitment for the study began in October 2021 with completion of recruitment at all participating centres anticipated by October 2022

Imaging Protocol, Feasibility, and Reproducibility of Cardiovascular Phenotyping in a Large Tri-Ethnic Population-Based Study of Older People: The Southall and Brent Revisited (SABRE) Study

Background: People of South Asian and African Caribbean ethnicities living in UK have a high risk of cardiometabolic disease. Limited data exist regarding detailed cardiometabolic phenotyping in this population. Methods enabling this are widely available, but the practical aspects of undertaking such studies in large and diverse samples are seldom reported.Methods: The Southall and Brent Revisited (SABRE) study is the UK's largest tri-ethnic longitudinal cohort. Over 1,400 surviving participants (58–85 years) attended the 2nd study visit (2008–2011); during which, comprehensive cardiovascular phenotyping, including 3D-echocardiography [3D-speckle-tracking (3D-STE)], computed tomography, coronary artery calcium scoring, pulse wave velocity, central blood pressure, carotid artery ultrasound, and retinal imaging, were performed. We describe the methods used with the aim of providing a guide to their feasibility and reproducibility in a large tri-ethnic population-based study of older people.Results: Conventional echocardiography and all vascular measurements showed high feasibility (&gt;90% analyzable of clinic attendees), but 3D-echocardiography (3DE) and 3D-STE were less feasible (71% 3DE acquisition feasibility and 38% 3D-STE feasibility of clinic attendees). 3D-STE feasibility differed by ethnicity, being lowest in South Asian participants and highest in African Caribbean participants (p &lt; 0.0001). Similar trends were observed in men (P &lt; 0.0001) and women (P = 0.005); however, in South Asians, there were more women with unreadable 3D-images compared to men (67 vs. 58%). Intra- and inter-observer variabilities were excellent for most of conventional and advanced echocardiographic measures. The test-retest reproducibility was good-excellent and fair-good for conventional and advanced echocardiographic measures, respectively, but lower than when re-reading the same images. All vascular measures demonstrated excellent or fair-good reproducibility.Conclusions: We describe the feasibility and reproducibility of detailed cardiovascular phenotyping in an ethnically diverse population. The data collected will lead to a better understanding of why people of South Asian and African Caribbean ancestry are at elevated risk of cardiometabolic diseases

Outcomes in patients with ischaemic stroke undergoing endovascular thrombectomy:Impact of atrial fibrillation

ObjectivesEndovascular thrombectomy (EVT) is associated with good clinical outcomes in ischaemic stroke, but the risk of intracerebral haemorrhage (ICH) and mortality remains common following ischaemic stroke. The effect of concomitant atrial fibrillation (AF) on clinical outcomes following acute ischaemic stroke in patients receiving EVT remains unclear. The aim is to investigate associations between AF and intracerebral haemorrhage and all-cause mortality at 90 days in patients with ischaemic stroke undergoing EVT.Materials and methodsA retrospective cohort was conducted using TriNetX, a global health research network. The network was searched for people aged ≥18 years with ischaemic stroke, EVT and AF recorded in electronic medical records between 01/09/2018 and 01/09/2021. These patients were compared to controls with ischaemic stroke, EVT and no AF. Propensity score matching for age, sex, race, comorbidities, National Institutes of Health Stroke Scale (NIHSS) scores, and prior use of anticoagulation was used to balance the cohorts with and without AF.ResultsIn total 3,106 patients were identified with history of ischaemic stroke treated by EVT. After propensity-score matching, 832 patients (mean age 68 ± 13; 47% female) with ischaemic stroke, EVT and AF, were compared to 832 patients (mean age 67 ± 12; 47% female) with ischaemic stroke, EVT and no history of AF. In the cohort with AF, 11.5% (n = 96) experienced ICH within 90 days following EVT, compared with 12.3% (n = 103) in patients without AF (Odds Ratio (OR) 0.92, 95% confidence interval (CI) 0.68-1.24; p = 0.59). In the patients with AF, mortality within 90 days following EVT was 18.7% (n = 156), compared with 22.5% in patients without AF (n = 187) (OR 0.79, 95% CI 0.63-1.01; p = 0.06).ConclusionIn patients with ischaemic stroke undergoing EVT, AF was not significantly associated with intracerebral haemorrhage or all-cause mortality at 90-day follow-up

Left Atrial Appendage Occlusion Versus Direct Oral Anticoagulants in the Prevention of Ischaemic Stroke in Patients with Atrial Fibrillation

