The Bone Cement Hypercoagulation Syndrome: Pathophysiology, Mortality, and Prevention.

Since Charnley introduced acrylic cement to seal metallic hip prostheses in the 1950s, reports of perioperative fatal cardiorespiratory and vascular dysfunctions have been published. Studies on humans and animals have shown neurogenic stimulation and substantial local and systemic activation of coagulation are caused by surgical bone marrow damage and chemical cell destruction by toxic monomeric methyl methacrylate from the implanted cement and other tissue-released substances. Venous blood-borne cell fragments and conjugates of activated cells from the surgical site are sequestered and trapped in the pulmonary microcirculation. A substantial hypercoagulation occurs in the lung circulation. Hypercoagulable blood is passed over to the arterial side and may cause vessel obliteration and organ damage. This process may affect the brain, heart, and kidneys and, through the release of vasoactive substances, introduce hemodynamic imbalances that can lead to fatal outcomes in susceptible populations such as elderly patients with hip fractures. The main underlying pathophysiologic processes leading to these occasionally devastating outcomes are a substantial activation of coagulation and cell destruction caused by the toxic substance released by curing bone cement and several vasoactive substances.

Malignant Pleural Mesothelioma: Current Understanding of the Immune Microenvironment and Treatments of a Rare Disease.

Malignant pleural mesothelioma is a rare disease with an annual incidence of around 3000 cases a year in the United States. Most cases are caused by asbestos exposure, with a latency period of up to 40 years. Pleural mesothelioma is an aggressive disease process with overall survival of roughly 6-12 months after the time of diagnosis. It is divided into three subtypes: epithelioid, mixed type, and sarcomatoid type, with the epithelioid subtype having the best overall survival. Often, the treatment is multimodality with surgery, chemotherapy, and radiation. The survival benefit is improved but remains marginal. New treatment options involving targeted immune therapies appear to offer some promise. The tumor microenvironment is the ecosystem within the tumor that interacts and influences the host immune system. Understanding this complex interaction and how the host immune system is involved in the progression of the disease process is important to define and guide potential treatment options for this devastating and rare disease.

Neoadjuvant Chemotherapy vs Chemoradiation Therapy Followed by Sleeve Resection for Resectable Lung Cancer.

BACKGROUND: Traditionally, neoadjuvant chemoradiation therapy is followed by resection in patients with locally advanced non-small cell lung cancer (NSCLC). The risks and benefits of this approach are not well defined in patients requiring a sleeve lung resection. In this context, we compare the short- and long-term outcomes of neoadjuvant chemotherapy alone vs chemoradiation therapy followed by sleeve lung resection. METHODS: We used the National Cancer Database to identify locally advanced NSCLC patients who received chemotherapy-alone or chemoradiation therapy in the neoadjuvant setting, followed by a sleeve lung resection, between 2006 and 2017. Our outcomes of interest were 30-day mortality, 90-day mortality, and overall survival. To minimize confounding by indication, we used propensity score adjustment, logistic regression, Kaplan-Meier survival analysis, and Cox proportional hazards models to identify associations. RESULTS: Of 176 patients undergoing sleeve lung resection, 92 (52.3%) received neoadjuvant chemotherapy-alone, and 84 (47.7%) received neoadjuvant chemoradiation therapy. Patients in both groups were well balanced in age, sex, race, Charlson-Deyo comorbidity index, insurance status, median income, and education (all P > .05). Similarly, the groups were well balanced in histology, tumor location, and stage (all P > .05). Patients receiving neoadjuvant chemoradiation therapy had higher 90-day mortality (11.96% vs 2.38%, P = .015), and there was no difference in overall survival between the neoadjuvant chemotherapy-alone vs chemoradiation therapy cohorts (P = .621). CONCLUSIONS: In this national study of patients with locally advanced resectable NSCLC requiring a sleeve lung resection, neoadjuvant chemoradiation therapy was associated with a 5-fold increase in 90-day mortality without an overall survival benefit over neoadjuvant chemotherapy-alone.

Inflammatory cytokines in robot-assisted thoracic surgery versus video-assisted thoracic surgery.

