Contemporary cancer treatment uses multiple modalities such as chemotherapy, targeted therapy and radiotherapy. These therapies, often used in combination, are associated with an increased risk of ...cardiotoxicity, specifically cardiomyopathy and heart failure. Cardiologists and oncologists are faced with the challenge of maximising the clinical benefit from cancer therapy while minimising the risk of early and late-onset cardiotoxicity. The current paradigm for cardiotoxicity detection and management relies primarily upon the assessment of left ventricular ejection fraction (LVEF). However, LVEF alone is limited in both diagnostic and prognostic ability. There is growing enthusiasm over the identification of newer biomarkers of cardiotoxicity that can detect cardiac injury at earlier stages of disease and could be used as an adjunctive prognostic measure to routine LVEF assessment. Thus, imaging and circulating biomarkers are currently under active investigation for use throughout the continuum of cancer care-for risk stratification of cardiotoxicity prior to treatment, detection of early cardiotoxicity during treatment and diagnosis of late cardiotoxicity in survivorship. Myocardial strain, cardiac troponin and brain natriuretic peptide are the most prominent biomarkers currently being studied, although data on novel circulating biomarkers are emerging.
Patients with metabolic syndrome have a greater risk of cardiovascular disease, although their susceptibility to chemotherapy-induced cardiac disease is not well documented. The aim of this ...meta-analysis was to assess associations between obesity or being overweight and cardiotoxicity from anthracyclines and sequential anthracyclines and trastuzumab in patients with breast cancer.
We performed a random-effects analysis and a network meta-analysis and assessed publication bias. We included 15 studies and 8,745 patients with breast cancers who were treated with anthracyclines and sequential anthracyclines and trastuzumab.
Combination of obesity and being overweight was significantly associated with a greater risk of developing cardiotoxicity after anthracyclines and a sequential anthracyclines and trastuzumab regimen in patients with breast cancer. Pooled odds ratio for cardiotoxicity was 1.38 (95% CI, 1.06 to 1.80; I(2) = 43%; N = 8,745) for overweight or obesity (body mass index > 25 kg/m(2)), 1.47 (95% CI, 0.95 to 2.28; I(2) = 47%; n = 2,615) for obesity, and 1.15 (95% CI, 0.83 to 1.58; I(2) = 27%; n = 2,708) for overweight. Associations were independent of study design, year of publication, drug regimen (anthracyclines alone v sequential anthracyclines and trastuzumab), or definitions of cardiotoxicity and of overweight or obesity. There was no evidence of publication bias; however, we could not separate the contributions of obesity-related cardiovascular risk factors, such as diabetes and hypertension, from that of obesity itself in this largely unadjusted analysis.
Our findings in a largely unadjusted analysis suggest that overweight and obesity are risk factors for cardiotoxicity from anthracyclines and sequential anthracyclines and trastuzumab.
Single molecule enzymology provides an opportunity to examine details of enzyme mechanisms that are not distinguishable in biomolecule ensemble studies. Here we report, for the first time, detection ...of the current produced in an electrocatalytic reaction by a single redox enzyme molecule when it collides with an ultramicroelectrode. The catalytic process provides amplification of the current from electron-transfer events at the catalyst leading to a measurable current. This new methodology monitors turnover of a single enzyme molecule. The methodology might complement existing single molecule techniques, giving further insights into enzymatic mechanisms and filling the gap between fundamental understanding of biocatalytic processes and their potential for bioenergy production.
Monitoring the cholesterol level is of great importance, especially for people with high risk of developing heart disease. Here we report on reagentless cholesterol detection in human plasma with a ...novel single-enzyme, membrane-free, self-powered biosensor, in which both cathodic and anodic bioelectrocatalytic reactions are powered by the same substrate. Cholesterol oxidase was immobilized in a sol–gel matrix on both the cathode and the anode. Hydrogen peroxide, a product of the enzymatic conversion of cholesterol, was electrocatalytically reduced, by the use of Prussian blue, at the cathode. In parallel, cholesterol oxidation catalyzed by mediated cholesterol oxidase occurred at the anode. The analytical performance was assessed for both electrode systems separately. The combination of the two electrodes, formed on high surface-area carbon cloth electrodes, resulted in a self-powered biosensor with enhanced sensitivity (26.0 mA M–1 cm–2), compared to either of the two individual electrodes, and a dynamic range up to 4.1 mM cholesterol. Reagentless cholesterol detection with both electrochemical systems and with the self-powered biosensor was performed and the results were compared with the standard method of colorimetric cholesterol quantification.
