Accumulation of senescent cells is an increasingly recognized factor in the development and progression of cardiovascular (CV) disease (CVD). Senescent cells of different types display a pro-inflammatory and matrix remodelling molecular programme, known as the 'senescence-associated secretory phenotype' (SASP), which has roots in (epi)genetic changes. Multiple therapeutic options (senolytics, anti-SASP senomorphics, and epigenetic reprogramming) that delete or ameliorate cellular senescence have recently emerged. Some drugs routinely used in the clinics also have anti-senescence effects. However, multiple challenges hinder the application of novel anti-senescence therapeutics in the clinical setting. Understanding the biology of cellular senescence, advantages and pitfalls of anti-senescence treatments, and patients who can profit from these interventions is necessary to introduce this novel therapeutic modality into the clinics. We provide a guide through the molecular machinery of senescent cells, systematize anti-senescence treatments, and propose a pathway towards senescence-adapted clinical trial design to aid future efforts.

To evaluate whether immune checkpoint inhibitor (ICI) therapy is associated with a higher incidence of hypertension (HTN) among cancer patients compared to those not treated with ICIs.

This retrospective cohort study utilized data from the TriNetX Research Network, a global database of de-identified electronic health records. Adult patients (≥18 years) with lung, breast, colon, kidney, or skin cancer were categorized based on ICI treatment. Patients with preexisting hypertension were excluded. Propensity score matching (1:1) based on demographics and comorbidities yielded two balanced cohorts of 24,956 patients each. The primary outcome was the incidence of hypertension within one year of cancer diagnosis.

The incidence of hypertension was significantly higher in the ICI group (13.2%) compared to the non-ICI group (9.7%). The risk ratio was 1.356 (95% CI: 1.271-1.446), and the odds ratio was 1.410 (95% CI: 1.311-1.516), both with p < 0.001. Kaplan-Meier analysis showed lower hypertension-free survival in the ICI group (log-rank p < 0.001; HR = 1.071).

ICI therapy is significantly associated with an increased risk of developing hypertension. These findings support the need for routine cardiovascular monitoring in patients receiving ICI treatment.

Anthracycline anti-cancer drugs, which are used in cancer chemotherapy, frequently cause cardiotoxicity, the incidence of which depends on cumulative doses. TXB-001 is a new candidate polymer-conjugated pirarubicin (THP) with higher THP purity and content compared to previous P-THP (polymerized THP) and is expected to exhibit lower cardiotoxicity and higher efficacy against cancer cells. We examined the effects of TXB-001 on cardiac function and the pharmacokinetics after its intravenous administration compared with those of existing anthracyclines (doxorubicin (DOX), DOXIL (liposomal formulation of DOX), THP) in mice. Echocardiography and electrocardiography showed that DOX caused cardiac dysfunction in mice, with associated changes in organ weights, blood chemical parameters, and mRNA/protein expressions. DOXIL and THP induced similar, but weaker changes than DOX. TXB-001 did not significantly affect cardiac function or associated changes under the conditions of this study. The results of the pharmacokinetic evaluation revealed that the distributions of DOXIL and TXB-001 from plasma to heart tissue were lower than those of DOX and THP, while the distribution of TXB-001 was lower than that of DOXIL. Furthermore, TXB-001 did not show cardiac accumulation in contrast to DOXIL. In addition, the anthracycline exposure level of TXB-001 in the heart was lower than those of DOX, DOXIL, and THP, with less exposure being regarded as one reason for the low or no cardiotoxicity of TXB-001 in mice. Collectively, these results suggest the potential of TXB-001 as an anti-cancer drug with fewer side effects than anthracyclines, particularly cardiotoxicity. Novel TXB-001 may become an effective anti-cancer drug with fewer cardiotoxicity.

In this Review, we present a comprehensive analysis of preclinical models used to study immune checkpoint inhibitor-associated myocarditis (hereafter ICI-myocarditis), a potentially lethal immune-related adverse event. We begin by providing an overview of immune checkpoint inhibitors, highlighting how their efficacy in cancer treatment is counterbalanced by their predisposition to cause immune-related adverse events. Next, we draw from human data to identify disease features that an effective mouse model should ideally mimic. After that, we present a critical evaluation of a wide variety of existing mouse models including genetic, pharmacological and humanized models. We summarize insights gathered about the underlying mechanisms of ICI-myocarditis and the role of mouse models in these discoveries. We conclude with a perspective on the future of preclinical models, highlighting potential model improvements and research directions that could strengthen our understanding of ICI-myocarditis, ultimately improving patient outcomes.

In recent years, the continuous optimization of anti-tumor therapy has greatly improved the cancer-specific survival rate for patients with breast cancer (BC). The prevention and treatment of breast cancer-related heart diseases have become a new breakthrough in improving the long-term survival for BC patient. The cardiac damages caused by BC treatment are increasingly prominent among BC patients, of which ischemic heart disease (IHD) is the most prominent. Besides, the systemic inflammatory response activated by tumor microenvironment c an induce and exacerbate IHD and increase the risk of myocardial infarction (MI). Conversely, IHD can also exert detrimental effects on tumors. MI not only increases the risk of BC, but also induces specialized immune cell to BC and accelerates the progression of BC. Meanwhile, the treatment of IHD can also promote BC metastasis and transition to more aggressive phenotypes. Although BC and IHD are diseases of two independent systems, their crosstalk increases the difficulty of anti-cancer treatment and IHD management, which reduces the survival for both diseases. Therefore, this review mainly explores the mutual influence and underlying mechanisms between BC and IHD, aiming to provide insights for improving the long-term survival for patients with BC or IHD.

