Cardiovascular Toxicities Associated with Novel Cellular Immune Therapies.

Over the past decade, T-cell directed therapies, including chimeric antigen receptor T-cell (CAR-T) and bispecific T-cell engager (BTE) therapy have reshaped the treatment of an expanding number of hematologic malignancies, while tumor infiltrating lymphocytes (TILs), a recently approved cellular therapy, targets solid tumor malignancies. Emerging data suggests that these therapies may be associated with a high incidence of serious cardiotoxicities, including atrial fibrillation, heart failure, ventricular arrhythmias, and other cardiovascular toxicities. The development of these events is a major limitation to long-term survival following these treatments. This review examines the current state of evidence, including reported incidence rates, risk factors, mechanisms, and management strategies of cardiovascular toxicities following treatment with these novel therapies. We specifically focus on CAR-T, BTE, and their relation to arrhythmias, heart failure, myocarditis, bleeding, and other major cardiovascular events. Beyond the relationship between cytokine release syndrome and cardiotoxicity, we describe other potential mechanisms and highlight key unanswered questions and future directions of research.

Sociodemographic disparities in cardiovascular mortality by self-rated physical health: A U.S. nationwide county-level analysis.

OBJECTIVE: We investigated the association between self-rated poor physical health (srPPH), a validated proxy measure of health-related quality of life, and age-adjusted cardiovascular mortality (AACVM) rates across overall U.S. counties and within various demographics. STUDY DESIGN: Nationwide county-level analysis. METHODS: We analyzed county-level data spanning 2010-2019 from the Behavioral Risk Factors Surveillance System (BRFSS) and the Centers for Disease Control and Prevention (CDC). This analysis included data from 2892 counties with complete records on srPPH and AACVM. srPPH was defined as the age-adjusted average number of days respondents reported being in poor physical health over the past 30 days. To estimate the average srPPH per resident in each county, the CDC utilized validated statistical models applied to BRFSS data. To assess the association between srPPH and AACVM, we employed Poisson Generalized Linear Mixed Models, generating incident rate ratios (IRRs). RESULTS: Out of the 307,045,647 residents living in 2892 U S. counties in 2010, 8,157,571 (2.7 %) cardiovascular deaths were recorded during the study period. Counties where residents reported the greatest number of physically unhealthy days-indicative of higher srPPH-experienced the highest AACVM rates, despite significant decreases in overall AACVM rates from 2010 to 2019. Moreover, srPPH was independently associated with higher AACVM rates (IRR: 1.018; 95 % CI: 1.011 to 1.025) across most demographic groups, except Hispanics. This association was particularly strong among middle-aged (45-64 years old) women and elderly (≥65 years old) non-Hispanic Black individuals. CONCLUSION: srPPH may serve as a valuable community health marker that can help identify populations at risk for cardiovascular mortality, independent of other social determinants of health. When used in combination with objective measures of cardiovascular health, this metric can enhance targeted screening and intervention efforts in high-risk populations.

An update on the safety of lanreotide autogel for the treatment of patients with neuroendocrine tumors.

INTRODUCTION: Neuroendocrine neoplasms (NENs) are a rare group of tumors originating from neuroendocrine cells in various organs. They include neuroendocrine tumors (NETs) and neuroendocrine carcinomas (NECs), which differ in biological behavior and prognosis. NETs are usually well-differentiated and slow-growing, while NECs are poorly differentiated and more aggressive. Management of NETs often involves somatostatin analogs like octreotide and lanreotide to control tumor growth and alleviate symptoms, especially in well-differentiated NETs. Lanreotide is used to control tumor growth, and both lanreotide and octreotide alleviate symptoms. Treatment approaches may vary depending on the specific type and grade of the neuroendocrine neoplasm. AREAS COVERED: This review provides an update on the safety of lanreotide autogel in treating patients with NETs, through a comprehensive review of clinical trials, post-marketing surveillance, real-world evidence, and its safety profile. Specific adverse events, side effects, and potential risks associated with lanreotide autogel are discussed, along with risk mitigation strategies and recommendations for patient monitoring. EXPERT OPINION: The findings highlight the overall safety of lanreotide autogel in managing NETs, focusing on its efficacy in controlling hormone secretion, tumor progression, and symptom management. New safety concerns and precautions are also addressed to help healthcare providers make informed decisions when prescribing lanreotide autogel.