PET/CT with the glucose analog (18)F-FDG has several potential applications for monitoring tumor response to therapy in patients with non-small cell lung cancer (NSCLC). A prerequisite for many of ...these applications is detailed knowledge of the repeatability of quantitative parameters derived from (18)F-FDG PET/CT studies.
The repeatability of the (18)F-FDG signal was evaluated in 2 prospective multicenter trials. Patients with advanced NSCLC (tumor stage III-IV) underwent two (18)F-FDG PET/CT studies while not receiving therapy. Tumor (18)F-FDG uptake was quantified by measurement of the maximum standardized uptake value within a lesion (SUVmax) and the average SUV within a small volume of interest around the site of maximum uptake (SUVpeak). Analysis was performed for the lesion in the chest with the highest (18)F-FDG uptake and a size of at least 2 cm (target lesion) as well as for up to 6 additional lesions per patient. Repeatability was assessed by Bland-Altman plots and calculation of 95% repeatability coefficients (RCs) of the log-transformed SUV differences.
Test-retest repeatability was assessed in 74 patients (34 from the ACRIN 6678 trial and 40 from the Merck MK-0646-008 trial). SUVpeak was 11.57 ± 7.89 g/mL for the ACRIN trial and 6.89 ± 3.02 for the Merck trial. The lower and upper RCs were -28% (95% confidence interval CI, -35% to -23%) and +39% (95% CI, 31% to 54%) in the ACRIN trial, indicating that a decrease of SUVpeak by more than 28% or an increase by more than 39% has a probability of less than 2.5%. The corresponding RCs from the Merck trial were -35% (95% CI, -42% to -29%) and +53% (95% CI, 41% to 72%). Repeatability was similar for SUVmax of the target lesion, averaged SUVmax, and averaged SUVpeak of up to 6 lesions per patient.
The variability of repeated measurements of tumor (18)F-FDG uptake in patients with NSCLC is somewhat larger than previously reported in smaller single-center studies but comparable to that of gastrointestinal malignancies in a previous multicenter trial. The variability of measurements supports the definitions of tumor response according to PET Response Criteria in Solid Tumors.
Little is known about the genetic alterations characteristic of small bowel adenocarcinoma (SBA). Our purpose was to identify targetable alterations and develop experimental models of this disease.
...Whole-exome sequencing (WES) was completed on 17 SBA patient samples and targeted-exome sequencing (TES) on 27 samples to confirm relevant driver mutations. Two SBA models with
kinase activating mutations were tested for sensitivity to anti-ERBB2 agents
and
. Biochemical changes were measured by reverse-phase protein arrays.
WES identified somatic mutations in 4 canonical pathways (WNT, ERBB2, STAT3, and chromatin remodeling), which were validated in the TES cohort. Although
mutations were present in only 23% of samples, additional WNT-related alterations were seen in 12%.
mutations and amplifications were present in 23% of samples. Patients with alterations in the ERBB2 signaling cascade (64%) demonstrated worse clinical outcomes (median survival 70.3 months vs. 109 months; log-rank HR = 2.4,
= 0.03). Two ERBB2-mutated (V842I and Y803H) cell lines were generated from SBA patient samples. Both demonstrated high sensitivity to ERBB2 inhibitor dacomitinib (IC
< 2.5 nmol/L). In xenografts derived from these samples, treatment with dacomitinib reduced tumor growth by 39% and 59%, respectively, whereas it had no effect in an SBA wild-type
model.
The
and
models of SBA developed here provide a valuable resource for understanding targetable mutations in this disease. Our findings support clinical efforts to target activating
mutations in patients with SBA that harbor these alterations.
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