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1.
Nutrients ; 12(11)2020 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-33228154

RESUMO

Bile acids (BAs) regulate dietary lipid hydrolysis and absorption in the proximal intestine. Several studies have highlighted a determinant role of circulating levels and/or metabolism of BAs in the pathogenesis of major cardiometabolic diseases. Whether changes in BA profiles are causative or are consequence of these diseases remains to be determined. Healthy male volunteers (n = 71) underwent a postprandial exploration following consumption of a hypercaloric high fat typical Western meal providing 1200 kcal. We investigated variations of circulating levels of 28 BA species, together with BA synthesis marker 7α-hydroxy-4-cholesten-3-one (C4) over an approximately diurnal 12 h period. Analysis of BA variations during the postprandial time course revealed two major phenotypes with opposite fluctuations, i.e., circulating levels of each individual species of unconjugated BAs were reduced after meal consumption whereas those of tauro- and glyco-conjugated BAs were increased. By an unbiased classification strategy based on absolute postprandial changes in BA species levels, we classified subjects into three distinct clusters; the two extreme clusters being characterized by the smallest absolute changes in either unconjugated-BAs or conjugated-BAs. Finally, we demonstrated that our clustering based on postprandial changes in BA profiles was associated with specific clinical and biochemical features, including postprandial triglyceride levels, BMI or waist circumference. Altogether, our study reveals that postprandial profiles/patterns of BAs in response to a hypercaloric high fat challenge is associated with healthy or unhealthy metabolic phenotypes that may help in the early identification of subjects at risk of developing metabolic disorders.

2.
Nat Commun ; 11(1): 5881, 2020 11 18.
Artigo em Inglês | MEDLINE | ID: mdl-33208748

RESUMO

Microbiota-host-diet interactions contribute to the development of metabolic diseases. Imidazole propionate is a novel microbially produced metabolite from histidine, which impairs glucose metabolism. Here, we show that subjects with prediabetes and diabetes in the MetaCardis cohort from three European countries have elevated serum imidazole propionate levels. Furthermore, imidazole propionate levels were increased in subjects with low bacterial gene richness and Bacteroides 2 enterotype, which have previously been associated with obesity. The Bacteroides 2 enterotype was also associated with increased abundance of the genes involved in imidazole propionate biosynthesis from dietary histidine. Since patients and controls did not differ in their histidine dietary intake, the elevated levels of imidazole propionate in type 2 diabetes likely reflects altered microbial metabolism of histidine, rather than histidine intake per se. Thus the microbiota may contribute to type 2 diabetes by generating imidazole propionate that can modulate host inflammation and metabolism.

3.
Oncologist ; 2020 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-33225544

RESUMO

BACKGROUND: To characterize outcomes of patients with isolated brain metastases managed with local therapy followed by immune checkpoint inhibitor (ICI) therapy. MATERIALS AND METHODS: Patients from 4 medical centers were included if they presented with isolated brain metastases treated with local therapy, and received adjuvant treatment with ICI. RESULTS: Eleven patients with median size of largest brain metastasis of 3.9 cm, treated with surgical resection (n=8) and/or stereotactic radiosurgery (SRS; n=6) were included. Ipilimumab/nivolumab was the adjuvant ICI used in 4 patients, of which 1 recurred (25%) and none died, compared with 3 of 7 (43%) who recurred and 2 of 7 (29%) who died following adjuvant treatment with ICI monotherapy. All recurrences were intracranial. CONCLUSION: Patients with isolated brain metastases treated with surgery or SRS appeared to benefit from adjuvant ICI, particularly with combination therapy. Recurrences in this setting appear to largely occur intracranially.

