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Immune checkpoint inhibitor toxicities: systems-based approaches to improve patient care and research.
Johnson DB, Reynolds KL, Sullivan RJ, Balko JM, Patrinely JR, Cappelli LC, Naidoo J, Moslehi JJ
(2020) Lancet Oncol 21: e398-e404
MeSH Terms: Antineoplastic Agents, Immunological, Humans, Medical Oncology, Neoplasms, Patient Care, Patient Education as Topic
Show Abstract · Added September 29, 2020
Immune checkpoint inhibitors (ICIs) have now been approved in numerous and diverse cancer types and combination regimens. Effective recognition and treatment of ICI toxicities, which might occur acutely, affect any organ system, and produce many distinct clinical syndromes, have emerged as essential goals of ICI management. Thus, developing robust diagnostic and management approaches for ICI toxicity across the health-care system is an urgent and unmet clinical need. In this Personal View, we describe barriers to high-quality care that have constrained the most effective management of patients with cancer receiving ICI treatment. We review education initiatives to enhance patient and physician awareness, which is necessary given the broad spectrum of ICI toxicities often experienced by patients, and assess various systems-based approaches that maximise the chances of appropriate management. In addition, we describe research pipelines that broaden evidence-based approaches and the pathobiology of these novel events. Developing effective, systematic approaches for the recognition and treatment of ICI toxicities will continue to grow in importance as these agents proliferate in cancer care.
Copyright © 2020 Elsevier Ltd. All rights reserved.
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Vascular medicine and cardio-oncology - A new, evolving clinical frontier.
Versmissen J, Power JR, Moslehi J
(2020) Vasc Med 25: 205-207
MeSH Terms: Antineoplastic Agents, Cancer Survivors, Cardiology, Heart Diseases, Humans, Medical Oncology, Neoplasms, Prognosis, Risk Assessment, Risk Factors, Specialization
Added September 29, 2020
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Immune checkpoint inhibitor-induced myositis, the earliest and most lethal complication among rheumatic and musculoskeletal toxicities.
Allenbach Y, Anquetil C, Manouchehri A, Benveniste O, Lambotte O, Lebrun-Vignes B, Spano JP, Ederhy S, Klatzmann D, Rosenzwajg M, Fautrel B, Cadranel J, Johnson DB, Moslehi JJ, Salem JE
(2020) Autoimmun Rev 19: 102586
MeSH Terms: Antineoplastic Agents, Immunological, Bayes Theorem, Humans, Myositis, Pharmacovigilance, Retrospective Studies
Show Abstract · Added September 29, 2020
BACKGROUND - In addition to restoring anti-tumor immune responses, immune checkpoint inhibitors (ICI) may also induce immune-related adverse events (irAE) that can affect any organ. We aim to determine the spectrum, timing, clinical features, and fatalities of rheumatic and musculoskeletal immune-related adverse events (RMS-irAE) associated with ICI.
PATIENTS METHODS - We performed an observational, retrospective, pharmacovigilance study using the World Health Organization international pharmacovigilance database, VigiBase, from inception to January 2019. RMS-irAE reporting rate on ICI versus full database was performed using disproportionality analysis with computation of reporting-odds-ratios (ROR) and a Bayesian disproportional estimate (information component, IC). IC (lower end of the IC 95% credibility interval) >0 is deemed significant.
RESULTS - We identified 1288 RMS-irAE significantly associated with ICI: polymyalgia rheumatica (n = 76, ROR = 14.6 [11.6-18.4], IC = 3.34), sarcoidosis (n = 94; ROR = 9.6 [7.9-11.9]; IC = 2.85), Sjogren's syndrome (n = 49; ROR = 6.9 [5.2-9.2]; IC = 2.24), myositis (n = 465; ROR = 4.9 [4.5-5.4]; IC = 2.12), arthritis (n = 606; ROR = 1.4 [1.3-1.5]; IC = 0.34) and scleroderma (n = 17; ROR = 2.0 [1.2-3.2]; IC = 0.17). Arthritis, myositis, and Sjogren's syndrome were over-reported in patients treated with ICI combination versus those treated with ICI monotherapy (ROR = 1.6-2.9, p < .05) and more frequently reported on anti-PD1/PDL1 monotherapy vs. anti-CTLA4 monotherapy (2.1-4.4, p < .05). Median time to onset occurred early for myositis (31 days [19.2-57.8]) and was the most delayed for scleroderma (395 days [323.8-457.2], p < .0001). The fatality rate for RMS-irAE ranged from 24% for myositis (n = 106/441) (up to 56.7% with concurrent myocarditis) to [0-6.7%] for other RMS-irAE (p < .0001).
