Cardiotoxicity Research Articles

Drug induced reversible cardiomyopathy reported for liposomal amphotericine B: a rare documented adverse event

Liposomal amphotericin B (LAmB), lipid formulation of amphotericin B (AmB) is used in the treatment of fungal infections, including invasive disease and cryptococcal meningitis and is associated with fewer nephrotoxic and infusion-related adverse effects than conventional amphotericin B. Cardiac toxicity due to LAmB is a rarely reported adverse event in literature. Here we report a case of 53 years female known case of vitiligo, Diabetes mellitus Type 2 diagnosed as case of sinonasal mucormycosis and started on inj LAmB, developed chest pain on day 4 of inj LAmB. ECG and 2D ECHO showed VPBs and ventricular ectopics that were transient and completely recovered on reducing the dose of LAmB. As LV function has recovered on reducing Liposomal AMB, and patient was not on any other cardiotoxic drugs. It was concluded that the patient developed Transient Cardiomyopathy also known as Takotsubo Cardiomyopathy likely due to Liposomal AMB that improved on reducing dose of the drug LAmB. Although very rare but reversible cardiomyopathy also known as Takotsubo Cardiomyopathy due to LAmB is a documented adverse effect. Therefore, ECG monitoring or cardiac monitoring (2D ECHO) should be done when patient is started on LAmB and if at any point cardiotoxicity is suspected then drug should be stopped or reduced in dose immediately. These adverse effects are reversible which recovere on stopping or reducing the dose of LAmB.

A systematic review, ANCOVA meta-analysis, and meta-regression of clinical trials : Orlistat and body mass index of overweight and obese patients

Background: Obesity or overfat (i.e., excessive fat accumulation in the host) contributes to cerebrocardiovascular and other diseases. Orlistat is a good obesity medication, unlike other drugs that have higher cardiac toxicity. It reversibly inhibits pancreatic and gastric lipases, and improves oxysterol metabolism. This study summarizes and elaborates the impact of orlistat on BMI in overweight and obese adult patients. Methods: All authors systematically searched and retrieved 288 controlled trial articles on orlistat and BMI from three databases, two registries, and citation searches using specific keywords. The quality and bias risks were determined by the Grading of Recommendations Assessment, Development, and Evaluation (GRADE), Risk of Bias in Non-Randomized Study (ROBINS-I), and modified Jadad scale. R version 4.2.2 software calculated the effect size and the analysis of covariance (ANCOVA) effect, and subsequently analyzed using metafor. Results: This novel meta-analysis included 114 studies with 24,600 overweight or obese participants. We showed that orlistat substantially reduced BMI (mean difference −0.78 [−0.94, −0.63], p < 0.0001; I2 = 90.19%, pheterogeneity < 0.0001). Similarly, meta-regression showed a significant impact of orlistat daily dose (ß = −0.0019), yet not for duration (ß = −0.0024) and location (ß = −0.8591, −0.0190). Conclusion: Orlistat has the capacity to reduce BMI in overweight and obese individuals. Medical practitioners shall prescribe orlistat as a BMI lowering agent to complement other intervention in those patients

Posttransplant cyclophosphamide: a universal graft versus host disease prophylaxis.

The purpose of this review is to outline current graft versus host disease (GvHD) prophylaxis, in the era of posttransplant cyclophosphamide (PTCY), in patients with malignant and nonmalignant hematologic disorders. The original combination of PTCY with a calcineurin inhibitor (CNI) and mycophenolate (MMF), reported from the Johns Hopkins University in Baltimore, was designed for patients receiving a graft from a donor mismatched at one haplotype, so called haploidentical donor (HAPLO). In the past decade, PTCY has been widely used in HAPLO transplants worldwide, confirming the amazing efficacy of PTCY in preventing GvHD in mismatched grafts. More recently, PTCY is being tested also in grafts from human leukocyte antigen (HLA) identical related or unrelated donors. In the present review we will also answer several open questions, such as: PTCY and cardiac toxicity; PTCY dose; PTCY timing; PTCY and antithymocyte globulin (ATG); engraftment kinetics; infections; PTCY and leukemia relapse; PTCY and HLA identical grafts. PTCY is currently one of the most effective measures to prevent GvHD, and can be customized in different transplant platforms, together with other immunosuppressive agents. There is place for improvement, and several possible modifications of PTCY dose and schedule can be tested in prospective trials.

