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Context: DNA mismatch repair (MMR) deficiency (dMMR) testing is now recommended in endometrial cancer. Defect identification in the molecules participating in this pathway, or the presence of microsatellite instability, are commonly employed for this purpose. Novel methods are continuously evolving to report dMMR/microsatellite instability and to easily perform routine diagnoses. Objective: The main aim of this study was to compare the concordance of the Idylla microsatellite instability test for the identification of dMMR endometrial cancer samples defined by immunohistochemistry and MMR genomic status. Design: We applied the Idylla MSI test to 126 early-stage endometrial cancer cases with MMR testing by immunohistochemistry and genomic characterization (methylation in MLH1 and sequence alterations in MLH1, PMS2, MSH2 and MSH6). Individual markers and overall specific performance indicators were explored. Results: The Idylla platform achieved a higher global concordance rate with MMR genomic status than with immunohistochemistry (75 % and 66 %, respectively). Sensitivity and specificity are also higher (75 % vs 66 % and 96 % vs 90 %, respectively). Clustering analysis split the patients into 2 well-differentiated clusters, the pMMR and the dMMR group, represented by MLH1/PMS2 loss and the MLH1 methylated promoter. Overall, immunohistochemistry and MMR genomic status identified more dMMR cases than did the Idylla test, although correlations were improved with a modified Idylla test cut-off. Conclusions: Performance of the Idylla test was better correlated with MMR genomic status than MMR immunohistochemistry status, which improved with a modified test cut-off. Further studies are needed to confirm the cut-off accuracy.

Abstract Cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors demonstrated activity in terms of progression-free survival (PFS) in advanced dedifferentiated liposarcoma (DD-LPS), a sarcoma with CDK4 amplification. CDK4 overexpression is by far more common than amplification in sarcomas and it might be a rational target for CDK inhibitors. Preclinical investigators of this study found that CDK4 overexpression, while not of CDKN2A, was the most consistent predictive factor for palbociclib efficacy in sarcomas. Advanced adult-type soft-tissue sarcoma, excluding DD-LPS, or bone sarcoma patients, progressing after at least one systemic line, whose tumors overexpressed CDK4, but not CDKN2A at baseline biopsy, were accrued in this single-arm phase II trial (EudraCT number: 2016-004039-19). With the main endpoint of a 6-month PFS rate, 40% was considered promising in this population. Palbociclib was administered orally at 125 mg/day for 21 days in 28-day cycles. A total of 214 patients with 236 CDK4/CDKN2A determinations were assessed for prescreening, archival material (141), and screening, baseline biopsy (95). There were 28 (29%) with favorable mRNA profiles from 95 screened patients at baseline. From 23 enrolled patients, 21 evaluable, the 6-month PFS rate was 29% (95% CI 9–48), and there were 6 patients out of 21 with a PFS longer than 6 months. The median PFS and overall survival were 4.2 (95% CI 3.6–4.8) and 12 (95% CI 8.7–15.4) months, respectively. Translational research showed a significant correlation between CDK4 mRNA and protein expression. Palbociclib was active in a variety of sarcoma subtypes, selected by CDK4/CDKN2A, and deserves further investigation in the sarcoma context.

In patients with progressive and symptomatic desmoid fibromatosis (DF) treatment with chemotherapy is typically prolonged, while surgery carries a high risk of relapse. Here, the authors report the results of a phase II clinical trial of short-course nab-paclitaxel in patients with progressive and symptomatic DF.

