scholarly journals New Mechanistic Insights, Novel Treatment Paradigms, and Clinical Progress in Cerebrovascular Diseases

2021 ◽  
Vol 13 ◽  
Author(s):  
Johannes Boltze ◽  
Jaroslaw A. Aronowski ◽  
Jerome Badaut ◽  
Marion S. Buckwalter ◽  
Mateo Caleo ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Targeted Delivery ◽  
Basic Science ◽  
Science Studies ◽  
Treatment Options ◽  
Experimental Studies ◽  
Treatment Strategies ◽  
Cerebrovascular Diseases ◽  
Stroke Recovery ◽  
Novel Treatment

The past decade has brought tremendous progress in diagnostic and therapeutic options for cerebrovascular diseases as exemplified by the advent of thrombectomy in ischemic stroke, benefitting a steeply increasing number of stroke patients and potentially paving the way for a renaissance of neuroprotectants. Progress in basic science has been equally impressive. Based on a deeper understanding of pathomechanisms underlying cerebrovascular diseases, new therapeutic targets have been identified and novel treatment strategies such as pre- and post-conditioning methods were developed. Moreover, translationally relevant aspects are increasingly recognized in basic science studies, which is believed to increase their predictive value and the relevance of obtained findings for clinical application.This review reports key results from some of the most remarkable and encouraging achievements in neurovascular research that have been reported at the 10th International Symposium on Neuroprotection and Neurorepair. Basic science topics discussed herein focus on aspects such as neuroinflammation, extracellular vesicles, and the role of sex and age on stroke recovery. Translational reports highlighted endovascular techniques and targeted delivery methods, neurorehabilitation, advanced functional testing approaches for experimental studies, pre-and post-conditioning approaches as well as novel imaging and treatment strategies. Beyond ischemic stroke, particular emphasis was given on activities in the fields of traumatic brain injury and cerebral hemorrhage in which promising preclinical and clinical results have been reported. Although the number of neutral outcomes in clinical trials is still remarkably high when targeting cerebrovascular diseases, we begin to evidence stepwise but continuous progress towards novel treatment options. Advances in preclinical and translational research as reported herein are believed to have formed a solid foundation for this progress.

scholarly journals A Novel Model for Encephalomyosynangiosis Surgery after Middle Cerebral Artery Occlusion-Induced Stroke in Mice

2021 ◽  
Author(s):  
Mitch Paro ◽  
Daylin Gamiotea Turro ◽  
Leslie Blumenfeld ◽  
Ketan R Bulsara ◽  
Rajkumar Verma
Keyword(s):  
Ischemic Stroke ◽  
Middle Cerebral Artery ◽  
Middle Cerebral Artery Occlusion ◽  
Cerebral Artery ◽  
Therapeutic Option ◽  
Treatment Options ◽  
Artery Occlusion ◽  
Novel Treatment ◽  
Graft Tissue ◽  
Cerebral Artery Occlusion

Background and Purpose: No effective treatment is available for most patients who suffer ischemic stroke. Development of novel treatment options is imperative. The brain attempts to self-heal after ischemic stroke via various mechanism mediated by restored blood circulation in affected region of brain but this process is limited by inadequate angiogenesis or neoangiogenesis. Encephalomyosynangiosis (EMS) is a neurosurgical procedure that achieves angiogenesis with low morbidity in patients with moyamoya disease, reducing risk of stroke. However, EMS, surgery has never been studied as an therapeutic option after ischemic stroke. Here we described a novel procedure and feasibility data for EMS after ischemic stroke in mice. Methods: A 60 mins of middle cerebral artery occlusion (MCAo) was used to induce ischemic stroke in mice. After 3-4 hours of MCAo onset/sham, EMS was performed. Mortality of EMS, MCAo and. MCAo+EMS mice was recorded up to 21 days after surgery. Graft tissue viability was measured using a nicotinamide adenine dinucleotide reduced tetrazolium reductase assay. Results: EMS surgery after ischemic stroke does not increase mortality compared to stroke alone. Graft muscle tissue remained viable 21 days after surgery. Conclusions: This novel protocol is effective and well-tolerated, may serve as novel platform for new angiogenesis and thus recovery after ischemic stroke. If successful in mice, EMS can a very feasible and novel treatment option for ischemic stroke in humans.

scholarly journals HIV Associated Risk Factors for Ischemic Stroke and Future Perspectives