A Comprehensive Review of Naringenin, a Promising Phytochemical with Therapeutic Potential.

Disorders, including cancer, metabolic disorders, and neurodegenerative diseases, can threaten human health; therefore, disease prevention is essential. Naringenin, a phytochemical with low toxicity, has been used in various disease prevention studies. This study aimed to comprehensively review the effects of naringenin on human health. First, we introduced the general characteristics of naringenin and its pharmacokinetic features when absorbed in the body. Next, we summarized the inhibitory effects of naringenin on colorectal, gastric, lung, breast, ovarian, cervical, prostate, bladder, liver, pancreatic, and skin cancers in preclinical studies. Lastly, we investigated the inhibitory effects of naringenin on metabolic disorders, including diabetes, obesity, hyperlipidemia, hypertension, cardiac toxicity, hypertrophy, steatosis, liver disease, and arteriosclerosis, as well as on neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease. In conclusion, naringenin may serve as a significant natural compound that benefits human health.

FNDC1 is a myokine that promotes myogenesis and muscle regeneration.

Myogenesis is essential for skeletal muscle formation and regeneration after injury, yet its regulators are largely unknown. Here we identified fibronectin type III domain containing 1 (FNDC1) as a previously uncharacterized myokine. In vitro studies showed that knockdown of Fndc1 in myoblasts reduces myotube formation, while overexpression of Fndc1 promotes myogenic differentiation. We further generated recombinant truncated mouse FNDC1 (mFNDC1), which retains reliable activity in promoting myoblast differentiation in vitro. Gain- and loss-of-function studies collectively showed that FNDC1 promotes cardiotoxin (CTX)-induced muscle regeneration in adult mice. Furthermore, recombinant FNDC1 treatment ameliorated pathological muscle phenotypes in the mdx mouse model of Duchenne muscular dystrophy. Mechanistically, FNDC1 bound to the integrin α5β1 and activated the downstream FAK/PI3K/AKT/mTOR pathway to promote myogenic differentiation. Pharmacological inhibition of integrin α5β1 or of the downstream FAK/PI3K/AKT/mTOR pathway abolished the pro-myogenic effect of FNDC1. Collectively, these results suggested that myokine FNDC1 might be used as a therapeutic agent to regulate myogenic differentiation and muscle regeneration for the treatment of acute and chronic muscle disease.

Cardiac toxicities of Bruton’s tyrosine kinase inhibitors: The risk of pericarditis and cardiac tamponade

Bruton’s tyrosine kinase (BTK) inhibitors are widely used in the management of chronic lymphocytic leukaemia (CLL) and other B-cell malignancies. Despite their therapeutic efficacy, BTK inhibitors are associated with cardiac toxicities, most notably atrial fibrillation and hypertension. However, our recent case series highlights the rare yet underappreciated risk of pericarditis and cardiac tamponade in patients treated with both first- and second-generation BTK inhibitors. This article highlights the need for vigilance in clinical practice and the importance of timely echocardiography. The challenges of early diagnosis are discussed, as well as the role of emerging technologies, such as point-of-care ultrasound and AI-based diagnostics. Ultimately, a cautious, informed approach is crucial to balance the benefits of BTK therapy with the risk of rare but life-threatening cardiac events.

The role of senescence in cancer therapy-associated cardiovascular toxicity

Cardiovascular diseases (CVDs) and cancer are the two leading causes of global mortality. Cancer treatments, including radiotherapy and chemotherapy, can have severe cardiotoxic side effects, raising concerns for cancer patients and increasing the financial burden on healthcare systems. Recent studies have shown a link between cancer therapy-induced cardiotoxicity and cardiac senescence. Specifically, systemic cancer therapies are known to induce cardiac senescence, which may directly result in cardiac dysfunction or enhance the vulnerability of the heart to other stressors. Besides anthracyclines, newer, more targeted therapies such as tyrosine kinase inhibitors (TKIs) have also been shown to induce cardiac senescence. Cellular senescence is triggered by DNA damage, oncogene activation, reactive oxygen and nitrogen species, and other stressors, leading to the secretion of proinflammatory factors, increased oxidative stress, and disruption of normal cellular functions. Understanding the molecular mechanisms of cardiac senescence induced by cancer therapy is essential for attenuating or even preventing clinically overt cardiotoxicity using senotherapies such as senolytics and senomorphics. In this review, cancer therapies that are associated with CVDs are described with an emphasis on the potential role of cardiac senescence in the disease progression. In addition, the known mechanisms by which anthracyclines, particularly doxorubicin (DOX), radiotherapy, and TKIs lead to cardiac senescence are highlighted. Finally, recent and novel senotherapies for treating cellular senescence are discussed with a focus on targeting cardiac senescence following cancer treatment. The field remains in its early stages, with further research required to clarify how cancer treatments contribute to cardiotoxicity. At the same time, identifying senotherapies that can be safely combined with cancer drugs is essential for targeting cardiac senescence and protecting cardiac health in cancer patients.

