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Abstract BRCA1 and BRCA2 are tumor suppressor genes that have been linked to inherited susceptibility of breast cancer. Germline BRCA1/2 pathogenic or likely pathogenic variants (gBRCAm) are clinically relevant for treatment selection in breast cancer because they confer sensitivity to poly(ADP-ribose) polymerase (PARP) inhibitors. BRCA1/2 mutation status may also impact decisions on other systemic therapies, risk-reducing measures, and choice of surgery. Consequently, demand for gBRCAm testing has increased. Several barriers to genetic testing exist, including limited access to testing facilities, trained counselors, and psychosocial support, as well as the financial burden of testing. Here, we describe current implications of gBRCAm testing for patients with breast cancer, summarize current approaches to gBRCAm testing, provide potential solutions to support wider adoption of mainstreaming testing practices, and consider future directions of testing.

Autologous cell therapy (ACT) is primarily used in diabetic patients with chronic limb-threatening ischemia (CLTI) who are not candidates for standard revascularization. According to current research, this therapy has been shown in some studies to be effective in improving ischemia parameters, decreasing the major amputation rate, and in foot ulcer healing. This review critically evaluates the efficacy of ACT in patients with no-option CLTI, discusses the use of mononuclear and mesenchymal stem cells, and compares the route of delivery of ACT. In addition to ACT, we also describe the use of new revascularization strategies, e.g., nanodiscs, microbeads, and epigenetics, that could enhance the therapeutic effect. The main aim is to summarize new findings on subcellular and molecular levels with the clinical aspects of ACT.

The topic of human circadian rhythms is not only attracting the attention of clinical researchers from various fields but also sparking a growing public interest. The circadian system comprises the central clock, located in the suprachiasmatic nucleus of the hypothalamus, and the peripheral clocks in various tissues that are interconnected; together they coordinate many daily activities, including sleep and wakefulness, physical activity, food intake, glucose sensitivity and cardiovascular functions. Disruption of circadian regulation seems to be associated with metabolic disorders (particularly impaired glucose tolerance) and cardiovascular disease. Previous clinical trials revealed that disturbance of the circadian system, specifically due to shift work, is associated with an increased risk of type 2 diabetes mellitus. This review is intended to provide clinicians who wish to implement knowledge of circadian disruption in diagnosis and strategies to avoid cardio-metabolic disease with a general overview of this topic.

Introduction Neoadjuvant systemic anticancer therapy (neoSACT) is increasingly used in the treatment of early breast cancer. Response to therapy is prognostic and allows locoregional and adjuvant systemic treatments to be tailored to minimise morbidity and optimise oncological outcomes and quality of life. Accurate information about locoregional treatments following neoSACT is vital to allow the translation of downstaging benefits into practice and facilitate meaningful interpretation of oncological outcomes, particularly locoregional recurrence. Reporting of locoregional treatments in neoSACT studies, however, is currently poor. The development of a core outcome set (COS) and reporting guidelines is one strategy by which this may be improved.Methods and analysis A COS for reporting locoregional treatment (surgery and radiotherapy) in neoSACT trials will be developed in accordance with Core Outcome Measures in Effectiveness Trials (COMET) and Core Outcome Set-Standards for Development guidelines. Reporting guidance will be developed concurrently.The project will have three phases: (1) generation of a long list of relevant outcome domains and reporting items from a systematic review of published neoSACT studies and interviews with key stakeholders. Identified items and domains will be categorised and formatted into Delphi consensus questionnaire items. (2) At least two rounds of an international online Delphi survey in which at least 250 key stakeholders (surgeons/oncologists/radiologists/pathologists/trialists/methodologists) will score the importance of reporting each outcome. (3) A consensus meeting with key stakeholders to discuss and agree the final COS and reporting guidance.Ethics and dissemination Ethical approval for the consensus process will be obtained from the Queen’s University Belfast Faculty Ethics Committee. The COS/reporting guidelines will be presented at international meetings and published in peer-reviewed journals. Dissemination materials will be produced in collaboration with our steering group and patient advocates so the results can be shared widely.Registration The study has been prospectively registered on the COMET website (https://www.comet-initiative.org/Studies/Details/2854).