4.
BMC Cancer ; 20(1): 1128, 2020 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-33225901

RESUMO

BACKGROUND: While immune-checkpoint inhibitors (ICIs) have transformed the field of oncology for advanced-stage cancers, they can lead to serious immune toxicities. Several systematic reviews have evaluated the risk of immune-related adverse events (irAEs); however, most have focused on published articles without evaluating trial registries. The objective of this methodological review was to compare the quality of reporting of safety information and in particular, serious irAEs (irSAEs), in both publications and ClinicalTrials.gov for all current FDA-approved ICIs. METHODS: PubMed was searched to retrieve all published phase III randomized controlled trials (RCTs) evaluating ICIs. For each eligible trial, we searched for corresponding registration on ClinicalTrials.gov and extracted relevant safety data from both the publication and results posted on registry. We then compared the quality of reporting and the value of safety data between both sources. RESULTS: Of 42 eligible published trials, 34 had results posted on ClinicalTrials.gov . Considerable variability was noted in the reporting of safety in both sources. SAEs were reported for all trial results in ClinicalTrials.gov compared to 23.5% of publications. An overall incidence for irAEs and irSAEs was reported in 58.8 and 8.8% of publications respectively, compared to 11.8 and 5.9% in registry results. Comparing the value of specific irSAEs was not possible between the two sources in 32/34 trials either due to different reporting formats (61.8%) or data not being reported in one or both sources (32.4%). From the 2 studies with compatible irSAE format, only 1 had matching data in both sources. CONCLUSIONS: The reporting of irAEs / irSAEs varies considerably in publications and registries, which outlines the importance of standardizing the terminologies and methodologies for reporting safety information relevant to ICIs.

5.
PLoS One ; 15(11): e0242840, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33227028

RESUMO

OBJECTIVE: To evaluate the diagnostic performance of the initial chest CT to diagnose COVID-19 related pneumonia in a French population of patients with respiratory symptoms according to the time from the onset of country-wide confinement to better understand what could be the role of the chest CT in the different phases of the epidemic. MATERIAL AND METHOD: Initial chest CT of 1064 patients with respiratory symptoms suspect of COVID-19 referred between March 18th, and May 12th 2020, were read according to a standardized procedure. The results of chest CTs were compared to the results of the RT-PCR. RESULTS: 546 (51%) patients were found to be positive for SARS-CoV2 at RT-PCR. The highest rate of positive RT-PCR was during the second week of confinement reaching 71.9%. After six weeks of confinement, the positive RT-PCR rate dropped significantly to 10.5% (p<0.001) and even 2.2% during the two last weeks. Overall, CT revealed patterns suggestive of COVID-19 in 603 patients (57%), whereas an alternative diagnosis was found in 246 patients (23%). CT was considered normal in 215 patients (20%) and inconclusive in 1 patient. The overall sensitivity of CT was 88%, specificity 76%, PPV 79%, and NPV 85%. At week-2, the same figures were 89%, 69%, 88% and 71% respectively and 60%, 84%, 30% and 95% respectively at week-6. At the end of confinement when the rate of positive PCR became extremely low the sensitivity, specificity, PPV and NPV of CT were 50%, 82%, 6% and 99% respectively. CONCLUSION: At the peak of the epidemic, chest CT had sufficiently high sensitivity and PPV to serve as a first-line positive diagnostic tool but at the end of the epidemic wave CT is more useful to exclude COVID-19 pneumonia.

7.
Autoimmun Rev ; : 102707, 2020 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-33197572

RESUMO

OBJECTIVES: IgA vasculitis (IgAV) is an immune complex small-vessel vasculitis. Drug-induced IgAV cases were rarely reported in the literature. Drug causality assessment is challenging as many other etiological factors can be involved. We performed a pharmacovigilance study to identify the main drugs reported to induce IgAV. METHODS: We used the French pharmacovigilance database (FPVD) and the WHO global individual case safety reports database (VigiBase) to retrieve IgAV cases. Cases from the FPVD were reviewed by two investigators using predefined criteria. Disproportionality analyses (case - non-case approach) were conducted in VigiBase to identify drugs significantly associated with IgAV reporting. RESULTS: Of the 467 IgAV cases retrieved from the FPVD, 115 (47 children and 68 adults) have been assessed as definite or probable, reported with 178 suspected drugs. Overall IgAV cases were mainly male (58%), with a median age of 33.5 (8.0-63.3) years. No death was reported. Besides, we identified 1558 possible IgAV cases in VigiBase. Among them, 40 were associated with a disproportionality in IgAV reporting. Drugs were mainly vaccines, antibiotics and TNF-α blockers, these finding being consistent in both databases. IgAV reporting with TNF-α blockers was significantly associated with their use in inflammatory bowel diseases, psoriasis or ankylosing spondylitis compared to other indications. CONCLUSIONS: Our systematic study enables the identification of culprit drugs in drug-induced IgAV. These results strengthen the immune pathophysiology of IgAV and the role of underlying disease. The list of suspected drugs may be useful for physicians to manage patients with IgAV and consider appropriate drug discontinuation. KEY MESSAGES: What is already known about this subject? IgA vasculitis has multifactorial etiology. To date, possible culprit drugs have been reported only in case reports. What does this study add? Using a dual pharmacovigilance-based approach, we identified drugs associated with the occurrence of IgA vasculitis, such as all types of vaccines, major antibiotics and immunomodulatory agents, mainly TNF-α blockers. How might this impact on clinical practice or future developments? Physicians should be aware of drug-induced IgA vasculitis and we provide evidence on the most frequent implicated drugs.

