Biological changes that occur during metastatic progression of breast cancer are still incompletely characterized. In this study, we compared intrinsic molecular subtypes and gene expression in 123 ...paired primary and metastatic tissues from breast cancer patients. Intrinsic subtype was identified using a PAM50 classifier and χ
tests determined the differences in variable distribution. The rate of subtype conversion was 0% in basal-like tumors, 23.1% in HER2-enriched (HER2-E) tumors, 30.0% in luminal B tumors, and 55.3% in luminal A tumors. In 40.2% of cases, luminal A tumors converted to luminal B tumors, whereas in 14.3% of cases luminal A and B tumors converted to HER2-E tumors. We identified 47 genes that were expressed differentially in metastatic versus primary disease. Metastatic tumors were enriched for proliferation-related and migration-related genes and diminished for luminal-related genes. Expression of proliferation-related genes were better at predicting overall survival in metastatic disease (OSmet) when analyzed in metastatic tissue rather than primary tissue. In contrast, a basal-like gene expression signature was better at predicting OSmet in primary disease compared with metastatic tissue. We observed correlations between time to tumor relapse and the magnitude of changes of proliferation, luminal B, or HER2-E signatures in metastatic versus primary disease. Although the intrinsic subtype was largely maintained during metastatic progression, luminal/HER2-negative tumors acquired a luminal B or HER2-E profile during metastatic progression, likely reflecting tumor evolution or acquisition of estrogen independence. Overall, our analysis revealed the value of stratifying gene expression by both cancer subtype and tissue type, providing clinicians more refined tools to evaluate prognosis and treatment.
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Trastuzumab is a drug used in HER2-positive breast cancer that increases patient survival. Due to cardiotoxicity is the most important side effect of trastuzumab treatment, cardiac monitoring should ...be a priority. The purpose of this study is to evaluate plasma NT-proBNP level and major cardiovascular risk factors as possible early predictors of trastuzumab-induced cardiotoxicity in HER2-positive breast cancer patients.
We conducted a retrospective observational study involving 66 patients with HER2-positive breast cancer treated with trastuzumab. Left ventricle ejection fraction (LVEF), NT-proBNP values, and the history of cardiovascular risk factors were collected. Cardiotoxicity was diagnosed considering a decrease of the LVEF from baseline or clinical manifestation of congestive heart failure. NT-proBNP cut-off points were considered to establish normal or abnormal values according to patient age.
27.3% of the patients suffered cardiotoxicity during trastuzumab treatment. Most cases were diagnosed due to the appearance of cardiac symptomatology (66.7%). Logistic regression analysis showed a significant association of diabetes mellitus (OR 5.9, 95% CI 1.2–28.5, p = 0.028) and high NT-proBNP levels (OR 22.0, 95% CI 5.7–85.4, p < 0.0001) with the development of trastuzumab-induced cardiotoxicity.
NT-proBNP levels above the upper limit of the normal range adjusted to age or diabetes mellitus seem to be associated with a higher risk of developing cardiotoxicity. However, some limitations of the present study make necessary further studies aimed to clarify whether NT-proBNP and diabetes-associated markers determinations can be useful in the monitoring of cardiotoxicity risk in breast cancer patients undergoing trastuzumab therapy.
•There is an inverse relationship between LVEF and NT-proBNP plasma levels.•NT-proBNP and Diabetes may be associated with trastuzumab-induced cardiotoxicity.•Further studies are required to clarify the role of NT-proBNP levels and Diabetes.
Prediabetes is a pathological condition in which the blood glucose concentration is higher than normal concentrations but lower than those considered necessary for a type 2 diabetes mellitus ...diagnosis. Various authors have indicated that the Mediterranean Diet is one of the dietary patterns with the most healthy outcomes, reducing high levels of HbA1c, triglycerides, BMI, and other anthropometric parameters. The main objective of this study was to determine the efficacy of the nutritional intervention for children with prediabetes, including the effectiveness of this nutritional education regarding anthropometric parameters. A randomized pilot trial with two groups, an experimental group (EG) and a control group (CG), using intervention in dietary habits with nutritional reinforcement was carried out on 29 children with prediabetes from a rural area. The nutritional intervention was analyzed through astrophotometric and glycemic measurements and validated surveys. Results: The results indicated improvement in eating habits, adherence to the Mediterranean diet, anthropometric measurements, mainly body mass index and perimeters, and analytical parameters, with a significant decrease in glycated hemoglobin in the EG compared to the CG (p < 0.001). Although the results showed that both groups’ anthropometric parameters improved, a more significant decrease was observed in the experimental group compared to the control.