Cardiovascular toxicities associated with bispecific T-cell engager therapy.

BACKGROUND: Bispecific T-cell engagers (BTEs) are novel agents used to treat hematological malignancies. Early trials were underpowered to define cardiovascular adverse events (CVAE) and no large-scale studies systematically examined the CVAEs associated with BTEs. METHODS: Leveraging the US Food and Drug Administration's Adverse Event Reporting System-(FAERS), we identified the relative frequency of CVAEs after initiation of five BTE products approved by the Food and Drug Administration between 2014 and 2023 for the treatment of hematological malignancies. Adjusted reporting ORs (aROR) were used to identify disproportionate reporting of CVAEs with BTEs compared with background rates in the database. Fatality rates and risk ratios (RRs) for each adverse event (AE) were calculated. RESULTS: From 3668 BTE-related cases reported to FAERS, 747 (20.4%) involved CVAEs. BTEs as a class were associated with fatal CVAEs (aROR 1.29 (95% CI 1.12 to 1.50)), an association mainly driven by teclistamab (aROR 2.44 (95% CI 1.65 to 3.60)). Teclistamab was also associated with a disproportionate risk of myocarditis (aROR 25.70 (95% CI 9.54 to 69.23)) and shock (aROR 3.63 (95% CI 2.30 to 5.74)), whereas blinatumomab was associated with a disproportionate risk of disseminated intravascular coagulation (aROR 3.02 (95% CI 1.98 to 4.60)) and hypotension (aROR 1.59 (95% CI 1.25 to 2.03)). CVAEs were more fatal compared with non-CVAEs (31.1% vs 17.4%; RR 1.76 (95% CI 1.54 to 2.03)). Most CVAEs (83.3%) did not overlap with cytokine release syndrome. CONCLUSION: In the first postmarketing surveillance study of BTEs, CVAEs were involved in approximately one in five AE reports and carried a significant mortality risk.

Lack of leisure time physical activity and variations in cardiovascular mortality across US communities: a comprehensive county-level analysis (2011-2019).

OBJECTIVES: To investigate the associations between county-level proportions of adults not engaging in leisure-time physical activity (no LTPA) and age-adjusted cardiovascular mortality (AACVM) rates in the overall US population and across demographics. METHODS: Analysing 2900 US counties from 2011 to 2019, we used the Centers for Disease Control and Prevention (CDC) databases to obtain annual AACVM rates. No LTPA data were sourced from the CDC's Behavioural Risk Factor Surveillance System survey and county-specific rates were calculated using a validated multilevel regression and poststratification modelling approach. Multiple regression models assessed associations with county characteristics such as socioeconomic, environmental, clinical and healthcare access factors. Poisson generalised linear mixed models were employed to calculate incidence rate ratios (IRR) and additional yearly deaths (AYD) per 100 000 persons. RESULTS: Of 309.9 million residents in 2900 counties in 2011, 7.38 million (2.4%) cardiovascular deaths occurred by 2019. County attributes such as socioeconomic, environmental and clinical factors accounted for up to 65% (adjusted R2=0.65) of variance in no LTPA rates. No LTPA rates associated with higher AACVM across demographics, notably among middle-aged adults (standardised IRR: 1.06; 95% CI (1.04 to 1.07)), particularly women (1.09; 95% CI (1.07 to 1.12)). The highest AYDs were among elderly non-Hispanic black individuals (AYD=68/100 000). CONCLUSIONS: Our study reveals a robust association between the high prevalence of no LTPA and elevated AACVM rates beyond other social determinants. The most at-risk groups were middle-aged women and elderly non-Hispanic black individuals. Further, county-level characteristics accounted for substantial variance in community LTPA rates. These results emphasise the need for targeted public health measures to boost physical activity, especially in high-risk communities, to reduce AACVM.

The underutilization of preventive cardiovascular measures in patients with cancer: an analysis of the Behavioural Risk Factor Surveillance System, 2011-22.

