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Abstract Background The risk of breast cancer patients for long-term side effects of therapy such as neurotoxicity and cardiotoxicity as well as late effects regarding comorbidities varies from individual to individual. Personalised follow-up care concepts that are tailored to individual needs and the risk of recurrences, side effects and late effects are lacking in routine care in Germany. Methods We describe the methodology of BETTER-CARE, a parallel-arm cluster-randomised controlled trial conducted at 15 intervention and 15 control centres, aiming to recruit 1140 patients, and the results of the pilot phase. The needs- and risk-adapted complex intervention, based on existing development frameworks, includes a multidisciplinary network and digital platforms for symptom and need documentation and just-in-time adaptive interventions. The control group comprises usual care according to clinical guidelines. The primary outcome is health-related quality of life (EORTC QLQ-C30 global health), and secondary outcomes include treatment adherence. Results The 2-month pilot phase comprising 16 patients in one intervention and one control pilot centre demonstrated the feasibility of the BETTER-CARE approach. Discussion BETTER-CARE is a feasible intervention and study concept, investigating individualised needs- and risk-adapted breast cancer follow-up care in Germany. If successful, the approach could be implemented in German routine care. Trial registration German Clinical Trial Register DRKS00028840. Registered on April 2022.

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.

More and more children and adolescents in Switzerland show serious deficits in their German language skills. In order to specifically promote the language skills of students with a non-German first language, special lessons in German as a second language (GasL) are therefore offered in addition to the regular lessons. The aim of this case study is to evaluate the impact of a pedagogically sound immersive virtual reality learning unit for GasL lessons, which offers students the opportunity to actively speak German and to demonstrate this in the context of two GasL lessons. The research design is based on the "Design Science Research Framework". In this context, the virtual reality learning unit was designed as an innovative prototype (artifact) and iteratively improved. The design considered the didactic framework of the official curriculum as well as the eleven general design guidelines for virtual reality learning units in an educational context. The virtual reality learning unit was tested in a field experiment with five students each at an elementary school and at a secondary school. The students found the virtual reality learning unit as a whole attractive and motivating. But there are operational challenges and necessary prerequisites that have to be considered and created in order to pragmatically and sustainably integrate immersive virtual reality learning units into the existing GasL lessons.

Abstract After menstruation the uterine spiral arteries are repaired through angiogenesis. This process is tightly regulated by the paracrine communication between endometrial stromal cells (EnSCs) and endothelial cells. Any molecular aberration in these processes can lead to complications in pregnancy including miscarriage or preeclampsia (PE). Placental growth factor (PlGF) is a known contributing factor for pathological angiogenesis but the mechanisms remain poorly understood. In this study, we investigated whether PlGF contributes to pathological uterine angiogenesis by disrupting EnSCs and endothelial paracrine communication. We observed that PlGF mediates a tonicity-independent activation of nuclear factor of activated T cells 5 (NFAT5) in EnSCs. NFAT5 activated downstream targets including SGK1, HIF-1α and VEGF-A. In depth characterization of PlGF - conditioned medium (CM) from EnSCs using mass spectrometry and ELISA methods revealed low VEGF-A and an abundance of extracellular matrix organization associated proteins. Secreted factors in PlGF-CM impeded normal angiogenic cues in endothelial cells (HUVECs) by downregulating Notch-VEGF signaling. Interestingly, PlGF-CM failed to support human placental (BeWo) cell invasion through HUVEC monolayer. Inhibition of SGK1 in EnSCs improved angiogenic effects in HUVECs and promoted BeWo invasion, revealing SGK1 as a key intermediate player modulating PlGF mediated anti-angiogenic signaling. Taken together, perturbed PlGF-NFAT5-SGK1 signaling in the endometrium can contribute to pathological uterine angiogenesis by negatively regulating EnSCs-endothelial crosstalk resulting in poor quality vessels in the uterine microenvironment. Taken together the signaling may impact on normal trophoblast invasion and thus placentation and, may be associated with an increased risk of complications such as PE.

