Severe Cardiac Toxicity Research Articles

Swimming training attenuates doxorubicin induced cardiomyopathy by targeting the mir-17-3p/KEAP1/NRF2 axis

Doxorubicin (DOX), as a first-line anticancer drug, is widely used in the treatment of various cancers. However, its clinical application is restricted due to its severe cardiac toxicity. Previous studies have indicated exercise training can alleviate the DOX-induced cardiotoxicity (DIC), but the underlying mechanism remains unclear. Our research has discovered, post-exercise, an elevated expression level of mir-17-3p, but in DIC its level decreases. Therefore, we further studied the effect of exercise mir-17-3p axis on DIC. In vivo, we simulated DIC mouse model, followed by an intervention using swimming and adenovirus to inhibit mir-17-3p. We found that inhibition of mir-17-3p can weaken the protection of exercise against DIC, presenting as weakened heart function. Besides, the levels of Malondialdehyde and Fe2+ in the cardiac tissue increased, along with diminished glutathione peroxidase 4 and Solute Carrier Family 7 Member 11 levels, and a decline in the concentration of glutathione, causing an increase in ferroptosis. Moreover, in vitro, we used dual-luciferase assay to confirm that Kelch Like ECH Associated Protein 1 (KEAP1) can be a target gene of mir-17-3p. We used Keap1/NFE2 Like BZIP Transcription Factor 2 (NRF2) inhibitor brusatol and Stimulator of Interferon Response CGAMP Interactor 1 (STING) agonist SR-717 to verify the mir-17-3p/KEAP1 axis can affect the Cyclic GMP-AMP Synthase (CGAS)/STING pathway, leading to further ferroptosis in DIC. This manifested as a reduction in ferroptosis. In summary, our research suggests swimming training enhances the levels of mir-17-3p, thereby activating the KEAP1/NRF2 pathway, and weakening the CGAS/STING pathway, improving ferroptosis in DIC.

Causes and characteristics of pre-engraftment mortality after allogeneic hematopoietic stem cell transplantation

Objective: To analyze the causes and demographic characteristics of pre-engraftment mortality in patients who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) and investigate the risk factors and measures for preventing pre-engraftment mortality. Methods: A retrospective case analysis, involving a total of 7 427 patients who underwent allo-HSCT at Peking University People's Hospital between January 2016 and July 2023, was conducted. Results: Among the 7 427 patients who underwent allo-HSCT, 56 cases (0.75% ) experienced pre-engraftment mortality. The median time to death for these 56 patients was +7 (-3 to +38) days after stem cell infusion. The median times to death for patients with acute leukemia (AL), severe aplastic anemia (SAA), and myelodysplastic syndrome (MDS) were +11 (-1 to +38), +3 (-1 to +34), and +16 (-1 to +38) days, respectively (P=0.013). The main causes of pre-engraftment mortality were infection (39.3% ), cardiac toxicity (28.6% ), and intracranial hemorrhage (26.8% ). Infection was the most common cause of pre-engraftment mortality in patients with AL and MDS (55.0% and 60.0% ), whereas cardiac toxicity was predominantly observed in patients with SAA (71.4% ), with no cases in patients with AL and only one case in patients with MDS. Among patients who died from intracranial hemorrhage, 53.3% had severe infections. The median times to death for infection, cardiac toxicity, and intracranial hemorrhage was +11 (-1 to +38), +2.5 (-1 to +17), and +8 (-3 to +37) days, respectively (P<0.001) . Conclusions: Infection is the primary cause of pre-engraftment mortality in allo-HSCT, and severe cardiac toxicity leading to pre-engraftment mortality should be closely monitored in patients with SAA.

4-Deoxy-ε-Pyrromycinone: A Promising Drug/Lead Compound to Treat Tumors.