Immune checkpoints, such as PD-1 and CTLA-4, are crucial regulators of immune responses, acting as gatekeepers to balance immunity against foreign antigens and self-tolerance. These checkpoints play a key role in maintaining cardiac homeostasis by preventing immune-mediated damage to critical organs like the heart. In this study, we explored the involvement of PD-1 and CTLA-4 in cardiovascular complications, particularly atherosclerosis and myocarditis, which can lead to heart failure. We conducted a comprehensive analysis using animal models and clinical data to assess the effects of immune checkpoint inhibition on cardiac function. Our findings indicate that disruption of PD-1 and CTLA-4 pathways exacerbates myocardial inflammation, accelerates atherosclerotic plaque formation, and promotes the development of heart failure. Additionally, we observed that immune checkpoint inhibition in these models led to increased infiltration of T lymphocytes, higher levels of pro-inflammatory cytokines, and enhanced tissue damage. These results suggest that PD-1 and CTLA-4 are critical in preserving cardiac health, and their inhibition can result in severe cardiovascular toxicity. Our study emphasizes the need for careful monitoring of cardiovascular health in patients undergoing immune checkpoint inhibitor therapies.

In comparison to earlier treatment standards (including chemotherapy, radiation therapy, and surgery), immunotherapy has significantly improved patients' survival and quality of life. Immunotherapy is ultimately a broad term that encompasses a variety of therapeutics. Immunotherapeutic approaches have firmly established themselves as a new pillar of cancer care, ranging from neoadjuvant and adjuvant strategies to the metastatic phase in various entities. In this review article, we highlight which immunotherapies are currently standard in oncological care, with a strong focus on immune checkpoint inhibitors (ICIs), their limitations, and the commonly occurring side effects.

Cancer immunotherapy is a well-established therapeutic approach for various types of cancer. However, its clinical utility is usually limited by cardiovascular adverse events. Immune Checkpoint Inhibitors (ICIs) can induce diverse forms of cardiotoxicity, with myocarditis being the most fatal complication. The underlying mechanism of its occurrence remains elusive. Therefore, this study aims to elucidate the impact of programmed death-1 (PD-1) inhibitor on myocarditis development in mice. Myeloid-epithelial-reproductive tyrosine kinase (MerTK) receptors, located on the surface of macrophages, play a pivotal role in phagocytic regulation. We established a mouse model of autoimmune myocarditis by injecting 6-week-old normal male BALB/c mice with PD-1 inhibitor and cardiac troponin I peptide fragments, which resulted in elevated levels of serum soluble MerTK (SolMer) and reduced numbers of MerTK-CD68 double-positive macrophages, accompanied by cardiac injury in mice. In vitro, PD-1 inhibitor promotes a disintegrin and metalloproteinase17 (ADAM17)-mediated shed of the MerTK, forming SolMer, through MKK3/P38 MAPK pathway, leading to downregulation of MerTK expression on the macrophage surface. This results in the inhibition of efferocytosis and impairment of tissue repair function, ultimately contributing to myocarditis development. TAPI-0 inhibited the activity of ADAM17, while SB203580 inhibited the phosphorylation of P38 MAPK. Both inhibitors effectively restored the inhibition of efferocytosis induced by the PD-1 inhibitor. In vitro, when the PD-1 receptor on the surface of RAW264.7 macrophages was knocked down and then stimulated with a PD-1 inhibitor, no further significant alterations in the pathway were elicited. In conclusion, the PD-1 inhibitor induces the shedding of MerTK in macrophages by binding to the PD-1 receptor on the surface of macrophages and activating the MKK3/P38 MAPK/ADAM17 pathway, leading to impaired efferocytosis. Elucidation of this molecular mechanism holds promise for improved prognosis and therapeutic strategies in cancer patients.

Immune checkpoint inhibitors (ICIs) have revolutionized treatment for advanced lung cancer, yet their cardiotoxicity, particularly immune checkpoint inhibitor-related myocarditis, poses significant clinical challenges. This study aims to create a predictive model using cardiac biomarkers to identify patients prone to myocarditis during treatment, thereby enhancing clinical decision-making and patient outcomes.

In this retrospective cohort study, 1,838 patients with locally advanced and metastatic lung cancer and abnormal baseline cardiac parameters receiving immunotherapy from June 2018 to August 2024 were analyzed, with a follow-up date cutoff of September 20, 2024. Patients were randomly divided into training (70%) and validation (30%) cohorts. Logistic regression analysis was conducted on demographic information, clinical characteristics, treatments, and cardiac parameters of these patients prior to immunotherapy. A nomogram was constructed via multivariable logistic regression, and AUC and Hosmer-Lemeshow tests were performed to verify the accuracy of the model.

Among 1,838 patients, 89 (4.84%) developed myocarditis. Independent predictors included α-HBDH > 910 U/L (OR = 10.57, 95%CI: 2.47-45.22, P = 0.001), CK-MB > 15 ng/mL (OR = 3.87, 95%CI: 1.06-14.11, P = 0.040), hs-cTnT elevation (14-28 pg/mL: OR = 4.19; 28-42 pg/mL: OR = 13.10; >42 pg/mL: OR = 25.43, P < 0.001), NT-proBNP > 3× age-adjusted upper limit (OR = 9.72, 95%CI: 1.09-86.73, P = 0.042), and Caprini score ≥ 4 (OR = 4.49, 95%CI: 2.26-8.90, P < 0.001). The nomogram demonstrated strong discrimination ability, with an AUC of 0.831 in the training cohort (sensitivity: 0.842, specificity: 0.717) and an AUC of 0.844 in the validation cohort.

This study establishes a validated risk assessment model integrating cardiac biomarkers (α-HBDH, CK-MB, hs-cTnT, NT-proBNP) and Caprini risk score to predict ICI-related myocarditis in lung cancer patients with cardiac abnormalities. The tool facilitates early identification of high-risk patients, enabling tailored monitoring and preemptive management. These findings underscore the critical role of baseline cardiac profiling in optimizing immunotherapy safety.