AIMS: This study aimed to characterize the influence of a cancer diagnosis on the use of preventive cardiovascular measures in patients with and without cardiovascular disease (CVD). METHODS AND RESULTS: Data from the Behavioural Risk Factor Surveillance System Survey (spanning 2011-22) were used. Multivariable logistic regression models adjusted for potential confounders were applied to calculate average marginal effects (AME), the average difference in the probability of using a given therapy between patients with and without cancer. Outcomes of interest included the use of pharmacological therapies, physical activity, smoking cessation, and post-CVD rehabilitation. Among 5 012 721 respondents, 579 114 reported a history of CVD (coronary disease or stroke), and 842 221 reported a diagnosis of cancer. The association between cancer and the use of pharmacological therapies varied between those with vs. without CVD (P-value for interaction: <0.001). Among patients with CVD, a cancer diagnosis was associated with a lower use of blood pressure-lowering medications {AME: -1.46% [95% confidence interval (CI): -2.19% to -0.73%]}, lipid-lowering medications [AME: -2.34% (95% CI: -4.03% to -0.66%)], and aspirin [AME: -6.05% (95% CI: -8.88% to -3.23%)]. Among patients without CVD, there were no statistically significant differences between patients with and without cancer regarding pharmacological therapies. Additionally, cancer was associated with a significantly lower likelihood of engaging in physical activity in the overall cohort and in using post-CVD rehabilitation regimens, particularly post-stroke rehabilitation. CONCLUSION: Preventive pharmacological agents are underutilized in those with cancer and concomitant CVD, and physical activity is underutilized in patients with cancer in those with or without CVD. LAY SUMMARY: •This paper compared the use of preventive cardiovascular measures, both pharmaceutical and non-pharmaceutical, in patients with and without cancer.•In patients with cardiovascular disease and cancer, there is a lower use of preventive cardiovascular medications compared with those with cardiovascular disease but without cancer. This includes a lower utilization of blood pressure-lowering medications, cholesterol-lowering medications, and aspirin.•Patients with cancer reported lower levels of exercise but higher levels of smoking cessation compared with those without cancer.

Factors Associated With Sex Disparities in Leisure-Time Physical Activity: An Analysis of the Behavioral Risk Factor Surveillance System, 2011 to 2021.

OBJECTIVE: To identify whether sex disparities in leisure-time physical activity (LTPA) vary across population subgroups. PARTICIPANTS AND METHODS: We used data from the Behavioral Risk Factor Surveillance System (BRFSS) spanning 2011 to 2021. We examined subgroups by age, race/ethnicity, income, employment, education, marital status, body mass index, and cardiometabolic comorbidities (diabetes, hypertension, and cardiovascular disease) to identify where sex disparities in LTPA are most pronounced. RESULTS: Among 4,415,992 respondents (57.4% [2,533,234] women and 42.6% [1,882,758] men), women were less likely than men to report LTPA (73.0% vs 76.8%; odds ratio [OR], 0.817; 95% CI, 0.809 to 0.825). The gap was widest between the youngest (OR for the 18- to 24-year age group, 0.71; 95% CI, 0.68 to 0.74) and oldest (OR for the 80 years or older age group, 0.71; 95% CI, 0.69 to 0.73) respondents but was narrower between middle-aged adults (OR for the 50- to 59-year age group, 0.95; 95% CI, 0.93 to 0.97). Disparity was greater among non-Hispanic Black participants (OR, 0.70; 95% CI, 0.68 to 0.72) and Hispanic participants (OR, 0.79; 95% CI, 0.77 to 0.81) than among non-Hispanic White participants (OR, 0.85; 95% CI, 0.84 to 0.86). Disparities were greater at the lowest income levels (OR, 0.81; 95% CI, 0.78 to 0.85) and lower at the highest income levels (OR, 0.94; 95% CI, 0.91 to 0.96). The disparity was greater in unemployed individuals (OR, 0.78; 95% CI, 0.76 to 0.80) compared with employed individuals (OR, 0.91; 95% CI, 0.90 to 0.92). Moreover, disparity was greater in individuals with a body mass index in the overweight or obese range and those with diabetes, hypertension, or cardiovascular disease. CONCLUSION: Women are less likely than men to engage in LTPA. These disparities are greatest among the young and elderly, Black and Hispanic individuals, lower income and unemployed individuals, and individuals with cardiometabolic disease. Targeted interventions are needed to reduce sex-related disparities.

Fixed-Dose Combination (Polypill) for Cardiovascular Disease Prevention: A Meta-Analysis.

