Peripheral Disease Research Articles

Восстановительная медицина как фактор адаптации населения к последствиям пандемии COVID-19

Situational conditions caused by the need to form a new approach to the organization of restorative and rehabilitation medicine contribute to the development of two directions of this process related to entrepreneurial activity: the commissioning of modern centers consolidating high-tech diagnostic and therapeutic base; the revival of the traditions of sanatorium treatment in Russia and the concept of the functioning of the sanatorium complex as an effective system prevention, rehabilitation and recovery. The subject of the study is the strategy of restorative medicine as a new direction of disease prevention in the conditions of restorative processes of the business environment after the restrictions imposed due to the coronavirus pandemic. The purpose of the work is to consider trends in the development of entrepreneurial services in the health and wellness and medical fields based on the analysis of scientific literature on the recovery of patients after infection with COVID—19 coronavirus infection at all stages of rehabilitation. It is concluded that timely rehabilitation is an important strategy for the treatment of peripheral nerve disease and peripheral nervous system diseases in the critical phase, which contributes to long-term recovery and functional independence of patients, as well as reduces the duration of adjuvant therapy. Entrepreneurial initiative can manifest itself in the development of a sanatorium-resort complex, as well as various centers providing comprehensive medical and wellness services.

Research progress on the screening questionnaire related to benign paroxysmal positional vertigo

Benign paroxysmal positional vertigo（BPPV） is the most common peripheral vestibular disease in clinical practice, which can easily lead to missed diagnosis and misdiagnosis. Many guidelines have emphasized that detailed medical history and Dix-Hallpike test are sufficient to complete the diagnosis of BPPV. However, when the patient is unable or refused to undergo the displacement test due to obesity, physical weakness, cervical or lumbar dysfunction, fear of dizziness, and the displacement test does not induce nystagmus or weak nystagmus, the detailed medical history provides a supplementary basis for the diagnosis of BPPV, and compulsive posture therapy and drug treatment can be carried out accordingly. In order to standardize consultations, shorten the time for patients to visit, and help clinicians make more accurate diagnoses, many scholars at home and abroad have designed relevant screening questionnaires based on the history of BPPV, which has achieved good results.This article is summarized as follows, in order to provide ideas and references for clinical inquiry.

Mini-Invasive Approach and Minor Amputation in the Management of Diabetic Foot Ulcer: A Retrospective Study of 110 Cases

Category:Diabetes; OtherIntroduction/Purpose:The diabetic foot is an increasing issue over the last years. The 25% of diabetic patients have a risk to develop a diabetic foot ulcer (DFU) in their lifetime, among these, the 28% of patients will result in an amputation. The amputation is associated with a high rate of complications. Therefore, percutaneous mini-invasive (PMI) approaches and minor amputations (MA) have a widespread use in the last years. The aim of our work is to evaluate the clinical and functional outcomes of PMI and MA in the treatment of recurrences and unhealed DFU after conservative treatment.Methods:We retrospectively enrolled 110 patients treated in our orthopedic department in Perugia between January 2012 and October 2019. Included were the patients underwent to a PMI or MA treatment after failed conservative treatment for 12 weeks. The PMI technique consist of flexor tenotomy, metatarsal osteotomy and resection arthroplasty sec. Kessler. DFU were classified according to the Texas Foot Ulcer Classification. Exclusion criteria were: patient affected by peripheral vasculopathy disease, previous major amputation, psychiatric disease. The patients were divided in 2 groups. The group A included 57 patients treated with PMI, mean age 62.8 y.o. (range 50-80). The group B included 53 patients treated with MI, mean age 66.2 y.o. (range 53-85). The mean follow up was 18 months (range 4-40 months). Clinical outcomes, complication's rate, functional scores (FFI and VAS- FA) were assessed. The statistical analysis was performed with the t-student test, the significativity value was set p<0.05.Results:In the group A, the patients had a healing's rate in 90,7 % of cases, the ulcer was healed in average in 5.77 weeks ( range 4-8.1). The postoperative complications accounts 35% of cases, including 2 cases of osteomyelitis, 1 acute Charcot foot, 1 case of acute renal insufficiency and pneumonia. Transfer ulcer occurred in 12.96%. Overall a reintervention with a mini-invasive approach was performed in 2 cases. Group B healed in 77% of cases, in a mean time of 9.11 weeks (range 8-13.3), no postoperative complication occurred. In 23% of patients occurred a transfer ulcer after an average time of 30 months, in 1 case a major amputation was mandatory. The mean value at postoperative follow-up was 78 for VAS-FA for group A and 72.2 for group B, the FFIindex was 70% for group A and 68% for group B.Conclusion:The PMI and AM are effective procedures for the treatment of DFU, associated with low complications rate, fast recovery and ulcer's healing process, low rate of recurrences and ulcer transfer. Overall the percutaneous technique show encouraging results, however, these procedures must be addressed to the patient's feature. As prospective, in the future percutaneous treatments might play a role in prevention's strategy.

