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Cancer and cardiovascular (CV) disease are the most prevalent diseases in the developed world. Evidence increasingly shows that these conditions are interlinked through common risk factors, coincident in an ageing population, and are connected biologically through some deleterious effects of anticancer treatment on CV health. Anticancer therapies can cause a wide spectrum of short- and long-term cardiotoxic effects. An explosion of novel cancer therapies has revolutionised this field and dramatically altered cancer prognosis. Nevertheless, these new therapies have introduced unexpected CV complications beyond heart failure. Common CV toxicities related to cancer therapy are defined, along with suggested strategies for prevention, detection and treatment. This ESMO consensus article proposes to define CV toxicities related to cancer or its therapies and provide guidance regarding prevention, screening, monitoring and treatment of CV toxicity. The majority of anticancer therapies are associated with some CV toxicity, ranging from asymptomatic and transient to more clinically significant and long-lasting cardiac events. It is critical however, that concerns about potential CV damage resulting from anticancer therapies should be weighed against the potential benefits of cancer therapy, including benefits in overall survival. CV disease in patients with cancer is complex and treatment needs to be individualised. The scope of cardio-oncology is wide and includes prevention, detection, monitoring and treatment of CV toxicity related to cancer therapy, and also ensuring the safe development of future novel cancer treatments that minimise the impact on CV health. It is anticipated that the management strategies discussed herein will be suitable for the majority of patients. Nonetheless, the clinical judgment of physicians remains extremely important; hence, when using these best clinical practices to inform treatment options and decisions, practitioners should also consider the individual circumstances of their patients on a case-by-case basis.

Purpose: AZD5991, a human MCL-1 inhibitor, was assessed for safety, tolerability, pharmacokinetics, and antitumor activity as monotherapy and in combination with venetoclax in patients with relapsed or refractory hematologic malignancies., Patients and Methods: In the monotherapy cohort (n = 61), patients with hematologic malignancies received AZD5991 intravenously in escalating doses either once or twice weekly, following intrapatient dose escalation, during a 3-week cycle. In the combination cohort (n = 17), patients with acute myeloid leukemia and myelodysplastic syndrome received escalating doses of AZD5991 and venetoclax during either a 3- or 4-week cycle. Primary objectives were safety and maximum tolerated dose; secondary objectives included plasma pharmacokinetics and antitumor activity., Results: The most common (≥30%) adverse events were diarrhea (59.0%), nausea (55.1%), and vomiting (47.4%). Four deaths occurred because of adverse events: cardiac arrest, sepsis, tumor lysis syndrome, and acute respiratory failure; only tumor lysis syndrome was related to AZD5991. Dose-limiting toxicities occurred in five patients. Three patients with myelodysplastic syndrome achieved an objective response: one marrow complete remission without hematologic improvement, one partial remission with AZD5991 monotherapy, and one marrow complete remission with AZD5991 + venetoclax. Asymptomatic elevations of troponin I or T were observed in eight (10.3%) patients. Post hoc retrospective analysis revealed elevated troponin T in 14/31 patients before any AZD5991 dose and in 54/65 patients after any AZD5991 dose at or after Cycle 1. No associations were found between elevated troponin and cardiovascular risk factors., Conclusions: Treatment with AZD5991 was associated with high incidence of laboratory troponin elevation and a low overall response rate., (©2024 The Authors; Published by the American Association for Cancer Research.)

The advent of immunological therapies has revolutionized the treatment of solid and haematological cancers over the last decade. Licensed therapies which activate the immune system to target cancer cells can be broadly divided into two classes. The first class are antibodies that inhibit immune checkpoint signalling, known as immune checkpoint inhibitors (ICIs). The second class are cell-based immune therapies including chimeric antigen receptor T lymphocyte (CAR-T) cell therapies, natural killer (NK) cell therapies, and tumour infiltrating lymphocyte (TIL) therapies. The clinical efficacy of all these treatments generally outweighs the risks, but there is a high rate of immune-related adverse events (irAEs), which are often unpredictable in timing with clinical sequalae ranging from mild (e.g. rash) to severe or even fatal (e.g. myocarditis, cytokine release syndrome) and reversible to permanent (e.g. endocrinopathies).The mechanisms underpinning irAE pathology vary across different irAE complications and syndromes, reflecting the broad clinical phenotypes observed and the variability of different individual immune responses, and are poorly understood overall. Immune-related cardiovascular toxicities have emerged, and our understanding has evolved from focussing initially on rare but fatal ICI-related myocarditis with cardiogenic shock to more common complications including less severe ICI-related myocarditis, pericarditis, arrhythmias, including conduction system disease and heart block, non-inflammatory heart failure, takotsubo syndrome and coronary artery disease. In this scientific statement on the cardiovascular toxicities of immune therapies for cancer, we summarize the pathophysiology, epidemiology, diagnosis, and management of ICI, CAR-T, NK, and TIL therapies. We also highlight gaps in the literature and where future research should focus., (© 2024 European Society of Cardiology.)