Anthraquinone drugs are widely used in the treatment of tumors. However, multidrug resistance and severe cardiac toxicity limit its use, which have led to the discovery of new analogues. In this paper, 4-Deoxy-ε-pyrromycinone (4-Deo), belonging to anthraquinone compounds, was first been studied with the anti-tumor effects and the safety in vitro and in vivo as a new anti-tumor drug or lead compound. The quantitative analysis of 4-Deo was established by UV methodology. The anti-cancer effect of 4-Deo in vitro was evaluated by cytotoxicity experiments of H22, HepG2 and Caco2, and the anti-cancer mechanism was explored by cell apoptosis and cycle. The tumor-bearing mouse model was established by subcutaneous inoculation of H22 cells to evaluate the anti-tumor effect of 4-Deo in vivo. The safety of 4-Deo was verified by the in vitro safety experiments of healthy cells and the in vivo safety experiments of H22 tumor-bearing mice. Tumor tissue sections were labeled with CRT, HMGB1, IL-6 and CD115 to explore the preliminary anti-cancer mechanism by immunohistochemistry. In vitro experiments demonstrated that 4-Deo could inhibit the growth of H22 by inducing cell necrosis and blocking cells in S phase, and 4-Deo has less damage to healthy cells. In vivo experiments showed that 4-Deo increased the positive area of CRT and HMGB1, which may inhibit tumor growth by triggering immunogenic cell death (ICD). In addition, 4-Deo reduced the positive area of CSF1R, and the anti-tumor effect may be achieved by blocking the transformation of tumor-associated macrophages (TAMs) to M2 phenotype. In summary, this paper demonstrated the promise of 4-Deo for cancer treatment in vitro and in vivo. This paper lays the foundation for the study of 4-Deo, which is beneficial for the further development anti-tumor drugs based on the lead compound of 4-Deo.

Developmental toxicity and mechanism of polychlorinated biphenyls 126 and nano-polystyrene combined exposure to zebrafish larvae

3,3′,4,4′,5-Pentachlorobiphenyl (PCB126) is the most toxic congener of dioxin-like polychlorinated biphenyls (DL PCBs), while nanoplastics (NPs) have recently emerged as significant marine pollutants, both posing threats to aquatic organisms and human health. They coexist in the environment, but their comprehensive toxicological effects remain unclear. In this study, zebrafish embryos were simultaneously exposed to PCB126 and 80-nanometer nanoplastyrene (NPS). Researchers utilized fluorescence microscopy, qPCR, histopathological examination, and transcriptomic sequencing to investigate the developmental toxicity of different concentrations of PCB126 and NPS individually or in combination on zebrafish embryos and larvae. Results indicate that the chorion significantly impedes the accumulation of NPS (p < 0.05). It is noteworthy that this barrier effect diminishes upon simultaneous exposure to PCB126. In this experiment, the semi-lethal concentration of PCB126 for larvae was determined to be 6.33 μg/L. Exposure to PCB126 induces various deformities, primarily mediated through the aryl hydrocarbon receptor (AHR). Similarly, exposure to NPS also activates AHR, leading to developmental impairments. Furthermore, transcriptomic sequencing revealed similar effects of PCB126 and NPS on the gene expression trends in zebrafish larvae, but combined exposure to both exacerbates the risk of cancer and induces more severe cardiac toxicity. At this level, co-exposure to PCB126 and NPS adversely affects the development of zebrafish larvae. This study contributes to a deeper understanding of the in vivo accumulation of DL polychlorinated biphenyls and microplastics in actual aquatic environments and their impact on fish development.

Clinical outcomes associated with orphenadrine deliberate self-poisoning: a retrospective poisons centre study

Introduction Orphenadrine overdoses can cause antimuscarinic toxicity, respiratory failure, refractory seizures and cardiotoxicity. The dose–toxicity relationship is poorly defined. Orphenadrine is marketed as immediate and sustained release formulations, and it is not known how the formulation impacts on toxicity. We determined the clinical toxicity of orphenadrine in patients referred to a regional poisons centre. Methods Retrospective case series of patients in New South Wales with orphenadrine deliberate self-poisoning from January 2016 to April 2022 referred to the New South Wales Poisons Information Centre. Demographics, history of exposure, treatment and outcomes were extracted from clinical databases. Receiver-operating characteristic curves were constructed to determine thresholds predicting toxicity. Results Forty-eight patients were identified, with information on clinical outcomes in 46 patients and doses in 41 patients. All patients were older than 12 years. The median orphenadrine dose was 770 mg (range 210–10,000 mg), 59 per cent as the immediate release formulation, and 67 per cent reported coingestants. Doses of sustained release formulations were significantly greater than immediate release formulations, median 2,750 mg versus 595 mg. Common clinical features were drowsiness (59 per cent), sinus tachycardia (37 per cent) and confusion (33 per cent). Three patients had mild hypotension, three were intubated for coma, and two had seizures; no patients suffered ventricular dysrhythmias. All patients survived, with 75 per cent being medically cleared within 24 hours of presentation. A dose–toxicity relationship was observed, but conclusions are limited by the small number of cases with moderate or severe toxicity. Discussion All patients survived, and severe cardiac and neurological toxicity were not observed. This contrasts to published case reports noting severe poisoning at similar or lower doses. Formulation may have an impact on outcomes, with lesser toxicity from sustained release products. Conclusions Orphenadrine doses up to 10 g were associated with antimuscarinic toxicity and sedation, but not severe cardiotoxicity. More research exploring the effect of dose and formulation on outcomes is required.