IntroductionOver the years, the molecular classification of endometrial carcinoma has evolved significantly. Both POLEmut and MMRdef cases share tumor biological similarities like high tumor mutational burden and induce strong lymphatic reactions. While therefore use case scenarios for pretesting with tumor-infiltrating lymphocytes to replace molecular analysis did not show promising results, such testing may be warranted in cases where an inverse prediction, such as that of POLEwt, is being considered. For that reason we used a spatial digital pathology method to quantitatively examine CD3+ and CD8+ immune infiltrates in comparison to conventional histopathological parameters, prognostics and as potential pretest before molecular analysis.MethodsWe applied a four-color multiplex immunofluorescence assay for pan-cytokeratin, CD3, CD8, and DAPI on 252 endometrial carcinomas as testing and compared it to further 213 cases as validation cohort from a similar multiplexing assay. We quantitatively assessed immune infiltrates in microscopic distances within the carcinoma, in a close distance of 50 microns, and in more distant areas.ResultsRegarding prognostics, high CD3+ and CD8+ densities in intra-tumoral and close subregions pointed toward a favorable outcome. However, TCGA subtyping outperforms prognostication of CD3 and CD8 based parameters. Different CD3+ and CD8+ densities were significantly associated with the TCGA subgroups, but not consistently for histopathological parameter. In the testing cohort, intra-tumoral densities of less than 50 intra-tumoral CD8+ cells/mm2 were the most suitable parameter to assume a POLEwt, irrespective of an MMRdef, NSMP or p53abn background. An application to the validation cohort corroborates these findings with an overall sensitivity of 95.5%.DiscussionMolecular confirmation of POLEmut cases remains the gold standard. Even if CD3+ and CD8+ cell densities appeared less prognostic than TCGA, low intra-tumoral CD8+ values predict a POLE wild-type at substantial percentage rates, but not vice versa. This inverse correlation might be useful to increase pretest probabilities in consecutive POLE testing. Molecular subtyping is currently not conducted in one-third of cases deemed low-risk based on conventional clinical and histopathological parameters. However, this percentage could potentially be increased to two-thirds by excluding sequencing of predicted POLE wild-type cases, which could be determined through precise quantification of intra-tumoral CD8+ cells.

Uterine sarcomas are very infrequent and heterogeneous entities. Due to its rarity, pathological diagnosis, surgical management, and systemic treatment are challenging. Treatment decision process in these tumors should be taken in a multidisciplinary tumor board. Available evidence is low and, in many cases, based on case series or clinical trials in which these tumors have been included with other soft tissue sarcoma. In these guidelines, we have tried to summarize the most relevant evidence in the diagnosis, staging, pathological disparities, surgical management, systemic treatment, and follow-up of uterine sarcomas.

Abstract Background Eribulin has shown antitumour activity in some soft tissue sarcomas (STSs), but it has only been approved for advanced liposarcoma (LPS). Methods In this study, we evaluated the effect of eribulin on proliferation, migration and invasion capabilities in LPS, leiomyosarcoma (LMS) and fibrosarcoma (FS) models, using both monolayer (2D) and three-dimensional (3D) spheroid cell cultures. Additionally, we explored combinations of eribulin with other drugs commonly used in the treatment of STS with the aim of increasing its antitumour activity. Results Eribulin showed activity inhibiting proliferation, 2D and 3D migration and invasion in most of the cell line models. Furthermore, we provide data that suggest, for the first time, a synergistic effect with ifosfamide in all models, and with pazopanib in LMS as well as in myxoid and pleomorphic LPS. Conclusions Our results support the effect of eribulin on LPS, LMS and FS cell line models. The combination of eribulin with ifosfamide or pazopanib has shown in vitro synergy, which warrants further clinical research.

Abstract Background To determine the state of current practice and to reach a consensus on recommendations for the management of advanced ovarian cancer using a Delphi survey with a group of Spanish gynecologists and medical oncologists specially dedicated to gynecological tumors. Methods The questionnaire was developed by the byline authors. All questions but one were answered using a 9-item Likert-like scale with three types of answers: frequency, relevance and agreement. We performed two rounds between December 2018 and July 2019. A consensus was considered reached when at least 75% of the answers were located within three consecutive points of the Likert scale. Results In the first round, 32 oncologists and gynecologists were invited to participate, and 31 (96.9%) completed the online questionnaire. In the second round, 27 (87.1%) completed the online questionnaire. The results for the questions on first-line management of advanced disease, treatment of patients with recurrent disease for whom platinum might be the best option, and treatment of patients with recurrent disease for whom platinum might not be the best option are presented. Conclusions This survey shows a snapshot of current recommendations by this selected group of physicians. Although the majority of the agreements and recommendations are aligned with the recently published ESMO-ESGO consensus, there are some discrepancies that can be explained by differences in the interpretation of certain clinical trials, reimbursement or accessibility issues.