Correction to: Anthracycline-induced cardiovascular toxicity: validation of the Heart Failure Association and International Cardio-Oncology Society risk score

Correction to: Anthracycline-induced cardiovascular toxicity: validation of the Heart Failure Association and International Cardio-Oncology Society risk score

Impact of deep inspiration breath hold, surface-guided radiotherapy, and daily CBCT on the organs at risk in breast cancer radiotherapy

The goal of the study was to assess the impact of deep inspiration breath hold technique (DIBH), surface-guided radiotherapy (SGRT), and daily kilovoltage cone-beam computed tomography (kV-CBCT) on the dose to organs at risk (OAR) in left-sided breast cancer radiotherapy. Twenty-six consecutive left-sided breast cancer patients treated using Volumetric Intensity Modulated Arc Therapy (VMAT), DIBH, SGRT, and a hypofractionated regimen were retrospectively evaluated in this study. Dose parameters were extracted from dose-volume histograms (DVH). The Wilcoxon Matched Pairs test was used to test dose parameters obtained in free breathing (FB) and DIBH for statistical significance. Multivariable analysis of variance (ANOVA) and receiver operating characteristics (ROC) analysis were used to identify parameters and cut-off points associated with the reduction of the mean heart dose (MHD) by DIBH. Based on published models, the risk of cardiac and lung toxicity (pneumonitis) using SGRT or daily kV-CBCT was estimated and compared. DIBH substantially reduced the MHD (median, 43.6%; range, 4.2% to 75.1%; P < 0.00001). The risk of cardiac toxicity using SGRT increased by 1%, compared to 3.6% to 20.5% using daily kV-CBCT. No significant difference in the risk of radiation-induced pneumonitis using SGRT versus daily kV-CBCT was detected. The ANOVA revealed the relative increase of the left lung volume by DIBH as the only significant impact factor for the MHD. The ROC analysis of this parameter showed an area under the curve (AUC) of 0.89 (95%CI, 0.71 to 0.98; P < 0.0001). DIBH can substantially reduce the MHD in left-sided breast cancer patients treated with modern radiotherapy techniques and hypofractionation. Patient setup using SGRT compared to daily kV-CBCT may be the preferred option for many patients. In our patient cohort, the relative reduction of the left lung volume by DIBH can be used as a predictor to select patients who benefit from DIBH.

Quantitative Structure-Activity Relationship Models to Predict Cardiac Adverse Effects.

Drug-induced cardiotoxicity represents one of the most common causes of attrition of drug candidates in preclinical and clinical development. For this reason, the evaluation of cardiac toxicity is essential during drug development and regulatory review. In the present study, drug-induced postmarket adverse event combinations from the FDA Adverse Event Reporting System were extracted for 2002 drugs using 243 cardiac toxicity-related preferred terms (PTs). These PTs were combined into 12 groups based on their clinical relevance to serve as training sets. The optimal classification scheme was determined using a combination of data sources that included drug labeling information, published literature, clinical study data, and postmarket surveillance data. Two commercial QSAR platforms were used to construct 12 models, including general cardiac toxicity, cardiac ischemia, heart failure, cardiac valve disease, myocardial disease, pericardial disease, structural heart disease, cardiac arrhythmia, Torsades de Pointes, long QT syndrome, atrial fibrillation and ventricular arrhythmia, and cardiac arrest. The cross-validated performance for the new models reached a sensitivity of up to 80% and negative predictivity of up to 80%. These new models covering a wide range of cardiac endpoints will provide fast, reliable, and comprehensive predictions of potential cardiotoxic compounds in drug discovery and regulatory safety assessment.