Toxic effects of the insecticide tolfenpyrad on zebrafish embryos: Cardiac toxicity and mitochondrial damage.

Tolfenpyrad, a highly effective and broad-spectrum insecticide and acaricide extensively utilized in agriculture, presents a potential hazard to nontarget organisms. This study was designed to explore the toxic mechanisms of tolfenpyrad on zebrafish embryos. Between 24 and 96 h after exposure of the fertilized embryos to tolfenpyrad at concentrations ranging from 0.001 to 0.016 mg/L (96 h-LC50 = 0.017 mg/L), lethal effects were apparent, accompanied with notable anomalies including pericardial edema, increased pericardial area, diminished heart rate, and an elongated distance between the venous sinus and the arterial bulb. Tolfenpyrad elicited noteworthy alterations in the expression of genes pertinent to cardiac development and apoptosis, with the most pronounced changes observed in the cardiac development-related genes of bone morphogenetic protein 2b (bmp2b) and p53 upregulated modulator of apoptosis (puma). The findings underscore that tolfenpyrad induces severe cardiac toxicity and mitochondrial damage in zebrafish embryos. This data is imperative for a comprehensive assessment of tolfenpyrad risks to aquatic ecosystems, particularly considering the limited knowledge regarding its detrimental impact on aquatic vertebrates.

Osimertinib-induced biventricular cardiomyopathy with abnormal cardiac MRI findings: a case report

BackgroundOsimertinib is a third-generation epidermal growth factor receptor (EGFR) inhibitor that is currently the first-line treatment for metastatic EGFR-mutated non-small-cell lung cancer (NSCLC) due to its favorable efficacy and tolerability profile compared to previous generations of EGFR inhibitors. However, it can cause uncommon, yet serious, cardiovascular adverse effects.Case PresentationWe present the case of a 63-year-old man with EGFR-mutated NSCLC treated with osimertinib who developed new-onset non-ischemic cardiomyopathy with biventricular dysfunction and heart failure in the context of an enlarging pericardial effusion. For the first time, we demonstrate cardiac MR imaging findings associated with osimertinib-associated cardiomyopathy, including focal late gadolinium enhancement and myocardial edema. The patient’s biventricular function normalized after initiation of goal-directed medical therapy for heart failure and holding osimertinib. The patient was subsequently started on afatinib, a second-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI), without recurrence of cardiomyopathy.ConclusionsThis case highlights the need to better understand osimertinib-induced cardiotoxicity and strategies to optimize oncologic care in patients who develop severe cardiac toxicities from cancer therapy. It further underlines the importance of specialized multidisciplinary care of cancer patients who develop cardiotoxicities to optimize their oncologic outcomes.

A structure-based approach to explore novel COX-2 inhibitors using pharmacophore modelling, 3D-QSAR analysis, virtual screening and dynamics simulation study

Anti-inflammatory medications are one of the most commonly preferred over-the-counter medications because inflammation and pain are closely related and caused by various disease conditions. Extensive research is mandatory to develop an effective anti-inflammatory therapy and good safety profile since both cyclooxygenase (COX-1 and COX-2) inhibition causes severe gastrointestinal irritation and cardiac toxicities. Only 190 molecules published in 2022 had selected for the investigation out of the many chemical architectures reported in the literature as COX-2 inhibitors. Using a four-point pharmacophore hypothesis AAAR2 (A-hydrogen bond acceptor and R- aromatic ring sites) generated from 138 molecules out of 190 with a site score of 0.84, a 3D atom-based QSAR model was built. With an outstanding correlation value of R2 0.92, fisher ratio of F 235.4, strong predictability of Q2 0.73, and Pearson-r 0.87, the 3D-QSAR model displays the highest and lowest efficient ligands reveals the favourable and unfavourable structural domains for the interaction toward COX-2. The selected 3D QSAR model is then utilised to screen compounds from bindingDB like a search engine. The molecules which passed the rule of five were chosen for further analysis after the screened molecules underwent an ADME analysis. Virtual screening (PDB ID-5KIR) was then used to identify 43 hit molecules, with the best docking scores falling between -11.07 and -9.55 kcal/mol, and these results were compared to the standard rofecoxib (docking score-9.479 kcal/mol). To evaluate the stable binding and interaction of the best molecule (Hit1), which is crucial for inhibiting COX-2, the molecular dynamics study was carried out for 100 ns.

TNF-α Inhibitors and Other Biologic Agents for the Treatment of Immune Checkpoint Inhibitor-Induced Myocarditis.