Anti-programmed death 1 (αPD1) immune checkpoint blockade is used in combination for cancer treatment but associated with cardiovascular toxicity. Leflunomide (Lef) can suppress the growth of several tumor and mitigate cardiac remodeling in mice. However, the role of Lef in αPD1-induced cardiotoxicity remains unclear. Here, we report that Lef treatment inhibits αPD1-related cardiotoxicity without compromising the efficacy of αPD1-mediated immunotherapy. Lef changes community structure of gut microbiota in αPD1-treated melanoma-bearing mice. Moreover, mice receiving microbiota transplants from Lef+αPD1-treated melanoma-bearing mice have better cardiac function compared to mice receiving transplants from αPD1-treated mice. Mechanistically, we analyze metabolomics and identify indole-3-propionic acid (IPA), which protects cardiac dysfunction in αPD1-treated mice. IPA can directly bind to the aryl hydrocarbon receptor and promote phosphoinositide 3-kinase expression, thus curtailing the cardiomyocyte response to immune injury. Our findings reveal that Lef mitigates αPD1-induced cardiac toxicity in melanoma-bearing mice through modulation of the microbiota-IPA-heart axis.

Immune checkpoint inhibitors (ICIs)-induced cardiac injury is a life-threatening immune-related adverse events (irAEs). However, the current understanding of its pathogenesis and therapeutic options is relatively limited. We aimed to provide a comprehensive overview of the myocardial inflammatory injury process and underlying mechanisms associated with ICIs.

We conducted a descriptive analysis of lung cancer patients with ICIs-induced myocarditis at our institution and validated our clinical findings using single-cell sequencing (scRNA-seq) data. Furthermore, we established animal and cellular models to investigate the underlying mechanisms.

Our findings revealed that lung cancer patients with ICIs-induced myocarditis exhibit an early increase in peripheral blood monocytes, which migrate to the heart and differentiate into macrophages, ultimately leading to myocardial inflammation. Mechanistically, programmed death-1 (PD-1) inhibition triggers myocardial inflammation through the activation of the signal transducer and activator of transcription 1 (STAT1)/nuclear factor kappa-B (NF-κB)/oligomerization domain (NOD)-like receptor thermal protein domain-associated protein 3 (NLRP3) signaling pathway and drives the polarization of macrophages towards the M1 phenotype. However, the ubiquitin (Ub)-autophagy pathway degrades NLRP3 inflammasomes, resulting in the gradual resolution of inflammation and the transition of M1 macrophages to the M2 phenotype. Finally, mouse experiments confirmed that NLRP3 inhibition using MCC950 effectively alleviates myocardial inflammatory injury.

We recommend monitoring fluctuations in peripheral blood monocyte counts in lung cancer patients undergoing ICIs treatment. Additionally, MCC950 holds potential as a therapeutic agent for ICIs-induced cardiac inflammation injury.

In addition to traditional risk factors, patients with breast cancer are at an increased risk of atrial fibrillation due to cancer itself and certain cancer therapies. Atrial fibrillation in these patients adds to their morbidity and mortality. The precise mechanisms leading to the increased atrial fibrillation in patients with breast cancer are not well understood. The main goal of atrial fibrillation management in this population is to facilitate uninterrupted cancer treatment while addressing the arrhythmia and other cardiovascular sequelae of cancer treatment. Rhythm control is often challenging to implement in patients with breast cancer during active antineoplastic therapy because of the need for uninterrupted anticoagulation, potential drug-drug interactions between cancer treatments and antiarrhythmic medications, and the increased likelihood of atrial fibrillation recurrence. Prevention of thromboembolism and anticoagulation can also be challenging in patients with breast cancer as a result of the increased risk of cancer-related procoagulant state and coagulopathies. The integration of a cardio-oncology team and a multidisciplinary approach are crucial for better outcomes. The therapeutic interventions should be tailored toward individual patients' profiles through a shared decision-making approach. The precise mechanisms leading to the increased atrial fibrillation in patients with breast cancer are not well understood, highlighting the gaps in our knowledge. More research is required to reduce these gaps, refine risk stratification, and optimize treatment strategies in these patients.

Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy, significantly improving survival across various malignancies. However, these therapies are associated with various types of immune-related adverse events (irAEs), including cardiotoxicity, a spectrum of rare but potentially life-threatening complications impacting significantly morbidity and mortality. Cardiovascular imaging has become key in cardio-oncology, providing essential diagnostic tools for early detection and monitoring. This review synthesizes current evidence and underlines the pivotal role of early and tailored imaging strategies in managing ICI-induced cardiotoxicity. By bridging the knowledge gap, it aims to provide targetable insights to optimize the clinical management in patients undergoing immunotherapy.

Background and Objectives: The prevalence of and risk factors for immune checkpoint inhibitor-associated diarrhea and colitis (IMDC) in the Chinese population are unclear. This study aimed to estimate IMDC incidence and identify potential risk factors. Materials and Methods: We reviewed the electronic medical records from Beijing Friendship Hospital (2015-2022) to identify the patients treated with immune checkpoint inhibitors. The primary outcome was IMDC occurrence. The demographics, cancer type, baseline labs, and concurrent medications were analyzed. The univariable and multivariable analyses validated the associated factors. Results: Among 1186 patients (median follow-up: 217 days), the IMDC incidence was 4.6%, with colitis at 0.67%. Digestive system tumors increased the IMDC risk (OR 2.79, 95% CI 1.42-5.75, p = 0.004), while platinum agents decreased it (OR 0.41, 95% CI 0.21-0.78, p = 0.008). PPIs, antibiotics, NSAIDs, and glucocorticoids showed no significant association. Colitis was the third most common irAE, leading to ICI discontinuation (15.6%). Conclusions: IMDC prevalence is 4.6% in the Chinese population, the third most frequent irAE causing ICI discontinuation. Digestive tumors and platinum agents are risk and protective factors, respectively, while other medications show no significant impact.