Abstract 4118444: Right Ventricular Contractile Reserve and Right Ventricular-Pulmonary Arterial Coupling Are Impaired in Long-Term Survivors of Childhood Cancers

Background: Childhood cancer survivors are at risk of right ventricular (RV) dysfunction in relation to cardiac toxicity due to chemotherapy and radiation therapy. This study tested the hypothesis that RV contractile reserve and RV-pulmonary arterial (PA) coupling are altered in long-term survivors of childhood cancers. Methods: Thirty survivors (60% men) aged 24.3 ± 5.2 years at 15.3 ± 6.3 years after completion of chemotherapy and thirty healthy control subjects (47% men) were studied. Resting and submaximal supine bicycle stress echocardiography was performed for assessment of RV fractional area change (FAC), tricuspid annular plane systolic excursion (TAPSE), left ventricular (LV) and RV longitudinal strain, mitral and tricuspid annular velocities and myocardial acceleration during isovolumic contraction (IVA). The slope of the RV force-frequency relationship was derived from the change in IVA with the change in heart rate during exercise (△IVA/△heart rate), while RV-PA coupling was determined by the ratio between TAPSE and pulmonary arterial acceleration time indexed to RV ejection time (PAATi). Results: At rest, tricuspid annular systolic velocity and RV systolic strain were significantly lower in survivors ( P &lt; 0.05 for both), while RV FAC, TAPSE and IVA were similar between the two groups ( P &gt; 0.05 for all). During submaximal exercise testing, all RV systolic functional indices were significantly lower in survivors than controls ( P &lt; 0.05 for all). The slope of the RV force-frequency relationship was significantly flatter in survivors compared to controls (0.038 ± 0.002 vs 0.059 ± 0.003 m/sec 2 beats/min, P &lt; 0.001). For RV-PA coupling, TAPSE/PAATi was similar between survivors and controls at baseline but became significantly lower in survivors during submaximal exercise ( P = 0.002). Conclusions: The RV contractile reserve and RV-PA coupling are impaired during exercise in long-term survivors of childhood cancers. Future studies aimed at determining the clinical and prognostic significance of these impairments are warranted.

CTNI-70. RESULTS FROM THE PHASE 1 AND PHASE 1 EXPANSION COHORTS OF SJ901: A PHASE 1/2 TRIAL OF SINGLE-AGENT MIRDAMETINIB (PD-0325901) IN CHILDREN, ADOLESCENTS, AND YOUNG ADULTS WITH LOW-GRADE GLIOMA

Abstract BACKGROUND Mirdametinib is an investigational, oral, selective MEK1/2 inhibitor (MEKi) with high blood-brain-barrier penetration. We hypothesized that mirdametinib would benefit patients with pediatric low-grade gliomas (pLGG) and launched SJ901 (NCT04923126) to determine the recommended Phase 2 dose (RP2D), safety, and efficacy. METHODS For Phase 1 and Phase 1 expansion patients were required to be ≥2 and &amp;lt;25 years-old, MEKi-naive, and have recurrent/progressive pLGG with biopsy-proven MAPK pathway activation (except BRAF V600). Three dose levels (DL1: 2 mg/m2/dose BID, DL2: 2.5mg/m2/dose BID, DL3: 3mg/m2/dose BID administered continuously in 28-day cycles) were evaluated with an expansion cohort to assess the highest tolerated dose level in a total of 12 patients. RP2D was defined as the dose causing ≤3 dose-limiting toxicities (DLTs) in 12 patients within the first cycle of therapy. RESULTS Between June 2021 and December 2023, 23 patients enrolled (DL1=5, DL2=6, and DL3=12). Median age was 8.4 years (2.5-21.9); 52% female. Alterations were seen in BRAF (n=12;52%), FGFR1 (n=5;22%), NF1 (n=3;13%), RAF1 (n=2;9%), and MYB (n=1;4%). The median follow-up time was 14.6 months (3.2-27.8). One DLT was observed (grade-3 thrombocytopenia). Seventeen (74%) patients completed or remain on-therapy; 4(17%) stopped for progression (2 FGFR1; 1 MYB; 1 BRAF); 2 discontinued for toxicities [1 grade-2 rash; 1 grade-4 creatine phosphokinase (CPK) elevation]. Dose modifying adverse events included weight gain, CPK elevations, and rash. No significant cardiac or retinal toxicity was observed. Twelve (63%) of 19 patients with measurable tumors achieved an objective response (1 major, 6 partial, 5 minor). The median time to ≥ minor response was 5.4 months (1.7-7.3). DL3 (3 mg/m2/dose BID) was declared the RP2D. CONCLUSIONS Mirdametinib is well-tolerated and has promising clinical activity in patients with recurrent/progressive pLGG. Phase 2 is ongoing to establish safety and efficacy in newly diagnosed, recurrent/refractory tumors, and in patients with prior MEKi exposure.