Abstract: Clonal hematopoiesis (CH) is an age-associated phenomenon leading to an increased risk of both hematologic malignancy and nonmalignant organ dysfunction. Increasingly available genetic testing has made the incidental discovery of CH clinically common yet evidence-based guidelines and effective management strategies to prevent adverse CH health outcomes are lacking. To address this gap, the prospective CHIVE (clonal hematopoiesis and inflammation in the vasculature) registry and biorepository was created to identify and monitor individuals at risk, support multidisciplinary CH clinics, and refine taxonomy and standards of practice for CH risk mitigation. Data from the first 181 patients enrolled in this prospective registry recapitulate the molecular epidemiology of CH from biobank-scale retrospective studies, with DNMT3A, TET2, ASXL1, and TP53 as the most commonly mutated genes. Blood counts across all hematopoietic lineages trended lower in patients with CH. In addition, patients with CH had higher rates of end organ dysfunction, in particular chronic kidney disease. Among patients with CH, variant allele frequency was independently associated with the presence of cytopenias and progression to hematologic malignancy, whereas other common high-risk CH clone features were not clear. Notably, accumulation of multiple distinct high-risk clone features was also associated with cytopenias and hematologic malignancy progression, supporting a recently published CH risk score. Surprisingly, ∼30% of patients enrolled in CHIVE from CH clinics were adjudicated as not having clonal hematopoiesis of indeterminate potential, highlighting the need for molecular standards and purpose-built assays in this field. Maintenance of this well-annotated cohort and continued expansion of CHIVE to multiple institutions are underway and will be critical to understanding how to thoughtfully care for this patient population., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Background: Immune-checkpoint inhibitors (ICI) have revolutionized cancer treatment by harnessing the immune system but ICI can induce life-threatening immune-related adverse events (irAE) affecting every organ., Methods: We extracted irAE from VigiBase, the international pharmacovigilance database, first reported in 2008 until 01/2023 to characterize irAE reporting trends, clinical features, risk factors and outcomes., Findings: We distinguished 25 types of irAE (n = 50,347cases, single irAE/case in 84.9%). Cases mainly involved anti-PD1 (programmed-death-1) monotherapy (62.4%) in male (61.7%) aged 64.3 ± 12.6 years. After 2020 vs. prior to 2016, proportion of anti-CTLA4 (Cytotoxic-T-Lymphocyte-Antigen-4) monotherapy prescription almost vanished (1.6% vs. 47%, respectively) contrasting with increased use of anti-PDL1 (PD1-ligand) monotherapy (18% vs. 0.9%) and anti-CTLA4+anti-PD(L)1 combination (20% vs. 8.9%). Anti-LAG3 (Lymphocyte-Activation-Gene-3) prescription was limited (<1%) in the studied timeframe. After 2020, over 14 different cancer types were treated vs. almost exclusively melanoma and lung cancers before 2016. Overall, the most reported irAE were skin reactions (22.9%), pneumonitis (18.5%), enterocolitis (14.4%) and thyroiditis (12.1%). ICI-myotoxicities (6.6%) included myositis, myocarditis and myasthenia-gravis like syndrome and were the most overlapping irAE (up to 30% overlap, vs. <3% in general for other inter-irAE overlap). The top factors associated with specific irAE (odds-ratio>5) were presence of thymic cancer for ICI-myotoxicities or hepatitis; presence of melanoma for vitiligo, uveitis or sarcoidosis; specific types of ICI regimen (anti-LAG3 for meningitis, anti-CTLA4 for hypophysitis); and specific reporting regions (eastern Asia for cholangitis). Median time-to-onset ranged from 31 to 273 days, being shortest for myotoxicities and most delayed for skin-bullous auto-immune reactions. Overall fatality was highest for myocarditis = 27.6%, myasthenia = 23.1%, severe cutaneous adverse reactions (SCAR) = 22.1%, myositis = 21.9%, pneumonitis = 21%, and encephalomyelitis = 18%; generally decreasing after 2020, except for myasthenia and SCAR. When reported, irAE recurrence rate after rechallenge was 28.9% (n = 275/951)., Interpretation: This up-to-date comprehensive worldwide pharmacovigilance study defines the spectrum, characteristics, and evolution of irAE reporting summarizing over a decade of use. Multiple risk factors and clinical peculiarities for specific irAE have been identified as signals to guide clinical practice and future research., Funding: Paul Gougis was supported by the academic program: "Contrats ED: Programme blanc Institut Curie PSL" for the conduct of his PhD. Baptiste Abbar was supported by "the Fondation ARC Pour le Rechercher Sur le Cancer". The RT2L research group (Institut Curie) was supported by the academic program "SHS INCa", Sanofi iTech award, and by Monoprix∗., Competing Interests: Dr Gougis declares participation to advisory board from BMS, travel support from Eisai, and an academic grant from Sanofi. Dr Abbar reports consulting fees or honoraria from Novartis, AstraZeneca, BMS, MSD, Astellas, and Sanofi. Dr Salem have participated to advisory boards, consultancy or received grants from BMS, Novartis, AstraZeneca, CRC-Oncology, EISAI, IPSEN, Bayer, Banook Group, and BeiGene. Dr Spano have participated to advisory boards, consultancy from Roche, MSD, BMS, Lilly, AstraZeneca, Daiichi-Sankyo, Mylan, Novartis, Pfizer, PFO, LeoPharma and Gilead, and Grant for MSDAvenir. Dr Moslehi served on advisory boards for Bristol-Myers Squibb, Takeda, AstraZeneca, Myovant, Kurome Therapeutics, Kiniksa Pharmaceuticals, Daiichi Sankyo, CRC Oncology, BeiGene, Prelude Therapeutics, TransThera Sciences, BitterRoot Bio, Deciphera, Regeneron, Teva and Cytokinetics and is supported by the NIH (R01HL141466, R01HL155990, R01HL156021, R01 HL160688, R01 HL170038). All other authors report no COI., (© 2024 The Author(s).)