Abstract Background EndoPredict (EP) is a clinically validated multianalyte gene expression test to predict distant metastasis in ER-positive, HER2-negative breast cancer treated with endocrine therapy alone. The test is based on the combined analysis of 12 genes in formalin-fixed, paraffin-embedded (FFPE) tissue by reverse transcription-quantitative real-time PCR (RT-qPCR). Recently, it was shown that EP is feasible for reliable decentralized assessment of gene expression. The aim of this study was the analytical validation of the performance characteristics of the assay and its verification in a molecular-pathological routine laboratory. Methods Gene expression values to calculate the EP score were assayed by one-step RT-qPCR using RNA from FFPE tumor tissue. Limit of blank, limit of detection, linear range, and PCR efficiency were assessed for each of the 12 PCR assays using serial samples dilutions. Different breast cancer samples were used to evaluate RNA input range, precision and inter-laboratory variability. Results PCR assays were linear up to Cq values between 35.1 and 37.2. Amplification efficiencies ranged from 75% to 101%. The RNA input range without considerable change of the EP score was between 0.16 and 18.5 ng/μl. Analysis of precision (variation of day, day time, instrument, operator, reagent lots) resulted in a total noise (standard deviation) of 0.16 EP score units on a scale from 0 to 15. The major part of the total noise (SD 0.14) was caused by the replicate-to-replicate noise of the PCR assays (repeatability) and was not associated with different operating conditions (reproducibility). Performance characteristics established in the manufacturer’s laboratory were verified in a routine molecular pathology laboratory. Comparison of 10 tumor samples analyzed in two different laboratories showed a Pearson coefficient of 0.995 and a mean deviation of 0.15 score units. Conclusions The EP test showed reproducible performance characteristics with good precision and negligible laboratory-to-laboratory variation. This study provides further evidence that the EP test is suitable for decentralized testing in specialized molecular pathological laboratories instead of a reference laboratory. This is a unique feature and a technical advance in comparison with existing RNA-based prognostic multigene expression tests.

Breast conserving therapy (BCT), consisting of breast conserving surgery and subsequent radiotherapy, is an equivalent option to mastectomy for women with early breast cancer. Although BCT after neoadjuvant systemic treatment (NAST) has been routinely recommend by international guidelines since many years, the rate of BCT worldwide varies largely and its potential is still underused. While the rate of BCT in western countries has increased over the past decades to currently about 70%, the rate of BCT is as low as 10% in other countries. In this review, we will evaluate the underused potential of breast conservation after NAST, identify causes, and discuss possible solutions. We identified clinical and non-clinical causes for the underuse of BCT after NAST including uncertainties within the community regarding oncologic outcomes, the correct tumor localization after NAST, the management of multifocal and multicentric tumors, margin assessment, disparities of socio-economic aspects on a patient and national level, and psychological biases affecting the shared decision-making process between patients and clinicians. Possible solutions to mitigate the underuse of BCT after NAST include interdisciplinary teams that keep the whole patient pathway in mind, optimized treatment counseling and shared decision-making, and targeted financial support to alleviate disparities.

Abstract Background In Her2-positive advanced breast cancer, the upfront use of trastuzumab is well established. Upon progression on first-line therapy, patients may be switched to lapatinib. Others however remain candidates for continued antibody treatment (treatment beyond progression). Here, we aimed to identify factors predicting for activity of second-line trastuzumab-based therapy. Methods Ninety-seven patients treated with > 1 line of trastuzumab-containing therapy were available for this analysis. Her2-status was determined by immunohistochemistry and re-analyzed by FISH if a score of 2+ was gained. Time to progression (TTP) on second-line therapy was defined as primary study endpoint. TTP and overall survival (OS) were estimated using the Kaplan-Meier product limit method. Multivariate analyses (Cox proportional hazards model, multinomial logistic regression) were applied in order to identify factors associated with TTP, response, OS, and incidence of brain metastases. p values < 0.05 were considered to indicate statistical significance. Results Median TTP on second-line trastuzumab-based therapy was 7 months (95% CI 5.74-8.26), and 8 months (95% CI 6.25-9.74) on first-line, respectively (n.s.). In the multivariate models, none of the clinical or histopthological features could reliably predict for activity of second-line trastuzumab-based treatment. OS was 43 months suggesting improved survival in patients treated with trastuzumab in multiple-lines. A significant deterioration of cardiac function was observed in three patients; 40.2% developed brain metastases while on second-line trastuzumab or thereafter. Conclusion Trastuzumab beyond progression showed considerable activity. None of the variables investigated correlated with activity of second-line therapy. In order to predict for activity of second-line trastuzumab, it appears necessary to evaluate factors known to confer trastuzumab-resistance.