Application of Nanofiber Material Based on Electrospinning Technology in Sports Rehabilitation of Basketball Player’s Wrist Joint

Wrist joint plays an indispensable role in our daily life. The injury of wrist joint has a great influence on the fine movement of the hand and upper limb. For example, you cannot do joint movements, you cannot carry things, and life is very inconvenient. It is necessary to distinguish the types of wrist disorders and take effective rehabilitation methods in time. Wrist joint has a great impact on people’s life and work, and the rehabilitation of wrist joint has become a research hotspot in rehabilitation medicine and medical engineering. Carpal tunnel syndrome is the most common peripheral nerve entrapment disease in clinical practice, with a very high incidence. According to data, the incidence of carpal tunnel syndrome in the general population abroad is 1%‐5%, while that in special populations is as high as 14.5% above. In order to solve the problem of rehabilitation of wrist joint, using electrospinning technology, the polymer solution is prepared into nanofiber materials with strong adsorption and good filterability under the action of high‐voltage electric field. And using some small‐sized nanofibers that are similar to organs in shape and structure, as well as their excellent degradability and biocompatibility, this material is used in the research of wrist joint movement rehabilitation. In this paper, sports rehabilitation training is carried out on the wrist joint of basketball players, and the nanofiber material is effectively combined with sports rehabilitation training. By comparing the rehabilitation of athletes who did not use nanofiber materials, the role of nanofiber materials in sports rehabilitation was studied. This article analyzes the three parts of the radial joint, the wrist joint, and the ulnar joint before and after the sports rehabilitation training for basketball players with functional impairments and compares the sports rehabilitation of the basketball players without nanofiber materials. This article analyzes the three parts of the radial joint, the wrist joint, and the ulnar joint before and after the sports rehabilitation training for basketball players with functional impairments and compares the sports rehabilitation of the basketball players without nanofiber materials.

Nickel-Titanium peripheral stents: can fracture mechanics shed light on their fatigue failure?

The major concern about Nickel-Titanium (Ni-Ti) stents, which are the gold standard in the treatment of occlusive peripheral disease, is fatigue and the consequent fracture in vivo. Indeed, their failure might be responsible for severe drawbacks, among which is the re-occlusion of the treated artery. Although many phenomenological approaches have been proposed to study this topic, the current literature lacks extensive knowledge on the Ni-Ti local damage mechanisms produced by the cyclic loads that promote crack nucleation and lead to the failure of thin struts, such as those of stents. Moreover, due to the super-elastic property of the alloy, the standard approach for interpreting the fracture of metals might be not accurate for this case. This work aims at increasing awareness of fatigue failure in superelastic Ni-Ti thin struts, such as those of stents. To do so, multi-wire specimens, sharing the same dimensions and thermo-mechanical treatment of the stent struts, were fatigue tested under different strain levels and the number of cycles to failure was recorded for each sample. Numerical simulations corroborated the experimental results to gain information on the local stress and strain fields during the fatigue cycles. A fracture mechanics-based fatigue model adopting the cyclic J-integral was here proposed, giving promising results for the interpretation of such failures.

Response to a letter by M. Slouma et al

A letter by Slouma et al highlights several important matters regarding the recently reported association of serum levels of interleukin (IL)-22 with the clinical diagnosis of axial spondyloarthritis (AxSpA).1 While the full spectrum of action and pathological significance of IL-22 has not been fully elaborated, the involvement of this cytokine in the pathogenesis of various systemic disorders has been demonstrated or suggested. Thus, the potential diagnostic utility of this test should be limited to the differentiation of AxSpA from non-inflammatory conditions, such as osteitis condensans ilii, fibromyalgia and myofascial pain, enthesopathy, facet joint disease, and diffuse idiopathic systemic hyperostosis, which were diagnosed in this study in the group of patients with an alternative to AxSpA diagnosis. We completely agree with Slouma et al that the presence of some chronic systemic disorders can cause a bias in the interpretation of the test. Thus, it is important to mention that none of the enrolled patients was diagnosed with any malignant or chronic disease with possible inflammatory pathogenesis, excluding 3 smokers with mild chronic obstructive pulmonary disease; serum levels of IL-22 were at the low end in these patients. The IL-22 levels did not depend on the presence of peripheral arthritis, uveitis, psoriasis, or inflammatory bowel disease in our study; however, the numbers of patients with the extra-spinal manifestations were too low to make statistical calculations. The total sample size of the study was also judged to be insufficient for making final recommendations on the practical utilization of IL-22 test for AxSpA diagnosis, and as it was advocated by Slouma et al, and also acknowledged in the manuscript, further prospective studies examining the diagnostic utility of IL-22 testing in patients with suspected AxSpA are warranted. The authors declare no conflict of interest.