Background: Immune checkpoint inhibitors (ICIs), antibodies targeting PD-1 (programmed cell death protein 1)/PD-L1 (programmed death-ligand 1) or CTLA4 (cytotoxic T-lymphocyte-associated protein 4), have revolutionized cancer management but are associated with devastating immune-related adverse events including myocarditis. The main risk factor for ICI myocarditis is the use of combination PD-1 and CTLA4 inhibition. ICI myocarditis is often fulminant and is pathologically characterized by myocardial infiltration of T lymphocytes and macrophages. Although much has been learned about the role of T-cells in ICI myocarditis, little is understood about the identity, transcriptional diversity, and functions of infiltrating macrophages., Methods: We used an established murine ICI myocarditis model ( Ctla4 +/- Pdcd1 -/- mice) to explore the cardiac immune landscape using single-cell RNA-sequencing, immunostaining, flow cytometry, in situ RNA hybridization, molecular imaging, and antibody neutralization studies., Results: We observed marked increases in CCR2 (C-C chemokine receptor type 2) + monocyte-derived macrophages and CD8 + T-cells in this model. The macrophage compartment was heterogeneous and displayed marked enrichment in an inflammatory CCR2 + subpopulation highly expressing Cxcl9 (chemokine [C-X-C motif] ligand 9), Cxcl10 (chemokine [C-X-C motif] ligand 10), Gbp2b (interferon-induced guanylate-binding protein 2b), and Fcgr4 (Fc receptor, IgG, low affinity IV) that originated from CCR2 + monocytes. It is important that a similar macrophage population expressing CXCL9 , CXCL10 , and CD16α (human homologue of mouse FcgR4) was expanded in patients with ICI myocarditis. In silico prediction of cell-cell communication suggested interactions between T-cells and Cxcl9 + Cxcl10 + macrophages via IFN-γ (interferon gamma) and CXCR3 (CXC chemokine receptor 3) signaling pathways. Depleting CD8 + T-cells or macrophages and blockade of IFN-γ signaling blunted the expansion of Cxcl9 + Cxcl10 + macrophages in the heart and attenuated myocarditis, suggesting that this interaction was necessary for disease pathogenesis., Conclusions: These data demonstrate that ICI myocarditis is associated with the expansion of a specific population of IFN-γ-induced inflammatory macrophages and suggest the possibility that IFN-γ blockade may be considered as a treatment option for this devastating condition., Competing Interests: Disclosures J.M. has served on advisory boards for Bristol-Myers Squibb, Takeda, AstraZeneca, Myovant, Kurome Therapeutics, Kiniksa Pharmaceuticals, Daiichi Sankyo, CRC Oncology, BeiGene, Prelude Therapeutics, TransThera Sciences, and Cytokinetics. The other authors report no conflicts.

Colorectal cancer (CRC) is the third most common cancer in the USA and worldwide. In the USA, nearly one-third of CRC cases are anatomically classified as rectal cancer. Over the past few decades, continued refinement of multimodality treatment and the introduction of new therapeutic agents have enhanced curative treatment rates and quality of life outcomes. As treatments improve and the incidence of young onset rectal cancer rises, the number of rectal cancer survivors grows each year. This trend highlights the growing importance of rectal cancer survivorship. Multimodality therapy with systemic chemotherapy, chemoradiation, and surgery can result in chronic toxicities in multiple organ systems, requiring a multi-disciplinary care model with services ranging from appropriate cancer surveillance to management of long-term toxicities and optimization of modifiable risk factors. Here, we review the evidence on these long-term toxicities and provide management considerations from consensus guidelines. Specific topics include bowel dysfunction from radiation and surgery, oxaliplatin-induced neuropathy, accelerated bone degeneration, the impact of fluoropyrimidines on long-term cardiovascular health, urinary incontinence, sexual dysfunction, and psychosocial distress. Additionally, we review modifiable risk factors to inform providers and rectal cancer survivors of various lifestyle and behavioral changes that can be made to improve their long-term health outcomes., (© 2022. The Author(s).)