Abstract To investigate the effect of physical activity (PA) (both general and its type) on self-esteem during and after cancer treatment. A systematic search was conducted across PubMed, Web of Science, Scopus, SPORTDiscuss, and PsycINFO from their inception to February 2024. The systematic review included 32 studies, with 15 studies (13 RCT and 2 quasi-experimental) and 3604 participants (66.7% female) included in the meta-analysis involving controlled trials using a control group and at least one PA intervention group. The study was registered in PROSPERO (CRD42022309771). Risk of bias for RCTs was assessed using the Cochrane Collaboration’s tool for assessing risk of bias (RoB2), and quasi-experimental studies with the Joanna Briggs Institute critical appraisal tool. PA significantly improved self-esteem during and after cancer treatment (pooled SMD = 0.32, p

Introducción: La alta prevalencia del sedentarismo y la insuficiente actividad física en la infancia es un problema persistente con graves repercusiones para la salud y el rendimiento escolar. Las escuelas, respaldadas por las leyes educativas que subrayan su importancia, deben fomentar hábitos y estilos de vida saludables y activos. Estrategias como los Escape Rooms, que motivan y fomentan la colaboración y la reflexión, podrían ser efectivas para enseñar al alumnado los beneficios de la actividad física y la reducción del sedentarismo para la salud física y mental. Objetivo: El objetivo de este trabajo es presentar una experiencia didáctica mediante el Escape Room “¡Sé inteligente, Muévete!” para que el alumnado de Educación Primaria conozca los efectos de los hábitos saludables y la actividad física en la salud mental y cerebral. Además, se evaluó la percepción de aprendizaje y disfrute de los y las participantes. Resultados: Los resultados mostraron una alta percepción de aprendizaje y disfrute. Las chicas puntuaron más alto en disfrute que los chicos, aunque sin diferencias estadísticamente significativas. No se encontraron diferencias estadísticamente significativas en la percepción de aprendizaje por curso, aunque los estudiantes de 3º curso puntuaron más alto que el resto de los grupos. En cuanto al disfrute, el alumnado de 6º curso percibió un menor disfrute que el resto de los cursos. Conclusiones: El Escape Room "¡Sé inteligente, Muévete!" mostró ser divertido y efectivo para adquirir conocimientos y reflexionar sobre los efectos de los hábitos saludables y la actividad física en la salud mental y cerebral.

Background Electrophysiological characterization of ventricular tachycardia (VT) isthmus sites is complex and time‐consuming. We aimed at developing and validating a global mapping strategy during programmed ventricular stimulation (PVS) to reveal the underlying electrophysiological properties of the infarct‐related substrate and to enable identification of highly heterogeneous activation sites associated with protected VT isthmus sites. Methods and Results Experimental study that included 22 pigs with established myocardial infarction undergoing in vivo characterization of the anatomical and functional myocardial substrate associated with potential arrhythmogenicity. High‐density sequential activation maps during ventricular pacing and VT were compared with single‐beat maps using a 64‐pole basket catheter positioned in the left ventricle. Further analyses were performed using a novel local activation time‐dispersion score to identify regional activation time heterogeneities on both baseline drive pacing and each of the extrastimuli of the PVS protocol. Basket catheter splines covered a median of 81.2% of the endocardial surface of the left ventricle. Basket‐catheter‐derived single‐beat activation maps (N=16) during pacing showed a linear relationship with high‐density sequential activation maps. Induction of ventricular arrhythmias was associated with higher local activation time‐dispersion score values on single‐beat global maps during PVS (N=6, 46 arrhythmia induction attempts). Single‐beat‐derived local activation time‐dispersion score maps during successive coupled extrastimuli of the PVS showed a progressive increase in the predictive performance to identify monomorphic VT isthmus sites within the scar region (area under the curve = 0.779 in S2, area under the curve = 0.859 in S4; N=7). Conclusions Sixty‐four‐pole‐derived single‐beat local activation time‐dispersion score global maps during PVS identify infarct‐related endocardial regions with highly heterogeneous activation times that are associated with protected VT isthmus sites.