Immune checkpoint inhibitors (ICPi) have significantly improved survival for patients with advanced cancers. However, the occurrence of ICPi-associated acute kidney injury (AKI) and its clinical impact remains unclear. This study evaluates the effects of ICPi-associated AKI (ICPi-AKI) on mortality, kidney and cardiovascular outcomes in patients undergoing ICPi treatments.

This multicentre retrospective cohort study with propensity score matching to balance baseline characteristics. The International Classification of Diseases, 10th Revision codes were used to identify individuals with cancer and treated with ICPi concurrently. Kaplan-Meier analyses coupled with log-rank tests were conducted to estimate the survival probabilities.

Data were sourced from the TriNetX database spanning records from 25 March 2011 to 5 April 2024.

Patients with cancer aged ≥18 years treated with ICPi with or without AKI occurrence.

The primary outcome was all-cause mortality, and secondary outcomes included major adverse kidney events (MAKE), major adverse cardiovascular events (MACE), the composite of MAKE or MACE with death, and end-stage renal disease.

The study identified 926 patients with cancer who developed ICPi-AKI (mean age, 67.1±11.8 years; 57.4% men). The control group consisted of 48 147 patients treated with ICPi but did not develop AKI (mean age, 65.3±13.1 years; 53.7% men). After matching, the ICPi-AKI group exhibited a higher risk of all-cause mortality (HR=1.27; 95% CI 1.02 to 1.61), MAKE (HR=3.83; 95% CI 1.72 to 8.40), MACE (HR=1.35; 95% CI 1.03 to 1.75)) compared with the non-ICPi-AKI group. Subgroup analyses confirmed these findings across various patient's characteristics.

Individuals with ICPi-AKI are associated with an increased risk of all-cause mortality, MAKE and MACE. Enhancing awareness and timely intervention for ICPi-AKI are crucial for improving prognosis and reducing complications among patients with cancer.

Doxorubicin (DOX)-induced cardiomyopathy (DIC) greatly limits its clinical application of the anticancer drug. Therefore, there is an immediate necessity to undertake intervention studies to minimize DIC, encompassing the screening of regulatory compounds and delving into the underlying regulatory mechanisms. A growing body of research suggests that ferroptosis is an essential process in the development of DIC. Here, we demonstrated that DOX causes elevated iron levels in cardiomyocytes and mouse hearts, and leads to ferroptosis and cardiac insufficiency. Next, we performed high-throughput screening of a library of herbal small molecule compounds for novel compounds that inhibit ferroptosis, using Fe2+ levels as a screening index for DIC prevention and treatment drugs. We found that Praeruptorin A (PA) was able to reduce Fe2+ concentration in cardiomyocytes, inhibit ferroptosis, and alleviate DIC and cardiac dysfunction in mice. Concurrently, PA exhibits a synergistic effect with DOX in suppressing the proliferation of carcinoma of breast MCF-7 cell in nude mice. Mechanistically, we found that PA inhibited the expression of divalent metal transporter protein 1 (DMT1), suppressed Fe2+ overload in cardiomyocytes, and inhibited ferroptosis, thereby alleviating DIC. Our study demonstrated the feasibility of high-throughput screening targeting the Fe2+ concentration, and elucidated the role and mechanism of PA in alleviating DIC, which provides a new possibility.

This study aimed to elaborate on the incidence, clinical features, and management of immune checkpoint inhibitors (ICIs) related cardiovascular adverse events (CVAEs) in real-world practice.

We performed a retrospective chart review study on patients receiving at least one dose of ICI therapy at a Chinese tertiary hospital from March 2020 to March 2021. CVAEs were identified through clinical assessment and the Naranjo algorithm. The management and outcomes of CVAEs were monitored over a median follow-up duration of 8 months.

Among the included 203 patients, 4.4% (9/203) developed CVAEs, including heart failure (n = 3), arrhythmia (n = 2), myocarditis (n = 2), and pericardial disease (n = 2), with a proportion (6/9) tending to be severe (grade 3 or grade 4). CVAEs were more common in older patients (mean age: 73.6 ± 9.2 years) and those with hypertension (p = 0.02) or heart failure (p = 0.01). Adherence to the American Society of Clinical Oncology (ASCO) guidelines for managing CVAEs was low (44%), with most cases showing partial resolution by the last follow-up.

We reported that the incidence of ICI-related CVAEs in the Chinese institution was higher than that in some prior studies. Adherence to guidelines for managing ICI-related CVAEs is found to be suboptimal in real-world practice and highlighted as a needed improvement.

Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy by unleashing the power of the immune system against malignant cells. However, their use is associated with a spectrum of adverse effects, including cardiovascular complications, which can pose significant clinical challenges. Several mechanisms contribute to cardiovascular toxicity associated with ICIs. First, the dysregulation of immune checkpoints, such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein-1 (PD-1) and its ligand (PD-L1), and molecular mimicry with cardiac autoantigens, leads to immune-related adverse events, including myocarditis and vasculitis. These events result from the aberrant activation of T cells against self-antigens within the myocardium or vascular endothelium. Second, the disruption of immune homeostasis by ICIs can lead to autoimmune-mediated inflammation of cardiac tissues, manifesting as cardiac dysfunction and heart failure, arrhythmias, or pericarditis. Furthermore, the upregulation of inflammatory cytokines, particularly tumor necrosis factor-alpha, interferon-γ, interleukin-1β, interleukin-6, and interleukin-17 contributes to cardiac and endothelial dysfunction, plaque destabilization, and thrombosis, exacerbating cardiovascular risk on the long term. Understanding the intricate mechanisms of cardiovascular side effects induced by ICIs is crucial for optimizing patient care and to ensure the safe and effective integration of immunotherapy into a broader range of cancer treatment protocols. The clinical implications of these mechanisms underscore the importance of vigilant monitoring and early detection of cardiovascular toxicity in patients receiving ICIs. Future use of these key pathological mediators as biomarkers may aid in prompt diagnosis of cardiotoxicity and will allow timely interventions.