Taiwaniaquinoids are a unique family of diterpenoids predominantly isolated from Taiwania cryptomerioides Hayata. Previously, we evaluated the antiproliferative effect of several synthetic ...taiwaniaquinoids against human lung (A-549), colon (T-84), and breast (MCF-7) tumor cell lines. Herein, we report the in vitro and in vivo antitumor activity of the most potent compounds. Their cytotoxic activity against healthy peripheral blood mononuclear cells (PBMCs) has also been examined. We underscore the limited toxicity of compound C36 in PBMCs and demonstrate that it exerts its antitumor effect in MCF-7 cells (IC50 = 1.8 µM) by triggering an increase in reactive oxygen species, increasing the cell population in the sub-G1 phase of the cell cycle (90 %), and ultimately activating apoptotic (49.6 %) rather than autophagic processes. Western blot results suggested that the underlying mechanism of the C36 apoptotic effects was linked to caspase 9 activation and a rise in the Bax/Bcl-2 ratio. In vivo analyses showed normal behavior and hematological parameters in C57BL/6 mice post C36 treatment. Moreover, no significant impact was observed on the biochemical parameters of these animals, indicating that C36 did not induce liver toxicity. Furthermore, C36 demonstrated a significant reduction in tumor growth in immune-competent C57BL/6 mice implanted with E0771 mouse mammary tumor cells, effectively improving survival rates. These findings position taiwaniaquinoids, particularly compound C36, as promising therapeutic candidates for human breast cancer.
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•Synthesized taiwaniaquinoids display potent cytotoxicity against cancer cells.•C36 exhibits low toxicity in normal cells, suggesting therapeutic potential.•C36 acts by generating ROS, halting the cell cycle and inducing apoptosis.•In vivo studies confirm the safety and anticancer efficacy of C36.
Obesity in adults is associated with left ventricular hypertrophy, dilatation, and myocardial fibrosis, as well as heart failure and coronary heart disease. These associations have been studied to a ...lesser extent in the paediatric population. This study aims to investigate the relationship between obesity and cardiac structure and function in the paediatric population. In a southern Spanish village, we selected all inhabitants aged 6–17 years stratifying by age, gender, and educational centres. We performed a complete transthoracic echocardiogram evaluating all the cardiac morphological and functional parameters commonly measured in an echocardiographic study. There were 212 children and adolescents included. Of them, 48.1% were males. The mean age was 10.9 ± 3.0 years. A total of 106 (50%) were normal weight, 57 (26.9%) overweight, and 49 (23.1%) obese. Sex and age were similar in all three groups. Overweight and obesity were associated with larger left ventricular end-diastolic and end-systolic volumes (
p
< 0.0005), greater left ventricular mass (
p
< 0.0005), and smaller ejection fraction (
p
< 0.0005). They were also associated with larger atrial, aortic, and right ventricular size. Lateral and mean
E
/
e
′ ratios were higher (
p
= 0.007 and
p
= 0.01 respectively). Body mass index was independently associated with all cavity size variables as well as left ventricular ejection fraction.
Conclusion:
Childhood obesity is independently associated with larger heart chambers, greater left ventricle mass, and smaller left ventricle ejection fraction.
What is Known:
•
Childhood obesity is related to the development of cardiovascular risk factors and is considered an epidemic of the twenty-first century; its prevalence is rising.
What is New:
•
Childhood overweight and obesity lead to changes in cardiac structure and function which, although not considered clinically pathological, are significant and a result of obesity, and which behave as unfavourable incipient alterations at an early age.