With anti-PD-1 antibodies serving as a representative drug, immune checkpoint inhibitors (ICIs) have become the main drugs used to treat many advanced malignant tumors. However, immune-related adverse events (irAEs), which might involve multiple organ disorders, should not be ignored. ICI-induced myocarditis is an uncommon but life-threatening irAE. Glucocorticoids are the first choice of treatment for patients with ICI-induced myocarditis, but high proportions of steroid-refractory and steroid-resistant cases persist. According to present guidelines, tumor necrosis factor alpha (TNF-α) inhibitors are recommended for patients who fail to respond to steroid therapy and suffer from severe cardiac toxicity, although evidence-based studies are lacking. On the other hand, TNF-α inhibitors are contraindicated in patients with moderate-to-severe heart failure. This review summarizes real-world data from TNF-α inhibitors and other biologic agents for ICI-induced myocarditis to provide more evidence of the efficacy and safety of TNF-α inhibitors and other biologic agents.

A two-decade review of butane toxicity as a substance of abuse.

Butane, an aliphatic hydrocarbon with explosive and flammable properties, is widely misused especially by young people. Acting as an asphyxiant gas, butane mainly targets the central nervous and cardiovascular systems. We aimed to review butane-attributed toxicities due to its harmful use or misuse reported in a two-decade period. We searched English-language publications reporting butane toxicities from 2000 up to 2021 and collected data on age, gender, route and source of exposure, country of origin, clinical presentation and outcome. Among 54 butane's harmful use/misuse cases identified in the literature, there were 11 survivors successfully discharged from the hospital. Patients were predominantly males with a mean age ± SD of 23 ± 13 years. The main route of exposure was inhalation. Manifestations were mainly cardiac and neurological. Majority of the cases were reported from Europe and Japan. To conclude, butane exposure is at risk of severe central nervous system and cardiac toxicities, which may result in a fatal outcome. Therefore, in the event of a sudden or suspicious death in a young individual, our findings suggest that butane's harmful use/misuse should be considered as a potential differential diagnosis.

Prophylactic Evidence of MSCs-Derived Exosomes in Doxorubicin/Trastuzumab-Induced Cardiotoxicity: Beyond Mechanistic Target of NRG-1/Erb Signaling Pathway

Trastuzumab (Trz) is a humanized monoclonal antibody targeting epidermal growth factor receptor 2 (HER2; ErbB2). The combined administration of Trz and doxorubicin (DOX) has shown potent anti-cancer efficacy; however, this regimen may be accompanied by severe cardiac toxicity. Mesenchymal stem cells (MSCs)-derived exosomes are nanosized vesicles that play a crucial role in cell–cell communication and have shown efficacy in the treatment of various diseases. In this study, we aim to investigate the cardioprotective effects of MSCs-derived exosomes in a DOX/Trz- mediated cardiotoxicity model, and the possible mechanisms underlying these effects are elucidated. Forty-nine male rats were randomly assigned into four groups: Group I (control); Group II (Dox/Trz); Group III (protective group); and Group IV (curative group). Cardiac hemodynamic parameters, serum markers of cardiac injury, oxidative stress indices, and cardiac histopathology were investigated. Further, transcript profile of specific cardiac tissue injury markers, apoptotic markers, and fibrotic markers were analyzed using qRT-PCR, while the protein expressions of pAkt/Akt, pERK/ERK, pJNK/JNK, pJNK/JNK, and pSTAT3/STAT3 were evaluated by ELISA. Additionally, cardiac mirR-21 and miR-26a were assessed. A combined administration of DOX/Trz disrupted redox and Ca2+ homeostasis in cardiac tissue induced myocardial fibrosis and myofibril loss and triggered cardiac DNA damage and apoptosis. This cardiotoxicity was accompanied by decreased NRG-1 mRNA expression, HER2 protein expression, and suppressed AKT and ERK phosphorylation, while triggering JNK phosphorylation. Histological and ultra-structural examination of cardiac specimens revealed features typical of cardiac tissue injury. Moreover, a significant decline in cardiac function was observed through biochemical testing of serum cardiac markers and echocardiography. In contrast, the intraperitoneal administration of MSCs-derived exosomes alleviated cardiac injury in both protective and curative protocols; however, superior effects were observed in the protective protocol. The results of the current study indicate the ability of MSCs-derived exosomes to protect from and attenuate DOX/Trz-induced cardiotoxicity. The NRG-1/HER2, MAPK, PI3K/AKT, PJNK/JNK, and PSTAT/STAT signaling pathways play roles in mediating these effects.

The Cardiotoxic Effect of Roundup® is not Induced by Glyphosate: A Non-specific Blockade of Human CaV1.2 Channels.