INTRODUCTION: This meta-analysis was performed to assess the efficacy of fixed-dose combination (polypill) in reducing the risk of mortality and cardiovascular events. METHODS: Medline, Scopus, Web of Science, and Cochrane Central were searched during May 2021. All randomized trials investigating the efficacy of antihypertensive and lipid-lowering ± antiplatelet drug combinations in patients at cardiovascular risk were included. Outcomes were presented as risk ratios or standardized mean differences with 95% CIs. RESULTS: A total of 16 trials (N = 26,567 participants) were included. The risk reduction for all-cause mortality (risk ratio = 0.90; 95% CI = 0.79, 1.01; I2 = 0%; moderate certainty) and major adverse cardiac events (risk ratio=0.84; 95% CI=0.68, 1.04; I2=51%; very low certainty) did not reach statistical significance in comparison with those of the control group. Subgroup analysis of studies that used an active control yielded similar results. However, significant reductions in major adverse cardiac event risk were observed in studies that exclusively targeted primary prevention, followed patients for ≥4 years, and had a low risk of bias. The polypill group had significantly higher adherence (risk ratio=1.18; 95% CI=1.06, 1.32; I2=96%; very low certainty) and comprable rates of adverse side effects (risk ratio=1.10; 95% CI=0.98, 1.23; I2=58%; moderate certainty) with those of the control group. Patients randomized to the polypill had significant reductions in systolic and diastolic blood pressure as well as in total and low-density lipoprotein cholesterol. DISCUSSION: Despite reductions in cardiovascular risk factors, the observed mortality benefit for the polypill did not reach statistical significance. Further studies are needed to validate its clinical benefits and determine the patient populations likely to achieve such benefits.

Long-term effectiveness of empiric cardio-protection in patients receiving cardiotoxic chemotherapies: A systematic review & bayesian network meta-analysis.

BACKGROUND: Cardioprotective therapies represent an important avenue to reduce treatment-limiting cardiotoxicities in patients receiving chemotherapy. However, the optimal duration, strategy and long-term efficacy of empiric cardio-protection remains unknown. METHODS: Leveraging the MEDLINE/Pubmed, CENTRAL and clinicaltrials.gov databases, we identified all randomised controlled trials investigating cardioprotective therapies from inception to November 2021 (PROSPERO-ID:CRD42021265006). Cardioprotective classes included ACEIs, ARBs, Beta-blockers, dexrazoxane (DEX), statins and mineralocorticoid receptor antagonists. The primary end-point was new-onset heart failure (HF). Secondary outcomes were the mean difference in left ventricular ejection fraction (LVEF) change, hypotension and all-cause mortality. Network meta-analyses were used to assess the cardioprotective effects of each therapy to deduce the most effective therapies. Both analyses were performed using a Bayesian random effects model to estimate risk ratios (RR) and 95% credible intervals (95% CrI). RESULTS: Overall, from 726 articles, 39 trials evaluating 5931 participants (38.0 ± 19.1 years, 72.0% females) were identified. The use of any cardioprotective strategy associated with reduction in new-onset HF (RR:0.32; 95% CrI:0.19-0.55), improved LVEF (mean difference: 3.92%; 95% CrI:2.81-5.07), increased hypotension (RR:3.27; 95% CrI:1.38-9.87) and no difference in mortality. Based on control arms, the number-needed-to-treat for 'any' cardioprotective therapy to prevent one incident HF event was 45, including a number-needed-to-treat of 21 with ≥1 year of therapy. Dexrazoxane was most effective at HF prevention (Surface Under the Cumulative Ranking curve: 81.47%), and mineralocorticoid receptor antagonists were most effective at preserving LVEF (Surface Under the Cumulative Ranking curve: 99.22%). CONCLUSION: Cardiotoxicity remains a challenge for patients requiring anticancer therapies. The initiation of extended duration cardioprotection reduces incident HF. Additional head-to-head trials are needed.

Galectin-3: A Novel Marker for the Prediction of Stroke Incidence and Clinical Prognosis.