CONCLUSIONS - Clinicians should be aware of the spectrum of RMS-irAE. Myositis can be particularly life-threatening, particularly when associated with myocarditis.
Copyright © 2020 Elsevier B.V. All rights reserved.
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COVID-19 and immune checkpoint inhibitors: initial considerations.
Sullivan RJ, Johnson DB, Rini BI, Neilan TG, Lovly CM, Moslehi JJ, Reynolds KL
(2020) J Immunother Cancer 8:
MeSH Terms: Antineoplastic Agents, Immunological, Coronavirus Infections, Humans, Molecular Targeted Therapy, Neoplasms, Pandemics, Pneumonia, Viral, Programmed Cell Death 1 Receptor
Show Abstract · Added May 29, 2020
COVID-19 infections are characterized by inflammation of the lungs and other organs that ranges from mild and asymptomatic to fulminant and fatal. Patients who are immunocompromised and those with cardiopulmonary comorbidities appear to be particularly afflicted by this illness. During pandemic conditions, many aspects of cancer care have been impacted. One important clinical question is how to manage patients who need anticancer therapy, including immune checkpoint inhibitors (ICIs) during these conditions. Herein, we consider diagnostic and therapeutic implications of using ICI during this unprecedented period of COVID-19 infections. In particular, we consider the impact of ICI on COVID-19 severity, decisions surrounding continuing or interrupting therapy, diagnostic measures in patients with symptoms or manifestations potentially consistent with either COVID-19 or ICI toxicity, and resumption of therapy in infected patients. While more robust data are needed to guide clinicians on management of patients with cancer who may be affected by COVID-19, we hope this commentary provides useful insights for the clinical community.
© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
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Cardiovascular Effects of Androgen Deprivation Therapy in Prostate Cancer: Contemporary Meta-Analyses.
Hu JR, Duncan MS, Morgans AK, Brown JD, Meijers WC, Freiberg MS, Salem JE, Beckman JA, Moslehi JJ
(2020) Arterioscler Thromb Vasc Biol 40: e55-e64
MeSH Terms: Androgen Antagonists, Antineoplastic Agents, Hormonal, Cardiotoxicity, Cardiovascular Diseases, Cardiovascular System, Humans, Male, Prostatic Neoplasms, Risk Assessment, Risk Factors, Treatment Outcome
Show Abstract · Added May 29, 2020
Androgen deprivation therapy is a cornerstone of prostate cancer treatment. Pharmacological androgen deprivation includes gonadotropin-releasing hormone agonism and antagonism, androgen receptor inhibition, and CYP17 (cytochrome P450 17A1) inhibition. Studies in the past decade have raised concerns about the potential for androgen deprivation therapy to increase the risk of adverse cardiovascular events such as myocardial infarction, stroke, and cardiovascular mortality, possibly by exacerbating cardiovascular risk factors. In this review, we summarize existing data on the cardiovascular effects of androgen deprivation therapy. Among the therapies, abiraterone stands out for increasing risk of cardiac events in meta-analyses of both randomized controlled trials and observational studies. We find a divergence between observational studies, which show consistent positive associations between androgen deprivation therapy use and cardiovascular disease, and randomized controlled trials, which do not show these associations reproducibly.
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11 MeSH Terms
Discovery and Structure-Based Optimization of Potent and Selective WD Repeat Domain 5 (WDR5) Inhibitors Containing a Dihydroisoquinolinone Bicyclic Core.
