Antithrombotic Therapy in the Prevention of Stroke

Overview: Ischemic stroke is a leading cause of death and disability throughout the world. Antithrombotic therapy, which includes both antiplatelet and anticoagulant agents, is a primary medication of choice for the secondary prevention of stroke. However, the choices vary with the need to incorporate evolving, newer information into the clinical scenario. There is also the need to factor in co-morbid medical conditions as well as the cost ramifications for a particular patient as well as compliance with the regimen. Pertinent Updates: In the acute setting, dual antiplatelet therapy from three weeks to up to three months has become recognized as a reasonable approach for patients with either minor stroke or transient ischemic attack or those with symptoms associated with higher-grade intracranial stenosis. This approach is favored for non-cardioembolic stroke as a cardiogenic mechanism tends to be best managed with attention to the cardiac condition as well as anticoagulant therapy. Risk stratification for recurrent stroke is important in weighing potential risk versus benefits. For example, prolonged dual antiplatelet therapy, with a combination such as aspirin and clopidogrel or aspirin and ticagrelor, tends to have negation of the potential clinical benefit of stroke prevention, over time, by the enhanced bleeding risk. Anticoagulant choices are now impacted by newer agents, initially identified as novel oral anticoagulants (NOACs), which also became associated with “non-vitamin K” agents as they are no longer considered novel. Alternatively, they are now often identified as direct oral anticoagulants (DOACs). They tend to be viewed as superior or non-inferior to warfarin with the caveat that warfarin is still viewed as the agent of choice for stroke prevention in patients with mechanical heart valves. Conclusion: Based upon cumulative information from multiple clinical trials of secondary prevention of stroke, there is an increasing array of approaches in an effort to provide optimal management. Antithrombotic therapy, including in combination with anticoagulant therapy, continues to evolve with the general caveat that “one size does not fit all”. In view of this, we desire to provide an evidence-based approach for the prevention of stroke with antithrombotic agents.

OP164 Extracorporeal Cytokine Adsorption Therapy: An Update Systematic Review Of Clinical Efficacy And Safety For Two Indications

IntroductionThe idea of using extracorporeal cytokine adsorption therapy (ECAT) is to remove cytokines from the blood in order to restore a balanced immune response. Yet, it is unclear as to whether the use of ECAT improves patient-relevant outcomes. Hence, the aim of this article is to synthesize the currently available evidence with regard to a potential clinical benefit of ECAT used in cardiac surgery or sepsis.MethodsWe conducted an updated systematic review summarizing the body of evidence with regard to a potential clinical benefit of ECAT. The study followed the PRISMA statement and the European Network for Health Technology Assessment (EUnetHTA) guidelines. The quality of the individual studies and the strength of the available evidence was assessed using the Cochrane risk of bias tool (v.1) and the GRADE approach respectively. Mortality, organ function, length of stay in the intensive care unit and length of hospitalization, as well as adverse events, were defined as critical outcomes.ResultsFor the preventive treatment of ECAT in patients undergoing cardiac surgery, we found very low-quality inconclusive evidence for mortality (5 randomized controlled trials (RCTs), n = 163), length of stay in the intensive care unit (5 RCTs, n = 163), and length of hospitalization (3 RCTs, n = 101). In addition, very low-quality inconclusive evidence was found for (serious) adverse events (4 RCTs, n = 148). For the therapeutic treatment of ECAT in patients with sepsis/ septic shock, we found very low-quality inconclusive evidence for mortality up to 60-day follow-up (2 RCTs, n = 117), organ function (2 RCTs, n = 117) and length of stay in the intensive care unit (1 study, n = 20). Similarly, very low-quality inconclusive evidence was found for (serious) adverse events (2 RCTs, n = 117). There are currently eighteen ongoing RCTs on the use of ECAT.ConclusionsThere is a lack of reliable data on the clinical benefit of using ECAT as an add-on treatment preventively in cardiac surgery and therapeutically in patients with sepsis or septic shock. While theoretical advantages are anticipated, the current available evidence is inconclusive and was not able to establish the efficacy and safety of ECAT in combination with standard care in the investigated indications. In light of the available RCTs, we strongly recommend the consideration of studies with patient-relevant endpoints and adequate statistical power, instead of investing further research funds on small studies that may not shed more light onto the potential clinical benefit of ECAT. The results of ongoing RCTs are awaited to guide the decision on whether further research funds should be invested in ECAT research or to conclude that the intervention may not show clinical benefits for patients.