Scaffold transforming and in-silico design of potential androgen receptor antagonists in prostate cancer therapy.

Androgens like testosterone and dihydrotestosterone are essential for the growth and development of the prostate gland. Androgenic receptors are overexpressed, which promotes the progression of prostate cancer; therefore, androgenic receptors are a key target in the therapy of prostate cancer. Enzalutamide is used to treat prostate cancer; however, it also causes toxicities such as cardiovascular toxicity, acute myocarditis, hypertension, and seizures. The objective of this research was to create novel and safer analogues of enzalutamide, followed by the prediction of the pharmacokinetic and toxicity characteristics of these enzalutamide analogues. Molecular docking studies of analogues were also done to guess how ligands will work biologically in treating prostate cancer. A total of 195 analogues were generated, and among them, 23 bioisosteres were selected for further pharmacokinetic, toxicological screening and docking studies. The predicted physical-chemical, medicinal, and ADMET characteristics of the designed bioisosteres were optimal to good compared to enzalutamide. Additionally, the drug likeness and drug score of analogues were superior to enzalutamide. According to docking studies of analogues, EZ12, EZ8, and EZ10 formed hydrogen bonds of SER778 with replaceable amide groups in enzalutamide molecules. SER778 residue may be responsible for antagonistic activity towards androgen receptors. Based on the results of the ADMET, drug likeness, drug score, and docking study of designed enzalutamide analogues, the ligands EZ12, EZ8, and EZ10 could be used to find more possible antiandrogen drugs that could be used to treat prostate cancer.

Cancer survivors and cardiovascular diseases: from preventive strategies to treatment.

During the last decades, progress in the treatment of oncological diseases has led to an increase in the survival of cancer patients: cancer survivors (CS). Thus, the incidence of CS has increased enormously, in both adult CS and childhood and adolescent CS. Unfortunately, CS treated with anthracyclines, chest radiotherapy (RT) and other potentially cardiotoxic drugs have a higher risk of cardiovascular (CV) toxicity: heart failure with reduced ejection fraction (HFrEF), valve diseases, coronary artery diseases, vascular diseases and pericardial diseases. In fact, chest irradiation can cause coronary artery diseases that can be latent until at least 10 years after exposure; also, valvular heart diseases can appear after >20 years following irradiation; heart failure may appear later, several years after anticancer drugs or RT. Therefore, it is very important to stratify the CV risk of cancer patients at the end of cardiotoxic drugs, to plan the most appropriate long-term surveillance program, in accordance with 2022 ESC Guidelines on Cardio-Oncology, to prevent late cardiovascular complications. Monitoring of cancer patients must not stop during anticancer treatment but it must continue afterwards, depending on the patient's CV risk. CV toxicity risk should be reassessed 5 years after therapy to organize long-term follow-up. Considering late cardiotoxicity in CS, our review aims to evaluate the incidence of cardiovascular diseases in CS, their mechanisms, surveillance protocols, preventive strategies, diagnosis and treatment.

Transforming Cardiotoxicity Detection in Cancer Therapies: The Promise of MicroRNAs as Precision Biomarkers.