Role of Interventional Cardiology to Understand the Basic Mechanisms Related to Coronary Atherosclerosis

Interventional cardiology has aided us in recognizing coronary atherosclerosis. It has allowed establishing a connection amongst the image of the Clinique of atherosclerosis of coronary arteries with underlined science of pathology that aids to set up, in reality, the evolution of plaques of atherosclerosis. Further studies that elaborated Coronary Atherosclerosis with a better understanding have assisted us in saving from coronary atherosclerosis in the following couple of decades. In this assessment, held in a miniature spectrum, diverse and exceptional contributions made by the technology of cardiology that is interventional has permitted us the expertise of the mechanisms of pathophysiology which are better and associated with coronary atherosclerotic disease of coronary arteries has been elaborated. In addition, keep in mind the upcoming scenarios might be primarily based on present-day projections of certain aspects. Interventional strategies are also utilized to shut defects of sepsis and affected person's ducts of arteries, stent and balloon the vessels those are stenosis that artificial valves can be implanted into ducts or to aberrant pathways of conduction can be ablated. Anesthesia suppliers require intensive information on pediatric cardiac pathology and the pathophysiology it would produce responses to the agents of anesthesia and intervention that has been prepared. Victory in these ground calls for numerous evaluations, loads of plotting, and assessment with precision and high-quality crew work—coronary artery ailment. Heart disease, which is considered the most common of its types, is Coronary Artery ailments, which happen as arteries, which are answerable for providing blood to the coronary heart muscle, harden and constrict.&#x0D; The peripheral disease of vessels: Peripheral disease occurs when vessels of the blood located out of the heart narrow, block, or spasm. This condition can occur in the veins or arteries. Narrowed blood vessels can occur in multiple sites in the neck, arms, abdomen, kidneys, and legs.&#x0D; Heart valve disease: Heart valve disease occurs when blood flow controlled by the valves into the heart's chambers cannot work correctly.

Anatomy of a Data Science Software Toolkit That Uses Machine Learning to Aid ‘Bench-to-Bedside’ Medical Research—With Essential Concepts of Data Mining and Analysis Explained

Data science and machine learning are buzzwords of the early 21st century. Now pervasive through human civilization, how do these concepts translate to use by researchers and clinicians in the life-science and medical field? Here, we describe a software toolkit, just large enough in scale, so that it can be maintained and extended by a small team, optimised for problems that arise in small/medium laboratories. In particular, this system may be managed from data ingestion statistics preparation predictions by a single person. At the system’s core is a graph type database, so that it is flexible in terms of irregular, constantly changing data types, as such data types are common during explorative research. At the system’s outermost shell, the concept of ’user stories’ is introduced to help the end-user researchers perform various tasks separated by their expertise: these range from simple data input, data curation, statistics, and finally to predictions via machine learning algorithms. We compiled a sizable list of already existing, modular Python platform libraries usable for data analysis that may be used as a reference in the field and may be incorporated into this software. We also provide an insight into basic concepts, such as labelled-unlabelled data, supervised vs. unsupervised learning, regression vs. classification, evaluation by different error metrics, and an advanced concept of cross-validation. Finally, we show some examples from our laboratory using our blood sample and blood clot data from thrombosis patients (sufferers from stroke, heart and peripheral thrombosis disease) and how such tools can help to set up realistic expectations and show caveats.

Single-Cell Regulatory Network Inference and Clustering Identifies Cell-Type Specific Expression Pattern of Transcription Factors in Mouse Sciatic Nerve.

Advances in single-cell RNA sequencing technologies and bioinformatics methods allow for both the identification of cell types in a complex tissue and the large-scale gene expression profiling of various cell types in a mixture. In this report, we analyzed a single-cell RNA sequencing (scRNA-seq) dataset for the intact adult mouse sciatic nerve and examined cell-type specific transcription factor expression and activity during peripheral nerve homeostasis. In total, we identified 238 transcription factors expressed in nine different cell types of intact mouse sciatic nerve. Vascular smooth muscle cells have the lowest number of transcription factors expressed with 17 transcription factors identified. Myelinating Schwann cells (mSCs) have the highest number of transcription factors expressed, with 61 transcription factors identified. We created a cell-type specific expression map for the identified 238 transcription factors. Our results not only provide valuable information about the expression pattern of transcription factors in different cell types of adult peripheral nerves but also facilitate future studies to understand the function of key transcription factors in the peripheral nerve homeostasis and disease.

Drug-Drug Interactions in Vestibular Diseases, Clinical Problems, and Medico-Legal Implications.

Peripheral vestibular disease can be treated with several approaches (e.g., maneuvers, surgery, or medical approach). Comorbidity is common in elderly patients, so polytherapy is used, but it can generate the development of drug–drug interactions (DDIs) that play a role in both adverse drug reactions and reduced adherence. For this reason, they need a complex kind of approach, considering all their individual characteristics. Physicians must be able to prescribe and deprescribe drugs based on a solid knowledge of pharmacokinetics, pharmacodynamics, and clinical indications. Moreover, full information is required to reach a real therapeutic alliance, to improve the safety of care and reduce possible malpractice claims related to drug–drug interactions. In this review, using PubMed, Embase, and Cochrane library, we searched articles published until 30 August 2021, and described both pharmacokinetic and pharmacodynamic DDIs in patients with vestibular disorders, focusing the interest on their clinical implications and on risk management strategies.

Diagnostic and Treatment Considerations in Restless Legs Syndrome Complicated by Diabetic Neuropathy.

