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Abstract Background Although adequate physical activity has been shown to be beneficial in early breast cancer, evidence in metastatic breast cancer is sparse and contradictory, which could be related to distinct effects of physical activity on the different molecular cancer subtypes. Therefore, we here evaluated the effect of physical activity on progression-free and overall survival (PFS, OS) in metastatic breast cancer, specifically looking at molecular subtypes. Methods International Physical Activity Questionnaire (IPAQ) questionnaires, filled out by patients enrolled in the prospective PRAEGNANT registry (NCT02338167; n = 1,270) were used to calculate metabolic equivalent task (MET) minutes, which were subsequently categorized into low (n = 138), moderate (n = 995) or high IPAQ categories (n = 137). Cox regression analyses were used to evaluate the impact of IPAQ categories and its interaction with molecular subtypes on PFS and OS. Results Patient and tumor characteristics were equally distributed across IPAQ categories. HER2pos, HRpos and TNBC were present in 23.1%, 65.7% and 11.2% of patients, respectively. IPAQ scores did not have an impact on PFS and OS in addition to established prognostic factors, either overall or in particular molecular subtypes (PFS: p = 0.33 and OS: p = 0.08, likelihood ratio test). Exploratory analyses showed higher overall survival rates for high IPAQ categories compared to low/moderate IPAQ categories in luminal B-like breast cancer. Conclusions Self-reported physical activity using the IPAQ questionnaire did not significantly affect PFS or OS in patients suffering from metastatic breast cancer. Nevertheless, some hypothesis-generating differences between molecular subtypes could be observed, which may be interesting to evaluate further.

Abstract Background Increased levels of physical activity are associated with a reduction of breast cancer mortality, especially in postmenopausal women with positive hormone receptor status. So far, previous observational case–control and cohort studies have focused on associations between overall leisure time physical activity and survival of women with breast cancer in general. Methods In this multicenter prospective cohort study, conducted in Germany between 30th August 2012 to 29th December 2017, we investigated general physical activity in a homogenous sample of n = 1440 postmenopausal women with advanced (inoperable locally advanced or metastatic), hormone receptor-positive breast cancer receiving the same therapy (everolimus and exemestane). Self-reported physical activity was assessed using the Godin Leisure Time Exercise Questionnaire (GLTEQ) before and every 3 months during treatment. Participants were then classified into “active” and “insufficiently active” to screen their activity behavior the week prior to medical treatment. In addition, changes in physical activity patterns were assessed. Adjusted Cox regression analyses were performed for the activity categories to determine hazard ratios (HR). Besides progression-free survival (PFS), adverse events (AEs), QoL, and fatigue were assessed every 3 months until study termination. Results Compared to “insufficiently active” patients, “active” individuals indicated a significantly longer PFS (HR: 0.84 [0.74; 0.984], p = .0295). No significant differences were observed for changes of physical activity behavior. Patients who reported to be “active” at baseline revealed significantly fewer AEs compared to “insufficiently” active patients. In detail, both severe and non-severe AEs occurred less frequently in the “active” patients group. In line with that, QoL and fatigue were better in physical “active” patients compared to their insufficient active counterparts at the last post-baseline assessment. Participants who remained or become active indicated less AEs, a higher QoL, and reduced fatigue levels. Conclusions Physical activity behavior prior to medical treatment might have prognostic value in patients with advanced breast cancer in terms of extending the PFS. Moreover, physical activity before and during treatment may reduce treatment-related side effects and improve patients’ QoL and fatigue. Trial registration EUPAS9462. Registered 30th October 2012 “retrospectively registered.”

Abstract Germline mutations in BRCA1 and BRCA2 (gBRCA1/2) are required for a PARP inhibitor therapy in patients with HER2-negative (HER2−) advanced breast cancer (aBC). However, little is known about the prognostic impact of gBRCA1/2 mutations in aBC patients treated with chemotherapy. This study aimed to investigate the frequencies and prognosis of germline and somatic BRCA1/2 mutations in HER2- aBC patients receiving the first chemotherapy in the advanced setting. Patients receiving their first chemotherapy for HER2- aBC were retrospectively selected from the prospective PRAEGNANT registry (NCT02338167). Genotyping of 26 cancer predisposition genes was performed with germline DNA of 471 patients and somatic tumor DNA of 94 patients. Mutation frequencies, progression-free and overall survival (PFS, OS) according to germline mutation status were assessed. gBRCA1/2 mutations were present in 23 patients (4.9%), and 33 patients (7.0%) had mutations in other cancer risk genes. Patients with a gBRCA1/2 mutation had a better OS compared to non-mutation carriers (HR: 0.38; 95%CI: 0.17–0.86). PFS comparison was not statistically significant. Mutations in other risk genes did not affect prognosis. Two somatic BRCA2 mutations were found in 94 patients without gBRCA1/2 mutations. Most frequently somatic mutated genes were TP53 (44.7%), CDH1 (10.6%) and PTEN (6.4%). In conclusion, aBC patients with gBRCA1/2 mutations had a more favorable prognosis under chemotherapy compared to non-mutation carriers. The mutation frequency of ~5% with gBRCA1/2 mutations together with improved outcome indicates that germline genotyping of all metastatic patients for whom a PARP inhibitor therapy is indicated should be considered.

