ABSTRACT

Crizotinib, a small-molecule tyrosine kinase inhibitor targeting ALK, MET and ROS1, is the first-line drug for ALK-positive metastatic non-small cell lung cancer and is associated with severe, sometimes fatal, cases of cardiac failure, which increases the risk of mortality. However, the underlying mechanism remains unclear, which causes the lack of therapeutic strategy. We established in vitro and in vivo models for crizotinib-induced cardiotoxicity and found that crizotinib caused left ventricular dysfunction, myocardial injury and pathological remodeling in mice and induced cardiomyocyte apoptosis and mitochondrial injury. In addition, we found that crizotinib prevented the degradation of MET protein by interrupting autophagosome-lysosome fusion and silence of MET or re-activating macroautophagy/autophagy flux rescued the cardiomyocytes death and mitochondrial injury caused by crizotinib, suggesting that impaired autophagy activity is the key reason for crizotinib-induced cardiotoxicity. We further confirmed that recovering the phosphorylation of PRKAA/AMPK (Ser485/491) by metformin re-activated autophagy flux in cardiomyocytes and metformin rescued crizotinib-induced cardiomyocyte injury and cardiac complications. In summary, we revealed a novel mechanism for crizotinib-induced cardiotoxicity, wherein the crizotinib-impaired autophagy process causes cardiomyocyte death and cardiac injury by inhibiting the degradation of MET protein, demonstrated a new function of impeded autophagosome-lysosome fusion in drugs-induced cardiotoxicity, pointed out the essential role of the phosphorylation of PRKAA (Ser485/491) in autophagosome-lysosome fusion and confirmed metformin as a potential therapeutic strategy for crizotinib-induced cardiotoxicity.

PMID:37733896 | DOI:10.1080/15548627.2023.2259216

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PubMed articles on: Cancer & VTE/PE

Generalizability of COBRA: A Parsimonious Perioperative Venous Thromboembolism Risk Assessment Model

J Surg Res. 2023 Sep 8;293:8-13. doi: 10.1016/j.jss.2023.08.008. Online ahead of print.

ABSTRACT

INTRODUCTION: Standardized use of venous thromboembolism (VTE) risk assessment models (RAMs) in surgical patients has been limited, in part due to the cumbersome workflow addition required to use available models. The COBRA score-capturing cancer diagnosis, (old) age, body mass index, race, and American Society of Anesthesiologists Physical Status score-has been reported as a potentially automatable VTE RAM that circumvents the cumbersome workflow addition that most RAMs represent. We aimed to test the ability of the COBRA model to effectively risk-stratify patients across various populations.

METHODS: Patients were included from the 2014-2019 American College of Surgeons National Surgical Quality Improvement Program (NSQIP) Participant Use Data File for two hospitals, representing colorectal, endocrine, breast, transplant, plastic, and general surgery services. COBRA score was calculated for each patient using preoperative characteristics. We calculated negative predictive value (NPV) for VTE outcomes and compared the COBRA score to NSQIP's expected VTE rate for all patients, between the two hospitals, and between subspecialty service lines.

RESULTS: Of the 10,711 patients included, those with COBRA <4

CONCLUSIONS: The COBRA score is concordant with the traditional gold standard NSQIP VTE RAM and demonstrates interhospital and service-specific generalizability, although performance was limited in especially low-risk patients. The model adequately risk-stratifies surgical patients preoperatively, potentially providing clinical decision support for perioperative workflows.

PMID:37690384 | DOI:10.1016/j.jss.2023.08.008

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PubMed articles on: Cardio-Oncology

Cardiovascular Imaging in Contemporary Cardio-Oncology: A Scientific Statement From the American Heart Association

Circulation. 2023 Sep 21. doi: 10.1161/CIR.0000000000001174. Online ahead of print.

ABSTRACT

Advances in cancer therapeutics have led to dramatic improvements in survival, now inclusive of nearly 20 million patients and rising. However, cardiovascular toxicities associated with specific cancer therapeutics adversely affect the outcomes of patients with cancer. Advances in cardiovascular imaging have solidified the critical role for robust methods for detecting, monitoring, and prognosticating cardiac risk among patients with cancer. However, decentralized evaluations have led to a lack of consensus on the optimal uses of imaging in contemporary cancer treatment (eg, immunotherapy, targeted, or biological therapy) settings. Similarly, available isolated preclinical and clinical studies have provided incomplete insights into the effectiveness of multiple modalities for cardiovascular imaging in cancer care. The aims of this scientific statement are to define the current state of evidence for cardiovascular imaging in the cancer treatment and survivorship settings and to propose novel methodological approaches to inform the optimal application of cardiovascular imaging in future clinical trials and registries. We also propose an evidence-based integrated approach to the use of cardiovascular imaging in routine clinical settings. This scientific statement summarizes and clarifies available evidence while providing guidance on the optimal uses of multimodality cardiovascular imaging in the era of emerging anticancer therapies.

PMID:37732422 | DOI:10.1161/CIR.0000000000001174

04:44

PubMed articles on: Cancer & VTE/PE

Pharmacological Thromboprophylaxis in People with Hemophilia Experiencing Orthopedic Surgery: What Does the Literature Say in 2023?

J Clin Med. 2023 Aug 26;12(17):5574. doi: 10.3390/jcm12175574.