Immune checkpoint inhibitors and chimeric antigen receptor T-cell therapy have revolutionized cancer treatment but can cause life-threatening cardiovascular toxicities through immune-related adverse events. Myocarditis is the most common and potentially fatal toxicity with immune checkpoint inhibitors. T-cell therapies can potentially lead to cytokine release syndrome. Diagnosis of ICI-myocarditis requires a multimodal approach, including biomarkers, imaging, and endomyocardial biopsy, while CRS is characterized by a clinical syndrome resembling distributive shock. Management involves discontinuing the offending therapy, immunosuppression with corticosteroids for ICI-myocarditis, and interleukin-6 antagonists for CRS. Collaboration between oncologists and cardiologists is crucial for early recognition and prompt treatment.

Cardiotoxicity from immune checkpoint inhibitor (ICI) therapy is a challenge in clinical practice, and the assessment of ICI-related myocarditis (ICI-M) is often complicated by a variable phenotype. Cardiac magnetic resonance imaging (CMR) is used frequently, but evidence is poor. Here, we aim to assess the role of CMR in the assessment of suspected ICI-M in a real-world clinical setting.

All patients receiving CMR at our centre for suspected ICI-M between September 2019 and January 2024 were included and retrospectively analysed. CMR parameters were correlated with clinical, laboratory and echocardiographic parameters and stratified for presence of myocarditis as per final diagnosis.

A total of 55 patients who received CMR for suspected ICI-M were analysed, including 25 patients with ICI-M and 30 patients with non-myocarditis cardiotoxicity (non-M). The mean age (ICI-M versus (vs.) non-M) was 65.7 ± 13.6 vs. 67.3 ± 9.9 (p = 0.61) years, 32.0 % vs. 26.7 % (p = 0.67) were female, and 40.0 % vs. 26.7 % (p = 0.29) had pre-existing coronary heart disease. Cardiac biomarkers and echocardiographic data did not differ between the groups. In CMR analysis, presence of LGE was associated with ICI-M (56.0 % in ICI-M vs. 26.7 % in non-M, p = 0.03). Myocardial oedema was generally rare and not associated with ICI-M.

In this real-life assessment of routine clinical practice, the diagnostic assessment of ICI-M is challenged by low sensitivity of common diagnostic measures, often requiring a multimodal approach. Presence of LGE in CMR is associated with ICI-M, but sensitivity and specificity are low. Prospective data to improve diagnostic criteria is needed.

Immunotherapy represents an emergent and heterogeneous group of anticancer treatments harnessing the human immune-surveillance system, including immune-checkpoint inhibitor monoclonal antibodies (mAbs), Chimeric Antigen Receptor T Cells (CAR-T) therapy, cancer vaccines and lymphocyte activation gene-3 (LAG-3) therapy. While remarkably effective against several malignancies, these therapies, often in combination with other cancer treatments, have showed unforeseen toxicity, including cardiovascular complications. The occurrence of immuno-mediated adverse (irAEs) events has been progressively reported in the last 10 years. These irAEs present an extended range of severity, from self-limiting to life-threatening conditions. Although recent guidelines in CardioOncology have provided important evidence in managing cancer treatments, they often encompass general approaches. However, a specific focus is required due to the particular etiology, unique risk factors, and associated side effects of immunotherapy. This review aims to deepen the understanding of the prevalence and nature of cardiovascular issues in patients undergoing immunotherapy, offering insights into strategies for risk stratification and management.

Cardiovascular disease and cancer are the leading causes of death in the Western world. The associated risk factors are increased by smoking, hypertension, diabetes, sedentary lifestyle, aging, unbalanced diet, and alcohol consumption. Therefore, the study of cellular metabolism has become of increasing importance, with current research focusing on the alterations and adjustments of the metabolism of cancer patients. This may also affect the efficacy and tolerability of anti-cancer therapies such as immune-checkpoint inhibition (ICI). This review will focus on metabolic adaptations and their consequences for various cell types, including cancer cells, cardiac myocytes, and immune cells. Focusing on ICI, we illustrate how anti-cancer therapies interact with metabolism. In addition to the desired tumor response, we highlight that ICI can also lead to a variety of side effects that may impact metabolism or vice versa. With regard to the cardiovascular system, ICI-induced cardiotoxicity is increasingly recognized as one of the most life-threatening adverse events with a mortality of up to 50%. As such, significant efforts are being made to assess the specific interactions and associated metabolic changes associated with ICIs to improve both efficacy and management of side effects.

Cardiac sarcomas are rare, aggressive malignancies originating from various cardiac cell types, presenting significant challenges in both diagnosis and treatment. This comprehensive review explores recent advancements in diagnosis and treatment of cardiac angiosarcoma, fibrosarcoma, leiomyosarcoma, and rhabdomyosarcoma. And we briefly discuss the exceedingly rare occurrence of cardiac osteosarcoma and present our perspectives on its treatment. Development of these tumors is influenced by genetic mutations, environmental factors, and chromosomal abnormalities, necessitating a multidisciplinary approach for accurate diagnosis and management. Advanced imaging techniques, biomarkers, and immunohistochemical analysis assist in confirming the diagnosis and guiding treatment decisions. Surgical resection, adjuvant therapies, and personalized treatment strategies based on genetic profiling offer promising avenues for improving patient outcomes. Emerging therapeutic approaches, such as targeted therapies and immunotherapies, have shown promising progress in recent years. Despite these advancements, the prognosis for patient with cardiac sarcomas remains poor, highlighting the urgent need for continued research to refine treatment methods and enhance long-term survival outcomes. Ongoing efforts and clinical trials are essential for advancing the management of these rare and aggressive tumors, ultimately improving quality of life for affected patients.