Self-efficacy is associated with both academic performance and attrition in higher education. Whether it is possible to measure students' academic self-efficacy after admission and prior to commencing higher education (i.e. pre-academic self-efficacy) in a valid and reliable way has hardly been studied. Aims: 1) to evaluate the construct validity and psychometric properties of two short scales to measure Pre-Academic Learning Self-Efficacy (PAL-SE) and Pre-Academic Exam Self-Efficacy (PAE-SE) using Rasch measurement models, 2) to investigate whether pre-academic self-efficacy was associated with half-year attrition across degree programs and institutions. Data consisted of 2686 Danish students admitted to nine different university degree programs across two institutions. Item analyses showed both scales to be essentially objective and construct valid, however, all items from the PAE-SE and two from the PAL-SE were locally dependent. Differential item functioning was found for the PAL-SE relative to degree programs. Reliability of the PAE-SE was 0.77, and varied for the PAL-SE from 0.79 to 0.86 across degree programs. Targeting was good only for the PAL-SE, thus we proceeded with the PAL-SE. PAL-SE was found to be associated with half-year attrition: A difference in PAL-SE from minimum to maximum was associated with a difference in half-year attrition of approximately 7%. This association was found both in the bivariate model and in the multivariate models with control of degree program, and with control of degree program and individual covariates such as earlier educational achievement and social background variables. Results thus also indicate that PAL-SE has a causal effect on half-year attrition.

Abstract Despite tremendous progress in deciphering breast cancer at the genomic level, the pronounced intra- and intertumoral heterogeneity remains a major obstacle to the advancement of novel and more effective treatment approaches. Frequent treatment failure and the development of treatment resistance highlight the need for patient-derived tumor models that reflect the individual tumors of breast cancer patients and allow a comprehensive analyses and parallel functional validation of individualized and therapeutically targetable vulnerabilities in protein signal transduction pathways. Here, we introduce the generation and application of breast cancer patient-derived 3D microtumors (BC-PDMs). Residual fresh tumor tissue specimens were collected from n = 102 patients diagnosed with breast cancer and subjected to BC-PDM isolation. BC-PDMs retained histopathological characteristics, and extracellular matrix (ECM) components together with key protein signaling pathway signatures of the corresponding primary tumor tissue. Accordingly, BC-PDMs reflect the inter- and intratumoral heterogeneity of breast cancer and its key signal transduction properties. DigiWest®-based protein expression profiling of identified treatment responder and non-responder BC-PDMs enabled the identification of potential resistance and sensitivity markers of individual drug treatments, including markers previously associated with treatment response and yet undescribed proteins. The combination of individualized drug testing with comprehensive protein profiling analyses of BC-PDMs may provide a valuable complement for personalized treatment stratification and response prediction for breast cancer.

Abstract Background Breast cancer is a metabolically heterogeneous disease, and although the concept of heterogeneous cancer metabolism is known, its precise role in human breast cancer is yet to be fully elucidated. Methods We investigated in an explorative approach a cohort of 42 primary mamma carcinoma patients with positron emission tomography/magnetic resonance imaging (PET/MR) prior to surgery, followed by histopathology and molecular diagnosis. From a subset of patients, which showed high metabolic heterogeneity based on tracer uptake and pathology classification, tumour centre and periphery specimen tissue samples were further investigated by a targeted breast cancer gene expression panel and quantitative metabolomics by nuclear magnetic resonance (NMR) spectroscopy. All data were analysed in a combinatory approach. Results [18F]FDG (2‐deoxy‐2‐[fluorine‐18]fluoro‐d‐glucose) tracer uptake confirmed dominance of glucose metabolism in the breast tumour centre, with lower levels in the periphery. Additionally, we observed differences in lipid and proliferation related genes between luminal A and B subtypes in the centre and periphery. Tumour periphery showed elevated acetate levels and enrichment in lipid metabolic pathways genes especially in luminal B. Furthermore, serine was increased in the periphery and higher expression of thymidylate synthase (TYMS) indicated one‐carbon metabolism increased in tumour periphery. The overall metabolic activity based on [18F]FDG uptake of luminal B subtype was higher than that of luminal A and the difference between the periphery and centre increased with tumour grade. Conclusion Our analysis indicates variations in metabolism among different breast cancer subtypes and sampling locations which details the heterogeneity of the breast tumours. Correlation analysis of [18F]FDG tracer uptake, transcriptome and tumour metabolites like acetate and serine facilitate the search for new candidates for metabolic tracers and permit distinguishing luminal A and B. This knowledge may help to differentiate subtypes preclinically or to provide patients guide for neoadjuvant therapy and optimised surgical protocols based on individual tumour metabolism.