Background: Cytokines play a crucial role in the inflammatory response and are essential modulators of injury repair mechanisms. While minimally invasive operations have been shown to induce lower levels of cytokines compared to open thoracotomy, the inflammatory cytokine profile difference between video-assisted (VATS) and robotic-assisted thoracic surgery (RATS) techniques has yet to be elucidated. Methods: In this prospective observational study of 45 patients undergoing RATS (n=30) or VATS (n=15) lung resection for malignancy, plasma levels of interleukin (IL)-1α, IL-1ß, IL-2, IL-4, IL-6, IL-8, IL-10, vascular endothelial growth factor (VEGF), interferon (IFN)-γ, tumor necrosis factor (TNF)-α, monocyte chemo-attractant protein (MCP)-1, and endothelial growth factor (EGF) were measured before and after surgery via immunoassay. Results: Levels of IL-6 and MCP-1 were significantly higher in patients undergoing VATS than in patients undergoing RATS (P<0.001 and P=0.005, respectively) 2 hours following surgery. MCP-1 levels were also found to be significantly higher in the VATS group (P<0.001) 24 hours following surgery. IL-1α, IL-1ß, IL-2, IL-4, IL-8, IL-10, IFN-γ, TNF-α, and EGF levels were not significantly different at any time-point comparing VATS to RATS. Conclusions: The VATS approach is associated with a more robust pro-inflammatory cytokine response through the upregulation of MCP-1 and IL-6 when compared to the RATS approach in patients undergoing anatomic lung resection. Further studies are necessary to validate the clinical significance of this finding.

Development and Implementation of an Online Global Pharmacovigilance Certificate Program During the COVID-19 Pandemic.

Pharmacovigilance plays a lifesaving role in the practice of medicine. In 2021, during the Coronavirus Infectious Disease 2019 (COVID-19) pandemic, Loyola University Chicago launched a graduate-level Pharmacovigilance Certificate Program (PV-CERT) and a pre-professional non-graduate Pharmacovigilance Certificate Course (EPEC-PV), to provide students a comprehensive and contemporary understanding of the principles and practices of pharmacovigilance. Formal training in pharmacovigilance through this course provided a structured understanding of how safety data are generated through clinical trials and from real-world evidence as well as the regulatory environment in which data are monitored and interpreted. Pharmacovigilance training is of critical importance, especially during the COVID-19 pandemic, during which several drugs were re-purposed for the management of various stages of COVID-19 without conventional safety data. Moreover, the safety of currently-used vaccines is of concern in some populations. Although anticoagulants and antithrombotic medications are crucial in the management of COVID-19, a clear pharmacovigilance program on their use in this indication is not established. As the century progresses, new diseases and infectious agents will require novel therapies for which the evaluation of benefits versus risks will be as essential as it has been for the current COVID-19 pandemic. As such, the Loyola course and accompanying programs on pharmacovigilance will play a key role in educating the next generation of professionals in pursuing careers in the development of therapies that ultimately improve patient outcomes while maintaining rigorous safety standards.

Differential Neutralization of Apixaban, Betrixaban, Edoxaban, and Rivaroxaban by Andexanet Alfa as Measured by Whole Blood Thromboelastographic Analysis.

INTRODUCTION: The available oral anti-Xa agents are routinely used for the management of thrombotic disorders. A molecularly modified recombinant coagulation FXa, also known as Andexanet Alfa (AA), that has been developed as an antidote to neutralize the bleeding effects of oral FXa inhibitors, such as Apixaban and Rivaroxaban. MATERIALS AND METHODS: This study utilized thromboelastography (TEG 5000 Hemostasis System), to investigate the neutralizing effects of AA at different concentrations of oral FXa inhibitors measuring such parameters as R-Time, K-Time, Angle, and Max Amplitude (MA). Apixaban, Betrixaban, Edoxaban, and Rivaroxaban were obtained commercially in powdered form. Each of these drugs was supplemented with freshly drawn whole citrated blood at a concentration of 1 µg/mL. And subsequently mixed with AA at 50 or 100 µg/mL. RESULTS: At a concentration of 1 µg/mL, all FXa inhibitors produced variable anticoagulant effects in the order of Edoxaban > Betrixaban > Rivaroxaban > Apixaban. AA at 100 µg/mL produced a complete neutralization of these inhibitors whereas at 50 µg/mL relatively weaker neutralization as measured by various parameters. CONCLUSION: These results suggest that regardless of the variable anticoagulant effects exhibited by the FXa Inhibitors, AA at FC = 100 µg/mL fully neutralized these agents as measured by the TEG parameters. AA was shown to be more effective in neutralizing Betrixaban and least effective in Apixaban. The neutralization of various FXa inhibitors was dose and donor-dependent warranting dosage adjustment for optimal outcomes.