Cardiotoxicity (CDTX) is a critical side effect of many cancer therapies, leading to increased morbidity and mortality if not addressed. Early detection of CDTX is essential, and while echocardiographic measures like global longitudinal strain offer promise in identifying early myocardial dysfunction, the search for reliable biomarkers continues. MicroRNAs (miRNAs) are emerging as important non-coding RNA molecules that regulate gene expression post-transcriptionally, influencing key biological processes such as the cell cycle, apoptosis, and stress responses. In cardiovascular diseases, miRNAs have demonstrated potential as biomarkers due to their stability in circulation and specific expression patterns that reflect pathological changes. Certain miRNAs have been linked to CDTX and hold promise for early detection, prognosis, and therapeutic targeting. These miRNAs not only assist in identifying early cardiac injury, but also offer opportunities for personalized interventions by modulating their expression to influence disease progression. As research advances, integrating miRNA profiling with traditional diagnostic methods could enhance the management of CDTX in cancer patients, paving the way for improved patient outcomes and more tailored therapeutic strategies. Further clinical studies are essential to validate the clinical utility of miRNAs in managing CDTX.

Effect of ethyl acetate extract from Usnea longissima on chemotherapy-associated multiple organ dysfunction in rats

BackgroundThe toxic effects of doxorubicin and cisplatin in various organs have been associated with oxidative stress. Studies have shown that Usnea longissima has strong antioxidant effects. This study aimed to investigate the protective effect of ethyl acetate extract from Usnea longissima (ULE), which is known to have strong antioxidant effects, on chemotherapeutic-induced heart, kidney, liver, and ovarian toxicity. MethodsAlbino Wistar female rats were divided into five groups (12 rats per group): healthy (HG), doxorubicin (DOX), Cisplatin (CIS), Doxorubicin+ ULE (DULE), Cisplatin+ ULE (CULE). In this experiment, ULE was given 100 mg/kg orally. After 1 hour, 2.5 mg/kg doxorubicin and 2.5 mg/kg cisplatin were administered intraperitoneally. Drug treatments continued once a day for seven days. At the end of seven days, six rats from each group were euthanized and heart, kidney, liver, and ovary tissues were analyzed biochemically. The remaining rats were left in the laboratory with male rats for 45 days for reproduction. ResultsULE inhibited chemotherapeutic-induced increase in malondialdehyde, tumor necrosis factor-alpha, and interleukin 6 and a decrease in total glutathione in liver, kidney, and ovarian tissues. ULE also inhibited the increase of blood urea nitrogen, creatinine, alanine aminotransferase, and aspartate aminotransferase in serum. ULE treatment had no protective effect against doxorubicin and cisplatin cardiac toxicity. On the other hand, ULE also decreased the delay in pregnancy induced by chemotherapy. ConclusionULE may be considered an adjuvant therapy in patients receiving chemotherapy to reduce liver, kidney, and ovarian toxicity.

Heart is a heavy burden: cardiac toxicity in radiation oncology.

Over the years, radiotherapy has seen continual improvements and has become a standard treatment for most malignant tumors. Cardiotoxicity is a well-known radiotherapy side effect, leading to the risk of long-term morbidity and mortality in cancer survivors. Therefore, minimizing radiotherapy-related cardiotoxicity remains an important challenge in cancer care management. Indeed, multiple dose constraints were proposed for the heart and its substructures. In addition, sparing techniques were developed to reduce the exposure of the heart to ionizing radiation and are currently used in daily clinical routine. The purpose of this review is to summarize the current knowledge about radiation-induced cardiotoxicity, to discuss the previously cardiac dose constraints, and to evaluate the various management strategies.

Superior outcomes and high-risk features with carfilzomib, lenalidomide, and dexamethasone combination therapy for patients with relapsed and refractory multiple myeloma: results of the multicenter KMMWP2201 study.

Carfilzomib, lenalidomide, and dexamethasone (KRd) combination therapy improves the survival of patients with relapsed and/or refractory multiple myeloma (RRMM). Nonetheless, evidence on the use of KRd in Asian populations remains scarce. Accordingly, this study aimed to investigate this regimen's efficacy in a large group of patients. This retrospective study included patients with RRMM who were treated with KRd at 21 centers between February 2018 and October 2020. Overall, 364 patients were included (median age, 63 years). The overall response rate was 90% in response-evaluable patients, including 69% who achieved a very good partial response or deeper responses. With a median follow-up duration of 34.8 months, the median progression-free survival (PFS) was 23.4 months and overall survival (OS) was 59.5 months. Among adverse factors affecting PFS, high-risk cytogenetics, extramedullary disease, and doubling of monoclonal protein within 2-3 months prior to start of KRd treatment significantly decreased PFS and OS in multivariate analyses. Patients who underwent post-KRd stem cell transplantation (i.e., delayed transplant) showed prolonged PFS and OS. Grade 3 or higher adverse events (AE) were observed in 56% of the patients, and non-fatal or fatal AE that resulted in discontinuation of KRd were reported in 7% and 2% of patients, respectively. Cardiovascular toxicity was comparable to that reported in the ASPIRE study. In summary, KRd was effective in a large, real-world cohort of patients with RRMM with long-term follow-up. These findings may further inform treatment choices in the treatment of patients with RRMM.