La generación de nuevos materiales genéticos para atender las diversas demandas del mercado de la madera requiere una constante evaluación de sus propiedades tecnológicas. En el presente estudio, se evaluó el contenido relativo de duramen y albura a tres alturas de fuste (0,10 m, 2,80 m y 5,50 m) así como la variación de densidad en dirección axial y radial de clones puros Eucalyptus grandis (rose gum) e híbridos (Eucalyptus grandis (rose gum) x Eucalyptus camaldulensis (red gum) y Eucalyptus grandis (rose gum) x Eucalyptus tereticornis (red irongum)) de 11 años de edad. Los clones puros mostraron un 10 % más de duramen que los híbridos. El material híbrido alcanzó el mayor valor medio de densidades, siendo más homogéneo en el perfil radial y axial. En general, la densidad presentó un patrón creciente en la dirección radial. No se encontraron diferencias significativas en la densidad para las alturas estudiadas en los clones híbridos, mientras que los clones puros presentaron valores de densidad significativamente mayores a 0,10 m. La densidad de la albura fue mayor que la del duramen para las tres alturas de fuste en todos los materiales genéticos. El análisis de los resultados indica que los clones híbridos podrían ser aptos para la producción de pulpa de celulosa debido a la menor proporción de duramen, lo cual facilita el proceso de blanqueo, así como para su uso como madera aserrada o contrachapado estructural por su mayor densidad y homogeneidad en altura.

Abstract Our objective was to test whether p53 expression status is associated with survival for women diagnosed with the most common ovarian carcinoma histotypes (high‐grade serous carcinoma [HGSC], endometrioid carcinoma [EC], and clear cell carcinoma [CCC]) using a large multi‐institutional cohort from the Ovarian Tumor Tissue Analysis (OTTA) consortium. p53 expression was assessed on 6,678 cases represented on tissue microarrays from 25 participating OTTA study sites using a previously validated immunohistochemical (IHC) assay as a surrogate for the presence and functional effect of TP53 mutations. Three abnormal expression patterns (overexpression, complete absence, and cytoplasmic) and the normal (wild type) pattern were recorded. Survival analyses were performed by histotype. The frequency of abnormal p53 expression was 93.4% (4,630/4,957) in HGSC compared to 11.9% (116/973) in EC and 11.5% (86/748) in CCC. In HGSC, there were no differences in overall survival across the abnormal p53 expression patterns. However, in EC and CCC, abnormal p53 expression was associated with an increased risk of death for women diagnosed with EC in multivariate analysis compared to normal p53 as the reference (hazard ratio [HR] = 2.18, 95% confidence interval [CI] 1.36–3.47, p = 0.0011) and with CCC (HR = 1.57, 95% CI 1.11–2.22, p = 0.012). Abnormal p53 was also associated with shorter overall survival in The International Federation of Gynecology and Obstetrics stage I/II EC and CCC. Our study provides further evidence that functional groups of TP53 mutations assessed by abnormal surrogate p53 IHC patterns are not associated with survival in HGSC. In contrast, we validate that abnormal p53 IHC is a strong independent prognostic marker for EC and demonstrate for the first time an independent prognostic association of abnormal p53 IHC with overall survival in patients with CCC.

Abstract Background Facing an increasing number of radiofrequency ablation (RF) and cryoballoon ablation (CB) procedures for treatment of AF radiation exposure and its reduction is a focus point for interventional electrophysiologists. Objective This study evaluated the procedural parameters of the different ablation methods focusing on radiation exposure and the BMI of the patients. Methods One thousand one hundred and thirty‐three first procedural cases of pulmonary vein isolation in patients with paroxysmal and persistent AF treated with RF and CB‐based techniques were analyzed retrospectively over a period of 7 years focusing on the endpoints dose area product (DAP, cGycm2), fluoroscopy time (FT, min) and procedural time (PT, min). Results Of the 1133 patients (mean age 63.4 ± 11.4 years, BMI 28.9 ± 4.7) 335 patients received an RF procedure, 211 patients were treated with the cryoballoon first generation (CB1), and 587 patients with cryoballoon second generation (CB2), respectively. The mean DAP for the PVI was 508 ± 654 cGycm2 in RF procedures, 1077 ± 683 cGycm2 in CB1‐procedures, and 587 ± 489 cGycm2 in CB2‐procedures with fluoroscopy times significantly shorter in RF procedures (9.6 ± 5.2 min) as compared to 17.7 ± 5.9 min in CB1‐ and 16.3 ± 6.3 min in CB2‐procedures (p