Application of Rotational Thromboelastometry in Patients with Acute Promyelocytic Leukemia.

INTRODUCTION: Hemorrhagic early death (HED) remains a major cause of treatment failure among patients with acute promyelocytic leukemia (APL). We aimed to investigate the prognostic potential of rotational thromboelastometry (ROTEM) for bleeding in patients with APL. MATERIALS AND METHODS: 31 newly-diagnosed APL patients (median age of 40 years; 14 female/17 male) that underwent treatment at the Clinic of Hematology UCCS from 2016-2020 with all-trans retinoic acid and anthracyclines were recruited. CBCs (complete blood count), conventional coagulation tests (CCTs), and ROTEM parameters obtained before treatment initiation were evaluated. RESULTS: All patients demonstrated at least one ROTEM parameter out of the reference range. ROTEM parameters associated with significant hemorrhage were EXTEM clotting time (CT) (P = 0.041) and INTEM amplitude 10 (A10) (P = 0.039), however, only EXTEM CT (P = 0.036) was associated with HED. Among CBCs and CCTs, only platelets were associated with significant bleeding (P = 0.015), while D-dimer was associated with both bleeding and HED (P = 0.001 and P = 0.002, respectively). CONCLUSION: Our results indicate that ROTEM parameters may reveal hypocoagulability in APL patients and have the potential to improve current hemorrhage prognostic methods. Additionally, these results suggest the combination of ROTEM and CCTs might be useful in identifying patients at risk for HED.

The impact of marginal lung function on outcomes in the era of minimally invasive thoracic surgery.

BACKGROUND: The effect of marginal lung function on outcomes after lung resection has traditionally been studied in the context of open thoracic surgery. Its impact on postoperative outcomes in the era of minimally invasive lung resection is unclear. METHODS: In this retrospective cohort study, we included adult patients who underwent minimally invasive lung resection at our institution between January 2017 and May 2020 for known malignancy or lung nodule. Marginal lung function was defined as pre-operative forced expiratory volume in 1 second (FEV1) and/or diffusion lung capacity of carbon monoxide <60% of predicted. Our outcomes included a composite outcome of pulmonary morbidity and/or 30- and 90-day mortality, and hospital length of stay. We used multivariable logistic and Poisson regression models to identify associations with outcomes, and Kaplan-Meier and Cox models to estimate survival. RESULTS: Of 300 patients, 88 (29%) had marginal lung function. Patients in the marginal group were more likely to be female (69% vs. 56%; P=0.028), and more likely to have: hypertension (HTN) (83% vs. 71%; P=0.028), chronic obstructive pulmonary disease (COPD) (38% vs. 12%; P<0.001), interstitial lung disease (ILD) (9% vs. 3%; P<0.019), and ischemic heart disease (28% vs. 18%; P=0.033). Patients were similar in terms of age (68±8 vs. 68±10 years; P=0.932), and other comorbidities. Anatomic lung resection comprised 56.8% of the marginal group vs. 74% in the non-marginal group (P=0.003). The most common complication was prolonged air leak (18.2% vs. 11.8%; P=0.479). Marginal lung function had a trend toward increased composite respiratory complications (22.7% vs. 15.1%; P=0.112) and 90-day mortality (5.7% vs. 4.2%; P=0.591), although they did not reach statistical significance. There was a statistically significant 1-day average increase in length of stay in the marginal lung function cohort (4.6 vs. 3.4 days; P<0.015) with a stronger association with diffusion lung capacity of carbon monoxide than FEV1. Survival was similar (marginal function HR =1.0; P=0.994). CONCLUSIONS: In the era of minimally invasive thoracic surgery, lung resection in patients with marginal lung function may be considered in select patients. These findings aid in the selection consideration and counseling of this patient population.

The Relationship Between Thrombo-Inflammatory Biomarkers and Cellular Indices of Inflammation in Lymphoma Patients.