CD73-Mediated Immunosuppression Is Linked to a Specific Fibroblast Population That Paves the Way for New Therapy in Breast Cancer

Background: Cancer-associated fibroblasts (CAF) are heterogeneous with multiple functions in breast cancer. Recently, we identified a specific CAF subpopulation (referred to as CAF-S1), which promotes immunosuppression and immunotherapy resistance. Methods and Results: Here, by studying a large collection of human samples, we highlight the key function of CD73/NT5E in CAF-S1-mediated immunosuppression in breast cancer. We first reveal that CD73 protein level specifically accumulates in CAF-S1 in breast cancer patients. Interestingly, infiltration of regulatory T lymphocytes (Tregs) is significantly correlated with CD73 expression in stroma but not in epithelium, indicating that CD73 contributes to immunosuppression when expressed in CAF-S1 and not in tumor cells. By performing functional assays based on relevant systems using primary CAF-S1 isolated from patients, we demonstrate that CAF-S1 increase the content in both PD-1+ and CTLA-4+ Tregs. Importantly, the use of a blocking anti-CD73 antibody on CAF-S1 reduces CAF-S1-mediated immunosuppression by preventing expression of these immune checkpoints on Tregs. Conclusions: Our data support the potential clinical benefit of using both anti-CD73 and immune-checkpoint inhibitors in breast cancer patients for inhibiting CAF-S1-mediated immunosuppression and enhancing anti-tumor immune response.

INNV-06. BRAF AND MEK DUAL INHIBITORS THERAPY IN RECURRENT OR ANAPLASTIC PLEOMORPHIC XANTHOASTROCYTOMA (PXA)

BACKGROUND AND OBJECTIVE Recurrent and anaplastic pleomorphic xanthoastrocytoma (PXA) tumors are challenging to treat due to their rarity and lack of management consensus. About 80% of PXAs harbor BRAF gene mutation. Although the development of BRAF inhibitors has dramatically improved the outcomes for patients with BRAF V600E mutant tumors, resistance develops in the majority of cases. We hypothesize that dual BRAF/MEK inhibitors therapy can improve tumor control and patient survival without added toxicity. METHODS Medical records from 2010 to 2021 in Memorial Hermann Texas Medical Center were reviewed. Patients diagnosed with PXA who received BRAF and/or MEK inhibitors therapies were identified. The data evaluated included age, sex, treatment received, side effects, and outcomes, as well as results from blood tests, pathology, next generation sequencing and MRI. Side effects were evaluated according to the CTCAE Version 5.0. RESULTS Five patients with recurrent or anaplastic PXA were identified. The median age at diagnosis was 22 years old (range 14-66 years old), with 60% male, and 60% grade III. All patients received BRAF/MEK dual inhibitors therapy at various stages of PXA treatment. The median follow-up was 72 months (range 17-108 months). One patient (66 years old) experienced short-term disease stability for 5 months and who died from tumor related brain hemorrhage while off therapy for 9 months. Four patients experienced long-term disease control (17, 22, 94, 108 months, respectively) while three of them remain on dual therapy and one patient died from systemic PXA progression. Dual BRAF/MEK inhibitors were well tolerated with only grade 1-2 adverse effects (AE) including skin rash, fatigue, mild abdominal discomfort, diarrhea. No grade III-V AE were detected. CONCLUSION BRAF/MEK dual inhibitor can provide potential clinical benefit to PXA patients with BRAF mutations. Our study supports the concurrent use of BRAF/MEK inhibitors for best tumor control without unexpected AE.

Pan-cancer landscape of CD274 (PD-L1) rearrangements in 283,050 patient samples, its correlation with PD-L1 protein expression, and immunotherapy response