Abstract Electromechanical characterization during atrial fibrillation (AF) remains a significant gap in the understanding of AF-related atrial myopathy. This study reports mechanistic insights into the electromechanical remodeling process associated with AF progression and further demonstrates its prognostic value in the clinic. In pigs, sequential electromechanical assessment during AF progression shows a progressive decrease in mechanical activity and early dissociation from its electrical counterpart. Atrial tissue samples from animals with AF reveal an abnormal increase in cardiomyocytes death and alterations in calcium handling proteins. High-throughput quantitative proteomics and immunoblotting analyses at different stages of AF progression identify downregulation of contractile proteins and progressive increase in atrial fibrosis. Moreover, advanced optical mapping techniques, applied to whole heart preparations during AF, demonstrate that AF-related remodeling decreases the frequency threshold for dissociation between transmembrane voltage signals and intracellular calcium transients compared to healthy controls. Single cell simulations of human atrial cardiomyocytes also confirm the experimental results. In patients, non-invasive assessment of the atrial electromechanical relationship further demonstrate that atrial electromechanical dissociation is an early prognostic indicator for acute and long-term rhythm control.

Scalable and high-throughput electrophysiological measurement systems are necessary to accelerate the elucidation of cardiac diseases in drug development. Optical mapping is the primary method of simultaneously measuring several key electrophysiological parameters, such as action potentials, intracellular free calcium and conduction velocity, at high spatiotemporal resolution. This tool has been applied to isolated whole-hearts, whole-hearts in-vivo, tissue-slices and cardiac monolayers/tissue-constructs. Although optical mapping of all of these substrates have contributed to our understanding of ion-channels and fibrillation dynamics, cardiac monolayers/tissue-constructs are scalable macroscopic substrates that are particularly amenable to high-throughput interrogation. Here, we describe and validate a scalable and fully-automated monolayer optical mapping robot that requires no human intervention and with reasonable costs. As a proof-of-principle demonstration, we performed parallelized macroscopic optical mapping of calcium dynamics in the well-established neonatal-rat-ventricular-myocyte monolayer plated on standard 35 mm dishes. Given the advancements in regenerative and personalized medicine, we also performed parallelized macroscopic optical mapping of voltage dynamics in human pluripotent stem cell-derived cardiomyocyte monolayers using a genetically encoded voltage indictor and a commonly-used voltage sensitive dye to demonstrate the versatility of our system.