Diabetic neuropathy from type I diabetes (DMI), type II diabetes (DMII), or gestational diabetes commonly occurs concurrently with restless legs syndrome (RLS) with an estimated prevalence in DMII specifically of 17.7 to 45%. The diagnosis of RLS can be obscured by symptoms of peripheral neuropathy, which may be similar to those of RLS, but also by other RLS mimics, including nocturnal leg cramps or akathisia. The purpose of this review is to outline a framework for considering comorbid diabetic neuropathy and RLS by discussing RLS and its association with peripheral nerve disease, diabetes, and sleep disruption. Treatment for patients with both diabetic neuropathy and RLS may differ from treatment of persons with solely RLS or diabetic neuropathy; key points in this difference are discussed. Finally, a treatment algorithm is provided to guide the approach to treating patients with comorbid RLS and diabetic neuropathy. There have been several revisions of the RLS diagnostic criteria which in addition to the main four essential criteria of having (1) an urge to move the legs which is (2) exacerbated by rest, (3) relieved temporarily by movement, and (4) occurs in the evening or night time, now includes a consideration for RLS mimics, requiring that (5) symptoms not be explained by any other symptoms. Additionally, the treatment of both diabetic neuropathy and RLS has evolved to focus first on controlling the blood glucose, avoiding exacerbating medications, supplementing with iron if serum ferritin is low, and starting pharmacotherapy with alpha-2-delta ligands such as gabapentin or pregabalin. Knowledge of the prevalence of peripheral neuropathy with RLS, revised RLS diagnostic criteria, and a general treatment algorithm for the combination of peripheral neuropathy and RLS is critical to providing appropriate care to patients suffering from these two diseases.

Comparison of Post-Operative Morbidity and Mortality in Patients Undergoing On-Pump versus Off-Pump CABG

Objective: The aim of this study is to compare in hospital morbidity and mortality in on pump versus off pump CABG. Methodology: All the patients undergoing CABG surgery were enrolled after taking informed consent. Demographic and postoperative variables were entered in the predesigned questionnaire and patients were followed for early outcomes after surgical procedure. Results: A total of 470 patients wasdivided in two groups 235 (on pump and off pump).The mean age of patients was 54.85 ± 9.57 (23-85).There were 400(85.1%) males and 70(14.9%) females. The total data of 470 patients was divided in two groups 235 in on Pump and 235 in off pump CABG.The mean age of patients was 54.85 ± 9.57 (23-85). There were 400(85.1%) males and 70(14.9%) females. Different clinical outcomes were compared in both groups (On-Pump versus Off-Pump CABG) by using Euro Score, we found Peripheral Disease in On-Pump CABG group compared with Off-Pump CABG as 11(4.68% vs 12(5.11%) with p-value=0.831 which was statistically insignificant, current data assessed lung disease in both groups as 11(4.68%) vs 13(5.53%) with statistically insignificant p-value (0.675). and unstable angina were 12(5.11%, p-value 1.00) patients founded and Peri and post myocardial infarction also assessed in both groups with p-value (0.74 &amp; 1.20). respectively.Data regarding in hospital mortality was analyzed and found that 7(2.98%) in on pump group compare with off pump group was According to our research mean number of grafts placed in On-Pump CABG were 9(3.83%) with statistically insignificant p-value (0.611). Conclusion:Proof is presented that surgery on beating heart (Off-Pump) is as safe and effective as Conventional CABG, and cheaper than conventional surgery. However, it is uncertain whether the cost savings are sustained over a longer period of time. Keywords: Coronary artery Bypass grafting surgery, On Pump Off Pump

Epicardial adipose tissue volume and myocardial ischemia in asymptomatic people living with diabetes: a cross-sectional study

BackgroundEpicardial adipose tissue (EAT) is considered a novel diagnostic marker for cardiometabolic disease. This study aimed to evaluate whether EAT volume was associated with stress-induced myocardial ischemia in asymptomatic people living with diabetes—independently of confounding factors—and whether it could predict this condition.MethodsWe included asymptomatic patients with diabetes and no coronary history, who had undergone both a stress a myocardial scintigraphy to diagnose myocardial ischemia, and a computed tomography to measure their coronary artery calcium (CAC) score. EAT volume was retrospectively measured from computed tomography imaging. Determinants of EAT volume and asymptomatic myocardial ischemia were evaluated.ResultsThe study population comprised 274 individuals, including 153 men. Mean (± standard deviation) age was 62 ± 9 years, and 243, 23 and 8 had type 2, type 1, or another type of diabetes, respectively. Mean body mass index was 30 ± 6 kg/m2, and mean EAT volume 96 ± 36 cm3. Myocardial ischemia was detected in 32 patients (11.7%). EAT volume was positively correlated with age, body mass index and triglyceridemia, but negatively correlated with HbA1c, HDL- and LDL-cholesterol levels. Furthermore, EAT volume was lower in people with retinopathy, but higher in men, in current smokers, in patients with nephropathy, those with a CAC score > 100 Agatston units, and finally in individuals with myocardial ischemia (110 ± 37 cm3 vs 94 ± 37 cm3 in those without myocardial ischemia, p < 0.05). The association between EAT volume and myocardial ischemia remained significant after adjustment for gender, diabetes duration, peripheral macrovascular disease and CAC score. We also found that area under the ROC curve analysis showed that EAT volume (AROC: 0.771 [95% confidence interval 0.683–0.858]) did not provide improved discrimination of myocardial ischemia over the following classic factors: gender, diabetes duration, peripheral macrovascular disease, retinopathy, nephropathy, smoking, atherogenic dyslipidemia, and CAC score (AROC 0.773 [0.683–0.862]).ConclusionsEAT may play a role in coronary atherosclerosis and coronary circulation in patients with diabetes. However, considering EAT volume is not a better marker for discriminating the risk of asymptomatic myocardial ischemia than classic clinical data.