Abstract Background Breast cancer screening is essential in detecting breast tumors, however, the examination is stressful. In this study we analyzed whether humor enhances patient satisfaction. Methods In this prospective randomized study 226 patients undergoing routine breast cancer screening at a single center during October 2020 to July 2021 were included. One hundred thirty-two were eligible for the study. Group 1 (66 patients) received an examination with humorous intervention, group 2 (66 patients) had a standard breast examination. In the humor group, the regular business card was replaced by a self-painted, humorous business card, which was handed to the patient at the beginning of the examination. Afterwards, patients were interviewed with a standardized questionnaire. Scores between the two study groups were compared with the Mann-Whitney U test or Fisher’s exact test. P-values were adjusted with the Holm’s method. Two-sided p-values

Abstract Background Lung inhomogeneity plays a pivotal role in the development of ventilator-induced lung injury (VILI), particularly in the context of pre-existing lung injury. The mechanisms that underlie this interaction are poorly understood. We aimed to elucidate the regional transcriptomic response to mechanical ventilation (MV), with or without pre-existing lung injury, and link this to the regional lung volume response to MV. Methods Adult female BALB/c mice were randomly assigned into one of four groups: Saline, MV, lipopolysaccharide (LPS) or LPS/MV. Lung volumes (tidal volume, Vt; end-expiratory volume, EEV) were measured at baseline or after 2 h of ventilation using four-dimensional computed tomography (4DCT). Regional lung tissue samples corresponding to specific imaging regions were analysed for the transcriptome response by RNA-Seq. Bioinformatics analyses were conducted and the regional expression of dysregulated gene clusters was then correlated with the lung volume response. Results MV in the absence of pre-existing lung injury was associated with regional variations in tidal stretch. The addition of LPS also caused regional increases in EEV. We identified 345, 141 and 184 region-specific differentially expressed genes in response to MV, LPS and LPS/MV, respectively. Amongst these candidate genes, up-regulation of genes related to immune responses were positively correlated with increased regional tidal stretch in the MV group, while dysregulation of genes associated with endothelial barrier related pathways were associated with increased regional EEV and Vt when MV was combined with LPS. Further protein–protein interaction analysis led to the identification of two protein clusters representing the PI3K/Akt and MEK/ERK signalling hubs which may explain the interaction between MV and LPS exposure. Conclusion The biological pathways associated with lung volume inhomogeneity during MV, and MV in the presence of pre-existing inflammation, differed. MV related tidal stretch induced up-regulation of immune response genes, while LPS combined with MV disrupted PI3K/Akt and MEK/ERK signalling.

Aim: We developed tailored axillary surgery (TAS) to reduce the axillary tumor volume in patients with clinically node-positive breast cancer to the point where radiotherapy can control it. The aim of this study was to quantify the extent of tumor load reduction achieved by TAS. Methods: International multicenter prospective study embedded in a randomized trial. TAS is a novel pragmatic concept for axillary surgery de-escalation that combines palpation-guided removal of suspicious nodes with the sentinel procedure and, optionally, imaging-guided localization. Pre-specified study endpoints quantified surgical extent and reduction of tumor load. Results: A total of 296 patients were included at 28 sites in four European countries, 125 (42.2%) of whom underwent neoadjuvant chemotherapy (NACT) and 71 (24.0%) achieved nodal pathologic complete response. Axillary metastases were detectable only by imaging in 145 (49.0%) patients. They were palpable in 151 (51.0%) patients, of whom 63 underwent NACT and 21 had residual palpable disease after NACT. TAS removed the biopsied and clipped node in 279 (94.3%) patients. In 225 patients with nodal disease at the time of surgery, TAS removed a median of five (IQR 3–7) nodes, two (IQR 1–4) of which were positive. Of these 225 patients, 100 underwent ALND after TAS, which removed a median of 14 (IQR 10–17) additional nodes and revealed additional positive nodes in 70/100 (70%) of patients. False-negative rate of TAS in patients who underwent subsequent ALND was 2.6%. Conclusions: TAS selectively reduced the tumor load in the axilla and remained much less radical than ALND.