Background: The PRIMA phase 3 trial showed niraparib significantly prolongs median progression-free survival (PFS) versus placebo in patients with advanced ovarian cancer (OC) responsive to first-line platinum-based chemotherapy, including those who had tumors with homologous recombination deficiency (HRd). This analysis of PRIMA examined the quality-adjusted PFS (QA-PFS) and quality-adjusted time without symptoms of disease or toxicity (Q-TWiST) of patients on maintenance niraparib versus placebo. Methods: Patients were randomized 2:1 to receive once-daily maintenance niraparib ( n = 487) or placebo ( n = 246). QA-PFS was defined as the PFS of patients adjusted for their health-related quality of life (HRQoL) prior to disease progression, measured using European Quality of Life Five-Dimension (EQ-5D) questionnaire index scores from the PRIMA trial. Q-TWiST was calculated by combining data on PFS, duration of symptomatic grade ⩾2 adverse events (fatigue or asthenia, nausea, vomiting, abdominal pain, and abdominal bloating) prior to disease progression, and EQ-5D index scores. Analyses used data collected up to the last date of PFS assessment (May 17, 2019). Results: The restricted mean QA-PFS was significantly longer with niraparib versus placebo in the HRd ( n = 373) and overall intention-to-treat (ITT; n = 733) populations (mean gains of 6.5 [95% confidence interval; CI, 3.9–8.9] and 4.1 [95% CI, 2.2–5.8] months, respectively). There were also significant improvements in restricted mean Q-TWiST for niraparib versus placebo (mean gains of 5.9 [95% CI, 3.5–8.6] and 3.5 [95% CI, 1.7–5.6] months, respectively) in the HRd and ITT populations. Conclusions: In patients with advanced OC, first-line niraparib maintenance was associated with significant gains in QA-PFS and Q-TWiST versus placebo. These findings demonstrate that niraparib maintenance treatment is associated with a PFS improvement and that treatment benefit is maintained even when HRQoL and/or toxicity data are combined with PFS in a single measure. Trial registration: ClinicalTrials.gov: NCT02655016; trial registration date: January 13, 2016 Plain language summary Background: In a large clinical trial called PRIMA, patients with advanced cancer of the ovary (ovarian cancer) were given either niraparib (a type of cancer medicine) or placebo (a pill containing no medicine/active substances) after having chemotherapy (another type of cancer medicine). Taking niraparib after chemotherapy is called maintenance therapy and aims to give patients more time before their cancer returns or gets worse than if they were not given any further treatment. In the PRIMA trial, patients who took niraparib did have more time before their cancer progressed than if they took placebo. However, it is important to consider patients’ quality of life, which can be made worse by cancer symptoms and/or side effects of treatment. Here, we assessed the overall benefit of niraparib for patients in PRIMA. Methods: Both the length of time before disease progression (or survival time) and quality of life were considered using two different analyses: ● The first analysis was called quality-adjusted PFS (QA-PFS) and looked at how long patients survived with good quality of life. ● The second analysis was called quality-adjusted time without symptoms of disease or toxicity (Q-TWiST) and looked at how long patients survived without cancer symptoms or treatment side effects. Results: The PRIMA trial included 733 patients; 487 took niraparib and 246 took placebo. Around half of the patients in both groups had a type of ovarian cancer that responds particularly well to drugs like niraparib – they are known as homologous recombination deficiency (HRd) patients. ● When information on quality of life (collected from patient questionnaires) and survival was combined in the QA-PFS analysis, HRd patients who took niraparib had approximately 6.5 months longer with a good quality of life before disease progression than those who took placebo. In the overall group of patients (including HRd patients and non-HRd patients), those who took niraparib had approximately 4 months longer than with placebo. ● Using the second analysis (Q-TWiST) to combine information on survival with cancer symptoms and treatment side effects, the HRd patients taking niraparib had approximately 6 months longer without cancer symptoms or treatment side effects (such as nausea or vomiting) than patients taking placebo. In the overall group of patients, those taking niraparib had approximately 3.5 months longer without these cancer symptoms/side effects than patients receiving placebo. Conclusions: These results show that the survival benefits of niraparib treatment remain when accounting for patients’ quality of life. These benefits were seen not only in HRd patients who are known to respond better to niraparib, but in the overall group of patients who took niraparib.