Anisocoria secondary to antiperspirant wipes in a pediatric population: a case series

Acute-onset anisocoria or mydriasis in children carries a broad differential diagnosis and includes both benign and life-threatening causes, ranging from systemic or topical drug use to peripheral or central nervous system disease. The topical anticholinergic agent glycopyrronium (approved by the Food and Drug Administration in June 2018) is used to treat hyperhidrosis. We present the first case series of pediatric patients presenting with acute mydriasis due to exposure to glycopyrronium wipes. Six cases (ages 12-16) were identified: 3 presented emergently and 3 to a primary care physician. Additional symptoms included blurry vision (4/6) and unilateral headache (1/6). In 3 cases, use of glycopyrronium wipes was not elicited initially, neuroimaging was obtained, and ophthalmology (2/3) or neurology (1/3) was consulted. One patient remained undiagnosed and presented emergently again 2 months later. In all patients, symptoms resolved without further treatment.

Abstract 12299: Molecular Imaging of Active Vascular Microcalcification in the Lower Extremities of Patients With Diabetes and Peripheral Arterial Disease

Introduction: Patients with diabetes mellitus (DM) have accelerated progression of peripheral arterial disease (PAD) with higher prevalence of arterial calcification, which can limit and make options for endovascular revascularization more challenging, contribute to worse treatment outcomes, and result in higher rates of amputation. Positron emission tomography (PET) imaging with fluorine-18 ( 18 F)-sodium fluoride (NaF) has shown utility for detecting active microcalcification of coronary arteries but remains relatively understudied in patients with PAD. We hypothesized that 18 F-NaF PET/CT imaging could be used to quantify DM-induced active microcalcification of lower extremity arteries. Methods: 18 F-NaF PET/CT imaging was performed in PAD patients with type 2 DM (n=11), PAD patients without DM (n=8), and healthy controls (n=6). Regions of interest were manually drawn bilaterally on each axial slice of CT images for the femoral, popliteal, anterior tibial, tibioperoneal trunk, posterior tibial, and peroneal arteries to quantify 18 F-NaF uptake. The maximum target-to-background ratio (TBR max ) was calculated for each artery of interest. Results: 18 F-NaF PET/CT imaging non-invasively detected significantly higher active microcalcification of the femoral-popliteal, anterior tibial, tibioperoneal trunk, and posterior tibial arteries in patients with DM and PAD compared to healthy controls ( Fig. 1 ). A noticeable trend (not significant) in increasing arterial retention of 18 F-NaF was found with increasing disease status (i.e., healthy, PAD only, PAD with DM) ( Fig. 1 ). Conclusions: 18 F-NaF PET/CT quantifies vessel-specific active calcification of above- and below-the-knee arteries in patients with DM and PAD. PET/CT may offer insight into early pathophysiology of peripheral disease in patients with DM, thereby improving personalized therapeutic approaches for a population that suffers from significant morbidity and mortality.

Abstract 10451: A Potential Therapeutic Antibody to Induce Collateral Formation in Cardiovascular Diseases

Introduction: Lack of efficient collateralisation during vascular occlusion leads to tissue ischemia in coronary, peripheral and cerebrovascular disease. Patients with peripheral, coronary, and cerebrovascular disease have elevated levels of the anti-angiogenic isoform of VEGF (VEGF-A 165 b), which correlate with poorer outcomes. In experimental animals, VEGF-A 165 b neutralisation improves blood flow and collateralisation after femoral or coronary artery ligation. Hypothesis: We tested the hypothesis that a potent, high affinity, humanised neutralising antibody to VEGF-A 165 b could have therapeutic potential in models of cardiovascular disease. Methods: A mouse monoclonal antibody to VEGF-A 165 b was humanised by cloning and site directed mutagenesis. Multiple clones were screened, and one with high affinity (measured by biolayer interferometry) was amplified. The efficacy in vitro was tested using endothelial cell migration assays and in vivo using the hindlimb ischemia (HLI) model in C57Bl6 mice fed a high fat high sucrose (HFHS) diet, and in Zucker Diabetic Fatty rats. Results: One clone (HC4LC2) had a VEGF-A 165 b affinity of 600pM. 0.3μg/ml of this clone reversed the inhibitory effect of recombinant human VEGF-A 165 b (31±4%, N=6 of VEGF-A 165 a alone) on migration of endothelial cells to 40ng/ml rhVEGF-A 165 a (89±9% N=3). Human monocyte dependent inhibition of VEGF-A 165 a mediated migration was dose dependently reversed by HC4LC2 (EC50, 55ng/ml, N=9 per concentration). HLI in HFHS mice impaired blood flow after 28 days in IgG treated mice (70±7.7% of pre-ischemic blood flow, N=6), which was restored to normal (93.3±5.5, p&lt;0.05, N=8) by intraperitoneal injection of 1mg/kg HC4LC2. Blood flow recovery after HLI was also seen in ZDF rats treated with HC4LC2 (106±16% of pre-ischemic flow, N=5) compared with IgG treated animals (76±.9%, N=5, p&lt;0.05, two-way ANOVA, all values mean ±SEM). Conclusions: These results indicate that HC4LC2 is a humanised, high affinity neutralising antibody to VEGF-A 165 b that could have therapeutic potential for patients with cardiovascular disease, by enhancing collateral formation.