The distribution of adverse events (AEs) triggered by immune checkpoint inhibitors (ICIs) across different cancer types has never been demonstrated.

Randomised controlled trials exclusively assessing ICI monotherapy in cohorts of over 100 patients were considered. Our primary outcome was a comprehensive summary of the distribution of all-grade treatment-related adverse events (TRAEs) as well as serious TRAEs (CTCAE grade 3 or higher) across different malignancies. The study is registered with PROSPERO CRD42023387934.

75 trials that enrolled over 100 patients were included. While investigating the incidence of each TRAE across various cancers, we found special linkages existed between certain TRAEs and particular cancer types. In anti-PD-1 monotherapy group, melanoma patients experienced the most frequent fatigue (31.1 %, 95 % CI 29.7%-32.5 %); the incidences of severe pneumonitis and other respiratory disorders were highest in Hodgkin lymphoma (4.1 %, 95 % CI 1.5%-8.6 %; 4.1 %, 95 % CI 1.5%-8.6 %, respectively). Among individuals undergoing single-agent anti-PD-L1, higher frequency of all-grade pruritus occurred in 19.0 % of renal cell carcinoma (RCC) patients (95 % CI 15.2%-23.2 %), and the highest probability of developing other severe musculoskeletal disorders was observed in patients with RCC (6.2 %, 95 % CI 4.0%-9.0 %). In anti-CTLA-4 monotherapy, the incidences of both all-grade and severe diarrhea occurred most frequently in prostate cancer patients (41.9 %, 95 % CI 37.9%-47.9; 14.8 %, 95 % CI 11.5%-18.7 %, respectively).

This is the first comprehensive study addressing the distribution of various TRAEs across cancer types. Our research emphasizes the significance of considering cancer-specific TRAEs when using ICIs for treatment.

Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment outcomes. However, the response varies across different populations, and their use may lead to life-threatening cardiovascular (CV) events. While pre-treatment reduced left ventricular ejection fraction (LVEF) is considered a marker for high-risk cardiotoxicity and a contraindication for anthracycline and HER2-targeted therapies, there is limited evidence on the safety and efficacy of ICIs therapy in patients presenting with pre-treatment reduced LVEF. The study aims to evaluate the safety and efficacy of ICIs therapy in patients with pre-treatment reduced LVEF.

Retrospective single center cohort of patients treated with ICIs therapy, who performed pre-treatment LVEF assessment. The primary endpoint was to evaluate the safety of ICIs among this population, assessed by CV events (composite of myocarditis, acute coronary syndrome, heart failure, and arrhythmias). The secondary endpoint was to evaluate the efficacy of ICIs, assessed by all-cause mortality and progression-free survival (PFS).

The cohort included 307 patients, with 30 (10%) presenting with pre-treatment reduced LVEF, with a mean LVEF of 39 ± 7%. While a significantly higher incidence of CV events was observed in the reduced LVEF group (37% vs. 14%, p = 0.004), following a multivariate Cox regression analysis including baseline CV diseases and risk factors, pre-treatment reduced LVEF did not remain a significant independent predictor (p = 0.358). No significant differences were observed between the groups regarding all-cause mortality and PFS.

Pre-treatment reduced LVEF was not identified as an independent marker for clinical outcomes in patients treated with ICIs therapy.

Immune checkpoint inhibitor (ICI) therapy has dramatically improved the prognosis for some cancers but can be associated with myocarditis, adverse cardiovascular events, and mortality.

The aim of this study was to develop an artificial intelligence (AI) model to predict the increased likelihood for the development of ICI-related myocarditis and adverse cardiovascular events.

Cancer patients treated with ICI at a tertiary institution from 2011 to 2022 were reviewed. Baseline characteristics, laboratory values, electrocardiograms, and cardiovascular clinical outcomes were extracted. A composite outcome of ICI-related myocarditis and major adverse cardiovascular events (transient ischemic attack/stroke, new diagnosis of heart failure, myocardial infarction, and cardiac death) was used to develop a multimodal joint fusion AI model by combining baseline tabular data with electrocardiogram (ECG) in a single end-to-end model. ECG data were parsed using 1-D convolution and tubular data using multilayer perceptron.

Of 2,258 cancer patients who had ICI therapy and troponin measurement (mean age 68.5 ± 11.5 years, 59.7% male), the composite of cardiovascular clinical adverse events, including ICI-related myocarditis and major adverse cardiovascular events, occurred in 264 (11.7%) unique patients, with 428 events overall (including 59 [3%] ICI-related myocarditis events and 59 [3%] cardiac deaths). The proposed joint fusion model outperformed individual ECG and baseline electronic medical record data and laboratory value models with an area under the operating characteristics curve of 0.72 (0.64 true positive rate and 0.98 negative predictive value).

A multimodal fusion AI model to predict myocarditis and adverse cardiovascular events in cancer patients starting ICI therapy had good prognostic performance. It may have clinical utility in identifying at-risk patients who may benefit from closer surveillance.

