Interactions between integrin α9ß1 and VCAM-1 promote neutrophil hyperactivation and mediate poststroke DVT.

ABSTRACT: Venous thromboembolic events are significant contributors to morbidity and mortality in patients with stroke. Neutrophils are among the first cells in the blood to respond to stroke and are known to promote deep vein thrombosis (DVT). Integrin α9 is a transmembrane glycoprotein highly expressed on neutrophils and stabilizes neutrophil adhesion to activated endothelium via vascular cell adhesion molecule 1 (VCAM-1). Nevertheless, the causative role of neutrophil integrin α9 in poststroke DVT remains unknown. Here, we found higher neutrophil integrin α9 and plasma VCAM-1 levels in humans and mice with stroke. Using mice with embolic stroke, we observed enhanced DVT severity in a novel model of poststroke DVT. Neutrophil-specific integrin α9-deficient mice (α9fl/flMrp8Cre+/-) exhibited a significant reduction in poststroke DVT severity along with decreased neutrophils and citrullinated histone H3 in thrombi. Unbiased transcriptomics indicated that α9/VCAM-1 interactions induced pathways related to neutrophil inflammation, exocytosis, NF-κB signaling, and chemotaxis. Mechanistic studies revealed that integrin α9/VCAM-1 interactions mediate neutrophil adhesion at the venous shear rate, promote neutrophil hyperactivation, increase phosphorylation of extracellular signal-regulated kinase, and induce endothelial cell apoptosis. Using pharmacogenomic profiling, virtual screening, and in vitro assays, we identified macitentan as a potent inhibitor of integrin α9/VCAM-1 interactions and neutrophil adhesion to activated endothelial cells. Macitentan reduced DVT severity in control mice with and without stroke, but not in α9fl/flMrp8Cre+/- mice, suggesting that macitentan improves DVT outcomes by inhibiting neutrophil integrin α9. Collectively, we uncovered a previously unrecognized and critical pathway involving the α9/VCAM-1 axis in neutrophil hyperactivation and DVT.

Fibrous Dysplasia Masquerading as Sternal Malignancy: A Rare and Challenging Presentation.

This case report presents a rare and challenging manifestation of polyostotic fibrous dysplasia (FD), a skeletal developmental anomaly characterized by the proliferation of fibrous connective tissue intermingled with irregular bony trabeculae. While monostotic FD is more common, polyostotic FD can occur in the context of McCune-Albright syndrome, a multisystem developmental disorder. Our patient, a 55-year-old female with a history of diabetes, hypothyroidism, and dyslipidemia, presented with progressively worsening dysphagia, sternal pain, and swelling over three years. Clinical examination revealed a tender and hard swelling in the upper sternal area, prompting further evaluation. Laboratory results, including bone turnover markers, were unremarkable. Imaging studies unveiled a sizable anterior mediastinal lesion with heterogeneous enhancement and coarse calcifications, initially raising concerns of malignancy. Subsequent positron emission tomography scan findings confirmed FD involvement in both the sternum and right femur. Histopathology of the mediastinal mass revealed a spindle cell neoplasm with bony metaplasia, consistent with FD, supported by immunohistochemistry. A multidisciplinary team affirmed the diagnosis of polyostotic FD, and follow-up imaging after one year demonstrated no significant change in lesion size, confirming a benign etiology. While bisphosphonate therapy was planned, regrettably, the patient was lost to follow-up. This case underscores the importance of a comprehensive, multidisciplinary approach in diagnosing and managing complex presentations of FD, ultimately contributing to improved patient care and outcomes in such instances.

Successful Use of Photodynamic Therapy in a Patient with Squamous Cell Carcinoma of the Lung and Diffuse Endobronchial Lesions.

Field cancerization, a phenomenon in which multiple tumors arise in a carcinogen damaged field could potentially explain the synchronous and metachronous premalignant or malignant lesions surrounding the primary tumor in smokers with aerodigestive malignancies. We report the case of a patient with invasive squamous cell carcinoma (SqCC) of the lung, complicated by multiple synchronous, radiologically silent endobronchial lesions. He underwent successful treatment with stereotactic body radiation therapy (SBRT) followed by adjuvant photodynamic therapy (PDT). We wish to highlight the need for more prospective clinical studies to determine which patient population would be appropriate for early bronchoscopic evaluation and the efficacy of using multimodal therapies like PDT for field cancerization. Further studies could not only give clinicians the opportunity to diagnose radiologically silent endobronchial lesions, but could also lead to using multimodal therapies against field cancerization.

Anti-cancer Drugs Associated Atrial Fibrillation-An Analysis of Real-World Pharmacovigilance Data.