Background: Immune checkpoint inhibitors (ICIs) are approved for multiple cancers but can result in ICI-associated myocarditis, an infrequent but life-threatening condition. Elevations in cardiac biomarkers, specifically troponin-I (cTnI), troponin-T (cTnT), and creatine kinase (CK), are used for diagnosis. However, the association between temporal elevations of these biomarkers with disease trajectory and outcomes has not been established., Methods: We analyzed the diagnostic accuracy and prognostic performances of cTnI, cTnT, and CK in patients with ICI myocarditis (n=60) through 1-year follow-up in 2 cardio-oncology units (APHP Sorbonne, Paris, France and Heidelberg, Germany). A total of 1751 (1 cTnT assay type), 920 (4 cTnI assay types), and 1191 CK sampling time points were available. Major adverse cardiomyotoxic events (MACE) were defined as heart failure, ventricular arrhythmia, atrioventricular or sinus block requiring pacemaker, respiratory muscle failure requiring mechanical ventilation, and sudden cardiac death. Diagnostic performance of cTnI and cTnT was also assessed in an international ICI myocarditis registry., Results: Within 72 hours of admission, cTnT, cTnI, and CK were increased compared with upper reference limits (URLs) in 56 of 57 (98%), 37 of 42 ([88%] P =0.03 versus cTnT), and 43 of 57 ([75%] P <0.001 versus cTnT), respectively. This increased rate of positivity for cTnT (93%) versus cTnI ([64%] P <0.001) on admission was confirmed in 87 independent cases from an international registry. In the Franco-German cohort, 24 of 60 (40%) patients developed ≥1 MACE (total, 52; median time to first MACE, 5 [interquartile range, 2-16] days). The highest value of cTnT:URL within the first 72 hours of admission performed best in terms of association with MACE within 90 days (area under the curve, 0.84) than CK:URL (area under the curve, 0.70). A cTnT:URL ≥32 within 72 hours of admission was the best cut-off associated with MACE within 90 days (hazard ratio, 11.1 [95% CI, 3.2-38.0]; P <0.001), after adjustment for age and sex. cTnT was increased in all patients within 72 hours of the first MACE (23 of 23 [100%]), whereas cTnI and CK values were less than the URL in 2 of 19 (11%) and 6 of 22 (27%) of patients ( P <0.001), respectively., Conclusions: cTnT is associated with MACE and is sensitive for diagnosis and surveillance in patients with ICI myocarditis. A cTnT:URL ratio <32 within 72 hours of diagnosis is associated with a subgroup at low risk for MACE. Potential differences in diagnostic and prognostic performances between cTnT and cTnI as a function of the assays used deserve further evaluation in ICI myocarditis., Competing Interests: Disclosures L.H.L. has served on the advisory board for Daiichi Sankyio, Senaca, and Servier, as an external expert for Astra Zeneca, and received speaker honoraria from Novartis and MSD. J.E.S. has served as a consultant for Bristol-Myers Squibb, AstraZeneca, BeiGene, IPSEN, EISAI, and Novartis, and received grants from Bristol-Myers Squibb and Novartis. N.L.P. is a Cancer Prevention Research Institute of Texas scholar and Andrew Sabin Family Foundation fellow, and is supported by the Cancer Prevention Research Institute of Texas (RP200670) and National Institutes of Health/National Cancer Institute (1P01CA261669-01). J.J.M. has served on advisory boards for Bristol-Myers Squibb, Takeda, AstraZeneca, Myovant, Kurome Therapeutics, Kiniksa Pharmaceuticals, Daiichi Sankyo, CRC Oncology, BeiGene, Prelude Therapeutics, TransThera Sciences, Antev Ltd, IQVIA, AskBio, Lapcorp, Paladin, Quell Therapeutics, and Cytokinetics.

Cardiac allograft vasculopathy (CAV) is a leading cause of late graft failure and mortality after heart transplantation (HT). Sharing some features with atherosclerosis, CAV results in diffuse narrowing of the epicardial coronaries and microvasculature, with consequent graft ischemia. Recently, clonal hematopoiesis of indeterminate potential (CHIP) has emerged as a risk factor for cardiovascular disease and mortality. We aimed to investigate the relationship between CHIP and posttransplant outcomes, including CAV. We analyzed 479 HT recipients with stored DNA samples at 2 high-volume transplant centers, Vanderbilt University Medical Center and Columbia University Irving Medical Center. We explored the association between the presence of CHIP mutations with CAV and mortality after HT. In this case-control analysis, carriers of CHIP mutations were not at increased risk of CAV or mortality after HT. In a large multicenter genomics study of the heart transplant population, the presence of CHIP mutations was not associated with an increased risk of CAV or posttransplant mortality., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Alexander G Bick reports a relationship with TenSixteen Bio that includes: consulting or advisory. Javid Moslehi reports a relationship with Bristol Myers Squibb, AstraZeneca, Myovant, Cytokinetics, Takeda, BeiGene, Kiniksa, Kurome Therapeutics, and Pfizer that includes: consulting or advisory., (Copyright © 2023 American Society of Transplantation & American Society of Transplant Surgeons. Published by Elsevier Inc. All rights reserved.)

The overall survival of advanced melanoma has improved dramatically. Immunotherapies, specifically checkpoint inhibitors, have played a large role in this improvement. These agents have also shown benefit in the adjuvant setting, are approved for treatment of resected stage II, III, and IV melanoma, and play an evolving role in the neoadjuvant setting. Although generally well tolerated, immune-related adverse events occur and can be severe. Here we focus on some severe and potentially long term toxicities, including cardiovascular and neurologic toxicities. Our understanding of the acute and long-term toxicities of immune checkpoint inhibitors continues to evolve. Oncologists must continue to balance cancer risk and treatment-related toxicities.