In Roundup®, the active principle glyphosate is formulated with adjuvants that help it to penetrate the plants' cell membranes. Several reports and reviews report cardiovascular effects of Roundup®, pointing the presence of arrhythmias as a potential consequence of Roundup® toxicity and death cause. However, it still remains debatable whether these cardiac events are related to glyphosate per se or to the Roundup® adjuvants. The present study aims to compare the pro-arrhythmogenic properties of Roundup® and glyphosate in an animal model and in human cardiomyocytes. In isolated guinea pig heart, the cardiotoxicity of Roundup® (significant effect on heart rate and depressive effect on ventricular contractility) was demonstrated with the highest concentrations (100µM). In human cardiomyocytes, the cardiotoxicity is confirmed by a marked effect on contractility and a strong effect on cell viability. Finally, this Roundup® depressive effect on heart contractility is due to a concentration-dependent blocking effect on cardiac calcium channel CaV1.2 with an IC50 value of 3.76µM. Surprisingly, no significant effect on each parameter has been shown with glyphosate. Glyphosate was devoid of major effect on cardiac calcium channel with a maximal effect at 100µM (- 27.2 ± 1.7%, p < 0.01). In conclusion, Roundup® could induce severe cardiac toxicity by a blockade of CaV1.2 channel, leading to a worsening of heart contractility and genesis of arrhythmias. This toxicity could not be attributed to glyphosate.

Fluvastatin alleviates doxorubicin-induced cardiac and renal toxicity in rats via regulation of oxidative stress, inflammation, and apoptosis associated genes expressions

Doxorubicin (DOXO) is a cytostatic agent used in the chemotherapy protocol of several cancers for more than 40 years, but usage of this drug in cancer treatment has been limited due to severe renal and cardiac tissue toxicities that may result in death in patients. Fluvastatin (FV) is a fully synthetic hydroxymethyl glutaryl coenzyme A (HMG-CoA) reductase inhibitor used as a cholesterol-lowering agent in patients with hypercholesterolemia. Previous studies revealed that FV also exhibits antioxidant, anti-inflammatory, and antitumor activity. Additionally, our previous study indicated that FV exerts a prophylactic effect on DOXO-induced testicular toxicity by preventing lipid peroxidation, supporting the antioxidant system, and regulating the blood-testis barrier-associated genes expression. Herein, we purposed to evaluate the possible therapeutic and the protective effects of FV on the DOXO-induced cardiac and renal toxicitiy model by histochemical, immunohistochemical, biochemical, and real-time polymerase chain reaction (real-time PCR) analyses. Results point out protective use of FV exerts a beneficial effect by repressing lipid peroxidation and by regulating the inducible nitric oxide synthase (iNOS), nitric oxide synthase endothelial (eNOS), nuclear factor kappa-B (NF-κB), and Caspase-3 (Casp3) protein and mRNA expressions, which play an important role in mediating DOXO-induced renal and cardiac toxicity mechanisms. In conclusion, FV may be a candidate agent for the prevention of renal and cardiac toxicities in cancer patients receiving DOXO chemotherapy.

The Evolution of Children's Oncology Group Hodgkin Lymphoma Trials: Predicted Impact on Late Cardiac Toxicity