Abstract The aim of this study was to evaluate the long-term efficacy of a single ultrasound-guided high-intensity focused ultrasound (US-HIFU) treatment in patients with breast fibroadenoma (FA) in terms of volume and pain reduction as well as palpation findings. From december 2013 until november 2014 27 women with a symptomatic FA were treated in one HIFU-session. Follow-up visits were performed after 7 days, 6 months and 1, 2, 3 and 5 years with clinical examination and ultrasound. One year after the procedure, a core needle biopsy of the residual lesion was offered. There was a significant volume reduction 6 months after HIFU from 1083.10 to 347.13 mm3 (p

Abstract Background Spinal cord stimulation (SCS) has demonstrated multiple benefits in treating chronic pain and other clinical disorders related to sensorimotor dysfunctions. However, the underlying mechanisms are still not fully understood, including how electrode placement in relation to the spinal cord neuroanatomy influences epidural spinal recordings (ESRs). To characterize this relationship, this study utilized stimulation applied at various anatomical sections of the spinal column, including at levels of the intervertebral disc and regions correlating to the dorsal root entry zone. Method Two electrode arrays were surgically implanted into the dorsal epidural space of the swine. The stimulation leads were positioned such that the caudal-most electrode contact was at the level of a thoracic intervertebral segment. Intraoperative cone beam computed tomography (CBCT) images were utilized to precisely determine the location of the epidural leads relative to the spinal column. High-resolution microCT imaging and 3D-model reconstructions of the explanted spinal cord illustrated precise positioning and dimensions of the epidural leads in relation to the surrounding neuroanatomy, including the spinal rootlets of the dorsal and ventral columns of the spinal cord. In a separate swine cohort, implanted epidural leads were used for SCS and recording evoked ESRs. Results Reconstructed 3D-models of the swine spinal cord with epidural lead implants demonstrated considerable distinctions in the dimensions of a single electrode contact on a standard industry epidural stimulation lead compared to dorsal rootlets at the dorsal root entry zone (DREZ). At the intervertebral segment, it was observed that a single electrode contact may cover 20-25% of the DREZ if positioned laterally. Electrode contacts were estimated to be ~0.75 mm from the margins of the DREZ when placed at the midline. Furthermore, ventral rootlets were observed to travel in proximity and parallel to dorsal rootlets at this level prior to separation into their respective sides of the spinal cord. Cathodic stimulation at the level of the intervertebral disc, compared to an ‘off-disc’ stimulation (7 mm rostral), demonstrated considerable variations in the features of recorded ESRs, such as amplitude and shape, and evoked unintended motor activation at lower stimulation thresholds. This substantial change may be due to the influence of nearby ventral roots. To further illustrate the influence of rootlet activation vs. dorsal column activation, the stimulation lead was displaced laterally at ~2.88 mm from the midline, resulting in variances in both evoked compound action potential (ECAP) components and electromyography (EMG) components in ESRs at lower stimulation thresholds. Conclusion The results of this study suggest that the ECAP and EMG components of recorded ESRs can vary depending on small differences in the location of the stimulating electrodes within the spinal anatomy, such as at the level of the intervertebral segment. Furthermore, the effects of sub-centimeter lateral displacement of the stimulation lead from the midline, leading to significant changes in electrophysiological metrics. The results of this pilot study reveal the importance of the small displacement of the electrodes that can cause significant changes to evoked responses SCS. These results may provide further valuable insights into the underlying mechanisms and assist in optimizing future SCS-related applications.

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.