Background: Diabetic patients (DPs) with foot ulcers can receive autologous cell therapy (ACT) as a last therapeutic option. Even DPs who have undergone organ transplantation and are using immunosuppressive (IS) drugs can be treated by ACT. The aim of our study was to analyze the effects of IS drugs on the characteristics of bone marrow-derived stem cells (BM-MSCs). Methods: The cells were isolated from the bone marrow of DPs, cultivated for 14–18 days, and phenotypically characterized using flow cytometry. These precursor cells were cultured in the presence of various IS drugs. The impact of IS drugs on metabolic activity was measured using a WST-1 assay, and the expression of genes for immunoregulatory molecules was detected through RT-PCR. Cell death was analyzed through the use of flow cytometry, and the production of cytokines was determined by ELISA. Results: The mononuclear fraction of cultured cells contained mesenchymal stem cells (CD45−CD73+CD90+CD105+), myeloid angiogenic cells (CD45+CD146−), and endothelial colony-forming cells (CD45−CD146+). IS drugs inhibited metabolic activity, the expression of genes for immunoregulatory molecules, the production of cytokines, and the viability of the cells. Conclusions: The results indicate that IS drugs in a dose-dependent manner had a negative impact on the properties of BM-MSCs used to treat ischemic diabetic foot ulcers, and that these drugs could affect the therapeutic potential of BM-MSCs.

Endothelial dysfunction (ED) is an important marker of future atherosclerosis and cardiovascular disease, especially in people with diabetes. This article summarizes the evidence on endothelial dysfunction in people with diabetes and adds different perspectives that can affect the presence and severity of ED and its consequences. We highlight that data on ED in type 1 diabetes are lacking and discuss the relationship between ED and arterial stiffness. Several interesting studies have been published showing that ED modulates microRNA, microvesicles, lipid levels, and the endoplasmatic reticulum. A better understanding of ED could provide important insights into the microvascular complications of diabetes, their treatment, and even their prevention.

Abstract Background The aim of the study is to investigate how well patients remember the radiologist’s name after a radiological examination, and whether giving the patient a business card improves the patient’s perception of the radiologist’s professionalism and esteem. Methods In this prospective and randomized two-centre study, a total of 141 patients with BI-RADS 1 and 2 scores were included. After screening examination comprising mammography and ultrasound by a radiologist, 71 patients received a business card (group 1), while 70 received no business card (group 2). Following the examination, patients were questioned about their experiences. Results The patients in group 1 could remember the name of the radiologist in 85% of cases. The patients in group 2, in contrast, could only remember the name in 7% of cases (p

Introduction. Autologous cell therapy (ACT) is one of the last options for limb salvage in patients with chronic limb-threatening ischemia (CLTI) and diabetic foot ulcers (DFU). However, some patients may still undergo a major amputation even after ACT, but the risk factors for this are not known. Therefore, the aim of our study was to assess the risk factors for major amputation in patients with CLTI and DFU during a 2-year follow-up after ACT. Methods. One hundred and thirteen patients after ACT were included in our study and divided into two groups: Group 1 with major amputation (AMP; n=37) and Group 2 without amputation (nAMP, n=76). The risk factors for major amputation were evaluated before ACT and included factors relating to the patient, the DFU, and the cell product. Results. The AMP group had significantly higher C-reactive protein (CRP) levels compared to the nAMP group (22.7 vs. 10.7 mg/L, p=0.024). In stepwise logistic regression, independent predictors for major amputation were mutation of the gene for methylenetetrahydrofolate reductase (MTHFR) with heterozygote and homozygote polymorphism 1298 (OR 4.33 [95% CI 1.05-17.6]), smoking (OR 3.83 [95% CI 1.18-12.5]), and CRP>10 mg/L (OR 2.76 [95% CI 0.93-8.21]). Lower transcutaneous oxygen pressure (TcPO2) values were observed in AMP patients compared to the nAMP group at one month (24.5 vs. 33.2, p=0.012) and at 3 months (31.1 vs. 40.9, p=0.009) after ACT. Conclusion. Our study showed that the risk for major amputation after ACT in patients with CLTI and DFU is increased by the presence of MTHFR heterozygote and homozygote gene mutations, smoking, and higher CRP at baseline. Lower TcPO2 at one and 3 months after ACT may also have a predictive value. Therefore, it is necessary to stop smoking before ACT, treat any infection, and, above all, consider antiaggregation or anticoagulant treatment after the procedure.

