ABSTRACT

Trastuzumab, the humanized monoclonal antibody specific for HER2 receptor, is the gold standard in the treatment of HER2+ breast cancer. Despite its high therapeutic efficacy, cardiotoxicity has emerged as a significant side effect. The molecular mechanisms involved are not well understood, but all converge on mitochondria. Mitochondrial Cx43 can confer cardioprotection by regulating mitochondrial calcium homeostasis, ROS production and propagation of apoptotic signals, and studies report that it is overexpressed both in ischemic preconditioning and in Doxorubicin-induced cardiotoxicity. This study was designed to evaluate whether mitochondrial Cx43 (mCx43) is also involved in Trastuzumab-induced cardiotoxicity. Here we demonstrated that mCx43 is overexpressed in Trastuzumab-treated H9c2 cells. Our data showed that inhibition of Cx43 translocation to mitochondria, obtained by radicicol pre-treatment, significantly increases cytosolic and mitochondrial superoxide formation, mitochondrial membrane depolarization and the consequent apoptosis induced by Trastuzumab. Our results support the hypothesis that disruption of mitochondrial function is the principal mechanism by which Trastuzumab elicits its cardiotoxicity and mCx43 appears to counteract the Trastuzumab-induced mitochondrial damage.

PMID:32599261 | DOI:10.1016/j.tiv.2020.104926

20:06

PubMed articles on: Cancer & VTE/PE

Direct Oral Anticoagulants In Patients With Hematologic Malignancies

Serrao A, et al. Hematol Oncol 2020.

ABSTRACT

The anticoagulant treatment for patients with hematologic malignancies is low molecular weight heparin (LMWH), considered the safest in this particular patients setting. Although direct oral anticoagulants (DOACs) have proven their efficacy and safety in patients with cancer, their use can be challenging in patients with hematologic malignancies due to the peculiarity of these neoplasms: high thrombotic risk, possible onset of thrombocytopenia and concomitant anticancer therapies. The aim of our study was to evaluate the efficacy and safety of DOACs for venous thromboembolism or atrial fibrillation in patients with hematologic malignancies and plasmatic DOACs level during anticancer therapy and at time of bleeding or thrombotic complications. We evaluated patients with hematologic malignancies treated with DOACs for venous thromboembolism or atrial fibrillation; therapy was maintained until the platelet count was ≥50x109 /L. In case of concomitant anticancer treatment and hemorrhagic or thrombotic events, we checked DOACs plasma levels (trough and peak). The patients evaluated were 135:104/135 were on anticancer therapy. We did not observe either thrombotic or major hemorrhagic adverse events. Minor bleedings occurred in 10 patients and clinical relevant non major (CRNM) in 2 patients. There was a statistically significant correlation between bleedings and myelodysplastic syndrome. DOACs resulted effective and safe in patients with hematologic malignancies. DOACs plasma level can be helpful in suggesting an early dose adjustment to prevent hemorrhagic adverse event in patients on concomitant anticancer therapy. Larger prospective studies including hematologic patients are warranted to confirm the safety and efficacy of DOACs. This article is protected by copyright. All rights reserved.

PMID:32588912 | DOI:10.1002/hon.2770

20:06

PubMed articles on: Cancer & VTE/PE

Effectiveness and safety of rivaroxaban versus warfarin in obese patients with acute venous thromboembolism: analysis of electronic health record data

Costa OS, et al. J Thromb Thrombolysis 2020.