INTRODUCTION: Thrombo-inflammatory biomarkers play an important role in the pathogenesis of lymphoma. We aimed to characterize the interrelationship of thrombo-inflammatory biomarkers and blood cellular indices in lymphoma patients. MATERIALS AND METHODS: Ninety-eight lymphoma patient samples were collected from Lymphoma Center of Clinic of Hematology, University of Belgrade, Serbia. Normal controls (n = 50) represented plasma from healthy individuals. Plasminogen activator inhibitor (PAI-1), D-Dimer, factor XIII, C-reactive protein (CRP), microparticles (Mp), Von Willebrand factor (vWF), total protein S, urokinase-type plasminogen activator (uPA), tumor necrosis factor (TNFα), ß2-glycoprotein I (ß2GPI), and fibronectin levels were measured utilizing commercially-available ELISA methods. Thrombin generation profile (TGA) was measured using a fluorometric kinetic assay. Platelets, leukocytes, lymphocytes, and neutrophils were measured in conjunction with the complete blood profile. RESULTS: Statistically significant differences were noted in levels of PAI-1, D-Dimer, factor XIII, CRP, microparticles, vWF, uPA, TNFα, ß2GPI, fibronectin, and TGA when compared to normal (all P values < .001). Platelet to leukocyte ratio (PLA) correlated to TNFα and fibronectin (R = -0.31 and -0.53, respectively) and the platelet to neutrophil ratio (PNR) correlated to factor XIII and ß2GPI (R = 0.40 and 0.40, respectively). CONCLUSION: Plasma samples from lymphoma patients demonstrated a significantly altered thrombo-inflammatory biomarker profile that has notable correlations to blood cellular indices.

Illuminating cell signaling with genetically encoded FRET biosensors in adult mouse cardiomyocytes.

FRET-based biosensor experiments in adult cardiomyocytes are a powerful way of dissecting the spatiotemporal dynamics of the complicated signaling networks that regulate cardiac health and disease. However, although much information has been gleaned from FRET studies on cardiomyocytes from larger species, experiments on adult cardiomyocytes from mice have been difficult at best. Thus the large variety of genetic mouse models cannot be easily used for this type of study. Here we develop cell culture conditions for adult mouse cardiomyocytes that permit robust expression of adenoviral FRET biosensors and reproducible FRET experimentation. We find that addition of 6.25 µM blebbistatin or 20 µM (S)-nitro-blebbistatin to a minimal essential medium containing 10 mM HEPES and 0.2% BSA maintains morphology of cardiomyocytes from physiological, pathological, and transgenic mouse models for up to 50 h after adenoviral infection. This provides a 10-15-h time window to perform reproducible FRET readings using a variety of CFP/YFP sensors between 30 and 50 h postinfection. The culture is applicable to cardiomyocytes isolated from transgenic mouse models as well as models with cardiac diseases. Therefore, this study helps scientists to disentangle complicated signaling networks important in health and disease of cardiomyocytes.

In Vivo Cannulation Methods for Cardiomyocytes Isolation from Heart Disease Models.

Isolation of high quality cardiomyocytes is critically important for achieving successful experiments in many cellular and molecular cardiology studies. Methods for isolating cardiomyocytes from the murine heart generally are time-sensitive and experience-dependent, and often fail to produce high quality cells. Major technical difficulties can be related to the surgical procedures needed to explant the heart and to cannulate the vessel to mount onto the Langendorff system before in vitro reperfusion can begin. During this period, transient hypoxia and ischemia may damage the heart, resulting in low yield and poor quality of cells, especially for heart disease models that have fragile cells. We have developed novel in vivo cannulation methods to minimize hypoxia and ischemia, and fine-tuned the entire protocol to produce high quality ventricular myocytes. The high cell quality has been confirmed using important structural and functional criteria such as morphology, t-tubule structure, action potential morphology, Ca2+ signaling, responsiveness to beta-adrenergic agonist, and ability to have robust contraction under mechanically loaded condition. Together these assessments show the preservation of the cardiac excitation-contraction machinery in cells isolated using this technique. The in vivo cannulation method enables consistent isolation of high-quality cardiomyocytes, even from heart disease models that were notoriously difficult for cell isolation using traditional methods.