Introduction: Sequential Hodgkin lymphoma (HL) trials of the Children's Oncology Group (COG) have tested treatment strategies intended to reduce late toxicity while maintaining high rates of cure. However, the long latency of the relevant late effects makes it impossible to observe in a timely way the degree to which modifications to protocol-directed treatment will achieve this goal. The purpose of this study was to estimate late cardiac disease risk associated with sequential COG trial protocols using established risk models.Methods: We estimated the late severe or fatal cardiac toxicity associated with three consecutive completed COG trials enrolling intermediate- and high-risk classical HL patients: AHOD0031 (2002-2009), AHOD0831 (2009-2012), and AHOD1331 (2015-2019). Patients were less than 22 years old at the time of trial enrollment. In addition, we applied the model to the ongoing S1826 trial protocol for patients ≥12 to <22 years of age. Eligible disease stages were IB, IAE, IIB, IIAE, IIIA, IVA with or without bulk disease and IA or IIA with bulk disease for AHOD0031; IIIB and IVB for AHOD0831; IIB with bulk, IIB, IVA and IVB for AHOD1331; and III and IV for S1826. When radiotherapy (RT) was indicated, prescribed RT was 21Gy involved-field radiotherapy (IFRT) in AHOD0031, 21Gy IFRT in AHOD0831, 21-30Gy involved-site radiotherapy (ISRT) in AHOD1331, and 30-36Gy ISRT in S1826. Cardiac toxicity included coronary artery disease, heart failure, valvular disease, pericardial disease and arrhythmias. Statistical models quantifying the association between age, sex, doxorubicin dose, alkylating agent exposure and cardiac radiation dose and late cardiac risk were derived from HL survivors in the Childhood Cancer Survivor Study (CCSS) (Bates 2019 J Clin Oncol 1;37(13):1090-1101 & Shrestha 2021 Radiother Oncol, in press). These demographic and dose-risk relationships were then applied to the delivered COG trial protocol exposures to predict the 30-year cumulative incidence (CI) of cardiac disease for trial patients. To estimate the average cardiac risk, we accounted for the chance of receiving mediastinal RT, mean cardiac radiation dose among those receiving mediastinal RT, and cumulative doxorubicin dose, according to respective trial data.Results: Based on the median age of enrolled patients, results are reported for modeled age 15 years at treatment. The cumulative planned doxorubicin dose was 200mg/m 2 on AHOD0031 and AHOD0831, and increased to 250mg/m 2 on AHOD1331 to improve progression-free survival compared to the prior trials for select groups of higher risk patients. Doxorubicin dose was 300mg/m 2 on S1826 to limit RT use to selected patients with persistent disease on positron emission tomography (PET) at the end of systemic therapy. Mediastinal RT was given to 62% of patients on AHOD0031 (mean heart dose 13.2Gy), 58% on AHOD0831 (mean heart dose 13.6Gy), and 53% on AHOD1331 (mean heart dose 10Gy). For S1826, we assumed a 5% rate of mediastinal RT use, mean heart dose of 10Gy, and no long term cardiac risk associated with nivolumab or brentuximab. For the average 15-year old patient, the predicted 30-year cumulative incidence of any cardiac disease was 8.8% in AHOD0031, 8.7% in AHOD0831, and 8.5% in AHOD1331 (Figure 1). Despite the increase in doxorubicin dose, the anticipated reduction in the utilization of mediastinal RT in S1826 is predicted to reduce the 30-year risk of cardiac disease to 7.8%. The predicted 30-year cumulative incidence of any cardiac disease, for the average 12-, 15-, and 18-year old males and females are shown in Table 1.Conclusions: From 2002 - 2019, reductions in the proportion of patients receiving mediastinal RT and smaller target volumes with ISRT produce lower cardiac radiation dose, which is predicted to offset increase in doxorubicin dose and produce a small reduction in late cardiac disease. Limiting RT use based on end of chemotherapy PET on S1826 is predicted to further reduce late cardiac disease among children with HL risk despite higher doxorubicin dose in this protocol. Increasing use of dexrazoxane may further mitigate risk for cardiac toxicity in more contemporary cohorts. Clarification of the impact of nivolumab, brentuximab and relapse therapy would allow for a more complete prediction of cardiac disease risk. [Display omitted] DisclosuresHerrera: Bristol Myers Squibb: Consultancy, Research Funding; Merck: Consultancy, Research Funding; Gilead Sciences: Research Funding; Genentech: Consultancy, Research Funding; Kite, a Gilead Company: Research Funding; Tubulis: Consultancy; Takeda: Consultancy; ADC Therapeutics: Consultancy, Research Funding; Seagen: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Karyopharm: Consultancy. Friedberg: Acerta: Other: DSMC ; Bayer: Other: DSMC ; Novartis: Other: DSMC .

Guidelines for the monitoring and management of iron overload in patients with haemoglobinopathies and rare anaemias.

Guidelines for the monitoring and management of iron overload in patients with haemoglobinopathies and rare anaemias.

Severe Cardiac Toxicity Induced by Cancer Therapies Requiring Intensive Care Unit Admission

A steadying increase of cancer survivors has been observed as a consequence of more effective therapies. However, chemotherapy regimens are often associated with significant toxicity, and cardiac damage emerges as a prominent clinical issue. Many mechanisms sustain chemotherapy-induced cardiac toxicity: direct myocyte damage, arrhythmia induction, coronary vasospasm, and accelerated atherosclerosis. Anthracyclines are the most studied cardiotoxic drugs and represent a clinical model for cardiac damage induced by chemotherapy. In patients suffering from advanced heart failure (HF) because of chemotherapy-related cardiomyopathy, when refractory to optimal medical therapy, mechanical circulatory support or heart transplantation represents an effective treatment. Here, the main mechanisms of cardiac toxicity induced by cancer therapies are analyzed, with a focus on patients requiring intensive care unit (ICU) admission during the course of the disease because of acute cardiac toxicity, takotsubo syndrome, and acute-on-chronic HF in patients suffering from chemotherapy-induced cardiomyopathy. In a subset of patients, cardiac toxicity can be acute and life-threatening, leading to overt cardiogenic shock. The management of critically ill cancer patients poses a unique challenge and requires a multidisciplinary approach. Moreover, no etiologic therapy is available, and only supportive measures can be implemented.