Abstract Background No review to date has evaluated the association between physical fitness and health-related quality of life (HRQoL) in healthy children and adolescents. The aims of this systematic review and meta-analysis were to examine the relationship between both cardiorespiratory fitness (CRF) and muscular fitness (MF) and HRQoL in healthy subjects under 18 years of age and to describe the dimensions of HRQoL in which these relationships are more robust. Methods The Medline, Embase, Cochrane Library, SCIELO, SPORTDiscus and PEDro databases were systematically searched to collect observational studies that examined the relationship between CRF and HRQoL and between MF and HRQoL in participants under 18 years of age without any diagnosed medical condition. Pooled effect sizes (ES) were estimated for the associations between both CRF and MF and the various HRQoL dimensions. Results The pooled ES (95% CI) estimates for the relationship between CRF and HRQoL were as follows: 0.19 (0.10 to 0.27) for physical well-being, 0.19 (0.07 to 0.32) for psychological well-being, 0.20 (− 0.14 to 0.55) for perceived health status, 0.10 (0.00 to 0.20) for self-perception/self-esteem, 0.07 (− 0.05 to 0.19) for quality of family relationship, 0.14 (0.04 to 0.25) for quality of peer relationship, 0.17 (0.04 to 0.29) for everyday functioning at school and 0.20 (0.12 to 0.28) for total HRQoL score. The pooled ES (95% CI) estimates for the relationship between MF and HRQoL were: 0.25 (0.12 to 0.37) for physical well-being, 0.11 (0.04 to 0.17) for psychological well-being, 0.08 (0.01 to 0.15) for quality of family relationship, 0.14 (0.03 to 0.25) for quality of peer relationship, and 0.09 (0.03 to 0.14) for total HRQoL score. Conclusions Our data suggest that both CRF and MF are positively associated with HRQoL, mainly in physical, psychological and peer relationships. Moreover, CRF is positively associated with school dimensions and MF is positively associated with family relationships. Trail registration Protocol PROSPERO registration number: CRD42015025823.

Ovarian cancer (OC) is a life-threatening tumor and the deadliest among gynecological cancers in developed countries. First line treatment with a carboplatin/paclitaxel regime is initially effective in the majority of patients, but most advanced OC will recur and develop drug resistance. Therefore, the identification of alternative therapies is needed. In this study, we employed a panel of high-grade serous ovarian cancer (HGSOC) cell lines, in monolayer and three-dimensional cell cultures. We evaluated the effects of a novel tubulin-binding agent, plocabulin, on proliferation, cell cycle, migration and invasion. We have also tested combinations of plocabulin with several drugs currently used in OC in clinical practice. Our results show a potent antitumor activity of plocabulin, inhibiting proliferation, disrupting microtubule network, and decreasing their migration and invasion capabilities. We did not observe any synergistic combination of plocabulin with cisplatin, doxorubicin, gemcitabine or trabectedin. In conclusion, plocabulin has a potent antitumoral effect in HGSOC cell lines that warrants further clinical investigation.

Abstract Background Although physical activity (PA) integrated in schools’ classrooms have shown a positive effect on children’s behaviors, its effectiveness on cognitive functions, PA levels and other health variables remains unclear. This article outlines the rationale and methods of two classroom-based PA interventions (MOVI-da10!) on improving adiposity, executive function and motor competence in preschool children. Methods A three-arm cluster-randomized controlled trial (RCT) was carried out including eight schools (rural and urban areas) from Cuenca province, Spain. The schools were allocated to one of three groups: MOVI-da10-Enriched! intervention (n = 3), MOVI-da10-Standard! intervention, (n = 2), and the control group (n = 3). Around 900 children aged 4 to 6 years old were assesed at baseline (September 2017) and at the end (June 2018) of the intervention. The primary outcomes were changes in body fat by bioimpedance, executive function and motor competence. During a school year (from October 2017 to May 2018), children belonging to the MOVI-da10-Enriched! group performed enriched PA integrated into the academic curriculum including two active breaks lasting 10 min, 5 days/week. The children belonging to the MOVI-da10-Standard! group performed PA breaks (with low cognitive demand, where curricular contents were not reinforced) including two active breaks lasting 10 min, 5 days/week. In the control group, regular PA continued. Discussion To our knowledge, MOVI-da10! is the first RCT to examine the effectiveness of two programs (enriched PA integrated into the academic curriculum and PA breaks only) versus a control group on improving adiposity, executive function and motor competence in preschool children. Trial registration NCT03236363 (clinicaltrials.gov), 31st July 2017.