Background: Two-dimensional speckle-tracking echocardiography (2DSTE) has been present for years. However, it is underutilized due to the expertise and time requirements for its analysis. Our aims ...were to provide strain values in a paediatric Spanish population and to assess the feasibility and reproducibility of a new strain software analysis in our environment. Methods: A cross-sectional study of 156 healthy children aged 6 to 17 years. Longitudinal strain (LS) analysis of the left ventricle, right ventricle, and left atrium was performed. Feasibility and reproducibility were assessed. The associations of clinical and echocardiographic variables with strain values were investigated by multivariate analysis. Results: Mean age was 11 ± 3 years (50% female). Feasibility of LS measurement ranged from 94.2% for left ventricle global LS (LVGLS) to 98.1% for other chamber strain parameters. Strain values were 26.7 ± 2.3% for LVGLS; 30.5 ± 4.4% and 26.9 ± 4% for right ventricle free wall LS (RVFWLS) and four chambers view LS (RV4CLS) respectively; and 57.8 ± 10.5%, 44.9 ± 9.5%, and 12.9 ± 5.5% for left atrium LS reservoir phase (LALSr), conduct phase (LALScd) and contraction phase (LALSct), also respectively. Body surface area (BSA) and age presented a negative correlation with strain values. Higher values were found in females than in males, except for LALScd. Excellent intra- and inter-observer reproducibility were found for right and left ventricular strain measurement, with intraclass correlation coefficients (ICC) ranging from 0.88 to 0.98, respectively. In conclusion, we described strain values in a healthy Spanish paediatric population. LS assessment by this new strain analysis software by semi-automatic manner was highly feasible and reproducible.
The prevalence of obesity continues to grow, resulting in metabolic syndrome and increasing economic burden for health systems. The objectives were to measure the ability of the NIM-MetS test, ...previously used in the adults, for the early and sustainable detection of the Metabolic Syndrome (MetS) in children and adolescents. Moreover, to determine the economic burden of the children with MetS. Furthermore, finally, to use and implement the NIM-MetS test, via a self-created online software, as a new method to determine the risk of MetS in children. The method used was an observational study using different instruments (NIM-MetS test, International Diabetes Federation (IDF), or Cook) and measures (body mass index). Additionally, the economic burden was estimated via a research strategy in different databases, e.g., PubMed, to identify previous papers. The results (N = 265 children, age from 10-12) showed that 23.1% had obesity and 7.2% hypertension. The prevalence of MetS using the NIM-Mets was 5.7, and the cost of these children was approximate 618,253,99 euros. Finally, a model was obtained and later implemented in a web platform via simulation. The NIM-MetS obtained is a non-invasive method for the diagnosis of risk of MetS in children.
Active targeting by surface-modified nanoplatforms enables a more precise and elevated accumulation of nanoparticles within the tumor, thereby enhancing drug delivery and efficacy for a successful ...cancer treatment. However, surface functionalization involves complex procedures that increase costs and timelines, presenting challenges for clinical implementation. Biomimetic nanoparticles (BNPs) have emerged as unique drug delivery platforms that overcome the limitations of actively targeted nanoparticles. Nevertheless, BNPs coated with unmodified cells show reduced functionalities such as specific tumor targeting, decreasing the therapeutic efficacy. Those challenges can be overcome by engineering non-patient-derived cells for BNP coating, but these are complex and cost-effective approaches that hinder their wider clinical application. Here we present an immune-driven strategy to improve nanotherapeutic delivery to tumors. Our unique perspective harnesses T-cell exhaustion and tumor immune evasion to develop a groundbreaking new class of BNPs crafted from exhausted T-cells (NExT) of triple-negative breast cancer (TNBC) patients by specific culture methods without sophisticated engineering.
NExT were generated by coating PLGA (poly(lactic-co-glycolic acid)) nanoparticles with TNBC-derived T-cells exhausted in vitro by acute activation. Physicochemical characterization of NExT was made by dynamic light scattering, electrophoretic light scattering and transmission electron microscopy, and preservation and orientation of immune checkpoint receptors by flow cytometry. The efficacy of chemotherapy-loaded NExT was assessed in TNBC cell lines in vitro. In vivo toxicity was made in CD1 mice. Biodistribution and therapeutic activity of NExT were determined in cell-line- and autologous patient-derived xenografts in immunodeficient mice.
