Cancer drugs and the heart: importance and management

Progress in the detection and treatment of cancer has led to an impressive reduction in both mortality and morbidity. Due to their mechanism of action, however, conventional chemotherapeutics and some of the newer anti-cancer signaling inhibitors carry a substantial risk of cardiovascular side effects that include cardiac dysfunction and heart failure, arterial hypertension, vasospastic and thromboembolic ischaemia, dysrhythmia, and QT prolongation. While some of these side effects are irreversible and cause progressive cardiovascular disease, others induce only temporary dysfunction with no apparent long-term sequelae for the patient. The challenge for the cardiovascular specialist is to balance the need for life-saving cancer treatment with the assessment of risk from cancer drug-associated cardiovascular side effects to prevent long-term damage. This review discusses concepts for timely diagnosis, intervention, and surveillance of cancer patients undergoing treatment, and provides approaches to clinical uncertaintie

Futility, appropriate care, and orders not to resuscitate: Who makes decisions and how?

Ethical issues in resuscitation arose once life-prolonging interventions advanced to the point where short-term cardiac resuscitation became plausible in patients in cases where imminent death was irreversible. The authors argue that ethical dilemmas arise from disputes over continued treatment when stakeholders either disagree about the meaning of appropriate care as a result of differing beliefs on the meaning of an acceptable outcome and/or the extent of a treatment’s probable efficacy. The authors conclude that even though communication and transparency can help prevent these ethical dilemmas, unavoidable conflict over proper interventions should be resolved through a decision-making process grounded in both medical reality and the principles of patient self-determination. Thoughtful regulatory guidance can aid the understanding of rights and responsibilities when the desirability, efficacy, and medical indication of life-prolonging interventions are in dispute. The authors outline such a process. The authors suggest that seeking clear regulation in this arena is a worthwhile ethical and practical objective for physicians to reduce both the likelihood of conflicts and the burden of unavoidable conflicts despite transparency and communication

Cancer drugs and the heart: importance and management.

Progress in the detection and treatment of cancer has led to an impressive reduction in both mortality and morbidity. Due to their mechanism of action, however, conventional chemotherapeutics and some of the newer anti-cancer signaling inhibitors carry a substantial risk of cardiovascular side effects that include cardiac dysfunction and heart failure, arterial hypertension, vasospastic and thromboembolic ischaemia, dysrhythmia, and QT prolongation. While some of these side effects are irreversible and cause progressive cardiovascular disease, others induce only temporary dysfunction with no apparent long-term sequelae for the patient. The challenge for the cardiovascular specialist is to balance the need for life-saving cancer treatment with the assessment of risk from cancer drug-associated cardiovascular side effects to prevent long-term damage. This review discusses concepts for timely diagnosis, intervention, and surveillance of cancer patients undergoing treatment, and provides approaches to clinical uncertainties

Oncolog, Volume 36, Issue 01, January-March 1991

Decision making in critical illness: Who knows best? Successful Hodgkin\u27s disease treatment can also preserve reproductive function Chromosomes and cancerhttps://openworks.mdanderson.org/oncolog/1033/thumbnail.jp

Body surface area and baseline blood pressure predict subclinical anthracycline cardiotoxicity in women treated for early breast cancer.