Doxorubicin (DOX), a potent antineoplastic agent, is commonly associated with cardiotoxicity, necessitating the development of strategies to reduce its adverse effects on cardiac function. Previous research has demonstrated a strong correlation between DOX-induced cardiotoxicity and the activation of oxidative stress pathways. This work introduces a novel antioxidant therapeutic approach, utilizing libraries of tannic acid and N-acetyl-L-cysteine-protected bimetallic cluster nanozymes. Through extensive screening for antioxidative enzyme-like activity, an optimal bimetallic nanozyme (AuRu) is identified that possess remarkable antioxidant characteristics, mimicking catalase-like enzymes. Theoretical calculations reveal the surface interactions of the prepared nanozymes that simulate the hydrogen peroxide decomposition process, showing that these bimetallic nanozymes readily undergo OH⁻ adsorption and O₂ desorption. To enhance cardiac targeting, the atrial natriuretic peptide is conjugated to the AuRu nanozyme. These cardiac-targeted bimetallic cluster nanozymes, with their anchoring capability, effectively reduce DOX-induced cardiomyocyte ferroptosis and PANoptosis without compromising tumor treatment efficacy. Thus, the therapeutic approach demonstrates significant reductions in chemotherapy-induced cardiac cell death and improvements in cardiac function, accompanied by exceptional in vivo biocompatibility and stability. This study presents a promising avenue for preventing chemotherapy-induced cardiotoxicity, offering potential clinical benefits for cancer patients.

Immune checkpoint inhibitors (ICIs) have shown remarkable efficacy against various cancers in clinical practice. However, ICIs can cause immune checkpoint inhibitor-associated pancreatic injury, often leading to drug withdrawal, and then patients must go to specialized treatment. The patients, their primary tumors are sensitive to ICIs therapy, may experience treatment delays due to such adverse reactions. Therefore, there is a need for systematic clinical researches on immune-related pancreatic toxicity to provide a clinical basis for its prevention and treatment.

This study involved the collection of data from patients treated with ICIs and addressed pancreatic injury with preemptive treatment before continuing ICIs therapy. Then, we also statistically analyzed the incidence of pancreatic injury in patients with different courses and combined treatment, and the success rate of rechallenge treatment.

The study included 62 patients, with 33.9% (21/62) experiencing varying degrees of pancreatic injury. Patients with pancreatic injury, 10 cases evolved into pancreatitis, representing 47.6% (10/21) in the pancreatic injury subgroup and 16.1% (10/62) of the total patient cohort. Preemptive treatment was administered to 47.6% (10/21) of patients with pancreatitis, the effective rate was 100%. Among these patients, 70% (7/10) underwent successful rechallenge with ICIs. The occurrence of pancreatic injury was positively correlated with the treatment duration (P < 0.05) but showed no significant correlation with combination therapies (P > 0.05).

The likelihood of pancreatic injury increased with longer treatment durations with ICIs; no significant association was found between the incidence of ICIs-related pancreatic damage and combination therapies. Preemptive treatment for immune-related pancreatitis is feasible, allowing some patients to successfully undergo rechallenge with ICIs therapy.

Immune checkpoint inhibitors (ICIs) are monoclonal antibodies that block inhibitors of T cell activation and function. With the widespread use of ICIs in cancer therapy, immune-related adverse events (irAEs) have gradually emerged as urgent clinical issues. Tumors not only exhibit high heterogeneity, and their response to ICIs varies, with "hot" tumors showing better anti-tumor effects but also a higher susceptibility to irAEs. The manifestation of irAEs displays a tumor-heterogeneous pattern, correlating with the tumor type in terms of the affected organs, incidence, median onset time, and severity. Understanding the mechanisms underlying the pathogenic patterns of irAEs can provide novel insights into the prevention and management of irAEs, guide the development of biomarkers, and contribute to a deeper understanding of the toxicological characteristics of ICIs. In this review, we explore the impact of tumor type on the therapeutic efficacy of ICIs and further elucidate how these tumor types influence the occurrence of irAEs. Finally, we assess key candidate biomarkers and their relevance to proposed irAE mechanisms. This paper also outlines management strategies for patients with various types of tumors, based on their disease patterns.

As the understanding of immune-related mechanisms in the development and progression of cancer advances, immunotherapies, notably Immune Checkpoint Inhibitors (ICIs), have become integral in comprehensive cancer treatment strategies. ICIs reactivate T-cell cytotoxicity against tumors by blocking immune suppressive signals on T cells, such as Programmed Death-1 (PD-1) and Cytotoxic T-lymphocyte Antigen-4 (CTLA-4). Despite their beneficial effects, ICIs are associated with immune-related adverse events (irAEs), manifesting as autoimmune side effects across various organ systems. A particularly alarming irAE is life-threatening myocarditis. This rare but severe side effect of ICIs leads to significant long-term cardiac complications, including arrhythmias and heart failure, and has been observed to have a mortality rate of up to 50% in affected patients. This greatly limits the clinical application of ICI-based immunotherapy. In this review, we provide a comprehensive summary of the current knowledge regarding the diagnosis and management of ICI-related myocarditis. We also discuss the utility of preclinical mouse models in understanding and addressing this critical challenge.

Cardiovascular disease is an increasing risk of morbidity and mortality in cancer patients, related to an growing number of aging survivors with pre-existing cardiovascular disease and the use of traditional and novel cancer therapies with cardiotoxic effects. While many cardiac complications are chronic processes that develop over time, there are many acute processes that may arise in hospitalized patients. It is important for hospitalists and critical care physicians to be familiar with the recognition and management of these conditions in this unique population. This article reviews the presentation and management of common cardiac urgencies in critically ill cancer patients including acute decompensated heart failure, acute coronary syndromes, arrhythmias, hypertensive crises, pulmonary embolism, pericardial tamponade and myocarditis.

There is an urgent need to better understand the diverse presentations, risk factors, and outcomes of immune checkpoint inhibitor (ICI)-associated cardiovascular toxicity. There remains a lack of consensus surrounding cardiovascular screening, risk stratification, and clinical decision-making in patients receiving ICIs.

We conducted a single center retrospective cohort study including 2165 cancer patients treated with ICIs between 2013 and 2020. The primary outcome was adverse cardiovascular events (ACE): a composite of myocardial infarction, coronary artery disease, stroke, peripheral vascular disease, arrhythmias, heart failure, valvular disease, pericardial disease, and myocarditis. Secondary outcomes included all-cause mortality and the individual components of ACE. We additionally conducted an imaging substudy examining imaging characteristics from echocardiography (echo) and cardiac magnetic resonance (CMR) imaging.