We report a cost-effective approach with a good performance that provides NExT naturally endowed with immune checkpoint receptors (PD1, LAG3, TIM3), augmenting specific tumor targeting by engaging cognate ligands, enhancing the therapeutic efficacy of chemotherapy, and disrupting the PD1/PDL1 axis in an immunotherapy-like way. Autologous patient-derived NExT revealed exceptional intratumor accumulation, heightened chemotherapeutic index and efficiency, and targeted the tumor stroma in a PDL1
patient-derived xenograft model of triple-negative breast cancer.
These advantages underline the potential of autologous patient-derived NExT to revolutionize tailored adoptive cancer nanotherapy and chemoimmunotherapy, which endorses their widespread clinical application of autologous patient-derived NExT.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Tamoxifen is a drug used for hormone receptor-positive breast cancers, primarily metabolised by the CYP2D6 enzyme into active metabolites such as endoxifen. CYP2D6 displays varying degrees of ...activity depending on its genotype. This study aims to analyse the effect of an early increase in tamoxifen dose in poor metabolisers (PM) on survival.
We enrolled 220 patients diagnosed with breast cancer who were treated with tamoxifen. CYP2D6 polymorphisms were determined, and the phenotype was estimated according to the Clinical Pharmacogenetics Implementation Consortium. Disease-free survival (DFS) and overall survival (OS) were analysed considering the entire patient group, and a subgroup of 110 patients selected by Propensity Score Matching (PSM). All women were treated with 20 mg/day of tamoxifen for 5 years, except PM, who initially received 20 mg/day for 4 months, followed by 40 mg/day for 4 months and 60 mg/day for 4 months before returning to the standard dose of 20 mg/day until completing 5 years of treatment.
The analysis of the influence of CYP2D6 polymorphisms in the complete group and in the PSM subgroup revealed no significant differences for DFS or OS. Furthermore, DFS and OS were analysed in relation to various covariates such as age, histological grade, nodal status, tumour size, HER-2, Ki-67, chemotherapy, and radiotherapy. Only age, histological grade, nodal status, and chemotherapy treatment demonstrated statistical significance.
An early increase in tamoxifen dose in PM patients is not associated with survival differences among CYP2D6 phenotypes.
•Early increase in tamoxifen dose in PM is not associated with survival differences.•Age, grade, nodal status, and chemotherapy treatment are related to survival.•Propensity Score Matching allows a robust adjustment for patient background factors.
Fluoropyrimidines (FPs) are commonly prescribed in many cancer streams. The EMA and FDA-approved drug labels for FPs recommend genotyping the DPYD*2A (rs3918290), *13 (rs55886062), *HapB3 ...(rs56038477), alleles, and DPYD rs67376798 before treatment starts. We implemented the DPYD genotyping in our daily clinical routine, but we still found patients showing severe adverse drug events (ADEs) to FPs. We studied among these patients the DPYD rs1801265, rs17376848, rs1801159, rs1801160, rs1801158, and rs2297595 as explanatory candidates of the interindividual differences for FP-related toxicities, examining the association with the response to FPs . We also studied the impact of DPYD testing for FP dose tailoring in our clinical practice and characterized the DPYD gene in our population. We found a total acceptance among physicians of therapeutic recommendations translated from the DPYD test, and this dose tailoring does not affect the treatment efficacy. We also found that the DPYD*4 (defined by rs1801158) allele is associated with a higher risk of ADEs (severity grade ≥ 3) in both the univariate (O.R. = 5.66; 95% C.I. = 1.35–23.67; p = 0.014) and multivariate analyses (O.R. = 5.73; 95% C.I. = 1.41–28.77; p = 0.019) among FP-treated patients based on the DPYD genotype. This makes it a candidate variant for implementation in clinical practice.
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