Background Sarcomas exhibit low expression of factors related to immune response, which could explain the modest activity of PD-1 inhibitors. A potential strategy to convert a cold into an inflamed microenvironment lies on a combination therapy. As tumor angiogenesis promotes immunosuppression, we designed a phase Ib/II trial to test the double inhibition of angiogenesis (sunitinib) and PD-1/PD-L1 axis (nivolumab).Methods This single-arm, phase Ib/II trial enrolled adult patients with selected subtypes of sarcoma. Phase Ib established two dose levels: level 0 with sunitinib 37.5 mg daily from day 1, plus nivolumab 3 mg/kg intravenously on day 15, and then every 2 weeks; and level −1 with sunitinib 37.5 mg on the first 14 days (induction) and then 25 mg per day plus nivolumab on the same schedule. The primary endpoint was to determine the recommended dose for phase II (phase I) and the 6-month progression-free survival rate, according to Response Evaluation Criteria in Solid Tumors 1.1 (phase II).Results From May 2017 to April 2019, 68 patients were enrolled: 16 in phase Ib and 52 in phase II. The recommended dose of sunitinib for phase II was 37.5 mg as induction and then 25 mg in combination with nivolumab. After a median follow-up of 17 months (4–26), the 6-month progression-free survival rate was 48% (95% CI 41% to 55%). The most common grade 3–4 adverse events included transaminitis (17.3%) and neutropenia (11.5%).Conclusions Sunitinib plus nivolumab is an active scheme with manageable toxicity in the treatment of selected patients with advanced soft tissue sarcoma, with almost half of patients free of progression at 6 months.Trial registration number NCT03277924.

OBJECTIVES:Previous research has studied the influence of physical fitness on academic achievement through executive functions. However, the nature of this relationship remains unclear. This study aimed to analyze how cardiorespiratory fitness (CRF) and executive functions are associated with academic achievement and to examine whether the relationship between CRF and academic achievement is mediated by executive functions in schoolchildren. METHODS:This was a cross-sectional study including 570 schoolchildren, aged 8 to 11 years, from Cuenca, Spain. Data were collected from September to October 2017. Sociodemographic variables, family socioeconomic status, pubertal status, academic achievement, CRF (20-meter shuttle run test) and executive functions (inhibition, cognitive flexibility and working memory, NIH Toolbox battery in Spanish, v 1.8; iPad Pro, Apple, Inc.) were measured. RESULTS:Overall, ANCOVA models controlling for age, gender and mother educational level showed higher scores in language and mathematics in children in higher categories of CRF, inhibition, cognitive flexibility and working memory than in children in lower categories. The effect sizes were moderate (p < 0.05, partial eta squared: from 0.05 to 0.12). Moreover, the mediation analysis showed that inhibition partially mediated the relationship between CRF and language (c' = 0.058; IC = [0.005; 0.028]) and mathematics (c' = 0.064; IC = [0.005; 0.030]) grades. Similarly, cognitive flexibility mediated CRF's relationship with language (c' = 0.059; IC = [0.003; 0.028]) and with mathematics (c' = 0.066; IC = [0.003; 0.029]); however, a significant relationship remained. For working memory, mediation analysis showed no significant results (c' = 0.92; IC = [-0.002;0.025] P > 0.05 in language; c' = 0.103; IC = [-0.002;0.029] P > 0.05 in mathematics). Mediation ranged from 13.38% to 36%. CONCLUSIONS:Children in higher categories of both CRF and executive function showed higher grades in mathematics and language. The findings indicated that a significant proportion of the positive influence of CRF on academic achievement was mediated by improvements in inhibition and cognitive flexibility. Thus, this study supports the hypothesis that improvements in CRF may contribute to increasing academic achievement not only through a direct mechanism but also through improvements in executive functions.