PurposeA polygenic risk score (PRS) consisting of 313 common genetic variants (PRS313) is associated with risk of breast cancer and contralateral breast cancer. This study aimed to evaluate the association of the PRS313 with clinicopathologic characteristics of, and survival following, breast cancer.MethodsWomen with invasive breast cancer were included, 98,397 of European ancestry and 12,920 of Asian ancestry, from the Breast Cancer Association Consortium (BCAC), and 683 women from the European MINDACT trial. Associations between PRS313 and clinicopathologic characteristics, including the 70-gene signature for MINDACT, were evaluated using logistic regression analyses. Associations of PRS313 (continuous, per standard deviation) with overall survival (OS) and breast cancer-specific survival (BCSS) were evaluated with Cox regression, adjusted for clinicopathologic characteristics and treatment.ResultsThe PRS313 was associated with more favorable tumor characteristics. In BCAC, increasing PRS313 was associated with lower grade, hormone receptor-positive status, and smaller tumor size. In MINDACT, PRS313 was associated with a low risk 70-gene signature. In European women from BCAC, higher PRS313 was associated with better OS and BCSS: hazard ratio (HR) 0.96 (95% CI, 0.94 to 0.97) and 0.96 (95% CI, 0.94 to 0.98), but the association disappeared after adjustment for clinicopathologic characteristics (and treatment): OS HR, 1.01 (95% CI, 0.98 to 1.05) and BCSS HR, 1.02 (95% CI, 0.98 to 1.07). The results in MINDACT and Asian women from BCAC were consistent.ConclusionAn increased PRS313 is associated with favorable tumor characteristics, but is not independently associated with prognosis. Thus, PRS313 has no role in the clinical management of primary breast cancer at the time of diagnosis. Nevertheless, breast cancer mortality rates will be higher for women with higher PRS313 as increasing PRS313 is associated with an increased risk of disease. This information is crucial for modeling effective stratified screening programs.

Abstract Cell stiffness is regulated by dynamic interaction between ras-related C3 botulinum toxin substrate 1 (Rac1) and p21 protein-activated kinase 1 (PAK1) proteins, besides other biochemical and molecular regulators. In this study, we investigated how the Placental Growth Factor (PlGF) changes endometrial mechanics by modifying the actin cytoskeleton at the maternal interface. We explored the global effects of PlGF in endometrial stromal cells (EnSCs) using the concerted approach of proteomics, atomic force microscopy (AFM), and electrical impedance spectroscopy (EIS). Proteomic analysis shows PlGF upregulated RhoGTPases activating proteins and extracellular matrix organization-associated proteins in EnSCs. Rac1 and PAK1 transcript levels, activity, and actin polymerization were significantly increased with PlGF treatment. AFM further revealed an increase in cell stiffness with PlGF treatment. The additive effect of PlGF on actin polymerization was suppressed with siRNA-mediated inhibition of Rac1, PAK1, and WAVE2. Interestingly, the increase in cell stiffness by PlGF treatment was pharmacologically reversed with pravastatin, resulting in improved trophoblast cell invasion. Taken together, aberrant PlGF levels in the endometrium can contribute to an altered pre-pregnancy maternal microenvironment and offer a unifying explanation for the pathological changes observed in conditions such as pre-eclampsia (PE).

BackgroundCyclin E1 (CCNE1) is a potential predictive marker and therapeutic target in tubo-ovarian high-grade serous carcinoma (HGSC). Smaller studies have revealed unfavorable associations for CCNE1 amplification and CCNE1 overexpression with survival, but to date no large-scale, histotype-specific validation has been performed. The hypothesis was that high-level amplification of CCNE1 and CCNE1 overexpression, as well as a combination of the two, are linked to shorter overall survival in HGSC.MethodsWithin the Ovarian Tumor Tissue Analysis consortium, amplification status and protein level in 3029 HGSC cases and mRNA expression in 2419 samples were investigated.ResultsHigh-level amplification (>8 copies by chromogenic in situ hybridization) was found in 8.6% of HGSC and overexpression (>60% with at least 5% demonstrating strong intensity by immunohistochemistry) was found in 22.4%. CCNE1 high-level amplification and overexpression both were linked to shorter overall survival in multivariate survival analysis adjusted for age and stage, with hazard stratification by study (hazard ratio [HR], 1.26; 95% CI, 1.08-1.47, p = .034, and HR, 1.18; 95% CI, 1.05-1.32, p = .015, respectively). This was also true for cases with combined high-level amplification/overexpression (HR, 1.26; 95% CI, 1.09-1.47, p = .033). CCNE1 mRNA expression was not associated with overall survival (HR, 1.00 per 1-SD increase; 95% CI, 0.94-1.06; p = .58). CCNE1 high-level amplification is mutually exclusive with the presence of germline BRCA1/2 pathogenic variants and shows an inverse association to RB1 loss.ConclusionThis study provides large-scale validation that CCNE1 high-level amplification is associated with shorter survival, supporting its utility as a prognostic biomarker in HGSC.