Introduction: Existing randomised controlled trials assessing the safety and efficacy of left atrial appendage occlusion (LAAO) in atrial fibrillation (AF) were of relatively small sample size or included patients who could receive oral anticoagulant treatment after device implantation. We compared the outcomes of patients with newly diagnosed AF who received percutaneous LAAO or direct oral anticoagulant (DOAC) treatment, in a large population from a global federated health network (TriNetX). Methods: Patients with AF treated with percutaneous LAAO were matched with those treated with DOAC between December 1, 2010, and October 1, 2018. Outcomes were all-cause mortality, ischaemic stroke, and intracranial haemorrhage (ICH) at 5 years. Results: We included 200 patients with AF, who received either LAAO or DOAC. The risk of all-cause mortality, ischaemic stroke, and ICH at 5 years was not significantly different between the two groups (risk ratio [RR] for all-cause mortality: 1.52, 95% confidence interval (CI): 0.97 2.38, RR for ischaemic stroke: 1.09, 95% CI: 0.51 2.36, and RR for ICH: 1.0, 95% CI: 0.44 2.30). Conclusion: Patients newly diagnosed with AF, eligible for DOAC, showed similar 5-year risk of death, ischaemic stroke, and ICH when comparing those who underwent percutaneous LAAO to those receiving DOAC. Future randomised controlled trials are needed to confirm the findings and advise changes in guidelines.</p

Paramedic Ability in Interpreting Electrocardiogram with ST-segment Elevation Myocardial Infarction (STEMI) in Saudi Arabia.

ObjectiveTo evaluate paramedic ability in recognizing 12-lead Electrocardiogram (ECG) with ST-segment Elevation myocardial infarction (STEMI) in Saudi Arabia.MethodsThis is a quantitative exploratory cross-sectional study using an electronic survey of paramedics was conducted between June and September 2021. The survey included demographics, educational and clinical experiences, and multiple 12-lead ECG strip questions to assess participants' ability to recognize STEMI. We reported the overall sensitivity, specificity, and correct proportions with 95% Confidence Intervals (CI).ResultsEighty-four paramedics completed the survey, and 65% of them were between 24 and 29 years old, with a median, of three years of field experience. Overall sensitivity and specificity were 58.39% (95% CI, 50.4% to 66.1%) and 29.01% (95% CI, 25.15% to 33.1%), respectively. In total, 67.1% correctly identified inferior STEMI, whereas only 50% correctly identified lateral STEMI. Both STEMIs were correctly identified by 41%, and the majority misinterpreted STEMI mimics (ECG rhythms with similar ECG morphology to STEMI). The proportion who correctly recognized left bundle branch block was 14.8%, pericarditis was 10.9%, and ventricular pacing was 1.4%. However, almost third of participants correctly identified right bundle branch block (32.9%) and left ventricle hypertrophy (30.7%). Overall, there was no correlation between the correct ECG interpretation of STEMIs and educational and clinical experiences.ConclusionParamedics were able to identify STEMI events in prehospital settings with moderate sensitivity and low specificity with limited ability to differentiate between STEMI and STEMI mimics. Therefore, additional training in ECG interpretation could improve their clinical decision-making, and to ensure that proper care and treatment is provided. Further research on a large, representative sample of paramedics across the country could provide more definitive evidence to establish a greater degree of accuracy in detecting STEMI in prehospital settings

Evaluation of Huawei Smart Wearables for Detection of Atrial Fibrillation in Patients Following Ischaemic Stroke:The Liverpool-Huawei Stroke Study

Atrial fibrillation (AF) often remains undetected following stroke. Documenting AF is critical to initiate oral anticoagulation, which has proven benefit in reducing recurrent stroke and mortality in patients with AF. The accuracy and acceptability of using smart wearables technology to detect AF in patients following stroke is unknown. The aims of the Liverpool-Huawei Stroke Study are to determine the effectiveness, cost-effectiveness and patient and staff acceptability of using Huawei smart wearables to detect AF following ischaemic stroke. The study plans to recruit 1000 adults aged ≥18 years following ischaemic stroke from participating hospitals over 12 months. All participants will be asked to wear a Huawei smart band for four weeks post-discharge. If participants do not have access to a compatible smartphone required for the study, they will be provided with a smartphone for the four-week AF monitoring period. Participants with suspected AF detected by the smart wearables, without previous known AF, will be referred for further evaluation. To determine the effectiveness of the Huawei smart wearables to detect AF, the positive predictive value will be determined. Patient acceptability of using this technology will also be examined. Additional follow-up assessments will be conducted at six and 12 months, and clinical outcomes recorded in relation to prevalent and incident AF post-stroke. The study opened for recruitment on 30/05/2022, and is currently open at four participating hospitals; the first 106 participants have been recruited. One further hospital is preparing to open for recruitment. This prospective study will examine the effectiveness and acceptability of the use of smart wearables in patients following ischaemic stroke. This could have important implications for detection of AF and therefore, earlier prophylaxis for recurrent stroke. The study is registered on https://www.isrctn.com/ (Identifier ISRCTN30693819)