Preclinical Characterization of a Next-Generation Brain Permeable, Paradox Breaker BRAF Inhibitor.

Disease progression in BRAF V600E/K positive melanomas to approved BRAF/MEK inhibitor therapies is associated with the development of resistance mediated by RAF dimer inducing mechanisms. Moreover, progressing disease after BRAFi/MEKi frequently involves brain metastasis. Here we present the development of a novel BRAF inhibitor (Compound Ia) designed to address the limitations of available BRAFi/MEKi. The novel, brain penetrant, paradox breaker BRAFi is comprehensively characterized in vitro, ex vivo, and in several preclinical in vivo models of melanoma mimicking peripheral disease, brain metastatic disease, and acquired resistance to first-generation BRAFi. Compound Ia manifested elevated potency and selectivity, which triggered cytotoxic activity restricted to BRAF-mutated models and did not induce RAF paradoxical activation. In comparison to approved BRAFi at clinical relevant doses, this novel agent showed a substantially improved activity in a number of diverse BRAF V600E models. In addition, as a single agent, it outperformed a currently approved BRAFi/MEKi combination in a model of acquired resistance to clinically available BRAFi. Compound Ia presents high central nervous system (CNS) penetration and triggered evident superiority over approved BRAFi in a macro-metastatic and in a disseminated micro-metastatic brain model. Potent inhibition of MAPK by Compound Ia was also demonstrated in patient-derived tumor samples. The novel BRAFi demonstrates preclinically the potential to outperform available targeted therapies for the treatment of BRAF-mutant tumors, thus supporting its clinical investigation.

EXTH-02. AAV MEDIATED BRAIN DELIVERY OF AN ADCC-ENHANCED ANTIBODY OBVIATES XENOGRAFT GROWTH IN MOUSE MODELS OF HER2+ BREAST CANCER BRAIN METASTASIS

Abstract BACKGROUND HER2+ tumors constitute approximately 20% of breast cancer patients and are characterized by overexpression of the growth factor receptor HER2 (ERBB2), a cell proliferation driver. Effective anti-HER2 therapies confer prolonged patient survival necessitating the need for transformative treatments targeting brain metastases, a major cause of mortality in ~30-50% of HER2+ metastatic breast cancer patients. HER2-directed antibody immunotherapy, while efficacious for peripheral disease, has limited central nervous system exposure (CNS). To overcome these challenges, we transduced CNS cells with a novel AAV vector carrying an anti-HER2 antibody payload. METHODS We assessed the biochemical equivalence and functional effectiveness of AAV vector-encoded antibodies using in vitro assays. After selecting promising vector-encoded antibody candidates, a novel, blood-brain barrier penetrant AAV capsid was administered via i.v. dosing to an orthotopic xenograft mouse model of HER2+ brain metastases. Bioluminescent imaging provided a longitudinal measure of brain tumor burden. At study termination, we measured antibody biodistribution in cerebrospinal fluid (CSF), serum, and brain homogenates with AlphaLISA assays. RESULTS Using HER2+ breast cancer cell lines, we determined that an antibody-dependent cell cytotoxicity (ADCC) enhanced anti-HER2 antibody was most effective and demonstrated that AAV-vector encoded forms of the antibody performed comparably to recombinant reference antibodies. Following i.v. administration of a HER2 antibody encoding AAV vector, we measured &amp;gt;1 ug/mL of the antibody in CSF. Importantly, AAV-mediated expression of the ADCC-enhanced HER2-directed antibody significantly abrogated tumor growth in orthotopic xenograft models. CONCLUSIONS Peripheral administration of an AAV vector was able to transduce brain tissue such that efficacious levels of HER2-directed antibodies were produced. This strategy was successful at preventing tumor growth in our physiologically relevant model of breast cancer brain metastases. Such a treatment modality should be further evaluated in patient derived PDX models to validate translational efficacy for human patients.