BackgroundLow-frequency variants play an important role in breast cancer (BC) susceptibility. Gene-based methods can increase power by combining multiple variants in the same gene and help identify target genes.MethodsWe evaluated the potential of gene-based aggregation in the Breast Cancer Association Consortium cohorts including 83,471 cases and 59,199 controls. Low-frequency variants were aggregated for individual genes' coding and regulatory regions. Association results in European ancestry samples were compared to single-marker association results in the same cohort. Gene-based associations were also combined in meta-analysis across individuals with European, Asian, African, and Latin American and Hispanic ancestry.ResultsIn European ancestry samples, 14 genes were significantly associated (q

Abstract BackgroundTissue reinforcement techniques with porcine acellular dermal matrices (ADMs) have been widely adopted as standard care in treating capsular contracture. However, the application of alternative xenograft or mesh materials has not been widely studied. ObjectivesTo examine the efficacy of OviTex PRS Reinforced Tissue Matrix (Resorbable) (TELA Bio, Malvern, PA), a hybrid ovine-reinforced mesh, in comparison with STRATTICE Reconstructive Tissue Matrix (Allergan, Irvine, CA), in patients with advanced capsular contracture. MethodsA retrospective review was conducted on patients who underwent breast revision surgery for Baker Grade III or IV capsular contracture. Patient data were reviewed for outcomes, complications, cost, and postoperative incidence of recurrent capsular contracture after treatment with each specific mesh. ResultsFifty-nine of 89 breasts (66.3%) were treated with OviTex and 30 (33.7%) were treated with STRATTICE. All patients experienced a reduction in Baker grades. In patients treated with OviTex, 96.6% (nnnnnP22 ConclusionsOviTex may be successfully utilized to treat capsular contracture. Patient outcomes may be superior to STRATTICE in recurrent capsular contracture, particularly when a previous ADM had been utilized. Cost data show improved savings with the use of OviTex compared with STRATTICE. Level of Evidence: 3

IntroductionThe curriculum for a da Vinci surgeon in gynecology requires special training before a surgeon performs their first independent case, but standardized, objective assessments of a trainee’s workflow or skills learned during clinical cases are lacking. This pilot study presents a methodology to evaluate intraoperative surgeon behavior in hysterectomy cases through standardized surgical step segmentation paired with objective performance indicators (OPIs) calculated directly from robotic data streams. This method can provide individual case analysis in a truly objective capacity.Materials and methodsSurgical data from six robot-assisted total laparoscopic hysterectomies (rTLH) performed by two experienced surgeons was collected prospectively using an Intuitive Data Recorder. Each rTLH video was annotated and segmented into specific, functional surgical steps based on the recorded video. Once annotated, OPIs were compared through workflow analysis and across surgeons during two critical surgical steps: colpotomy and vaginal cuff closure.ResultsThrough visualization of the individual steps over time, we observe workflow consistencies and variabilities across individual surgeons of a similar experience level at the same hospital, creating unique surgeon behavior signatures across each surgical case. OPI differences across surgeons were observed for both the colpotomy and vaginal cuff closure steps, specifically reflecting camera movement, energy usage and clutching behaviors. Comparing colpotomy and vaginal cuff closure time needed for the step and the events of energy use were significantly different (p

Key Clinical Message This current case series adds to the spectrum of Arthrogryposis renal dysfunction cholestasis (ARC)‐associated variants. Increased awareness and early genetic testing for ARC are suggested in cases with failure to thrive, renal tubular dysfunction, and rickets, even when the degree of cholestasis is mild. Prompt identification and intervention may improve the quality of life.