Our understanding of tumorigenesis and cancer progression as well as clinical therapies for different cancer types have evolved dramatically in recent years. However, even with this progress, there are big challenges for scientists and oncologists to tackle, ranging from unpacking the molecular and cellular mechanisms involved to therapeutics and biomarker development to quality of life in the aftermath of therapy. In this article, we asked researchers to comment on the questions that they think are important to address in the coming years., Competing Interests: Declaration of interests R.B. is a shareholder of Agendia and Oncosence, is a member of the board of directors for and has received research funding from Lixte Biotechnology holdings, and receives research funding from Heparegenix GmbH. J.A.J. has received honoraria for speaking at research symposia organized by Bristol Meyers Squibb and Glenmark Pharmaceuticals and currently serves on the scientific advisory board of Pionyr Immunotherapeutics. S.L. receives research funding to her institution from Novartis, Bristol Meyers Squibb, Merck, Puma Biotechnology, Eli Lilly, Nektar Therapeutics, Astra Zeneca, and Seattle Genetics; has acted as consultant (not compensated) to Seattle Genetics, Novartis, Bristol Meyers Squibb, Merck, AstraZeneca, Eli Lilly, Pfizer, Gilead Therapeutics, and Roche-Genentech; and has acted as consultant (paid to her institution) to Aduro Biotech, Novartis, GlaxoSmithKline, Roche-Genentech, Astra Zeneca, Silverback Therapeutics, G1 Therapeutics, PUMA Biotechnologies, Pfizer, Gilead Therapeutics, Seattle Genetics, Daiichi Sankyo, Merck, Amunix, Tallac Therapeutics, Eli Lilly, and Bristol Meyers Squibb. S.L. is supported by the National Breast Cancer Foundation of Australia Endowed Chair and the Breast Cancer Research Foundation, New York. J.M. has served on advisory boards for Bristol-Myers Squibb, Takeda, AstraZeneca, Myovant, Kurome Therapeutics, Kiniksa Pharmaceuticals, Daiichi Sankyo, CRC Oncology, BeiGene, Prelude Therapeutics, TransThera Sciences, and Cytokinetics. J.M. is supported by the NIH (R01HL141466, R01HL155990, R01HL156021, and R01HL160688). J.M. has patents pending related to the treatment of immune-related adverse events including ICI-myocarditis. W.R.S. is a Board or SAB member and holds equity in Ideaya Biosciences, Civetta Therapeutics, Red Ridge Bio, 2Seventy Bio, and Scorpion Therapeutics; has consulted for Array, Astex, Epidarex Capital, Ipsen, Merck Pharmaceuticals, Pierre Fabre, Sanofi, Servier, and Syndax Pharmaceuticals; and receives research funding from Pfizer, Merck, Bristol-Myers, Boehringer-Ingelheim, Ideaya Biosciences, Calico Biosciences, and Ridgeline Discovery. W.R.S. is a co-patent holder on EGFR mutation diagnostic patents. J.S. is an employee of Pfizer, Inc., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objectives: Palpitations are common and have a negative impact on women's quality of life. While evidence suggests that inflammatory mechanisms may play a role in the development of palpitations, no studies have evaluated for this association in patients with breast cancer who report palpitations prior to surgery. The purpose of this pilot study was to evaluate for associations between the occurrence of palpitations and single nucleotide polymorphisms (SNPs) in genes for pro- and anti-inflammatory cytokines, their receptors, and transcriptional regulators., Methods: Patients were recruited prior to surgery and completed a self-report questionnaire on the occurrence of palpitations. Genotyping of SNPs in cytokine genes was performed using a custom array. Multiple logistic regression analyses were done to identify associations between the occurrence of palpitations and SNPs in fifteen candidate genes., Results: Of the 82 SNPs evaluated in the bivariate analyses, eleven SNPs in 6 genes were associated with the occurrence of palpitations. After controlling for functional status, the occurrence of back pain, and self-reported and genomic estimates of race/ethnicity, 3 SNPs in 3 different genes (i.e., interleukin (IL) 1-beta (IL1B) rs1143643, IL10 rs3024505, IL13 rs1295686) were associated with the occurrence of palpitations prior to surgery (all p ≤ .038)., Conclusions: While these preliminary findings warrant replication, they suggest that inflammatory mechanisms may contribute to the subjective sensation of palpitations in women prior to breast cancer surgery.