Tian J, Teuscher KB, Aho ER, Alvarado JR, Mills JJ, Meyers KM, Gogliotti RD, Han C, Macdonald JD, Sai J, Shaw JG, Sensintaffar JL, Zhao B, Rietz TA, Thomas LR, Payne WG, Moore WJ, Stott GM, Kondo J, Inoue M, Coffey RJ, Tansey WP, Stauffer SR, Lee T, Fesik SW
(2020) J Med Chem 63: 656-675
MeSH Terms: Antineoplastic Agents, Bridged Bicyclo Compounds, Heterocyclic, Cell Cycle, Cell Line, Tumor, Cell Proliferation, Chromatin, Crystallography, X-Ray, Drug Design, Drug Discovery, Epigenetic Repression, Genes, myc, Humans, Intracellular Signaling Peptides and Proteins, Quinolones, Structure-Activity Relationship, WD40 Repeats
Show Abstract · Added March 3, 2020
WD repeat domain 5 (WDR5) is a member of the WD40-repeat protein family that plays a critical role in multiple chromatin-centric processes. Overexpression of WDR5 correlates with a poor clinical outcome in many human cancers, and WDR5 itself has emerged as an attractive target for therapy. Most drug-discovery efforts center on the WIN site of WDR5 that is responsible for the recruitment of WDR5 to chromatin. Here, we describe discovery of a novel WDR5 WIN site antagonists containing a dihydroisoquinolinone bicyclic core using a structure-based design. These compounds exhibit picomolar binding affinity and selective concentration-dependent antiproliferative activities in sensitive MLL-fusion cell lines. Furthermore, these WDR5 WIN site binders inhibit proliferation in MYC-driven cancer cells and reduce MYC recruitment to chromatin at MYC/WDR5 co-bound genes. Thus, these molecules are useful probes to study the implication of WDR5 inhibition in cancers and serve as a potential starting point toward the discovery of anti-WDR5 therapeutics.
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16 MeSH Terms
Novel three-dimensional cultures provide insights into thyroid cancer behavior.
Lee MA, Bergdorf KN, Phifer CJ, Jones CY, Byon SY, Sawyer LM, Bauer JA, Weiss VL
(2020) Endocr Relat Cancer 27: 111-121
MeSH Terms: Actin Cytoskeleton, Antineoplastic Agents, Apoptosis, Cell Culture Techniques, Cell Movement, Cell Proliferation, High-Throughput Screening Assays, Humans, Imidazoles, Oximes, Spheroids, Cellular, Thyroid Neoplasms, Tumor Cells, Cultured
Show Abstract · Added March 3, 2020
Thyroid cancer has the fastest growing incidence of any cancer in the United States, as measured by the number of new cases per year. Despite advances in tissue culture techniques, a robust model for thyroid cancer spheroid culture is yet to be developed. Using eight established thyroid cancer cell lines, we created an efficient and cost-effective 3D culture system that can enhance our understanding of in vivo treatment response. We found that all eight cell lines readily form spheroids in culture with unique morphology, size, and cytoskeletal organization. In addition, we developed a high-throughput workflow that allows for drug screening of spheroids. Using this approach, we found that spheroids from K1 and TPC1 cells demonstrate significant differences in their sensitivities to dabrafenib treatment that closely model expected patient drug response. In addition, K1 spheroids have increased sensitivity to dabrafenib when compared to monolayer K1 cultures. Utilizing traditional 2D cultures of these cell lines, we evaluated the mechanisms of this drug response, showing dramatic and acute changes in their actin cytoskeleton as well as inhibition of migratory behavior in response to dabrafenib treatment. Our study is the first to describe the development of a robust spheroid system from established cultured thyroid cancer cell lines and adaptation to a high-throughput format. We show that combining 3D culture with traditional 2D methods provides a complementary and powerful approach to uncover drug sensitivity and mechanisms of inhibition in thyroid cancer.
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13 MeSH Terms
Cancer Treatment-Associated Pericardial Disease: Epidemiology, Clinical Presentation, Diagnosis, and Management.