8.
Int J Cardiol ; 2020 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-33075384

RESUMO

The antiretroviral drug lopinavir/ritonavir has been recently repurposed for the treatment of COVID-19. Its empirical use has been associated with multiple cardiac adverse reactions pertaining to its ancillary multi-channel blocking properties, vaguely characterized until now. We aimed to characterize qualitatively the cardiotoxicity associated with lopinavir/ritonavir in the setting of COVID-19. Spontaneous notifications of cardiac adverse drug reactions reported to the national Pharmacovigilance Network were collected for 8 weeks since March 1st 2020. The Nice Regional Center of Pharmacovigilance, whose scope of expertise is drug-induced long QT syndrome, analyzed the cases, including the reassessment of all available ECGs. QTc ≥ 500 ms and delta QTc > 60 ms from baseline were deemed serious. Twenty-two cases presented with 28 cardiac adverse reactions associated with the empirical use of lopinavir/ritonavir in a hospital setting. Most adverse reactions reflected lopinavir/ritonavir potency to block voltage-gated potassium channels with 5 ventricular arrhythmias and 17 QTc prolongations. An average QTc augmentation of 97 ± 69 ms was reported. Twelve QTc prolongations were deemed serious. Other cases were likely related to lopinavir/ritonavir potency to block sodium channels: 1 case of bundle branch block and 5 recurrent bradycardias. The incidence of cardiac adverse reactions of lopinavir/ritonavir was estimated between 0.3% and 0.4%. These cardiac adverse drug reactions offer a new insight in its ancillary multi-channel blocking functions. Lopinavir/ritonavir cardiotoxicity may be of concern for its empirical use during the COVID-19 pandemic. Caution should be exerted relative to this risk where lopinavir/ritonavir summary of product characteristics should be implemented accordingly.

9.
Pharmaceuticals (Basel) ; 13(10)2020 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-33096756

RESUMO

BACKGROUND: Gemcitabine is a nucleoside analog, widely used either alone or in combination, for the treatment of multiple cancers. However, gemcitabine may also be associated with cardiovascular adverse-drug-reactions (CV-ADR). METHODS: First, we searched for all cases of cardiotoxicity associated with gemcitabine, published in MEDLINE on 30 May 2019. Then, we used VigiBase, the World Health Organization's global database of individual case safety reports, to compare CV-ADR reporting associated with gemcitabine against the full database between inception and 1 April 2019. We used the information component (IC), an indicator value for disproportionate Bayesian reporting. A positive lower end of the 95% credibility interval for the IC (IC025) ≥ 0, is deemed significant. RESULTS: In VigiBase, 46,898 reports were associated with gemcitabine on a total of 18,908,940 in the full database. Gemcitabine was associated with higher reporting for myocardial ischemia (MI, n: 119), pericardial diseases (n: 164), supraventricular arrhythmias (SVA, n: 308) and heart failure (HF, n: 484) versus full database with IC025 ranging between 0.40 and 2.81. CV-ADR were associated with cardiovascular death in up to 17% of cases. CONCLUSION: Treatment with gemcitabine is associated with potentially lethal CV-ADRs, including MI, pericardial diseases, SVA and HF. These events should be considered in patient care and clinical trial design.