In our cohort, 44% (n = 962/2165) of patients experienced ACE. In a multivariable analysis, dual ICI therapy (hazard ratio [HR] 1.23, confidence interval [CI] 1.04-1.45), age (HR 1.01, CI 1.00-1.01), male sex (HR 1.18, CI 1.02-1.36), prior arrhythmia (HR 1.22, CI 1.03-1.43), lung cancer (HR 1.17, CI 1.01-1.37), and central nervous system (CNS) malignancy (HR 1.23, CI 1.02-1.47), were independently associated with increased ACE. ACE was independently associated with a 2.7-fold increased risk of mortality (P<0.001). Dual ICI therapy was also associated with a 2.0-fold increased risk of myo/pericarditis (P = 0.045), with myo/pericarditis being associated with a 2.9-fold increased risk of mortality (P<0.001). However, the cardiovascular risks of dual ICI therapy were offset by its mortality benefit, with dual ICI therapy being associated with a ~25% or 1.3-fold decrease in mortality. Of those with echo prior to ICI initiation, 26% (n = 115/442) had abnormal left ventricular ejection fraction or global longitudinal strain, and of those with echo after ICI initiation, 28% (n = 207/740) had abnormalities. Of those who had CMR imaging prior to ICI initiation, 43% (n = 9/21) already had left ventricular dysfunction, 50% (n = 10/20) had right ventricular dysfunction, 32% (n = 6/19) had left ventricular late gadolinium enhancement, and 9% (n = 1/11) had abnormal T2 imaging.

Dual ICI therapy, prior arrhythmia, older age, lung and CNS malignancies were independently associated with an increased risk of ACE, and dual ICI therapy was also independently associated with an increased risk of myo/pericarditis, highlighting the utmost importance of cardiovascular risk factor optimization in this particularly high-risk population. Fortunately, the occurrence of myo/pericarditis was relatively uncommon, and the overall cardiovascular risks of dual ICI therapy appeared to be offset by a significant mortality benefit. The use of multimodal cardiac imaging can be helpful in stratifying risk and guiding preventative cardiovascular management in patients receiving ICIs.

This review details the significant advancement in knowledge of Immune-checkpoint inhibitor (ICI) and its potential deleterious cardiac immune-related adverse effects (irAE). We explore their mechanisms on the cardiac tissue, providing guidance on risk factors, clinical presentations, diagnostic strategies along with treatment.

Recent findings have provided insights of cardiac irAEs that exist beyond the previously well-known ICI-induced myocarditis. We have a better understanding of the wide variety of cardiac irAEs pathologies both early and late onset. Moreover, there is more data on mechanisms of cardiotoxicity and patient and therapy-related risk factors, supporting closer routine cardiac monitoring with biomarkers and imaging for prevention and early detection. Diagnosing cardiac irAEs is a challenge given its broad clinical presentation. A high-level of suspicion in addition to early work-up is crucial to prevent serious cardiac events. A multi-disciplinary team including Cardiologists and Oncologists is essential for closely monitor patients' cardiac status on ICI therapy. There is a need of updated guidelines to establish clear recommendations in patients on ICIs.

Advances in cancer treatment have improved in patient survival rate. On the other hand, management of cardiovascular complications has been increasingly required in cancer patients. Thus, cardio-oncology has attracted the attention by both oncologists and cardiologists. Cardiovascular imaging has played a key role for non-invasive assessment of cardiovascular alterations complimentary to biomarkers and clinical assessment. Suitable imaging selection and interpretation may allow early diagnosis of cardiovascular injury with potential implications for therapeutic management and improved outcomes after cancer therapy. Echocardiography has been commonly used to evaluate cardiac dysfunction in cardio-oncology area. Cardiac CT is valuable for assessing structural abnormalities of the myocardium, coronary arteries, and aorta. Molecular imaging has an important role in the assessment of the pathophysiology and future treatment strategy of cardiovascular dysfunction. Cardiac MRI is valuable for characterization of myocardial tissue. PET and SPECT molecular imaging has potential roles for quantitative assessment of cardiovascular disorders. Particularly, FDG-PET is considered as an elegant approach for simultaneous assessment of tumor response to cancer therapy and early detection of possible cardiovascular involvement as well. This review describes the promising potential of these non-invasive cardiovascular imaging modalities in cardio-oncology.

Stroke is an often underrecognized albeit significant complication in patients with brain cancer, arising from the intricate interplay between cancer biology and cerebrovascular health. This review delves into the multifactorial pathophysiological framework linking brain cancer to elevated stroke risk, with particular emphasis on the crucial role of the neurotoxic microenvironment (NTME). The NTME, characterized by oxidative stress, neuroinflammation, and blood-brain barrier (BBB) disruption, creates a milieu that promotes and sustains vascular and neuronal injury. Key pathogenic factors driving brain cancer-related stroke include cancer-related hypercoagulability, inflammatory and immunological mechanisms, and other tumor-associated processes, including direct tumor compression, infection-related sequelae, and treatment-related complications. Recent advances in genomic and proteomic profiling present promising opportunities for personalized medicine, enabling the identification of biomarkers-such as oncogenes and tumor suppressor genes-that predict stroke susceptibility and inform individualized therapeutic strategies. Targeting the NTME through antioxidants to alleviate oxidative stress, anti-inflammatory agents to mitigate neuroinflammation, and therapies aimed at reinforcing the BBB could pave the way for more effective stroke prevention and management strategies. This integrative approach holds the potential to reduce both the incidence and severity of stroke, ultimately improving clinical outcomes and quality of life for brain cancer patients. Further research and well-designed clinical trials are essential to validate these strategies and integrate them into routine clinical practice, thereby redefining the management of stroke risk in brain cancer patients.