Immune-related adverse events (irAEs) associated with immune checkpoint inhibitor (ICI) therapy may vary substantially in their clinical presentation, including natural history, outcomes to treatment, and patterns. The application of clinical guidelines for irAE management can be challenging for practitioners due to a lack of common or consistently applied terminology. Furthermore, given the growing body of clinical experience and published data on irAEs, there is a greater appreciation for the heterogeneous natural histories, responses to treatment, and patterns of these toxicities, which is not currently reflected in irAE guidelines. Furthermore, there are no prospective trial data to inform the management of the distinct presentations of irAEs. Recognizing a need for uniform terminology for the natural history, response to treatment, and patterns of irAEs, the Society for Immunotherapy of Cancer (SITC) convened a consensus panel composed of leading international experts from academic medicine, industry, and regulatory agencies. Using a modified Delphi consensus process, the expert panel developed clinical definitions for irAE terminology used in the literature, encompassing terms related to irAE natural history (ie, re-emergent, chronic active, chronic inactive, delayed/late onset), response to treatment (ie, steroid unresponsive, steroid dependent), and patterns (ie, multisystem irAEs). SITC developed these definitions to support the adoption of a standardized vocabulary for irAEs, which will have implications for the uniform application of irAE clinical practice guidelines and to enable future irAE clinical trials., Competing Interests: Competing interests: JN—Consulting fees: AstraZeneca, Bristol Myers-Squibb, Roche/Genentech, Takeda, Pfizer, Daiichi Sankyo; Contracted research: AstraZeneca, Merck; Data Safety Monitoring Board: Daiichi Sankyo; NPI: 1710327721. LCC—Consulting fees: AbbVie; Contracted research: Bristol-Myers Squibb. CM—Nothing to Disclose. MBA—Consulting fees: Aveo, BMS, Eisai, Exelixis, Genentech, Iovance, Merck, Novartis, Pfizer, Roche, Pyxis, Werewolf, Asher Bio, Calithera, Idera, Agenus, Apexigen, Neoleukin, Adagene, AstraZeneca, Elpis, ScholarRock, Surface, ValoHealth, Sanofi, Fathom; Ownership Interest Less Than 5%: Werewolf, Pyxis, Elpis; NPI: 1306874201. JRB—Consulting fees: Amgen, BMS, Genentech/Roche, Eli Lilly, GlaxoSmithKline, Merck, Sanofi, Regeneron; Contracted research: AstraZeneca, BMS, Genentech/Roche, Merck, RAPT Therapeutics, Revolution Medicines; Data and Safety Monitoring Board/Committees: GlaxoSmithKline, Sanofi. SC—Consulting fees: Amgen, AstraZeneca, Ultrahuman, Oncovita; Fees for Non-CE Services: Amgen, AstraZeneca, BMS, Janssen, Merck, MSD, Novartis and Roche; Contracted Research: Amgen, Merck, Sanofi Aventis; As part of the Drug Development Department (DITEP) at Gustave Roussy, Principal/sub-Investigator of Clinical Trials Research Grants from, Non-financial support (drug supplied) from: Principal/sub-Investigator of Clinical Trials for: Abbvie, Adaptimmune, Adlai Nortye USA, Aduro Biotech, Agios Pharmaceuticals, Amgen, Argen-X Bvba, Astex Pharmaceuticals, Astra Zeneca Ab, Aveo, Basilea Pharmaceutica International, Bayer Healthcare Ag, Bbb Technologies Bv, Beigene, BicycleTx, Blueprint Medicines, Boehringer Ingelheim, Boston Pharmaceuticals, Bristol Myers Squibb, Ca, Celgene Corporation, Chugai Pharmaceutical Co, Clovis Oncology, Cullinan-Apollo, Curevac, Daiichi Sankyo, Debiopharm, Eisai, Eisai, Eli Lilly, Exelixis, Faron Pharmaceuticals, Forma Tharapeutics, Gamamabs, Genentech, Glaxosmithkline, H3 Biomedicine, Hoffmann La Roche Ag, Imcheck Therapeutics, Innate Pharma, Institut De Recherche Pierre Fabre, Iris Servier, Iteos Belgium SA, Janssen Cilag, Janssen Research Foundation, Kura Oncology, Kyowa Kirin Pharm. Dev, Lilly France, Loxo Oncology, Lytix Biopharma As, Medimmune, Menarini Ricerche, Merck Sharp & Dohme Chibret, Merrimack Pharmaceuticals, Merus, Millennium Pharmaceuticals, Molecular Partners Ag, Nanobiotix, Nektar Therapeutics, Novartis Pharma, Octimet Oncology Nv, Oncoethix, Oncopeptides, Orion Pharma, Ose Pharma, Pfizer, Pharma Mar, Pierre Fabre, Medicament, Roche, Sanofi Aventis, Seattle Genetics, Sotio A.S, Syros Pharmaceuticals, Taiho Pharma, Tesaro, Turning Point Therapeutics, XencorResearch Grants from Astrazeneca, BMS, Boehringer Ingelheim, GSK, INCA, Janssen Cilag, Merck, Novartis, Pfizer, Roche, Sanofi, Non-financial support (drug supplied) from Astrazeneca, Bayer, BMS, Boringher Ingelheim, GSK, Medimmune, Merck, NH TherAGuiX, Pfizer, Roche. DF—Salary: Palleon Pharmaceuticals; Ownership Interest Less Than 5 Percent: Palleon Pharmaceuticals. LMK—Salary: AstraZeneca; Ownership Interest Less Than 5 Percent: AstraZeneca. JM—Consulting fees: Novartis, Pfizer, Bristol-Myers Squibb, Takeda, Pharmacyclics, Audentes Pharmaceuticals, AstraZeneca, Deciphera, Ipsen, Boston, Biomedical, ImmunoCore, GlaxoSmithKline, Janssen, Myovant, Amgen, Boehringer, Cytokinetics. MCP— Employee of Merck Sharp & Dohme, a subsidiary of Merck & Co, Rahway, NJ, USA, and own stock (less than 5%) in Merck & Co, Rahway, NJ, US. JR—Nothing to Disclose. CR—Consulting fees: BMS, Roche, Pierre Fabre, Novartis, Sanofi, MSD, Pfizer, AstraZeneca. ES—NPI: 1467480160. MES-A—Consulting fees: Avenue Therapeutics ChemoCentryx, Celgene (All unrelated to the topic of interest. KS—Nothing to Disclose. MT—Nothing to Disclose. JW—Royalty: Less than 2000 dollars from a TIL