11.
Pharmaceuticals (Basel) ; 13(10)2020 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-33080877

RESUMO

Tocilizumab, an anti-interleukin-6 receptor, administrated during the right timeframe may be beneficial against coronavirus-disease-2019 (COVID-19) pneumonia. All patients admitted for severe COVID-19 pneumonia (SpO2 ≤ 96% despite O2-support ≥ 6 L/min) without invasive mechanical ventilation were included in a retrospective cohort study in a primary care hospital. The treatment effect of a single-dose, 400 mg, of tocilizumab was assessed by comparing those who received tocilizumab to those who did not. Selection bias was mitigated using three statistical methods. Primary outcome measure was a composite of mortality and ventilation at day 28. A total of 246 patients were included (106 were treated with tocilizumab). Overall, 105 (42.7%) patients presented the primary outcome, with 71 (28.9%) deaths during the 28-day follow-up. Propensity-score-matched 84 pairs of comparable patients. In the matched cohort (n = 168), tocilizumab was associated with fewer primary outcomes than the control group (hazard ratio (HR) = 0.49 (95% confidence interval (95%CI) = 0.3-0.81), p-value = 0.005). These results were similar in the overall cohort (n = 246), with Cox multivariable analysis yielding a protective association between tocilizumab and primary outcome (adjusted HR = 0.26 (95%CI = 0.135-0.51, p = 0.0001), confirmed by inverse probability score weighting (IPSW) analysis (p < 0.0001). Analyses on mortality only, with 28 days of follow-up, yielded similar results. In this study, tocilizumab 400 mg in a single-dose was associated with improved survival without mechanical ventilation in patients with severe COVID-19.

12.
PLoS One ; 15(10): e0240711, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33075088

RESUMO

Prognostic factors of coronavirus disease 2019 (COVID-19) patients among European population are lacking. Our objective was to identify early prognostic factors upon admission to optimize the management of COVID-19 patients hospitalized in a medical ward. This French single-center prospective cohort study evaluated 152 patients with positive severe acute respiratory syndrome coronavirus 2 real-time reverse transcriptase-polymerase chain reaction assay, hospitalized in the Internal Medicine and Clinical Immunology Department, at Pitié-Salpêtrière's Hospital, in Paris, France, a tertiary care university hospital. Predictive factors of intensive care unit (ICU) transfer or death at day 14 (D14), of being discharge alive and severe status at D14 (remaining with ventilation, or death) were evaluated in multivariable logistic regression models; models' performances, including discrimination and calibration, were assessed (C-index, calibration curve, R2, Brier score). A validation was performed on an external sample of 132 patients hospitalized in a French hospital close to Paris, in Aulnay-sous-Bois, Île-de-France. The probability of ICU transfer or death was 32% (47/147) (95% CI 25-40). Older age (OR 2.61, 95% CI 0.96-7.10), poorer respiratory presentation (OR 4.04 per 1-point increment on World Health Organization (WHO) clinical scale, 95% CI 1.76-9.25), higher CRP-level (OR 1.63 per 100mg/L increment, 95% CI 0.98-2.71) and lower lymphocytes count (OR 0.36 per 1000/mm3 increment, 95% CI 0.13-0.99) were associated with an increased risk of ICU requirement or death. A 9-point ordinal scale scoring system defined low (score 0-2), moderate (score 3-5), and high (score 6-8) risk patients, with predicted respectively 2%, 25% and 81% risk of ICU transfer or death at D14. Therefore, in this prospective cohort study of laboratory-confirmed COVID-19 patients hospitalized in a medical ward in France, a simplified scoring system at admission predicted the outcome at D14.