Ala CK, Klein AL, Moslehi JJ
(2019) Curr Cardiol Rep 21: 156
MeSH Terms: Antineoplastic Agents, Immunological, Cardiotoxicity, Cardiovascular Diseases, Humans, Immunotherapy, Neoplasms, Pericarditis, Pericardium, Risk Factors
Show Abstract · Added January 15, 2020
PURPOSE OF REVIEW - Cancer therapeutics have seen tremendous growth in the last decade and have been effective in the treatment of several cancer types. However, with advanced therapies like kinase inhibitors and immunotherapies, there have been unintended consequences of cardiotoxicities. While traditional chemotherapy and radiation-induced cardiotoxicity have been well studied, further research is needed to understand the adverse effects of newer regimens.
RECENT FINDINGS - Both immune-mediated and non-immune-medicated cytotoxicity have been noted with targeted therapies such as tyrosine kinase inhibitors and immune checkpoint inhibitors. In this manuscript, we describe the pericardial syndromes associated with cancer therapies and propose management strategies. Pericardial effusion and pericarditis are common presentations in cancer patients and often difficult to diagnose. Concomitant myocarditis may also present with pericardial toxicity, especially with immunotherapies. In addition to proper history and physical, additional testing such as cardiovascular imaging and tissue histology need to be obtained as appropriate. Holding the offending oncology drug, and institution of anti-inflammatory medications, and immunosuppressants such as steroids are indicated. A high index of suspicion, use of standardized definitions, and comprehensive evaluation are needed for early identification, appropriate treatment, and better outcomes for patients with cancer treatment-associated pericardial disease. Further research is needed to understand the pathophysiology and to evaluate how the management of pericardial conditions in these patients differ from traditional management and also evaluate new therapies.
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9 MeSH Terms
BRAF molecular testing in cytopathology: Implications for diagnosis, prognosis, and targeted therapeutics.
Bergdorf KN, Lee LA, Weiss VL
(2020) Cancer Cytopathol 128: 9-11
MeSH Terms: Antineoplastic Agents, Genetic Testing, Humans, MAP Kinase Signaling System, Molecular Targeted Therapy, Mutation, Neoplasms, Phosphorylation, Precision Medicine, Prognosis, Proto-Oncogene Proteins B-raf
Added March 3, 2020
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11 MeSH Terms
Mechanisms and clinical course of cardiovascular toxicity of cancer treatment I. Oncology.
Yeh ETH, Ewer MS, Moslehi J, Dlugosz-Danecka M, Banchs J, Chang HM, Minotti G
(2019) Semin Oncol 46: 397-402
MeSH Terms: Antineoplastic Agents, Antineoplastic Combined Chemotherapy Protocols, Cardiotoxicity, Cardiovascular Diseases, DNA Topoisomerases, Type II, Humans, Medical Oncology, Molecular Targeted Therapy, Neoplasms, Poly-ADP-Ribose Binding Proteins
Show Abstract · Added January 15, 2020
The opening session of Second International Colloquium on Cardio-Oncology addressed two areas of vital interest. The first reviewed new thoughts related to established agents. While anthracycline cardiotoxicity has been studied and reviewed extensively, ongoing research attempting to understand why it appears the mechanism(s) of toxicity differs from that of oncologic efficacy continue to evoke comment and intriguing speculation. Better understanding of the role of β-topoisomerase II in toxicity has advanced our understanding of the cascade of events that lead to heart failure. Additionally, the cardioprotective role of dexrazoxane fits well with our new understanding of how β-topoisomerase II works. Beyond the anthracyclines, new insight is providing us insight to better understand the impact on cardiac function seen with other agents including those targeting HER2 and several tyrosine-kinase inhibitors. Unlike the anthracyclines, these agents affect cardiac function in ways that are less direct, and therefore have different characteristics and should be thought of in alternate ways. This new knowledge regarding established agents furthers our understanding of the spectrum of cardiotoxicity and cardiac dysfunction in the cancer patient. The session also addressed cardiovascular toxicities of newer and established agents beyond myocardial dysfunction including effects on the vasculature. These agents cause changes that may be temporary or permanent, and that range from subclinical to life-threatening. The session ended with a discussion of the cardiac effects of immune checkpoint inhibitors. These agents can cause rare and sometimes fatal cardiac inflammation, for which long-term follow up may be required.
Copyright © 2019 Elsevier Inc. All rights reserved.
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10 MeSH Terms