5-fluorouracil and cardiotoxicity: a review Sara, Jaskanwal D.; Kaur, Jasvinder; Khodadadi, Ryan ...
Therapeutic Advances in Medical Oncology,
01/2018, Letnik:
10
Book Review, Journal Article
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Fluoropyrimidines such as 5-fluorouracil (5-FU) form the foundation of a wide variety of chemotherapy regimens. 5-FU is in fact the third most commonly used chemotherapeutic agent in the treatment of ...solid malignancies across the world. As with all chemotherapy, balancing the potential benefits of therapy against the risks of drug-related toxicity is crucial when clinicians and patients make shared decisions about treatment. 5-FU is the second most common chemotherapeutic drug associated with cardiotoxicity after anthracyclines, which can manifest as chest pain, acute coronary syndrome/myocardial infarction or death. Nevertheless a widespread appreciation of 5-FU-related cardiotoxicity and its implications is lacking amongst clinicians. In this review, we outline the incidence, possible risk factors, and likely pathophysiological mechanisms that may account for 5-FU-related cardiotoxicity and also highlight potential management strategies for this poorly understood clinical entity.
The discovery of the ubiquitin system was awarded with the Nobel Prize in Chemistry in 2004. Labeling of intracellular proteins for degradation by a multienzymatic complex, called the proteasome, was ...identified as the main function of this system. Subsequently, it was discovered that the attachment of ubiquitin to proteins can modify their function without degradation. Finally, a number of other molecules were recognized to be conjugated to proteins in a manner similar to ubiquitin and were henceforth called ubiquitin-like proteins. This review provides an overview of this class of molecules and its implication for function, subcellular location, and half-life of proteins.
Physicians are now asked though to go beyond their habits by the AUC mandate of the Centers for Medicare & Medicaid Services (CMS), which ties reimbursement for advance imaging studies, which include ...the mentioned cardiac tests, to the use of clinical decision support tools for AUC. ...patients unable to exercise are already at a higher risk of poor outcome, for example, due to frailty secondary to comorbidities other than CAD 20. ...some patients might have a low pre-test likelihood of CAD but are still at high risk. ...to re-emphasize, non-invasive stress tests are ordered based on the pre-test probability of CAD and render a probability of mortality that may or may not relate to CAD. In agreement, a substudy from the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial found that stratifying patients by number of coronary arteries involved is a better predictor of outcome than the extent of myocardial ischemia on stress testing 23. ...a significant plaque burden can be present, accommodated by positive, outward remodeling and layered with patients with ischaemic heart disease: expert panel of the EANM cardiovascular committee and EACVI, Eur Heart J Cardiovasc Imaging, Vol. 16, 2015, 1289-1298 13 O. Gaemperli, F.M. Bengel, P.A. Kaufmann, Cardiac hybrid imaging, Eur Heart J, Vol. 32, 2011, 2100-2108 14 J.M. Lee, C.H. Kim, B.K. Koo, D. Hwang, J. Park, J. Zhang, Integrated myocardial perfusion imaging diagnostics improve detection of functionally significant coronary artery stenosis by 13N-ammonia positron emission tomography, Circ Cardiovasc Imaging, Vol. 9, 2016 15...
To define the effect of a history of cancer on in-hospital and long-term mortality after primary percutaneous coronary intervention (PCI) for ST-segment elevation myocardial infarction (STEMI).
In ...this retrospective cohort study of 2346 patients with STEMI enrolled in the Mayo Clinic PCI registry from November 1, 2000, through October 31, 2010, we identified 261 patients (11.1%) with a history of cancer. The in-hospital and long-term outcomes (median follow-up, 6.2 years; interquartile range=4.3-8.5 years), including cardiac and noncardiac death and heart failure hospitalization, of these patients were compared with those of 1313 cancer-negative patients matched on age, sex, family history of coronary artery disease, and date of STEMI.
Patients with cancer had higher in-hospital noncardiac (1.9% vs 0.4%; P=.03) but similar cardiac (5.8% vs 4.6%; P=.37) mortality as matched controls. The group at highest acute mortality risk were those diagnosed as having cancer within 6 months before STEMI (hazard ratio HR=7.0; 95% CI, 1.4-34.4; P=.02). At 5 years, patients with cancer had similar cardiac mortality (4.2% vs 5.8%; HR=1.27; 95% CI, 0.77-2.10; P=.35) despite more heart failure hospitalizations (15% vs 10%; HR=1.72; 95% CI, 1.18-2.50; P=.01) but faced higher noncardiac mortality (30.0% vs 11.0%; HR=3.01; 95% CI, 2.33-3.88; P<.001) than controls, attributable solely to cancer-related deaths.