Assuntos
Betacoronavirus/genética , Infecções por Coronavirus/epidemiologia , Previsões/métodos , Mortalidade Hospitalar/tendências , Hospitalização , Unidades de Terapia Intensiva , Transferência de Pacientes/tendências , Pneumonia Viral/epidemiologia , Idoso , Idoso de 80 Anos ou mais , Infecções por Coronavirus/mortalidade , Infecções por Coronavirus/virologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pandemias , Paris/epidemiologia , Alta do Paciente , Pneumonia Viral/mortalidade , Pneumonia Viral/virologia , Prognóstico , Estudos Prospectivos , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa
13.
Circulation ; 2020 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-33092403

RESUMO

Background: Ibrutinib is a Bruton's tyrosine kinase (BTK) inhibitor with remarkable efficacy against B-cell cancers. Ibrutinib also increases the risk of atrial fibrillation (AF) which remains poorly understood. Methods: We performed electrophysiology studies on mice treated with ibrutinib to assess inducibility of AF. Chemoproteomic analysis of cardiac lysates identified candidate ibrutinib targets, which were further evaluated in genetic mouse models and additional pharmacologic experiments. The pharmacovigilance database, VigiBase® was queried to determine whether drug inhibition of an identified candidate kinase was associated with increased reporting of AF. Results: We demonstrate that treatment of mice with ibrutinib for four weeks results in inducible AF, left atrial enlargement, myocardial fibrosis and inflammation. This effect was reproduced in mice lacking BTK but not in mice treated with four-weeks of acalabrutinib, a more specific BTK inhibitor, demonstrating that AF is an off-target side effect. Chemoproteomic profiling identified a short list of candidate kinases that was narrowed by additional experimentation leaving C-terminal src kinase (CSK) as the strongest candidate for ibrutinib induced AF. Cardiac specific Csk knockout in mice led to increased AF, left atrial enlargement, fibrosis, and inflammation, phenocopying ibrutinib treatment. Disproportionality analyses in Vigibase® confirmed increased reporting of AF associated with kinase inhibitors blocking Csk vs non-Csk inhibitors, with a reporting odds-ratio of 8.0 [95% CI 7.3-8.7, p<0.0001]. Conclusions: These data identify Csk inhibition as the mechanism by which ibrutinib leads to AF. Clinical Trial Registration: URL: www.clinicaltrials.gov Unique Identifier: NCT03530215.

16.
J Am Heart Assoc ; 9(18): e018403, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32893704

RESUMO

The considerable progress made in the field of cancer treatment has led to a dramatic improvement in the prognosis of patients with cancer. However, toxicities resulting from these treatments represent a cost that can be harmful to short- and long-term outcomes. Adverse events affecting the cardiovascular system are one of the greatest challenges in the overall management of patients with cancer, as they can compromise the success of the optimal treatment against the tumor. Such adverse events are associated not only with older chemotherapy drugs such as anthracyclines but also with many targeted therapies and immunotherapies. Recognizing this concern, several American and European governing societies in oncology and cardiology have published guidelines on the cardiovascular monitoring of patients receiving potentially cardiotoxic cancer therapies, as well as on the management of cardiovascular toxicities. However, the low level of evidence supporting these guidelines has led to numerous discrepancies, leaving clinicians without a consensus strategy to apply. A cardio-oncology expert panel from the French Working Group of Cardio-Oncology has undertaken an ambitious effort to analyze and harmonize the most recent American and European guidelines to propose roadmaps and decision algorithms that would be easy for clinicians to use in their daily practice. In this statement, the experts addressed the cardiovascular monitoring strategies for the cancer drugs associated with the highest risk of cardiovascular toxicities, as well as the management of such toxicities.

17.
Am J Epidemiol ; 2020 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-32964219

RESUMO

We aimed to investigate the association between anticancer drugs and cardiovascular-related hospitalization (CVRH) in metastatic colorectal cancer (mCRC) patients. A cohort study was conducted using the French county Calvados registry of digestive tumors. Incident mCRC cases between 2008 and 2014 were included. The follow-up end date was December 2016. Data from the county hospital center pharmacy and medical information departments were matched with the registry data. A competing risk approach was used. Statistical tests were two-sided. A total of 1,116 mCRC patients were included; they were administered 12,374 rounds of treatment; fluorouracil, oxaliplatin, irinotecan and bevacizumab were most common. A total of 208 CVRH events occurred in 145 patients (13.0%). The International Cancer Survival Standards type 1 standardized incidence was 84.0 CVRH per 1,000 person-years (95% confidence interval: 72.6-95.5). Anticancer drugs were not associated with a higher incidence of CVRH. Men, elderly patients, patients with a prior history of CVRH and patients with a higher Charlson comorbidity index were associated with a higher incidence of CVRH. CVRH was significantly associated with a higher all-cause mortality (multivariable hazard ratio for death 1.58, 95%CI 1.28-1.95). Anticancer drugs were not associated with a higher incidence of CVRH in mCRC patients.