BACKGROUND AND AIMS: Anthracyclines are highly effective chemotherapeutic agents which may cause long-term cardiac damage (chronic anthracycline cardiotoxicity) and heart failure. The pathogenesis of anthracycline cardiotoxicity remains incompletely understood and individual susceptibility difficult to predict. We sought clinical features which might contribute to improved risk assessment. METHODS: Subjects were women with early breast cancer, free of pre-existing cardiac disease. Left ventricular ejection fraction was measured using cardiovascular magnetic resonance before and >12 months after anthracycline-based chemotherapy (>3 months post-Trastuzumab). Variables associated with subclinical cardiotoxicity (defined as a fall in left ventricular ejection fraction of ≥5%) were identified by logistic regression. RESULTS: One hundred and sixty-five women (mean age 48.3 years at enrollment) completed the study 21.7 months [IQR 18.0-26.8] after starting chemotherapy. All received anthracyclines (98.8% epirubicin, cumulative dose 400 [300-450] mg/m2); 18% Trastuzumab. Baseline blood pressure was elevated (≥140/90mmHg, mean 147.3/86.1mmHg) in 18 subjects. Thirty-four subjects (20.7%) were identified with subclinical cardiotoxicity, independent predictors of which were the number of anthracycline cycles (odds ratio, OR 1.64 [1.17-2.30] per cycle), blood pressure ≥140/90mmHg (OR 5.36 [1.73-17.61]), body surface area (OR 2.08 [1.36-3.20] per standard deviation (0.16m2) increase), and Trastuzumab therapy (OR 3.35 [1.18-9.51]). The resultant predictive-model had an area under the receiver operating characteristics curve of 0.78 [0.70-0.86]. CONCLUSIONS: We found subclinical cardiotoxicity to be common even within this low risk cohort. Risk of cardiotoxicity was associated with modestly elevated baseline blood pressure-indicating that close attention should be paid to blood pressure in patients considered for anthracycline based chemotherapy. The association with higher body surface area suggests that indexing of anthracycline doses to surface area may not be appropriate for all, and points to the need for additional research in this area

Circadian Control of Dendrite Morphology in the Visual System of Drosophila melanogaster

In the first optic neuropil (lamina) of the fly's visual system, monopolar cells L1 and L2 and glia show circadian rhythms in morphological plasticity. They change their size and shape during the day and night. The most pronounced changes have been detected in circadian size of the L2 axons. Looking for a functional significance of the circadian plasticity observed in axons, we examined the morphological plasticity of the L2 dendrites. They extend from axons and harbor postsynaptic sites of tetrad synaptic contacts from the photoreceptor terminals.The plasticity of L2 dendrites was evaluated by measuring an outline of the L2 dendritic trees. These were from confocal images of cross sections of L2 cells labeled with GFP. They were in wild-type and clock mutant flies held under different light conditions and sacrified at different time points. We found that the L2 dendrites are longest at the beginning of the day in both males and females. This rhythm observed under a day/night regime (LD) was maintained in constant darkness (DD) but not in continuous light (LL). This rhythm was not present in the arrhythmic per(01) mutant in LD or in DD. In the clock photoreceptor cry(b) mutant the rhythm was maintained but its pattern was different than that observed in wild-type flies.The results obtained showed that the L2 dendrites exhibit circadian structural plasticity. Their morphology is controlled by the per gene-dependent circadian clock. The L2 dendrites are longest at the beginning of the day when the daytime tetrad presynaptic sites are most numerous and L2 axons are swollen. The presence of the rhythm, but with a different pattern in cry(b) mutants in LD and DD indicates a new role of cry in the visual system. The new role is in maintaining the circadian pattern of changes of the L2 dendrite length and shape

Impact on Malaria Parasite Multiplication Rates in Infected Volunteers of the Protein-in-Adjuvant Vaccine AMA1-C1/Alhydrogel+CPG 7909