growth patent by Moffitt Cancer Center; IP Rights: Named on a PD-1 biomarker patent by Biodesix, and on a CTLA4 biomarker patent by Moffitt Cancer Center, and a TIL growth patent by Moffitt Cancer Center; Consulting fees: Ad Boards for: BMS, GSK, Merck, Genentech, Astra Zeneca, Pfizer, Celldex, Biond, Evaxion, Regeneron, Alkermes, Novartis, Incyte, Moderna, Cytomx, Ultimovacs and Sellas; NPI: 1053348706; Ownership Interest Less Than 5 Percent: Biond, Neximmune MESA: Consultant fees: Pfizer, Eli Lilly, BMS. SITC Staff—CG, AK, NL, SMW: Nothing to Disclose., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: Immune checkpoint blocker (ICB) associated myocarditis (ICB-myocarditis) may present similarly and/or overlap with other cardiac pathology including acute coronary syndrome presenting a challenge for prompt clinical diagnosis., Methods: An international registry was used to retrospectively identify cases of ICB-myocarditis. Presence of coronary artery disease (CAD) was defined as coronary artery stenosis >70% in patients undergoing coronary angiogram., Results: Among 261 patients with clinically suspected ICB-myocarditis who underwent a coronary angiography, CAD was present in 59/261 patients (22.6%). Coronary revascularization was performed during the index hospitalisation in 19/59 (32.2%) patients. Patients undergoing coronary revascularization less frequently received steroids administration within 24 h of admission compared to the other groups (p = 0.029). Myocarditis-related 90-day mortality was 9/17 (52.7%) in the revascularised cohort, compared to 5/31 (16.1%) in those not revascularized and 25/156 (16.0%) in those without CAD (p = 0.001). Immune-related adverse event-related 90-day mortality was 9/17 (52.7%) in the revascularized cohort, compared to 6/31 (19.4%) in those not revascularized and 31/156 (19.9%) in no CAD groups (p = 0.007). All-cause 90-day mortality was 11/17 (64.7%) in the revascularized cohort, compared to 13/31 (41.9%) in no revascularization and 60/158 (38.0%) in no CAD groups (p = 0.10). After adjustment of age and sex, coronary revascularization remained associated with ICB-myocarditis-related death at 90 days (hazard ratio [HR] = 4.03, 95% confidence interval [CI] 1.84-8.84, p < 0.001) and was marginally associated with all-cause death (HR = 1.88, 95% CI, 0.98-3.61, p = 0.057)., Conclusion: CAD may exist concomitantly with ICB-myocarditis and may portend a poorer outcome when revascularization is performed. This is potentially mediated through delayed diagnosis and treatment or more severe presentation of ICB-myocarditis., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: LL has served on the advisory board for Daiichi Sankyio, Senaca, Astra Zeneca and Servier, as an external expert for Astra Zeneca and received speakers' honoraria from Novartis and MSD. LL is receiving grants from the German Center for Cardiovascular Research (DZHK), German Reuter Foundation (DFG) LE3570/2-1; 3570/3-1 and grant 01KC2006B from the Federal Ministry for Education and Research (BMBF). DA received speakers’ honoraria from BMS, Ipsen and participated to ad-boards from Sanofi and AstraZeneca. KT has received honoraria from Bristol Myers Squibb, Pfizer, Ono Pharmaceutical, Merck BioPharma, Bayer, and grants from Otsuka, Daiichi, Sankyo and Takeda. JM has served on advisory boards for Bristol Myers Squibb, Takeda, Regeneron, Audentes, Deciphera, Ipsen, Janssen, ImmunoCore, Boston Biomedical, Amgen, Myovant, Triple Gene/Precigen, Cytokinetics and AstraZeneca and supported by NIH grants (R01HL141466, R01HL155990, R01HL156021). JES have received consultancy fees from BMS, BeiGene, AstraZeneca, Novartis, and grants from BMS, Novartis, French Agence Nationale de la Recherche, Fondation Coeur et Recherche, Fédération Française de Cardiologie. All other authors have nothing to declare., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

This report summarizes the presentations, discussions, and recommendations of the most recent American Geriatrics Society and National Institute on Aging research conference, "Cancer and Cardiovascular Disease," on October 18-19, 2021. The purpose of this virtual meeting was to address the interface between cancer and heart disease, which are the two leading causes of death among older Americans. Age-related physiologic changes are implicated in the pathogenesis of both conditions. Emerging data suggest that cancer-related cardiovascular disease (CVD) involves disrupted cell signaling and cellular senescence. The risk factors for CVD are also risk factors for cancer and an increased likelihood of cancer death, and people who have both cancer and CVD do more poorly than those who have only cancer or only CVD. Issues addressed in this bench-to-bedside conference include mechanisms of cancer and CVD co-development in older adults, cardiotoxic effects of cancer therapy, and management of comorbid cancer and CVD. Presenters discussed approaches to ensure equitable access to clinical trials and health care for diverse populations of adults with CVD and cancer, mechanisms of cancer therapy cardiotoxicity, and management of comorbid CVD and cancer, including the role of patient values and preferences in treatment decisions. Workshop participants identified many research gaps and questions that could lead to an enhanced understanding of comorbid CVD and cancer and to better and more equitable management strategies., (© 2022 The American Geriatrics Society.)