One in 10 patients in this contemporary registry of patients undergoing primary PCI for STEMI has a history of cancer. These patients have more than a 3 times higher acute in-hospital and long-term noncardiac mortality risk but no increased acute or long-term cardiac mortality risk with guideline-recommended cardiac care.
Classical activation of M1 macrophages with lipopolysaccharide (LPS) is associated with a metabolic switch from oxidative phosphorylation to glycolysis. However, the generalizability of such ...metabolic remodeling to other modes of M1 macrophage stimulation, e.g. type II interferons (IFNs) such as IFNγ, has remained unknown as has the functional significance of aerobic glycolysis during macrophage activation. Here we demonstrate that IFNγ induces a rapid activation of aerobic glycolysis followed by a reduction in oxidative phosphorylation in M1 macrophages. Elevated glycolytic flux sustains cell viability and inflammatory activity, while limiting reliance on mitochondrial oxidative metabolism. Adenosine triphosphate (ATP) distributed by aerobic glycolysis is critical for sustaining IFN-γ triggered JAK (Janus tyrosine kinase)-STAT-1 (Signal Transducer and Activator of Transcription 1) signaling with phosphorylation of the transcription factor STAT-1 as its signature trait. Inhibition of aerobic glycolysis not only blocks the M1 phenotype and pro-inflammatory cytokine/chemokine production in murine macrophages and also human monocytes/macrophages. These findings extend on the potential functional role of immuno-metabolism from LPS- to IFNγ-linked diseases such as atherosclerosis and autoimmune disease.
•Interferon gamma (IFNγ) induces a rapid switch to aerobic glycolysis in M1 macrophages sustaining two signaling pathways.•Repurposing of the mitochondria, including reactive oxygen species production, allows for HIF-1α and IL-1β production.•ATP production by glycolysis allows for JAK activity, STAT-1 phosphorylation, iNOS and thereby nitric oxide production.
Inflammatory cells like macrophages, upon activation, switch their energy metabolism from the mitochondria to the processing of glucose. This switch feeds into the inflammatory action of macrophages and links it to the glucose concentration in the cell environment. Accordingly, under conditions of high glucose concentrations, as seen in patients with diabetes, a higher level of inflammatory activity might be seen. Performing these studies with the macrophage activator interferon gamma that plays a role in the development of narrowing of arteries (atherosclerosis) furthers the potential link of these findings to the more diffuse and aggressive nature of atherosclerosis in diabetic patients.
Combined anthracycline-trastuzumab chemotherapy has been associated with LV dysfunction. We aimed to assess early changes in left ventricular (LV) and right ventricular (RV) mechanics associated with ...combined anthracycline-trastuzumab treatment for breast cancer. As well as explore whether early changes in 2-dimensional (2D)-speckle tracking echocardiography (STE) could predict later chemotherapy-induced cardiotoxicity.
Sixty-six patients with breast cancer who received anthracycline-trastuzumab treatment were included (mean ±SD age, 52 9 years). Echocardiograms were available for analysis with 2D-STE at the following time points: pretreatment (T0), first cycle (T1), and second cycle (T2) of combined chemotherapy. All patients had a normal pretreatment LV ejection fraction (LVEF). Cardiotoxicity was defined as a decrease in LVEF of at least 10 percentage points from baseline on follow-up echocardiography.
Cardiotoxicity developed in 13 of the 66 patients (20%). The mean (±SD) LVEF at T0 was 66% (±6); at T1 60% (±7); and at T2, 54% (±6). For the 53 patients without cardiotoxicity, the LVEF was 65% (±4%) at T0, 63% (±5%) at T1, and 62% (±4) at T2. Global longitudinal strain (GLS) at T1 was the strongest indicator of subsequent cardiotoxicity (area under the curve, 0.85; cutoff value, - 14.06; sensitivity, 91%; specificity, 83%; P = .003). Compared with baseline (T0), left ventricular longitudinal strain, LV circumferential strain, circumferential peak systolic strain rate (SR), circumferential peak early diastolic SR, right ventricular longitudinal strain, and longitudinal peak systolic SR at T1 and T2 were reduced significantly in patients with cardiotoxicity (P < .05).
Anthracycline-trastuzumab treatment leads to early deterioration of LV GLS, circumferential strain, and systolic SR. Right ventricular GLS and SR were also affected. Early changes in GLS are good predictors of subsequent development of anthracycline-trastuzumab-induced cardiotoxicity.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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