2020 ◽  
Vol 21 (15) ◽  
pp. 5306
Author(s):  
Saifudeen Ismael ◽  
Mohammad Moshahid Khan ◽  
Prashant Kumar ◽  
Sunitha Kodidela ◽  
Golnoush Mirzahosseini ◽  
...  
Keyword(s):  
Risk Factors ◽  
Ischemic Stroke ◽  
Hiv Infection ◽  
Opportunistic Infections ◽  
Experimental Studies ◽  
Chronic Administration ◽  
Cerebrovascular Diseases ◽  
Vascular Abnormalities ◽  
Increased Risk ◽  
The Impact

Although retroviral therapy (ART) has changed the HIV infection from a fatal event to a chronic disease, treated HIV patients demonstrate high prevalence of HIV associated comorbidities including cardio/cerebrovascular diseases. The incidence of stroke in HIV infected subjects is three times higher than that of uninfected controls. Several clinical and postmortem studies have documented the higher incidence of ischemic stroke in HIV infected patients. The etiology of stroke in HIV infected patients remains unknown; however, several factors such as coagulopathies, opportunistic infections, vascular abnormalities, atherosclerosis and diabetes can contribute to the pathogenesis of stroke. In addition, chronic administration of ART contributes to the increased risk of stroke in HIV infected patients. Concurrently, experimental studies in murine model of ischemic stroke demonstrated that HIV infection worsens stroke outcome, increases blood brain barrier permeability and increases neuroinflammation. Additionally, residual HIV viral proteins, such as Trans-Activator of Transcription, glycoprotein 120 and Negative regulatory factor, contribute to the pathogenesis. This review presents comprehensive information detailing the risk factors contributing to ischemic stroke in HIV infected patients. It also outlines experimental evidence demonstrating the impact of HIV infection on stroke outcomes, in addition to possible novel therapeutic approaches to improve these outcomes.

scholarly journals Treatment Strategies for Tandem Occlusions in Acute Ischemic Stroke

2020 ◽  
Vol 37 (02) ◽  
pp. 207-213
Author(s):  
Joseph J. Gemmete ◽  
Zachary Wilseck ◽  
Aditya S. Pandey ◽  
Neeraj Chaudhary
Keyword(s):  
Ischemic Stroke ◽  
Acute Ischemic Stroke ◽  
Mechanical Thrombectomy ◽  
Treatment Options ◽  
Treatment Strategies ◽  
Carotid Revascularization ◽  
Tandem Occlusion ◽  
Coil Occlusion ◽  
Optimal Treatment Strategy

AbstractThere is no consensus for the treatment of a tandem occlusion (TO) in a patient presenting with an acute ischemic stroke. In this review article, we will focus on the controversial treatment strategies for TOs. First, we will discuss treatment options including retrograde, antegrade, and delayed approaches. Second, the role of carotid stent placement versus balloon angioplasty for the extracranial occlusion will be presented. Third, anticoagulation and antiplatelet regimens for the treatment TOs published in the literature will be reviewed. Finally, we will discuss whether there is a role for coil occlusion of the cervical carotid artery or whether staged carotid revascularization days after mechanical thrombectomy of the intracranial occlusion maybe appropriate. The optimal treatment strategy of TO has not been established and further larger trials need to be performed to answer the question.

scholarly journals Caveolae-Mediated Endothelial Transcytosis across the Blood-Brain Barrier in Acute Ischemic Stroke

2021 ◽  
Vol 10 (17) ◽  
pp. 3795
Author(s):  
Min Zhou ◽  
Samuel X. Shi ◽  
Ning Liu ◽  
Yinghua Jiang ◽  
Mardeen S. Karim ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Blood Brain Barrier ◽  
Molecular Mechanisms ◽  
Treatment Options ◽  
Treatment Strategies ◽  
Hemorrhagic Transformation ◽  
Brain Barrier ◽  
Blood Brain ◽  
Entry Points

Blood-brain barrier (BBB) disruption following ischemic stroke (IS) contributes to hemorrhagic transformation, brain edema, increased neural dysfunction, secondary injury, and mortality. Brain endothelial cells form a para and transcellular barrier to most blood-borne solutes via tight junctions (TJs) and rare transcytotic vesicles. The prevailing view attributes the destruction of TJs to the resulting BBB damage following IS. Recent studies define a stepwise impairment of the transcellular barrier followed by the paracellular barrier which accounts for the BBB leakage in IS. The increased endothelial transcytosis that has been proven to be caveolae-mediated, precedes and is independent of TJs disintegration. Thus, our understanding of post stroke BBB deficits needs to be revised. These recent findings could provide a conceptual basis for the development of alternative treatment strategies. Presently, our concept of how BBB endothelial transcytosis develops is incomplete, and treatment options remain limited. This review summarizes the cellular structure and biological classification of endothelial transcytosis at the BBB and reviews related molecular mechanisms. Meanwhile, relevant transcytosis-targeted therapeutic strategies for IS and research entry points are prospected.