BackgroundImmune checkpoint inhibitors (ICIs) benefit patients with multiple cancer types, however, additional predictive biomarkers of response are needed. CD274 (programmed cell death ligand-1, PD-L1) gene rearrangements are positively associated with PD-L1 expression and may confer benefit to ICI, thus a pan-cancer characterization of these alterations is needed.MethodsWe analyzed 283,050 patient samples across multiple tumor types that underwent comprehensive genomic profiling for activating CD274 rearrangements and other alterations. The DAKO 22C3 Tumor Proportion Scoring (TPS) method was used for PD-L1 immunohistochemistry (IHC) testing in a small subset with available data (n=55,423). A retrospective deidentified real-world clinico-genomic database (CGDB) was examined for ICI treatment outcomes. We also report a detailed case of CD274-rearranged metastatic rectal adenocarcinoma.ResultsWe identified 145 samples with functional rearrangements in CD274. There were significant enrichments for PIK3CA, JAK2, PDCD1LG2, CREBBP, and PBRM1 co-mutations (ORs=2.1, 16.7, 17.8, 3.6, and 3.4, respectively, p<0.01). Genomic human papillomavirus (HPV)-16, Epstein-Barr virus, and mismatch repair genes also co-occurred (OR=6.2, 8.4, and 4.3, respectively, p<0.05). Median tumor mutational burden (TMB) was higher compared with CD274 wild-type samples (7.0 vs 3.5 mutations/Mb, p=1.7e-11), with disease-specific TMB enrichment in non-small cell lung, colorectal, unknown primary, and stomach cancers. PD-L1 IHC skewed toward positivity (N=39/43 samples with ≥1% positivity). Of eight patients from the CGDB, three remained on ICI treatment after 6 months. Separately, one patient with metastatic rectal adenocarcinoma experienced a pathologic complete response on chemoimmunotherapy.ConclusionsCD274 gene rearrangements are associated with increased PD-L1 IHC scores, higher TMB, and potential clinical benefit in ICI-treated patients with cancer.

Thrombolytic Therapy in Pulmonary Thromboembolism

Acute pulmonary thromboembolism (PE) is a common disorder with significant mortality and morbidity. Timely recognition and prompt therapy of this disorder is essential to prevent adverse consequences. Thrombolytic therapy has an important role in the management of high-risk pulmonary embolism patients, where it can be lifesaving. However, the potential clinical benefit of thrombolytic therapy needs to balanced against the risk of major bleeding associated with the use of these agents. Hence patient selection is of paramount importance in determining the success of this therapy. Management strategies in PE are centered around the concept of risk stratification of the cases. In this chapter we briefly discuss the risk categorization of PE cases, followed by a more elaborative discussion of the role of thrombolytic therapy in the management of patients with high risk or intermediate risk PE.

Probiotics in the comprehensive prevention of respiratory infections in children

Вирусные инфекции дыхательных путей являются наиболее частой причиной инфекционных заболеваний, особенно у детей. В большинстве случаев, особенно при поражении верхних дыхательных путей, острые респираторные вирусные инфекции протекают в легкой или среднетяжелой форме и часто купируются самостоятельно. Фармакологические средства для лечения или профилактики данных инфекций у детей в настоящее время ограничены. Многочисленные исследования доказали эффективность пробиотиков в лечении и профилактике заболеваний желудочно-кишечного тракта, таких как инфекционные и антибиотик-ассоциированные диареи, диареи путешественников, некротизирующий энтероколит, инфекция Helicobacter pylori, а также атопических заболеваний. Становится актуальным изучение эффективности пробиотиков в качестве средств профилактики острых респираторных инфекций среди детей и взрослых. Данные in vitro демонстрируют, что пробиотики обладают штаммоспецифическим иммуномодулирующим действием на иммунные клетки. Показано, что пробиотики эффективны в подавлении репликации различных респираторных вирусов, включая вирусы гриппа и респираторно-синцитиальный вирус. Подобные эффекты были продемонстрированы на мышах, было показано, что пробиотики способны снижать титры вируса в тканях легких и модулировать экспрессию противовирусных и провоспалительных генов до и после вирусной инфекции. Доклинические исследования также показывают уменьшение симптомов заболевания у мышей, что указывает на потенциальную клиническую пользу. Данные литературы по изучению применения пробиотиков и синбиотиков при вирусных инфекциях респираторного тракта показывают, что их использование связано с более низкой частотой и меньшей продолжительностью легких форм респираторной инфекции как у детей, так и у взрослых. Целесообразно дальнейшее проведение исследований для получения адекватных выводов об эффективности пробиотиков и синбиотиков при острых респираторных инфекциях. Viral infections of the respiratory tract are the most common cause of infectious diseases, especially in children. In most cases, especially when the upper respiratory tract is affected, acute respiratory viral infections are mild to moderate and often stop spontaneously. Pharmacological agents for the treatment or prevention of these infections in children are currently limited. Numerous studies have proven the effectiveness of probiotics in the treatment and prevention of diseases of the gastrointestinal tract, such as infectious and antibiotic-associated diarrhea, traveler's diarrhea, necrotizing enterocolitis, Helicobacter pylori infection, as well as atopic diseases. It is becoming urgent to study the effectiveness of probiotics as prophylactic agents for acute respiratory infections. among children and adults. In vitro data demonstrate that probiotics have strain-specific immunomodulatory effects on immune cells. Probiotics have been shown to be effective in suppressing the replication of various respiratory viruses, including influenza viruses and respiratory syncytial virus. Similar effects have been demonstrated in mice with the ability of probiotics to reduce viral titers in lung tissues and modulate the expression of antiviral and pro-inflammatory genes before and after viral infection. Preclinical studies also show improvement in symptoms in mice, indicating potential clinical benefit. Literature data on the use of probiotics and synbiotics for viral infections of the respiratory tract show that their use is associated with a lower frequency and duration of mild forms of respiratory infection in both children and adults. It is advisable to further conduct research necessary to obtain adequate conclusions about the effectiveness of probiotics and synbiotics in acute respiratory infections.