Aconitine poisoning due to confusion of aconite leaves with lovage

Due to a mix-up an older couple (69 years and 71years) ate a meal with herbs from their garden that contained leaves of monkshood (Aconitum napellus). The monkshood plants grew close to the herbs in their garden. Both patients developed the typical symptoms of aconitine poisoning with paresthesia, hypotension and bradycardia. Over the course of time both developed cardiac arrhythmia with ventricular extrasystoles and required monitoring on the intensive care unit (ICU). The husband was more severely affected and needed catecholamines for successful treatment of hypotension (70/40 mmHg) and bradycardia (45 bpm). The toxicological analysis of the patients' serum taken 3.5 h after ingestion led to the detection of 1.8 ng/ml and 2.0 ng/ml aconitine, respectively. The patients were discharged in good general condition after 1 and 2 days, respectively. Monkshood (Aconitum napellus) is one of the most toxic native plants that can also be found in gardens due to its popularity as an ornamental plant. All parts of the plant contain toxic diterpenoid alkaloids, such as aconitine. Aconitine causes persistent activation of the fast voltage-gated sodium channels resulting in severe cardiac and neurological toxicity. Treatment of aconitine-induced ventricular arrhythmias is challenging as they are often refractory to electrical cardioversion and antiarrhythmic drugs.

Mesothelin Is a Novel Disease Marker and Potential Therapeutic Target in Pediatric Acute Myeloid Leukemia

Acute myeloid leukemia (AML) remains a significant therapeutic challenge in children with only 50% cure rate with highly intensive cytotoxic chemotherapy. Further intensification is limited by acute and late effects, including severe infectious and cardiac toxicities; therefore, alternative therapeutic strategies are needed. As part of the NCI/COG TARGET AML Initiative, using transcriptome sequencing (RNA Seq) in 635 children and 178 adult AML, we demonstrated that mesothelin (MSLN) was highly-overexpressed in over one-third of pediatric AML. This transcript is not expressed in normal hematopoiesis, making it an ideal target for therapeutic intervention. MSLN is a cell-surface protein normally found in pleura and peritoneum and overexpressed in a variety of solid tumors, such as mesothelioma. The protein product of the MSLN gene exists in 4 forms in the body, including cell surface MSLN, soluble MSLN, and soluble megakaryocyte potentiating factor (MPF), which is the N-terminus of the MSLN pro-protein. Elevated serum soluble MSLN is an established diagnostic test for mesothelioma, with an FDA-approved ELISA-based assay (Mesomark™).Three different AML RNA Seq data sets totaling 813 cases, including TARGET validation cohort (n= 475), TARGET discovery phase (n= 160), and TCGA AML (n= 178), were interrogated for expression of MSLN, with normal marrow cases as a control. MSLN transcript expression at >5 transcripts per million (TPM) was observed in 268 patients (range 0-1225 TPM) with observed prevalence of 48% in TARGET discovery set, 33% in TARGET validation and 15% in adult TCGA set with a collective prevalence of 33% in the entire cohort. MSLN expression was enriched in patients with t(8;21), inv(16), and KMT2A fusions and rare in those with common AML-associated mutations (FLT3- ITD, NPM1, CEBPa mutations). MSLN was not expressed in 20 normal marrow samples (<1 TPM in all cases).We conducted orthogonal validation of the transcriptome data by evaluating diagnostic specimens from an independent cohort of 323 newly diagnosed pediatric AML patients for the presence of MSLN using quantitative RT-PCR and ELISA. RNA extracted from leukemic blasts or plasma obtained from diagnostic specimens were tested for MSLN expression by quantitative RT-PCR or sandwich ELISA, respectively. Optimized q-RT-PCR identified 36% of patients with MSLN expression. Similarly, sandwich ELISA (similar to Mesomark™) confirmed expression of soluble MSLN in 34% of patients tested, with strong concordance between the two tests (p <0.0001). We have also optimized diagnostic multi-dimensional flow cytometry (MDF) and MPF ELISA for evaluation of MSLN.Mesothelin is a cell surface protein highly expressed in AML blasts but absent in other hematopoietic cells, making it an attractive target for immunotherapy. We sought to test the principle of MSLN targeting in leukemia with antibody-drug conjugate (ADC) anetumab ravtansine (AR; BAY94-9343), comprised of an anti-MSLN antibody conjugated to tubulin inhibitor DM4. MSLN -overexpressing cells were created by lentivirally-transducing MSLN into K562 cells (K562+ MSLN). K562+ MSLN exhibited exquisite sensitivity to AR in vitro with an IC50 of 1.4 nM, compared to 360 nM in the non-transduced K562 and 250-260 nM in isotype control conditions (Fig. 1). In vitro cytotoxicity of AR in two primary pediatric MSLN + AML samples also demonstrated MSLN -dependent killing. Additionally, mice bearing K562+ MSLN xenografts were treated in vivo with AR, which demonstrated significant MSLN -dependent efficacy, resulting in median survival of 87 days compared to 32-41 days in control conditions, including chemotherapy with daunorubicin and cytarabine (Fig. 2).MSLN is a cell-surface protein uniquely overexpressed in one-third of pediatric AML, as well as a subset of adult AML. We have shown that MSLN can be detected through several sensitive diagnostic mechanisms including MDF, q-RT-PCR and serum soluble MSLN, making it an optimal marker for disease monitoring. The leukemic expression of MSLN and absence from normal hematopoietic tissue make it an ideal target for immunotherapeutic targeting, and our findings demonstrate that MSLN can be exploited for therapeutic benefit using ADCs. Further studies in MSLN + AML on optimal detection and immunotherapeutic strategies are needed, as MSLN shows great promise for enhanced disease monitoring and leukemia-specific therapeutic targeting. [Display omitted] DisclosuresLoken:Hematologics Inc: Employment, Equity Ownership. Pardo:Hematologics Inc: Employment.