Stroke, whether ischemic or haemorrhagic, is one of the main causes of mortality and disability all over the world, which entails huge burdens in both healthcare environments as well as social and economic aspects of life. Therefore, there is a continuous search for novel reliable biomarkers that can enhance the recognition of stroke events in a timely manner and predict the clinical outcomes following a stroke event. Galectins are a group of proteins expressed by many types of cells and tissues including vasculature, certain immune cells, fibroblasts, and gastrointestinal epithelial cells. These proteins vary in their structure and configuration according to their type and have a diversity of functions according to the type of tissue they are expressed in. Among these proteins, a few studies investigated mainly the roles played by galectin-1 (Gal-1) and galectin-3 (Gal-3) in the molecular mechanisms of atherosclerosis and in brain tissue remodeling after a stroke event. In this review, we present an updated overview of the current understanding of Gal-3's functions and implications in stroke occurrence and the response of the brain tissue to stroke events, which may be a key to its utility as a predictor of stroke incidence and clinical prognosis in the future.

Patent Foramen Ovale Closure and Decompression Sickness Among Divers.

BACKGROUND: Decompression sickness is a diving-related disease that results in various clinical manifestations, ranging from joint pain to severe pulmonary and CNS affection. Complications of this disease may sometimes persist even after treatment with hyperbaric oxygen therapy. In addition, it may hamper the quality of life by forcing divers to restrict their recreational practice. The presence of a patent foramen ovale (PFO) increases the risk of decompression sickness by facilitating air embolization. Therefore, PFO closure may play a role in reducing such complications. However, PFO closure remains associated with its own set of risks and complications. We sought to assess the benefit and harm of PFO closure for the prevention of decompression sickness in divers. METHODS: We conducted a comprehensive search of MEDLINE, Embase, CENTRAL, and Web of Science. Two-armed studies comparing the incidence of decompression sickness with or without PFO closure were included. We used a random-effects model to compute risk ratios comparing groups undergoing PFO closure to those not undergoing PFO closure. RESULTS: Four observational studies with a total of 309 divers (PFO closure: 141 and no closure: 168) met inclusion criteria. PFO closure was associated with a significantly lower incidence of decompression sickness (PFO-closure: 2.84%; no closure: 11.3%; RR: 0.29; 95% CI: 0.10 to 0.89; NNTB = 11), with low heterogeneity (I2 = 0%). The mean follow-up was 6.12 years (Standard deviation 0.70). Adverse events occurred in 7.63% of PFO closures, including tachyarrhythmias and bleeding. CONCLUSION: PFO closure may potentially reduce the risk of decompression sickness among divers; however, it is not free of potential downsides, with nearly one in thirteen patients in our analysis experiencing an adverse event.

Neural Stem Cell-Based Therapies and Glioblastoma Management: Current Evidence and Clinical Challenges.

Gliomas, which account for nearly a quarter of all primary CNS tumors, present significant contemporary therapeutic challenges, particularly the highest-grade variant (glioblastoma multiforme), which has an especially poor prognosis. These difficulties are due to the tumor's aggressiveness and the adverse effects of radio/chemotherapy on the brain. Stem cell therapy is an exciting area of research being explored for several medical issues. Neural stem cells, normally present in the subventricular zone and the hippocampus, preferentially migrate to tumor masses. Thus, they have two main advantages: They can minimize the side effects associated with systemic radio/chemotherapy while simultaneously maximizing drug delivery to the tumor site. Another feature of stem cell therapy is the variety of treatment approaches it allows. Stem cells can be genetically engineered into expressing a wide variety of immunomodulatory substances that can inhibit tumor growth. They can also be used as delivery vehicles for oncolytic viral vectors, which can then be used to combat the tumorous mass. An alternative approach would be to combine stem cells with prodrugs, which can subsequently convert them into the active form upon migration to the tumor mass. As with any therapeutic modality still in its infancy, much of the research regarding their use is primarily based upon knowledge gained from animal studies, and a number of ongoing clinical trials are currently investigating their effectiveness in humans. The aim of this review is to highlight the current state of stem cell therapy in the treatment of gliomas, exploring the different mechanistic approaches, clinical applicability, and the existing limitations.

Minimally invasive surgery versus transcatheter aortic valve replacement: a systematic review and meta-analysis.