Autologous Stem Cell Transplant Outcome in Classic Hodgkin Lymphoma Patients in the Era of Post-Transplant Brentuximab Vedotin Consolidation

Introduction:Patients newly diagnosed with classic Hodgkin lymphoma (CHL) have over 80% chance of remission with first-line chemotherapy, such as ABVD (adriamycin, bleomycin, vinblastine, dacarbazine) regime. However, 10-40% of patients relapse eventually and require salvage therapy. High-dose therapy with autologous stem cell transplantation (ASCT) remains the standard of care for patients with relapsed or refractory CHL, offering a cure rate of around 50%. This may be further improved to around 60% with post-transplant consolidation with brentuximab vedotin (BV). Post-SCT BV consolidation has been offered to all patients, regardless of the risk group, in British Columbia since late 2015. We set out to review the ASCT outcome in CHL patients in the recent decade at our institution.Methods:All adult patients who received ASCT for relapsed or refractory CHL between July 2011 and June 2020 were included in this retrospective analysis. Information pertaining to their demographics, disease characteristics, treatment history, transplant details, clinical outcomes and post-relapse therapy was obtained by review of electronic data. The data cut-off date was June 28, 2021. Survival outcomes were censored at the last known clinic visit for patients without relapse or death during follow up. Survival analysis was performed using Kaplan-Meier survival function and log-rank test. Pearson's chi-square test and ANOVA were used for comparison between cohorts. The statistical program used was Stata® version 16.1 (Texas, USA).Results:114 patients underwent ASCT for relapsed/refractory CHL. Bulky disease and extranodal involvement were seen in 11% and 40% respectively at relapse. Looking at the ‘high risk criteria’ as defined in the AETHERA trial: 45/114 (40%) patients had primary refractory CHL, 21/114 (18%) had relapsed within 12 months of completing the front-line chemotherapy and 15/114 (13%) had relapsed beyond one year of completing initial treatment but with an extranodal disease.The most commonly used salvage chemotherapy regime was GDP (gemcitabine, dexamethasone, cisplatin; 111/114; 97%). 10/114 (9%) patients received BV after failing salvage chemotherapy pre-SCT. The median number of lines of therapy pre-SCT was two (range 2-5). 94/108 (98%) had a chemosensitive disease with 35/108 (32%) achieving complete remission. 6/108 (6%) patients had a progressive disease at the time of SCT. For the transplant, all patients had a peripheral blood stem cell source and the conditioning regime was either Carmustine/Etoposide/Cytarabine/Melphalan (76%) or Etoposide/Melphalan (24%).After median follow up of 62.2 months, 50/114 (44%) patients relapsed with median relapse-free survival of 20.2 months (range 0.9 - 113.5) and 16/114 (14%) died. The direct cause of death was lymphoma progression in all but three patients (PJP pneumonia, pulmonary fibrosis, traumatic subdural hematoma).Whereas only 4/51 (8%) patients (2 without relapse) received post-SCT BV consolidation via a compassionate access program between July 2011 and October 2015 (cohort 1), 45/63 (71%) patients (33 in remission) received routine BV consolidation between November 2015 and June 2020 (cohort 2). In cohort 2, 44% had primary refractory CHL compared to 33% in cohort 1 but the number of ‘low risk’ patients was similar at 29% (Table 1). The most common reason for no post-SCT BV consolidation in cohort 2 was patient refusal (7/18; 40%). Other causes included BV pre-SCT, early disease progression and patient comorbidities. Only 9/42 (21%) patients with available data in cohort 2 completed the planned 16 cycles of BV consolidation. The median number of cycles was 10.5 (range 1-16). The most common reasons for early termination of BV consolidation were peripheral neuropathy (22/33; 67%) and disease progression (9/33; 27%). There was no statistically significant difference in PFS or OS demonstrated between the two cohorts (Graphs 1, 2).Conclusion:After median follow up of 5 years, 86% of patients remain alive and 56% are alive in remission. In British Columbia, post-SCT BV consolidation has been widely adopted with over 70% of patients receiving at least one cycle since late 2015. Successful completion of post-SCT BV consolidation is, however, limited by a high rate of treatment-limiting peripheral neuropathy. Relapse-free survival benefit of routine post-SCT BV consolidation is not demonstrated in this single-centre cohort. [Display omitted] DisclosuresWhite: Novartis: Honoraria. Sutherland: Janssen: Consultancy, Research Funding; GSK: Research Funding; Karyopharm: Research Funding; Celgene: Consultancy; Amgen: Consultancy. Sanford: Abbvie: Membership on an entity's Board of Directors or advisory committees; Stellar: Membership on an entity's Board of Directors or advisory committees. Abou Mourad: Amgen: Consultancy; Paladin: Consultancy; Pfizer: Consultancy. Song: Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Takeda: Consultancy, Honoraria; GlaxoSmithKline: Honoraria; Kite, a Gilead Company: Honoraria; Bristol Myers Squibb: Honoraria; Sanofi: Honoraria.

