ABSTRACT

BACKGROUND: Aponermin, a circularly permuted tumor necrosis factor-related apoptosis-inducing ligand, is a potential death receptor 4/5-targeted antitumour candidate. Previous phase 1/2 studies have demonstrated the efficacy of aponermin in patients with relapsed or refractory multiple myeloma (RRMM). To confirm the superiority of aponermin plus thalidomide and dexamethasone (aponermin group) over placebo plus thalidomide and dexamethasone (placebo group) in RRMM, a randomized, double-blinded, placebo controlled phase 3 trial was performed.

METHODS: Four hundred seventeen patients with RRMM who had previously received at least two regimens were randomly assigned (2:1) to receive aponermin, thalidomide, and dexamethasone or placebo, thalidomide, and dexamethasone. The primary endpoint was progression-free survival (PFS). Key secondary endpoints included overall survival (OS) and overall response rate (ORR).

RESULTS: A total of 415 patients received at least one dose of trial treatment (276 vs. 139). The median PFS was 5.5 months in the aponermin group and 3.1 months in the placebo group (hazard ratio, 0.62; 95% confidence interval [CI], 0.49-0.78; P < 0.001). The median OS was 22.4 months for the aponermin group and 16.4 months for the placebo group (hazard ratio, 0.70; 95% CI, 0.55-0.89; P = 0.003). Significantly higher rates of ORR (30.4% vs. 13.7%, P < 0.001) and very good partial response or better (14.1% vs. 2.2%, P < 0.0001) were achieved in the aponermin group than in the placebo group. Treatment with aponermin caused hepatotoxicity in some patients, as indicated by the elevated alanine transaminase, aspartate transaminase, or lactate dehydrogenase levels (52.2% vs. 24.5%, 51.1% vs. 19.4% and 44.9% vs. 21.6%, respectively), mostly grade 1/2, transient and reversible. The main grade 3/4 adverse events included neutropenia, pneumonia and hyperglycemia. The incidence of serious adverse events was similar between the two groups (40.6% vs. 37.4%). There was no evidence that aponermin leads to hematological toxicity, nephrotoxicity, cardiotoxicity, or secondary tumors.

CONCLUSIONS: Aponermin plus thalidomide and dexamethasone significantly improved PFS, OS and ORR with manageable side effects in RRMM patients who had received at least two prior therapies. These results support the use of aponermin, thalidomide, and dexamethasone as a treatment option for RRMM patients.

TRIAL REGISTRATION: The trial was registered at http://www.chictr.org.cn as ChiCTR-IPR-15006024, 17/11/2014.

PMID:37838670 | PMC:PMC10576321 | DOI:10.1186/s12885-023-11489-8

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PubMed articles on: Cardio-Oncology

Clinical Utility and Prognostic Value of Coronary Computed Tomography Angiography in Patients With Cancer

Am J Cardiol. 2023 Oct 3;207:448-454. doi: 10.1016/j.amjcard.2023.08.121. Online ahead of print.

ABSTRACT

There is growing interest in the role of coronary computed tomography angiography (CTA) in cardio-oncology. However, there is a paucity of real-world experience and outcome data for patients with cancer. This study sought to determine the clinical utility and prognostic value of coronary CTA in patients with cancer. In this prospective, single-center study, we recruited patients with cancer who underwent coronary CTA. Coronary artery disease (CAD) extent was classified as normal, nonobstructive (1% to 49% stenosis), and potentially obstructive (≥50% stenosis). Patients were followed up for a median of 9 months (interquartile range 3 to 30 months) for cancer-related deaths and major adverse cardiovascular events (MACEs) defined as nonfatal myocardial infarction, urgent unplanned revascularization, or cardiovascular death. The mean age of patients (n = 113) was 61 ± 12 years, and 68 were female (60%). The most common underlying cancers were breast (29%) and lymphoma (13%). A total of 25 patients had potentially obstructive CAD, most commonly of the left anterior descending artery. After coronary CTA, 88% statin-naive patients with potentially obstructive CAD were initiated on statin therapy. A total of 28/32 patients who were taking fluoropyrimidine chemotherapy (5-fluorouracil or capecitabine) continued therapy, of whom none had MACEs. Overall, there were no episodes of MACEs in this cohort and 11% had cancer-related deaths. Coronary CTA has an important role in the clinical decision-making in patients with cancer to detect CAD, initiate primary preventative therapy, and guide coronary revascularization. No MACEs occurred. Using this coronary CTA-guided approach, preventative therapy was initiated, and most patients continued prognostically important cancer therapy.

PMID:37797552 | DOI:10.1016/j.amjcard.2023.08.121

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PubMed articles on: Cardio-Oncology

Allogeneic mitochondrial transplantation ameliorates cardiac dysfunction due to doxorubicin: An in vivo study

Biomed Pharmacother. 2023 Oct 7;168:115651. doi: 10.1016/j.biopha.2023.115651. Online ahead of print.