Transcatheter aortic valve replacement (TAVR) has recently been approved for use in patients who are at intermediate and low surgical risk. Moreover, recent years have witnessed a renewed interest in minimally invasive aortic valve replacement (miAVR). The present meta-analysis compared the outcomes of TAVR and miAVR in the management of aortic stenosis (AS). We conducted an electronic search across six databases from 2002 (TAVR inception) to December 2019. Data from relevant studies regarding the clinical and length of hospitalisation outcomes were extracted and analysed using R software. We identified a total of 11 cohort studies, of which seven were matched/propensity matched. Our analysis demonstrated higher rates of midterm mortality (≥1 year) with TAVR (risk ratio (RR): 1.93, 95% CI: 1.16 to 3.22), but no significant differences with respect to 1 month mortality (RR: 1.00, 95% CI: 0.55 to 1.81), stroke (RR: 1.08, 95% CI: 0.40 to 2.87) and bleeding (RR: 1.45, 95% CI: 0.56 to 3.75) rates. Patients undergoing TAVR were more likely to experience paravalvular leakage (RR: 14.89, 95% CI: 6.89 to 32.16), yet less likely to suffer acute kidney injury (RR: 0.38, 95% CI: 0.21 to 0.69) compared with miAVR. The duration of hospitalisation was significantly longer in the miAVR group (mean difference: 1.92 (0.61 to 3.24)). Grading of Recommendations Assessment, Development and Evaluation assessment revealed ≤moderate quality of evidence in all outcomes. TAVR was associated with lower acute kidney injury rate and shorter length of hospitalisation, yet higher risks of midterm mortality and paravalvular leakage. Given the increasing adoption of both techniques, there is an urgent need for head-to-head randomised trials with adequate follow-up periods.

Aortic Dissection: A Review of the Pathophysiology, Management and Prospective Advances.

Aortic dissection is an emergent medical condition, generally affecting the elderly, characterized by a separation of the aortic wall layers and subsequent creation of a pseudolumen that may compress the true aortic lumen. Predisposing factors mediate their risk by either increasing tension on the wall or by causing structural degeneration. They include hypertension, atherosclerosis, and a number of connective tissue diseases. If it goes undetected, aortic dissection carries a significant mortality risk; therefore, a high degree of clinical suspicion and a prompt diagnosis are required to maximize survival chances. Imaging methods, most commonly a CT scan, are essential for diagnosis; however, several studies have also investigated the effect of several biomarkers to aid in the detection of the condition. The choice of intervention varies depending on the type of dissection, with open surgical repair remaining of choice in those with type. In dissections, however, the role of conventional open surgery has considerably diminished in complicated type B dissections, with endovascular repair, a much less invasive technique, proving to be more effective. In uncomplicated type B dissections, where medical choice reigned supreme as the optimal intervention, endovascular repair is being explored as a viable option which may reduce long- term mortality outcomes, although the ideal intervention in this situation is far from settled.

Clinical Review of COVID-19; Pathogenesis, Diagnosis, and Management.

Severe acute respiratory syndrome-coronavirus (SARS-CoV-2, or COVID-19 virus) is a worldwide pandemic pathogen infecting 210 territories. It belongs to the family coronaviriadae and the order Nidovirales. The SARS-CoV-2 virus is a positive-sense single-stranded RNA enveloped virus that includes spike proteins projecting from the envelope. The spike (S) protein interacts with the human angiotensin-converting enzyme 2 (ACE2) receptor, which plays a role in the viral entry into the cell. The SARS-CoV-2 virus is zoonotic; the wet animal market where live animals are sold is expected to be the source of infection. It is the third zoonotic coronavirus, after SARS-CoV and MERS-CoV. Transmission of the virus among humans is confirmed by direct contact, droplet infection, fecal-oral, and blood transmission. The symptoms of COVID 19 include fever, dry cough, headache, and difficulty in breathing. COVID 19 complications, including the development of acute respiratory distress syndrome (ARDS), acute organ injury, secondary infection, and shock, are common in immunocompromised and elderly patients. Up till now, there is no established treatment for COVID-19, and supportive measures including mechanical ventilation and the use of nonspecific anti-viral therapies such as Remdesevir, Liponavir, and chloroquine, are currently applied in severe cases. Also, until now, there is no approved vaccine for COVID-19. In this review, we have provided an update on the SARS-COV2 virus, focusing on the epidemiology, pathogenesis, clinical presentations, treatment options, and preventive measures associated with COVID-19 cases.