Therapeutic Targeting of Mertk and BCL-2 in T-Cell and Early T-Precursor Acute Lymphoblastic Leukemia

IntroductionT-cell acute lymphoblastic leukemia (T-ALL) accounts for 15% of childhood ALL and is associated with inferior outcomes relative to B-cell ALL. Early T-precursor ALL (ETP-ALL) is a subset of T-ALL characterized by an immature T cell phenotype, resistance to therapy, and high rates of induction failure. MERTK receptor tyrosine kinase is ectopically expressed in 40-50% of T-ALLs, particularly those with an immature T cell phenotype, suggesting a role in ETP-ALL. Inhibition of MERTK using shRNA delayed leukemia progression and prolonged survival in a T-ALL xenograft model, implicating MERTK as a therapeutic target. MRX-2843 is an orally available dual MERTK/FLT3 inhibitor currently in phase I clinical trials. The anti-apoptotic protein B-cell lymphoma-2 (BCL-2) is specifically expressed in immature T cell precursors, is preferentially expressed in ETP-ALL compared to other T-ALLs, is essential for ETP-ALL cell survival, and is regulated downstream of MERTK in acute leukemia cells. Thus, combination therapies targeting these two proteins may be particularly effective to treat ETP-ALL.MethodsLoucy and PEER ETP-ALL cell lines were cultured with vehicle or MRX-2843. Phosphorylated and total MERTK were assessed by immunoblot. Relative cell numbers were measured using Presto Blue reagent. Cells were stained with PoPro-1-iodide and propidium iodide and apoptotic and dead cells were quantitated by flow cytometry. T-ALL patient samples were cultured with UNC2025, a close analogue of MRX-2843, and relative cell numbers were assessed using MTS reagent. Orthotopic xenografts were established in NSG or NSGS mice using luciferase-expressing Jurkat cells (T-ALL), luciferase-expressing Loucy cells (ETP-ALL) or an ETP-ALL patient sample and leukemia burden was monitored by bioluminescence imaging or flow cytometry. MRX-2843 (65 mg/kg or 75 mg/kg) or saline vehicle were administered orally once daily. Differences in disease burden were assessed with the Mann-Whitney-U test or one-way ANOVA. Survival was determined by Kaplan-Meier analysis. Loucy and PEER cells were plated and screened in quadruplicate against >150 pairwise combinations of MRX-2843 and the BCL-2 inhibitor venetoclax in a high-throughput format. Synergy was calculated using the response additivity model.ResultsTreatment with MRX-2843 mediated a dose-dependent decrease in phosphorylated MERTK, inhibited expansion of ETP-ALL cells, and induced cell death in vitro. Fifty-four percent (21/39) of primary T-ALL patient samples were sensitive to UNC2025 with an IC 50≤550 nM, including 2/5 (40%) pediatric samples and 10/19 (53%) adolescent/young adult samples. Treatment with MRX-2843 significantly reduced leukemia burden in cell line-derived T-ALL and ETP-ALL xenograft models and prolonged survival by 50% and 13% in the T-ALL (n=10, p<0.0001) and ETP-ALL (n=10, p=0.0136) models, respectively. Similarly, in a patient-derived ETP-ALL xenograft model, treatment with MRX-2843 reduced peripheral blood disease burden by 83% and spleen weight by 64% compared to vehicle-treated mice (n=8, p<0.001) and prolonged survival by 41% (n=8, p=0.0016). MRX-2843 mediated anti-leukemia activity in combination with venetoclax and a dose ratio of 1:20 MRX-2843:venetoclax provided optimal synergy in Loucy and PEER ETP-ALL cells in vitro (Figure 1).ConclusionsMRX-2843 has therapeutic activity in ETP-ALL cell culture and xenograft models and over half of T-ALL patient samples were sensitive to MERTK/FLT3 inhibition. MRX-2843 also mediated synergistic anti-leukemia activity against ETP-ALL cells in combination with venetoclax, with an optimal molar ratio of 1:20. These data demonstrate the therapeutic potential of MRX-2843 in patients with T-ALL, suggest that MRX-2843 may be particularly active alone and in combination with venetoclax in the ETP-ALL subset, and provide rationale for clinical testing of MRX-2843, with the ultimate goal to progress to trials evaluating MRX-2843 in combination with other agents. Toward this end, MRX-2843 monotherapy will be tested in patients with relapsed leukemia in an upcoming clinical trial (NCT04872478). [Display omitted] DisclosuresWang: Meryx: Other: Equity ownership; University of North Carolina: Patents & Royalties. Frye: University of North Carolina: Patents & Royalties; Meryx: Membership on an entity's Board of Directors or advisory committees, Other: Equity ownership. Earp: Meryx: Membership on an entity's Board of Directors or advisory committees, Other: Equity ownership. Tyner: Petra: Research Funding; Incyte: Research Funding; Takeda: Research Funding; Janssen: Research Funding; Astrazeneca: Research Funding; Array: Research Funding; Constellation: Research Funding; Seattle Genetics: Research Funding; Schrodinger: Research Funding; Genentech: Research Funding; Gilead: Research Funding; Agios: Research Funding. DeRyckere: Meryx: Other: Equity ownership. Graham: Meryx: Membership on an entity's Board of Directors or advisory committees, Other: Equity ownership.