DDRE-21. LOMUSTINE AND TARGETED-CYTOKINE THERAPY: A BENEFICIAL LIAISON FOR RECURRENT GLIOBLASTOMA

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi78-vi79
Author(s):  
Tobias Weiss ◽  
Thomas Look ◽  
Emanuele Puca ◽  
Roberto De Luca ◽  
Teresa Hemmerle ◽  
...  
Keyword(s):  
Immune Cells ◽  
Targeted Delivery ◽  
Ex Vivo ◽  
Treatment Options ◽  
Treatment Strategies ◽  
Tumor Stroma ◽  
Recurrent Glioblastoma ◽  
Strong Increase ◽  
Anti Tumor Activity ◽  
Ongoing Phase

Abstract Treatment options for recurrent glioblastoma are limited and except from regorafenib (potentially), no other agent has demonstrated superior activity to lomustine. Therefore, there is an urgent need for more effective treatment strategies for recurrent glioblastoma. We investigated the combination of lomustine or bevacizumab that are frequently used for recurrent glioblastoma with L19TNF (onfekafusp alfa), a systemically administered tumor-stroma targeting antibody-cytokine fusion protein that enables a targeted delivery of tumor-necrosis factor (TNF)a to the tumor. In immunocompetent orthotopic glioma mouse models, the combination of lomustine and L19TNF demonstrated the strongest anti-tumor activity, acted in synergy and cured a majority of tumor-bearing mice, whereas lomustine or L19TNF monotherapy only had only very limited anti-tumor activity. Ex vivo profiling of the tumors and tumor-infiltrating immune cells from immunocompetent or immunodeficient hosts demonstrated immune-dependent cytotoxic and cytostatic effects on the glioma cells, and a strong increase of tumor-infiltrating immune cells upon combination therapy in immunocompetent models. Based on these encouraging results, we translate this combinatorial therapy to patients with recurrent glioblastoma. For the first patients, the treatment with lomustine and L19TNF was well tolerated and led to stable disease with a reduction in tumor perfusion. More patients are recruited in an ongoing phase I/II clinical trial with lomustine and L19TNF for patients with recurrent glioblastoma (NCT04573192).

Metabolic Syndrome is a Risk Factor for Post-Operative Adhesions: Need for Novel Treatment Strategies

2018 ◽  
Vol 51 (01) ◽  
pp. 35-41 ◽  
Author(s):  
Yair Pilpel ◽  
Guy Pines ◽  
Andreas Birkenfeld ◽  
Stefan Bornstein ◽  
Rafael Miller
Keyword(s):  
Metabolic Syndrome ◽  
Treatment Options ◽  
Treatment Strategies ◽  
Therapeutic Strategies ◽  
Postoperative Adhesions ◽  
Invasive Procedures ◽  
Novel Treatment ◽  
Number Of Patients ◽  
Wide Range ◽  
Novel Treatment Strategies

AbstractMetabolic syndrome is a group of disorders which include obesity, diabetes, dyslipidemias, and hypertension. This condition is rapidly increasing in an aging population. The rates of surgery in older patients is also growing and a wide range of operations including minimally invasive procedures is now available for this segment of the population. The number of patients suffering from postoperative adhesions is therefore correspondingly increasing. In addition to preventing and treating the metabolic disease itself, improved therapeutic strategies for the prevention of surgical adhesions have to be developed. Here we review the existing and novel treatment options.

scholarly journals Lumbar Degenerative Disc Disease: Current and Future Concepts of Diagnosis and Management

2012 ◽  
Vol 2012 ◽  
pp. 1-7 ◽  
Author(s):  
Fadi Taher ◽  
David Essig ◽  
Darren R. Lebl ◽  
Alexander P. Hughes ◽  
Andrew A. Sama ◽  
...  
Keyword(s):  
Disc Degeneration ◽  
Degenerative Disc Disease ◽  
Lumbar Disc ◽  
Symptomatic Relief ◽  
Treatment Options ◽  
Treatment Strategies ◽  
Lumbar Disc Degeneration ◽  
Disc Disease ◽  
Degenerative Disc ◽  
Novel Treatment