Background: Several anti-cancer drugs have been linked to new onset atrial fibrillation (AF) but the true association of these drugs with AF is unknown. The FDA Adverse Event Reporting System (FAERS), a publicly available pharmacovigilance mechanism provided by the FDA, collects adverse event reports from the United States and other countries, thus providing real-world data. Objectives: To identify anti-cancer drugs associated with AF using the FAERS database. Methods: The FAERS database was searched for all drugs reporting AF as an adverse event (AE). The top 30 anti-cancer drugs reporting AF cases were shortlisted and analyzed. Proportional reporting ratio (PRR) was used to measure disproportionality in reporting of adverse events for these drugs. Results: When analyzed for AF as a percentage of all reported AE for a particular drug, Ibrutinib had the highest percentage (5.3%) followed distantly by venetoclax (1.6%), bortezomib (1.6%), carfilzomib (1.5%), and nilotinib (1.4%). The percentage of cardiac AE attributable to AF was also highest for ibrutinib (41.5%), followed by venetoclax (28.4%), pomalidomide (23.9%), bortezomib (18.2%), and lenalidomide (18.2%). Drugs with the highest PRR for AF included ibrutinib (5.96, 95% CI= 5.70-6.23), bortezomib (1.65, 95% CI = 1.52-1.79), venetoclax (1.65, 95% CI = 1.46-1.85), carfilzomib (1.53, 95% CI = 1.33-1.77), and nilotinib (1.46, 95% CI = 1.31-1.63). Conclusions: While newer anti-cancer drugs have improved the prognosis in cancer patients, it is important to identify any arrhythmias they may cause early on to prevent increased morbidity and mortality. Prospective studies are needed to better understand the true incidence of new onset AF associated with anti-cancer drugs.

Cardiovascular complications associated with novel agents in the chronic lymphocytic leukemia armamentarium: A pharmacovigilance analysis.

INTRODUCTION: Over the last few years, improved outcomes in patients with chronic lymphocytic leukemia (CLL) have been credited to the introduction of novel agents for its treatment. However, the overall cardiovascular safety profile of these agents has not been studied adequately. METHODS: We searched the Food and Drug Administration Adverse Event Reporting System (FAERS) database for adverse events reported for several of these novel agents: ibrutinib, acalabrutinib, venetoclax, and idelalisib. RESULTS: A total of 6074 cardiac adverse events were identified; ibrutinib (4832/36581; 13.2%) was found to have the highest risk of cardiac adverse events. The frequency of atrial fibrillation was highest (41.5%) in the ibrutinib group, while the idelalisib and acalabrutinib groups had the highest reported frequencies of heart failure (25.1%) and myocardial infarction (13.6%), respectively. Hypertension was noted to be relatively higher in the acalabrutinib (25.6%) and venetoclax (11.8%) groups. Overall reported mortality associated with cardiac events was highest in the venetoclax (29.4%) and idelalisib (27.1%) groups. CONCLUSION: Novel agents in the CLL armamentarium have been associated with several cardiovascular adverse events. Further studies are needed to identify high-risk groups that would benefit from robust cardiovascular surveillance after initiation of treatment with these novel agents.

Do the 2013 United States Preventive Services Task Force guidelines for lung cancer screening fail high-risk African American smokers? An institutional retrospective observational cohort study.

BACKGROUND: Lung cancer cause nearly 1.76 million deaths worldwide in 2018. In 2011, the National-Lung-Cancer-Screening-Trial showed 20% relative risk reduction with LDCT and subsequently led to the current USPSTF screening guidelines. However, the predominant focus on elderly, Caucasian questions its generalizability to communities with young, African Americans such as our institution. Hence, the objective of our study is to investigate the need to modify the current screening guidelines at our institution by assessing the applicability of newer individual risk-based prediction models for LDCT screening. METHODS: This is a retrospective observational cohort study of newly diagnosed lung cancer patients at LSU Health Sciences Center Shreveport from 2011 to 2015. One-third of the patients did not meet the current USPSTF screening guidelines. We categorized them into high-risk (groups1 and 2), moderate-risk, and low-risk according to 2018 NCCN Lung Cancer Screening Guidelines Version 1.2020. The high-risk groups were differentiated using the Tammemagi lung cancer risk calculator. RESULTS: Among those who did not meet the screening guidelines, nearly 50% were African American, 95% with known smoking history, and 80% diagnosed at advanced stage at the time of diagnosis. After employing the Tammemagi Risk based calculator, 12.5% were categorized into high-risk group 2, who are also eligible for annual LDCT. CONCLUSION: The current USPSTF guidelines have failed in our population consisting of young African American smokers, questioning the health disparity in medicine. By employing individual risk-based prediction models, we could potentially identify tailored high-risk populations leading to appropriate use of LDCT screening.

Excellent response to chemotherapy post immunotherapy.

INTRODUCTION: Immunotherapy in the form of immune checkpoint inhibitors has changed the landscape of cancer treatment. Newer monoclonal antibodies are coming up and are being tested in various cancers during different stages of treatment. With the increasing use of immune checkpoint inhibitors in the management of various types of cancers, the question is raised as to what next can be offered to a patient who has progressed on this newer treatment. Does Sequence matter? There have been reports of improved responses to chemotherapy after immunotherapy in the form of vaccines. Here we present a case series of 6 patients who progressed on immunotherapy with immune checkpoint inhibitors after initial modality of treatment (chemotherapy/radiation), subsequently received chemotherapy with excellent response. METHODS: We have a cohort of six patients who had disease progression on second line Immunotherapy for solid or hematological malignancies and had ECOG < 2. All these patients received third line salvage chemotherapy. Three patients had metastatic head and neck cancer, 2 had non-small cell lung cancer (NSCLC), and one had T -cell rich B- cell lymphoma. Prior review and approval were obtained from our institutional review board. RESULTS: All patients had an excellent response to chemotherapy in third line setting, after immune checkpoint inhibitors and most of them achieved a complete response. CONCLUSION: Targeting cancer with chemotherapy after failure of immunotherapy is a valid option and can lead to better response rates and PFS which may lead to OS. This effect may be secondary to immunotherapy removing the inhibition exerted by tumor cells or other immune cells initially followed by cytotoxic chemotherapy mediated killing of tumor cells.