Abstract Background Multiparametric positron emission tomography/magnetic resonance imaging (mpPET/MRI) shows clinical potential for detection and classification of breast lesions. Yet, the contribution of features for computer-aided segmentation and diagnosis (CAD) need to be better understood. We proposed a data-driven machine learning approach for a CAD system combining dynamic contrast-enhanced (DCE)-MRI, diffusion-weighted imaging (DWI), and 18F-fluorodeoxyglucose (18F-FDG)-PET. Methods The CAD incorporated a random forest (RF) classifier combined with mpPET/MRI intensity-based features for lesion segmentation and shape features, kinetic and spatio-temporal texture features, for lesion classification. The CAD pipeline detected and segmented suspicious regions and classified lesions as benign or malignant. The inherent feature selection method of RF and alternatively the minimum-redundancy-maximum-relevance feature ranking method were used. Results In 34 patients, we report a detection rate of 10/12 (83.3%) and 22/22 (100%) for benign and malignant lesions, respectively, a Dice similarity coefficient of 0.665 for segmentation, and a classification performance with an area under the curve at receiver operating characteristics analysis of 0.978, a sensitivity of 0.946, and a specificity of 0.936. Segmentation but not classification performance of DCE-MRI improved with information from DWI and FDG-PET. Feature ranking revealed that kinetic and spatio-temporal texture features had the highest contribution for lesion classification. 18F-FDG-PET and morphologic features were less predictive. Conclusion Our CAD enables the assessment of the relevance of mpPET/MRI features on segmentation and classification accuracy. It may aid as a novel computational tool for exploring different modalities/features and their contributions for the detection and classification of breast lesions.

Marine citizen science is emerging with promising opportunities for science, policy and public but there is still no comprehensive overview of the current state in Europe. Based on 127 projects identified for the North Sea area we estimate there might be as much as 500 marine and coastal citizen science projects running in Europe, i.e., one marine citizen science project per ∼85 km of coastline, with an exponential growth since 1990. Beach-based projects are more accessible and hence most popular (60% of the projects), and the mean duration of the projects is 18–20 years. Current trends, topics, organizers, aims, and types of programme in terms of participation are presented in this overview. Progress in marine citizen science is specially enabled and promoted through technological developments. Recent technological advances and best practise examples are provided here, untapping the potential of smart mobile apps, do-it-yourself (DIY) technologies, drones, and artificial intelligence (AI) web services.

The European-Commission-funded project 'Citclops' (Citizens' observatory for coast and ocean optical monitoring) developed methods, tools and sensors, which can be used by citizens to monitor natural waters, with a strong focus on long-term data series related to environmental sciences. The new sensors, based on optical technologies, respond to a number of scientific, technical and societal objectives, ranging from more precise monitoring of key environmental descriptors of the aquatic environment (water colour, transparency and fluorescence) to an improved management of data collected with citizen participation. The sensors were tested, calibrated, integrated on several platforms, scientifically validated and demonstrated in the field. The new methods and tools were tested in a citizen-science context. The general conclusion is that citizens are valuable contributors in quality and quantity to the objective of collecting, integrating and analysing fragmented and diverse environmental data. An integration of these data into data-analysis tools has a large potential to support authoritative monitoring and decision-making. In this paper, the project's objectives, results, technical achievements and lessons learned are presented.