Premature phase II study of amrubicin as palliative chemotherapy for previously treated malignant pleural mesothelioma

BackgroundTreatment options for malignant pleural mesothelioma (MPM) are limited. Anthracyclines are considered key drugs for treating MPM. However, their use is limited by severe cardiac toxicities. Amrubicin (AMR) is a next‐generation anthracycline that is commonly used to treat lung cancer. Here, we conducted a phase II trial of this drug in patients with previously treated MPM.MethodsEligible patients with MPM having adequate organ function and a performance status of 0–2 were enrolled after disease progression following pemetrexed/platinum therapy. Patients received 35 mg/m2 AMR on days 1–3 every three weeks until tumor progression or the appearance of unacceptable toxicities. The primary endpoint was the objective response rate. Median progression‐free survival (PFS), overall survival (OS), number of treatment cycles, and adverse events were evaluated as secondary endpoints.ResultsThis trial was discontinued because of low accrual. From September 2013 to July 2018, five patients with MPM were enrolled. Stable disease (SD) was observed in three patients (60%), and progressive disease was noted in two patients (40%). The median PFS was 2.4 (range, 1.2–11.2) months, and the median OS was 9.1 (range, 6.2–22.0) months. The median number of treatment cycles was three (range, 2–11). Grade 1/2 toxicities were observed in all patients. Grade 3/4 neutropenia was observed in four patients (80%), but there were no cases of febrile neutropenia.ConclusionsDespite the absence of the responders, the observation of SD in three patients suggests that AMR could have potential for treating MPM.

Ellagic acid alleviates clozapine‑induced oxidative stress and mitochondrial dysfunction in cardiomyocytes

Clozapine (CLZ) as an antipsychotic agent is very effective in treating of psychosis disorders and resistant schizophrenia, but the risk of severe cardiac toxicity effects restricts its clinical use. There are several interrelated hypotheses to explain clozapine-induced cardiotoxicity which all of them may be related to oxidative stress. Therefore, the current study investigated the harmful effects of clozapine on cardiomyocytes and assessed the cytoprotective effect of ellagic acid (EA). Freshly isolated adult rat ventricular cardiomyocytes were incubated for 4 h at 37 °C with 00.05% ethanol as control, CLZ (50 µM), CLZ (50 µM) + a series of EA concentrations (10, 20 and 50 µM) and EA (50 µM). To evaluate the protective effect of EA, the markers of cell viability, reactive oxygen species (ROS) formation, mitochondria membrane potential (ΔΨm) collapse, lysosomal membrane integrity, malondialdehyde (MDA) and oxidized/reduced glutathione (GSH/GSSG) content were checked by biochemical and flowcytometry techniques. Our results demonstrated that EA (10, 20 and 50 µM) effectively inhibited CLZ-induced cytotoxicity which is associated with ROS overproduction and amelioration of mitochondrial and lysosomal damages. In addition, EA (10, 20 and 50 µM) in the presence of CLZ reduced the production of MDA as a specific marker lipid peroxidation and GSSG. Collectively, these findings suggested that EA protects cardiomyocytes from oxidative injury through inhibiting ROS formation, mitochondria dysfunction, and lysosomal damages, which suggest a potential therapeutic strategy of EA for CLZ-induced oxidative stress and cardiotoxicity.