Here, we report on the production of nanoripples on the surface of ZnO bulk substrates by ion beam erosion with 20 keV Ar+ ions at an oblique incidence (60°). The ripple patterns, analyzed by atomic force microscopy, follow a power law dependence for both the roughness and the wavelength. At high fluences these ripples show coarsening and asymmetric shapes, which become independent of the beam direction and evidence additional mechanisms for the pattern development. The shallow damaged layer is not fully amorphized by this process, as confirmed by medium energy ion scattering. A detailed study of the damage-induced changes on the optical properties was carried out by means of spectroscopic ellipsometry. Using a 3-layer model based on Tauc-Lorenz and critical point parameter band oscillators, the optical constants of the damaged layer were determined. The results showed a progressive reduction in the refractive index and enhanced absorption below the bandgap with the fluence.

To compare the concordance in risk classification between the EndoPredict and the MammaPrint scores obtained for the same cancer samples on 40 estrogen-receptor positive/HER2-negative breast carcinomas.Formalin-fixed, paraffin-embedded invasive breast carcinoma tissues that were previously analyzed with MammaPrint as part of routine care of the patients, and were classified as high-risk (20 patients) and low-risk (20 patients), were selected to be analyzed by the EndoPredict assay, a second generation gene expression test that combines expression of 8 genes (EP score) with two clinicopathological variables (tumor size and nodal status, EPclin score).The EP score classified 15 patients as low-risk and 25 patients as high-risk. EPclin re-classified 5 of the 25 EP high-risk patients into low-risk, resulting in a total of 20 high-risk and 20 low-risk tumors. EP score and MammaPrint score were significantly correlated (p = 0.008). Twelve of 20 samples classified as low-risk by MammaPrint were also low-risk by EP score (60%). 17 of 20 MammaPrint high-risk tumors were also high-risk by EP score. The overall concordance between EP score and MammaPrint was 72.5% (κ = 0.45, (95% CI, 0.182 to 0.718)). EPclin score also correlated with MammaPrint results (p = 0.004). Discrepancies between both tests occurred in 10 cases: 5 MammaPrint low-risk patients were classified as EPclin high-risk and 5 high-risk MammaPrint were classified as low-risk by EPclin and overall concordance of 75% (κ = 0.5, (95% CI, 0.232 to 0.768)).This pilot study demonstrates a limited concordance between MammaPrint and EndoPredict. Differences in results could be explained by the inclusion of different gene sets in each platform, the use of different methodology, and the inclusion of clinicopathological parameters, such as tumor size and nodal status, in the EndoPredict test.

INTRODUCTION: Gene profiling may improve prognostic accuracy in patients with early breast cancer, but this technology is not widely available. We used commercial assays for qRT-PCR to assess the performance of the gene profiles included in the 70-Gene Signature, the Recurrence Score and the Two-Gene Ratio. METHODS: 153 patients with early breast cancer and a minimum follow-up of 5 years were included. All tumours were positive for hormonal receptors and 38% had positive lymph nodes; 64% of patients received adjuvant chemotherapy. RNA was extracted from formalin-fixed paraffin-embedded (FFPE) specimens using a specific kit. qRT-PCR amplifications were performed with TaqMan Gene Expression Assays products. We applied the three gene-expression-based models to our patient cohort to compare the predictions derived from these gene sets. RESULTS: After a median follow-up of 91 months, 22% of patients relapsed. The distant metastasis-free survival (DMFS) at 5 years was calculated for each profile. For the 70-Gene Signature, DMFS was 95% -good prognosis- versus 66% -poor prognosis. In the case of the Recurrence Score, DMFS was 98%, 81% and 69% for low, intermediate and high-risk groups, respectively. Finally, for the Two-Gene Ratio, DMFS was 86% versus 70%. The 70-Gene Signature and the Recurrence Score were highly informative in identifying patients with distant metastasis, even in multivariate analysis. CONCLUSION: Commercially available assays for qRT-PCR can be used to assess the prognostic utility of previously published gene expression profiles in FFPE material from patients with early breast cancer. Our results, with the use of a different platform and with different material, confirm the robustness of the 70-Gene Signature and represent an independent test for the Recurrence Score, using different primer/probe sets.