Lipoprotein(a): An update on its role in human health and disease

Over the past few years, there has been an undiminished interest on lipoprotein(a) [Lp(a)]. High Lp(a) levels have been proposed as an independent causal risk factor for atherosclerotic cardiovascular disease (CVD). The main question that remains to be answered, however, is the potential clinical benefit of Lp(a) reduction. This will contribute to the enrichment of our knowledge on the exact pathophysiological role of this lipoprotein. This narrative review aims to summarize currently available data on the structure, metabolism, and pathogenicity of Lp(a).

ATH434 Reverses Colorectal Dysfunction in the A53T Mouse Model of Parkinson’s Disease

Background: Gastrointestinal (GI) complications, that severely impact patient quality of life, are a common occurrence in patients with Parkinson’s disease (PD). Damage to enteric neurons and the accumulation of alpha-synuclein in the enteric nervous system (ENS) are thought to contribute to this phenotype. Copper or iron chelators, that bind excess or labile metal ions, can prevent aggregation of alpha-synuclein in the brain and alleviate motor-symptoms in preclinical models of PD. Objective: We investigated the effect of ATH434 (formally PBT434), a small molecule, orally bioavailable, moderate-affinity iron chelator, on colonic propulsion and whole gut transit in A53T alpha-synuclein transgenic mice. Methods: Mice were fed ATH434 (30 mg/kg/day) for either 4 months (beginning at ∼15 months of age), after the onset of slowed propulsion (“treatment group”), or for 3 months (beginning at ∼12 months of age), prior to slowed propulsion (“prevention group”). Results: ATH434, given after dysfunction was established, resulted in a reversal of slowed colonic propulsion and gut transit deficits in A53T mice to WT levels. In addition, ATH434 administered from 12 months prevented the slowed bead expulsion at 15 months but did not alter deficits in gut transit time when compared to vehicle-treated A53T mice. The proportion of neurons with nuclear Hu+ translocation, an indicator of neuronal stress in the ENS, was significantly greater in A53T than WT mice, and was reduced in both groups when ATH434 was administered. Conclusion: ATH434 can reverse some of the GI deficits and enteric neuropathy that occur in a mouse model of PD, and thus may have potential clinical benefit in alleviating the GI dysfunctions associated with PD.

Cryopreservation moderates the thrombogenicity of arterial allografts during storage

Introduction Management of vascular infections represents a major challenge in vascular surgery. The use of cryopreserved vascular allografts could be a feasible therapeutic option, but the optimal conditions for their production and use are not precisely defined. Aims To evaluate the effects of cryopreservation and the duration of storage on the thrombogenicity of femoral artery allografts. Methods In our prospective study, eleven multi-organ-donation-harvested human femoral arteries were examined at five time points during storage at -80°C: before cryopreservation as a fresh native sample and immediately, one, twelve and twenty-four weeks after the cryopreservation. Cross-sections of allografts were perfused with heparin-anticoagulated blood at shear-rates relevant to medium-sized arteries. The deposited platelets and fibrin were immunostained. The thrombogenicity of the intima, media and adventitia layers of the artery grafts was assessed quantitatively from the relative area covered by fibrin- and platelet-related fluorescent signal in the confocal micrographs. Results Regression analysis of the fibrin and platelet coverage in the course of the 24-week storage excluded the possibility for increase in the graft thrombogenicity in the course of time and supported the hypothesis for a descending trend in fibrin generation and platelet deposition on the arterial wall. The fibrin deposition in the cryopreserved samples did not exceed the level detected in any of the three layers of the native graft. However, an early (up to week 12) shift above the native sample level was observed in the platelet adhesion to the media. Conclusions The hemostatic potential of cryopreserved arterial allografts was retained, whereas their thrombogenic potential declined during the 6-month storage. The only transient prothrombotic change was observed in the media layer, where the platelet deposition exceeded that of the fresh native grafts in the initial twelve weeks after cryopreservation, suggesting a potential clinical benefit from antiplatelet therapy in this time-window.