Background: The fetal autonomic nervous system (ANS) is believed to be negatively affected by maternal adverse emotional states. In this study, we evaluated how depression, anxiety and stress during pregnancy are related to fetal heart rate variability (HRV) as recorded with magnetocardiography (MCG). We also considered metabolic factors such as maternal adiposity and circulating levels of cortisol during gestation. Furthermore, we followed up these fetuses after birth, recording HRV and saliva levels of cortisol in these infants to establish any effects postpartum. Methods: We calculated HRV in spontaneous MCG recordings from 32 healthy fetuses between 32 and 38 weeks of gestational age. Maternal emotional state was assessed using standardized questionnaires about anxiety, depression and stress. An overall indicator of maternal well-being was calculated by z-scoring each individual questionnaire and summation. We used a median split to divide the group into high and low z-scores (HZS and LZS), respectively. Standard HRV measures were determined in the time and frequency domain. T-test analyses were performed between LZS and HZS, with the HRV and the metabolic measures as the dependent variables. Results: We found an impaired HRV in the HZS group both during pregnancy and after birth. No differences were observed between LZS and HZS for metabolic factors. Depression and anxiety symptoms seem to affect HRV differently. No relationship was found between maternal and infant cortisol levels. Conclusions: On the basis of our results on different HRV parameters, we propose that maternal emotional state might affect the development of the fetal nervous system in utero.

Simple Summary: This study investigates how frequently breast cancer patients develop mental disorders compared to a control group without breast cancer. We analyzed data from over 11,000 breast cancer patients and nearly 32,000 healthy controls, finding that breast cancer patients were significantly more likely to suffer from mental disorders. Anxiety disorders, hypochondria, adjustment disorders, and depression were particularly common. This study also examined factors such as the type of therapy: endocrine therapy and breast reconstruction were strongly associated with psychological distress, and simple-mastectomy patients showed the lowest rates of mental illness. This work is of particular importance because it highlights how significantly the mental health of breast cancer patients can deteriorate due to their diagnosis and treatment. Thus, psychological counseling should be part of every treatment for breast cancer, especially when endocrine therapy is recommended. The practice of recommending breast reconstruction after mastectomy should be reconsidered, as it could have a negative effect on mental health. Background/Objectives: With breast cancer (BC) survival improving due to optimized therapy, enhancing quality of life has become increasingly important. Both diagnosis and treatment, with their potential side effects, pose risks to mental well-being. Our study aimed to analyze the incidence and potential risk factors for mental disorders in BC patients. Methods: This retrospective analysis used claims data from AOK Baden-Wuerttemberg, including 11,553 BC patients diagnosed via ICD code C50 between 2010 and 2020 and 31,944 age-matched controls. Patients with mental disorders in the 12 months prior to diagnosis were excluded. Mental disorders were categorized into eight groups based on ICD codes: anxiety, obsessive compulsive disorder, adjustment disorder, dissociative disorder, hypochondriac disorder, affective disorder, mania, and other neuroses. Results: Mental disorders were significantly more common in BC patients than in controls (64.2% vs. 38.1%, p < 0.01, OR 2.91, 95%CI [2.79, 3.04]). In particular, hypochondriac, anxiety, affective, and adjustment disorders occurred significantly more often in BC patients. No differences were found for mania, bipolar disease, other neuroses, obsessive compulsive-, or dissociative disorders. Furthermore, endocrine therapy was associated with psychological comorbidities (OR 1.69, p < 0.001, 95%CI [1.53, 1.86]), while primarily metastasized patients (stage C) had a lower risk than adjuvant patients in stage A (OR 0.55, p < 0.0001, 95%CI [0.49, 0.61]). Regarding surgical treatment, mastectomy patients showed lower rates of mental illnesses (61.2%) than those with breast-conserving treatment (71.6%), or especially breast reconstruction (78.4%, p < 0.01). Breast reconstruction was also associated with more hypochondriac (p < 0.01) and adjustment disorders (p < 0.01). Conclusions: So, BC patients experience significantly more mental disorders than controls, particularly when treated with endocrine therapy and breast reconstructive surgery. [ABSTRACT FROM AUTHOR]