IntroductionCirculating levels of the antiangiogenic protein vasoinhibin, a fragment of prolactin, are of interest in vasoproliferative retinopathies, preeclampsia, and peripartum cardiomyopathy; however, it is difficult to determine the circulating levels of vasoinhibin due to the lack of quantitative assays. MethodsThis study used human serum samples to assess the concentration and bioactivity of vasoinhibin using a novel enzyme-linked immunosorbent assay (ELISA) for human vasoinhibin, which employs an anti-vasoinhibin monoclonal antibody, a human umbilical vein endothelial cell (HUVEC) proliferation assay, and a chick chorioallantoic membrane (CAM) angiogenesis assay. ResultsSerum samples from 17 pregnant women without (one group) and with preeclampsia and pregnancy induced hypertension (another group) demonstrated endogenous vasoinhibin concentrations in the range of 5–340 ng/ml. Immunoactive vasoinhibin levels were significantly higher in preeclampsia serum compared to healthy pregnancy serum (mean 63.09 ± 22.15 SD vs. 19.67 ± 13.34 ng/ml, p = 0.0003), as was the bioactive vasoinhibin level as determined by the HUVEC proliferation assay (56.12 ± 19.83 vs. 13.38 ± 4.88 ng/ml, p < 0.0001). There was a correlation between the concentration of vasoinhibin measured by ELISA and the HUVEC proliferation assay (Pearson r = 0.95, p < 0.0001). Healthy serum demonstrated a proangiogenic effect in the CAM assay (p < 0.05, compared to control), while serum from preeclamptic patients demonstrated an antiangiogenic effect (p < 0.05 vs. control), as did recombinant human vasoinhibin and a synthetic circular retro-inverse vasoinhibin analogue (CRIVi45-51). The antiangiogenic effects in the CAM assay and the inhibition of HUVEC proliferation were abolished by addition of the ELISA anti-vasoinhibin monoclonal antibody, but not by mouse IgG. DiscussionThese results demonstrate the first quantitation of endogenous vasoinhibin in human sera and the elevation of it levels and antiangiogenic activity in sera from women with preeclampsia. The development and implementation of a quantitative assay for vasoinhibin overcomes a long-standing barrier and suggests the thorough clinical verification of vasoinhibin as a relevant biomarker.

Abstract Humans spontaneously take the perspective of others when encoding spatial information in a scene, especially with agentive action cues present. This functional near-infrared spectroscopy (fNIRS) study explored how action observation influences implicit spatial perspective-taking (SPT) by adapting a left–right spatial judgment task to investigate whether transformation strategies underlying altercentric SPT can be predicted on the basis of cortical activation. Strategies associated with two opposing neurocognitive accounts (embodied versus disembodied) and their proposed neural correlates (human mirror neuron system; hMNS versus cognitive control network; CCN) are hypothesized. Exploratory analyses with 117 subjects uncover an interplay between perspective-taking and post-hoc factor, consistency of selection, in regions alluding to involvement of the CCN. Descriptively, inconsistent altercentric SPT elicited greater activation than consistent altercentric SPT and/or inconsistent egocentric SPT in the left inferior frontal gyrus (IFG), left dorsolateral prefrontal cortex (DLPFC) and left motor cortex (MC), but not the inferior parietal lobules (IPL). Despite the presence of grasping cues, spontaneous embodied strategies were not evident during implicit altercentric SPT. Instead, neural trends in the inconsistent subgroups (22 subjects; 13 altercentric; 9 egocentric) suggest that inconsistency in selection modulates the decision-making process and plausibly taps on deliberate and effortful disembodied strategies driven by the CCN. Implications for future research are discussed.