18.
Cardiovasc Diabetol ; 19(1): 140, 2020 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-32948184

RESUMO

BACKGROUND: Lower limb arterial calcification is a frequent, underestimated but serious complication of diabetes. The DIACART study is a prospective cohort study designed to evaluate the determinants of the progression of lower limb arterial calcification in 198 patients with type 2 diabetes. METHODS: Lower limb arterial calcification scores were determined by computed tomography at baseline and after a mean follow up of 31.20 ± 3.86 months. Serum RANKL (Receptor Activator of Nuclear factor kB Ligand) and bone remodeling, inflammatory and metabolic parameters were measured at baseline. The predictive effect of these markers on calcification progression was analyzed by a multivariate linear regression model. RESULTS: At baseline, mean ± SD and median lower limb arterial calcification scores were, 2364 ± 5613 and 527 respectively and at the end of the study, 3739 ± 6886 and 1355 respectively. Using multivariate analysis, the progression of lower limb arterial log calcification score was found to be associated with (ß coefficient [slope], 95% CI, p-value) baseline log(calcification score) (1.02, 1.00-1.04, p < 0.001), triglycerides (0.11, 0.03-0.20, p = 0.007), log(RANKL) (0.07, 0.02-0.11, p = 0.016), previous ischemic cardiomyopathy (0.36, 0.15-0.57, p = 0.001), statin use (0.39, 0.06-0.72, p = 0.023) and duration of follow up (0.04, 0.01-0.06, p = 0.004). CONCLUSION: In patients with type 2 diabetes, lower limb arterial calcification is frequent and can progress rapidly. Circulating RANKL and triglycerides are independently associated with this progression. These results open new therapeutic perspectives in peripheral diabetic calcifying arteriopathy. Trial registration NCT02431234.

19.
Artigo em Inglês | MEDLINE | ID: mdl-32871087

RESUMO

T cells have a central role in immune system balance. When activated, they may lead to autoimmune diseases. When too anergic, they contribute to infection spread and cancer proliferation. Immune checkpoint proteins regulate T cell function, including cytotoxic T lymphocyte antigen-4 (CTLA-4) and programmed cell death-1 (PD-1) and its ligand (PD-L1). These nodes of self-tolerance may be exploited pharmacologically to downregulate (CTLA-4 agonists) and activate [CTLA-4 and PD-1/PD-L1 antagonists, also called immune checkpoint inhibitors (ICIs)] the immune system. CTLA-4 agonists are used to treat rheumatologic immune disorders and graft rejection. CTLA-4, PD-1, and PD-L1 antagonists are approved for multiple cancer types and are being investigated for chronic viral infections. Notably, ICIs may be associated with immune-related adverse events (irAEs), which can be highly morbid or fatal. CTLA-4 agonism has been a promising method to reverse such life-threatening irAEs. Herein, we review the clinical pharmacology of these immune checkpoint agents with a focus on their interplay in human diseases. Expected final online publication date for the Annual Review of Pharmacology and Toxicology, Volume 61 is January 8, 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

20.
Artigo em Inglês | MEDLINE | ID: mdl-32776859

RESUMO

Immune checkpoint inhibitors (ICIs) attenuate mechanisms of self-tolerance in the immune system, enabling T cell responses to cancerous tissues and revolutionizing care for cancer patients. However, by lowering barriers against self-reactivity, ICIs often result in varying degrees of autoimmunity. Cardiovascular complications, particularly myocarditis but also arrhythmias, pericarditis, and vasculitis, have emerged as significant complications associated with ICIs. In this review, we examine the clinical aspects and basic science principles that underlie ICI-associated myocarditis and other cardiovascular toxicities. In addition, we discuss current therapeutic approaches. We believe a better mechanistic understanding of ICI-associated toxicities can lead to improved patient outcomes by reducing treatment-related morbidity. Expected final online publication date for the Annual Review of Pharmacology and Toxicology, Volume 61 is January 8, 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

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