ABSTRACT

Damage to the mitochondria may lead to serious conditions that are difficult to treat. Doxorubicin is one of the most widely used chemotherapeutic drugs for the treatment of malignancies in children and adults, and reportedly causes damage to the mitochondria. Unfortunately, the dangerous cardiac side effects of doxorubicin appear when the patient is in the midst of a vigorous fight against the disease, either by taking doxorubicin alone or in combination with other drugs. This study aimed to determine whether exogenous healthy and functional mitochondria are internalized by cells, can it help the survival of these cells, and can reduce cardiotoxicity. For this purpose, isolated, pure, and functional exogenous mitochondria were injected into the tail vein of a rat model of doxorubicin-induced cardiotoxicity. After that, the heart function of the rats and their antioxidant status, inflammatory markers, and histopathological examination were investigated. Our findings show that intravenous mitochondrial transplantation provided efficient mitochondrial uptake and reduced cardiotoxicity by reducing ROS production, lipid peroxidation, and inflammation. In addition, the levels of ATP and antioxidant enzymes increased after mitochondrial transplantation; therefore all of these complex processes resulted in the reduction of apoptosis and necrosis in rat heart tissue. These promising results open the way to more effective cancer treatment without the side effects of related drugs. Transplanting exogenous mitochondria probably enhances the cell's mitochondrial network, potentially treating mitochondria-related disorders such as cardiovascular and neurodegenerative diseases, although the exact relationship between mitochondrial damage and these conditions remains unclear.

PMID:37812888 | DOI:10.1016/j.biopha.2023.115651

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PubMed articles on: Cardio-Oncology

Angiotensin IV ameliorates doxorubicin-induced cardiotoxicity by increasing glutathione peroxidase 4 and alleviating ferroptosis

Toxicol Appl Pharmacol. 2023 Oct 12;479:116713. doi: 10.1016/j.taap.2023.116713. Online ahead of print.

ABSTRACT

BACKGROUND: Doxorubicin (DOX)-induced cardiotoxicity is an important cause of poor prognosis in cancer patients treated with DOX. Angiotensin IV (Ang IV) has multiple protective effects against cardiovascular diseases, including diabetic cardiomyopathy and myocardial infarction, but its role in DOX-induced cardiotoxicity is currently unclear. In this study, we investigated the effects of Ang IV on DOX-induced cardiotoxicity.

METHODS: The viability of primary cardiomyocytes was measured by Cell Counting Kit-8 assays and Hoechst 33342/propidium iodide staining in vitro. ELISAs (serum cTnT and CK-MB) and echocardiography were performed to assess myocardial injury and cardiac function in vivo. Phalloidin staining, haematoxylin and eosin staining and wheat germ agglutinin staining were conducted to detect cardiomyocyte atrophy. We also performed C11 BODIPY staining, measured the levels of Ptgs2 and malondialdehyde and detected the concentrations of ferrous ions, glutathione and oxidized glutathione to indicate ferroptosis.

RESULTS: Ang IV not only attenuated DOX-induced atrophy and cardiomyocyte injury in vitro but also alleviated myocardial injury and improved cardiac function in DOX-treated mice in vivo. Moreover, Ang IV reversed DOX-induced downregulation of glutathione peroxidase 4 (GPX4) and inhibited ferroptosis both in vitro and in vivo. Knockdown of GPX4 by siRNA abolished the cardioprotective effects of Ang IV. Furthermore, Ang IV increased GPX4 levels and ameliorated ferroptosis in RAS-selective lethal 3-treated primary cardiomyocytes.

CONCLUSIONS: Ang IV ameliorates DOX-induced cardiotoxicity by upregulating GPX4 and inhibiting ferroptosis. Ang IV may be a promising candidate to protect against DOX-induced cardiotoxicity in the future.

PMID:37838222 | DOI:10.1016/j.taap.2023.116713

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PubMed articles on: Cardio-Oncology

Anthracycline‑induced delayed‑onset cardiac toxicity: A case report and literature review

Exp Ther Med. 2023 Sep 13;26(5):505. doi: 10.3892/etm.2023.12204. eCollection 2023 Nov.

ABSTRACT

Anthracyclic (ANT) drugs are widely used for patients with malignant tumors and can markedly prolong the disease-free survival rate of patients. As its clinical application becomes more common, information regarding serious cardiotoxicity as a result of ANT treatment is becoming understood. However, to the best of our knowledge, delayed-onset cardiotoxicity due to ANT use has not been studied sufficiently. The present report describes a 36-year-old male patient who presented to Guiqian International General Hospital (Guiyang, China) with a complaint of dyspnea in the last 10 days. Substantially elevated B-type natriuretic peptide levels and echocardiography showing enlargement of the entire heart, of the patient suggested that severe heart failure was the cause of his symptoms. However, the cause of this potential heart failure was not apparent until the patient was questioned about his cancer treatment history. Following consultation to evaluate the assessment of end-stage heart failure, currently only anti-heart failure treatment and symptomatic treatment can be provided. The present report describes this case and reviews the existing literature to provide a basis for the diagnosis and treatment of patients with delayed-onset heart failure following ANT treatment.

PMID:37822590 | PMC:PMC10562964 | DOI:10.3892/etm.2023.12204

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PubMed articles on: Cardio-Oncology

Cardio-Oncology Rehabilitation Programs-The Next Phase in Improving Care for Cancer Survivors

JAMA Cardiol. 2023 Oct 11. doi: 10.1001/jamacardio.2023.3568. Online ahead of print.

NO ABSTRACT

PMID:37819675 | DOI:10.1001/jamacardio.2023.3568

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PubMed articles on: Cancer & VTE/PE

In vivo evaluation of the pharmacokinetic interactions between almonertinib and rivaroxaban, almonertinib and apixaban

Front Pharmacol. 2023 Oct 4;14:1263975. doi: 10.3389/fphar.2023.1263975. eCollection 2023.