Severe cardiotoxic characteristics associated with allogeneic hematopoietic stem cell transplantation preconditioning in patients with aplastic anemia

Objective: To delineate the clinical characteristics and outcomes associated with severe cardiac toxicity during the preconditioning phase of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients with aplastic anemia (AA). Methods: This retrospective case series study included 31 patients with severe AA who underwent allo-HSCT and were diagnosed with severe cardiac toxicity at the Hematology Department of Peking University People's Hospital from August 2012 to June 2022. The clinical manifestations of severe cardiac toxicity observed during the preconditioning process were assessed. Patient survival was assessed using the Kaplan-Meier method. Results: In this cohort of 31 patients, the median follow-up period was 9 days (range: 4-365 days). Severe cardiac toxicity manifested within 6 days after the initial cyclophosphamide (Cy) administration. Twenty patients died within 30 days of initiating Cy preconditioning, of which 16 patients died due to severe cardiac toxicity within 25 days. Patients whose cardiac function improved within 30 days post-preconditioning showed a median survival duration of 222 days (n=11). Troponin I (TNI) levels in patients who died within 30 days of initiating Cy preconditioning began increasing on day 5 post-Cy, peaking sharply by day 9 after a notable rise on day 8. B-type natriuretic peptide (BNP) levels in patients who died within 30 days of initiating Cy preconditioning started to rise from day 1, stabilized between days 2 and 5, and then doubled daily from days 6 to 8, remaining elevated thereafter. Notably, the initial increases in BNP and TNI correlated with electrocardiogram (ECG) signs of low voltage and T-wave inversion in 83.87% of cases (n=26). Most patients (n=28, 90.32%) were administered corticosteroid therapy. In those with restored cardiac function, the ejection fraction returned to >50% within 30 days of initiating Cy preconditioning. Conclusions: Patients with severe cardiac toxicity during the preconditioning phase of allo-HSCT typically exhibit early, sustained, and marked elevations in myocardial damage markers, including BNP and TNI, accompanied by ECG abnormalities following Cy administration, with BNP often increasing first. These indicators are associated with rapid disease progression and high mortality. Prompt initiation of treatment upon clinical diagnosis is critical for improving survival outcomes.

Temperature and Ultrasound-Responsive Nanoassemblies for Enhanced Organ Targeting and Reduced Cardiac Toxicity.

Biocompatible nanocarriers are widely employed as drug-delivery vehicles for treatment. Nevertheless, indiscriminate drug release, insufficient organ-specific targeting, and systemic toxicity hamper nanocarrier effectiveness. Stimuli-responsive nano-sized drug delivery systems (DDS) are an important strategy for enhancing drug delivery efficiency and reducing unexpected drug release. This study introduces a temperature- and ultrasound-responsive nano-DDS in which the copolymer p-(MEO2MA-co-THPMA) is grafted onto mesoporous iron oxide nanoparticles (MIONs) to construct an MPL-p nano-DDS. The copolymer acts as a nanopore gatekeeper, assuming an open conformation at sub-physiological temperatures that allows drug encapsulation and a closed conformation at physiological temperatures that prevents unexpected drug release during circulation. Lactoferrin was conjugated to the nanoparticle surface via polyethylene glycol to gain organ-targeting ability. External ultrasonic irradiation of the nanoparticles in the targeted organs caused a conformational change of the copolymer and reopened the pores, facilitating controlled drug release. MPL-p exhibited excellent biocompatibility and rare drug release in circulation. When targeting delivery to the brain, ultrasound promoted the release of the loaded drugs in the brain without accumulation in other organs, avoiding the related adverse reactions, specifically those affecting the heart. This study established a novel temperature- and ultrasound-responsive DDS that reduced systemic adverse reactions compared with traditional DDS, especially in the heart, and demonstrated excellent organ delivery efficiency.