Cardiovascular disease is the major cause of morbidity and mortality in breast cancer survivors. Chemotherapy contributes to this risk. We aimed to define the mechanisms of long-term vascular dysfunction caused by neoadjuvant chemotherapy (NACT) and identify novel therapeutic targets. We studied arteries from postmenopausal women who had undergone breast cancer treatment using docetaxel, doxorubicin, and cyclophosphamide (NACT) and from women with no history of such treatment matched for key clinical parameters. We explored mechanisms in WT and Nox4-/- mice and in human microvascular endothelial cells. Endothelium-dependent, NO-mediated vasodilatation was severely impaired in patients after NACT, while endothelium-independent responses remained normal. This was mimicked by a 24-hour exposure of arteries to NACT agents ex vivo. When applied individually, only docetaxel impaired endothelial function in human vessels. Mechanistic studies showed that NACT increased inhibitory eNOS phosphorylation of threonine 495 in a Rho-associated protein kinase-dependent (ROCK-dependent) manner and augmented vascular superoxide and hydrogen peroxide production and NADPH oxidase activity. Docetaxel increased expression of the NADPH oxidase NOX4 in endothelial and smooth muscle cells and NOX2 in the endothelium. A NOX4 increase in human arteries may be mediated epigenetically by diminished DNA methylation of the NOX4 promoter. Docetaxel induced endothelial dysfunction and hypertension in mice, and these were prevented in Nox4-/- mice and by pharmacological inhibition of Nox4 or Rock. Commonly used chemotherapeutic agents and, in particular, docetaxel alter vascular function by promoting the inhibitory phosphorylation of eNOS and enhancing ROS production by NADPH oxidases.

Cardiovascular (CV) toxicities of the Bruton tyrosine kinase (BTK) inhibitor ibrutinib may limit use of this effective therapy in patients with chronic lymphocytic leukemia (CLL). Acalabrutinib is a second-generation BTK inhibitor with greater BTK selectivity. This analysis characterizes pooled CV adverse events (AE) data in patients with CLL who received acalabrutinib monotherapy in clinical trials (clinicaltrials gov. Identifier: NCT02029443, NCT02475681, NCT02970318 and NCT02337829). Acalabrutinib was given orally at total daily doses of 100-400 mg, later switched to 100 mg twice daily, and continued until disease progression or toxicity. Data from 762 patients (median age: 67 years [range, 32-89]; median follow-up: 25.9 months [range, 0-58.5]) were analyzed. Cardiac AE of any grade were reported in 129 patients (17%; grade ≥3, n=37 [5%]) and led to treatment discontinuation in seven patients (1%). The most common any-grade cardiac AE were atrial fibrillation/flutter (5%), palpitations (3%), and tachycardia (2%). Overall, 91% of patients with cardiac AE had CV risk factors before acalabrutinib treatment. Among 38 patients with atrial fibrillation/flutter events, seven (18%) had prior history of arrhythmia or atrial fibrillation/flutter. Hypertension AE were reported in 67 patients (9%), 43 (64%) of whom had a preexisting history of hypertension; no patients discontinued treatment due to hypertension. No sudden cardiac deaths were reported. Overall, these data demonstrate a low incidence of new-onset cardiac AE with acalabrutinib in patients with CLL. Findings from the head-to-head, randomized trial of ibrutinib and acalabrutinib in patients with highrisk CLL (clinicaltrials gov. Identifier: NCT02477696) prospectively assess differences in CV toxicity between the two agents.

Cardiovascular disease and cancer are the two leading causes of morbidity and mortality in the world. The emerging field of cardio-oncology has revealed that these seemingly disparate disease processes are intertwined, owing to the cardiovascular sequelae of anticancer therapies, shared risk factors that predispose individuals to both cardiovascular disease and cancer, as well the possible potentiation of cancer growth by cardiac dysfunction. As a result, interest has increased in understanding the fundamental biological mechanisms that are central to the relationship between cardiovascular disease and cancer. Metabolism, appropriate regulation of energy, energy substrate utilization, and macromolecular synthesis and breakdown are fundamental processes for cellular and organismal survival. In this Review, we explore the emerging data identifying metabolic dysregulation as an important theme in cardio-oncology. We discuss the growing recognition of metabolic reprogramming in cardiovascular disease and cancer and view the novel area of cardio-oncology through the lens of metabolism., (© 2022. Springer Nature Limited.)