ABSTRACT

There is limited data evaluating clinical outcomes of rivaroxaban versus warfarin in obese patients with venous thromboembolism (VTE). Our objective was to evaluate the effectiveness and safety of rivaroxaban versus warfarin in obese VTE patients. We performed a cohort analysis using Optum® De-Identified Electronic Health Record data from 11/1/2012 to 9/30/2018. Patients with a body mass index (BMI) ≥ 30 kg/m2 admitted to the hospital, emergency department or observation unit for VTE, prescribed rivaroxaban or warfarin as their first oral anticoagulant (OAC) within 7-days and had ≥12-months of EHR activity prior were included. We excluded patients with OAC use at baseline or cancer. Patients were 1:1 matched (standard differences<0.10).2 were performed. Risk was compared using Cox regression and reported as hazard ratios (HRs) with 95% confidence intervals (CI). We identified 6755 rivaroxaban and 6755 warfarin users with BMI ≥ 30 kg/m2 and incident VTE. At 3-, 6- and 12-months, rivaroxaban was associated with a reduced hazard of recurrent VTE compared to warfarin (HR 0.61, 95%CI 0.51-0.72; HR 0.65, 95%CI 0.55-0.77; HR 0.63, 95%CI 0.54-0.74) with no difference in major bleeding (HR 0.99, 95%CI 0.68-1.44; HR 0.90, 95%CI 0.64-1.26; HR 1.00, 95%CI 0.73-1.36). No statistical difference was found across BMI categories for either recurrent VTE (p-interaction≥0.43) or major bleeding (p-interaction ≥ 0.58) at any time point. In obese VTE patients, prescription of rivaroxaban was associated with a significantly reduced risk of recurrent VTE versus warfarin, without impacting major bleeding. Our findings remained consistent across BMI classes.

PMID:32588288 | DOI:10.1007/s11239-020-02199-0

20:06

PubMed articles on: Cardio-Oncology

A Comprehensive Review of Clinical Cardiotoxicity Incidence of FDA-Approved Small-Molecule Kinase Inhibitors

Jin Y, et al. Front Pharmacol 2020 - Review.

ABSTRACT

Numerous protein kinases encoded in the genome have become attractive targets for the treatment of different types of cancer. As of January 2020, a total of 52 small-molecule kinase inhibitors (SMKIs) have been approved by the FDA. With the numerous clinical trials and a heavy focus on drug safety, SMKI-induced cardiotoxicity, which is a life-threatening risk, has greatly attracted the attention of researchers. In this review, the SMKIs with cardiotoxicity incidence were described exhaustively. The data were collected from 42 clinical trials, 25 FDA-published documents, seven meta-analysis/systematic reviews, three case reports and more than 50 other types of articles. To date, 73% (38 of 52) of SMKIs have reported treatment-related cardiotoxicity. Among the 38 SMKIs with known cardiotoxicity, the rates of incidence of cardiac adverse events were QT prolongation: 47% (18 of 38), hypertension: 40% (15 of 38), left ventricular dysfunction: 34% (13 of 38), arrhythmia: 34% (13 of 38), heart failure: 26% (10 of 38) and ischemia or myocardial infarction: 29% (11 of 38). In the development process of novel SMKIs, more attention should be paid to balancing the treatment efficacy and the risk of cardiotoxicity. In preclinical drug studies, producing an accurate and reliable cardiotoxicity evaluation model is of key importance. To avoid the clinical potential cardiotoxicity risk and discontinuation of a highly effective drug, patients treated with SMKIs should be proactively monitored on the basis of a global standard. Moreover, the underlying mechanisms of SMKI-induced cardiotoxicity need to be further studied to develop new therapies for SMKI-induced cardiotoxicity.

PMID:32595510 | PMC:PMC7303342 | DOI:10.3389/fphar.2020.00891

20:06

PubMed articles on: Cancer & VTE/PE

Pulmonary embolism and acro-ischemia in a lung cancer patient with COVID-19

González Del Portillo E and Pérez-Romasanta LA. Med Clin (Barc) 2020.

NO ABSTRACT

PMID:32586671 | PMC:PMC7274584 | DOI:10.1016/j.medcli.2020.05.023

20:06

PubMed articles on: Cardio-Oncology

Speckle-Tracking Echocardiography in Cardio-Oncology and Beyond

Quintana RA, et al. Tex Heart Inst J 2020.