BACKGROUND: Inhibition of parasite growth is a major objective of blood-stage malaria vaccines. The in vitro assay of parasite growth inhibitory activity (GIA) is widely used as a surrogate marker for malaria vaccine efficacy in the down-selection of candidate blood-stage vaccines. Here we report the first study to examine the relationship between in vivo Plasmodium falciparum growth rates and in vitro GIA in humans experimentally infected with blood-stage malaria. METHODS: In this phase I/IIa open-label clinical trial five healthy malaria-naive volunteers were immunised with AMA1/C1-Alhydrogel+CPG 7909, and together with three unvaccinated controls were challenged by intravenous inoculation of P. falciparum infected erythrocytes. RESULTS: A significant correlation was observed between parasite multiplication rate in 48 hours (PMR) and both vaccine-induced growth-inhibitory activity (Pearson r = -0.93 [95% CI: -1.0, -0.27] P = 0.02) and AMA1 antibody titres in the vaccine group (Pearson r = -0.93 [95% CI: -0.99, -0.25] P = 0.02). However immunisation failed to reduce overall mean PMR in the vaccine group in comparison to the controls (vaccinee 16 fold [95% CI: 12, 22], control 17 fold [CI: 0, 65] P = 0.70). Therefore no impact on pre-patent period was observed (vaccine group median 8.5 days [range 7.5-9], control group median 9 days [range 7-9]). CONCLUSIONS: Despite the first observation in human experimental malaria infection of a significant association between vaccine-induced in vitro growth inhibitory activity and in vivo parasite multiplication rate, this did not translate into any observable clinically relevant vaccine effect in this small group of volunteers. TRIAL REGISTRATION: ClinicalTrials.gov [NCT00984763]

COMPASS identifies T-cell subsets correlated with clinical outcomes.

Advances in flow cytometry and other single-cell technologies have enabled high-dimensional, high-throughput measurements of individual cells as well as the interrogation of cell population heterogeneity. However, in many instances, computational tools to analyze the wealth of data generated by these technologies are lacking. Here, we present a computational framework for unbiased combinatorial polyfunctionality analysis of antigen-specific T-cell subsets (COMPASS). COMPASS uses a Bayesian hierarchical framework to model all observed cell subsets and select those most likely to have antigen-specific responses. Cell-subset responses are quantified by posterior probabilities, and human subject-level responses are quantified by two summary statistics that describe the quality of an individual's polyfunctional response and can be correlated directly with clinical outcome. Using three clinical data sets of cytokine production, we demonstrate how COMPASS improves characterization of antigen-specific T cells and reveals cellular 'correlates of protection/immunity' in the RV144 HIV vaccine efficacy trial that are missed by other methods. COMPASS is available as open-source software

Perturbing Dynamin Reveals Potent Effects on the Drosophila Circadian Clock

BACKGROUND: Transcriptional feedback loops are central to circadian clock function. However, the role of neural activity and membrane events in molecular rhythms in the fruit fly Drosophila is unclear. To address this question, we expressed a temperature-sensitive, dominant negative allele of the fly homolog of dynamin called shibire(ts1) (shi(ts1)), an active component in membrane vesicle scission. PRINCIPAL FINDINGS: Broad expression in clock cells resulted in unexpectedly long, robust periods (>28 hours) comparable to perturbation of core clock components, suggesting an unappreciated role of membrane dynamics in setting period. Expression in the pacemaker lateral ventral neurons (LNv) was necessary and sufficient for this effect. Manipulation of other endocytic components exacerbated shi(ts1)'s behavioral effects, suggesting its mechanism is specific to endocytic regulation. PKA overexpression rescued period effects suggesting shi(ts1) may downregulate PKA pathways. Levels of the clock component PERIOD were reduced in the shi(ts1)-expressing pacemaker small LNv of flies held at a fully restrictive temperature (29 degrees C). Less restrictive conditions (25 degrees C) delayed cycling proportional to observed behavioral changes. Levels of the neuropeptide PIGMENT-DISPERSING FACTOR (PDF), the only known LNv neurotransmitter, were also reduced, but PERIOD cycling was still delayed in flies lacking PDF, implicating a PDF-independent process. Further, shi(ts1) expression in the eye also results in reduced PER protein and per and vri transcript levels, suggesting that shibire-dependent signaling extends to peripheral clocks. The level of nuclear CLK, transcriptional activator of many core clock genes, is also reduced in shi(ts1) flies, and Clk overexpression suppresses the period-altering effects of shi(ts1). CONCLUSIONS: We propose that membrane protein turnover through endocytic regulation of PKA pathways modulates the core clock by altering CLK levels and/or activity. These results suggest an important role for membrane scission in setting circadian period