Low back pain as a result of degenerative disc disease imparts a large socioeconomic impact on the health care system. Traditional concepts for treatment of lumbar disc degeneration have aimed at symptomatic relief by limiting motion in the lumbar spine, but novel treatment strategies involving stem cells, growth factors, and gene therapy have the theoretical potential to prevent, slow, or even reverse disc degeneration. Understanding the pathophysiological basis of disc degeneration is essential for the development of treatment strategies that target the underlying mechanisms of disc degeneration rather than the downstream symptom of pain. Such strategies ideally aim to induce disc regeneration or to replace the degenerated disc. However, at present, treatment options for degenerative disc disease remain suboptimal, and development and outcomes of novel treatment options currently have to be considered unpredictable.

scholarly journals Making the Leap: from Experimental Psychopathology to Clinical Trials

2021 ◽  
Author(s):  
Simon Edward Blackwell ◽  
Marcella Lydia Woud
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Basic Science ◽  
Experimental Studies ◽  
Treatment Development ◽  
Experimental Psychopathology ◽  
Clinical Trial Research ◽  
Novel Treatment ◽  
Trials Methodology ◽  
Translational Process

One important aim of experimental psychopathology research is to inform development of new interventions derived from basic science. However, testing whether a newly developed intervention is in fact effective requires moving from experimental studies to clinical trials, and this transition can pose many problems. These problems stem not only from the inherent complexity of even the simplest clinical trial, but also from differences between experimental psychopathology and clinical trial research that may not always be obvious to researchers immersed in only one of these specialist areas. In this paper we explore some of these complexities, and discuss when a clinical trial may, or may not be, the best next step in the translational process. We then consider some of the ins and outs of clinical trials methodology, from design and planning through to reporting, with the aim of providing a guide for experimental psychopathology researchers thinking of making the leap from their experimental studies of mechanisms to clinical trials of novel interventions. We hope that this can help increase the chance of successful clinical translation and novel treatment development from basic science.

Targeting glioblastoma with novel immunocytokines.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 2558-2558
Author(s):  
Patrick Roth ◽  
Tobias Weiss ◽  
Emanuele Puca ◽  
Manuela Silginer ◽  
Teresa Hemmerle ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Fusion Protein ◽  
Inflammatory Cytokines ◽  
Targeted Delivery ◽  
Treatment Options ◽  
Blood Perfusion ◽  
Recurrent Glioblastoma ◽  
Who Grade ◽  
Novel Treatment ◽  
Pro Inflammatory Cytokines

2558 Background: There is an urgent need for novel treatment options for patients with glioblastoma, the most frequent malignant primary brain tumor. In contrast to other types of cancer, immunotherapeutic approaches have so far not been successful against glioblastoma. Converting the glioma microenvironment from a "cold" and immunosuppressive status into a more "hot" and immunopermissive phenotype may allow for clinically meaningful anti-tumor immune responses. Methods: We explored the activity of novel immunocytokines based on the L19 antibody, specific to a tumor-associated epitope of extracellular fibronectin, for the targeted delivery of three pro-inflammatory cytokines (IL-2, IL-12, TNF) to the microenvironment of gliomas. Following an extensive preclinical assessment in 2 orthotopic immunocompetent mouse glioma models, we used a fully-human L19-hTNF fusion protein to treat human patients with recurrent glioblastoma. Results: Intravenous administration of L19-mIL12 or L19-mTNF prolonged survival and cured a proportion of tumor-bearing mice while no effect was seen with L19-IL2. When L19-mIL12 or L19-mTNF were administered to glioma-bearing RAG−/− mice, no therapeutic activity was observed which suggests adaptive immunity as an underlying mechanism. On a mechanistic level, both immunocytokines induced the infiltration of the tumor site with lymphocytes and promoted the expression of pro-inflammatory cytokines in the tumor microenvironment. In addition, L19-mTNF induced tumor necrosis. Based on these preclinical findings, we initiated a phase I/II clinical trial with a fully-human L19-hTNF fusion protein for patients with isocitrate dehydrogenase (IDH1R132H) wildtype WHO Grade III or IV glioma at first relapse (NCT03779230). Treatment was safe and well tolerated in the first three glioblastoma patients. Administration of L19-hTNF resulted in reduced regional blood perfusion in the tumor region and was associated with more necrotic areas within the tumor as well as an increased number of tumor-infiltrating CD4 and CD8 T cells. Conclusions: The data obtained with the comprehensive preclinical characterization and subsequent clinical translation form the basis for future studies with immunocytokines as novel treatment option for patients with malignant brain tumors. Clinical trial information: NCT03779230 .

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