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Metastatic breast cancer (mBC) remains incurable and liver metastases (LM) are observed in approximately 50% of all patients with mBC. In some cases, surgical resection of breast cancer liver metastases (BCLM) is associated with prolonged survival. However, there are currently no validated marker to identify these patients. The interactions between the metastatic cancer cells and the liver microenvironment result in two main histopathological growth patterns (HGP): replacement (r-HGP), characterized by a direct contact between the cancer cells and the hepatocytes, and desmoplastic (d-HGP), in which a fibrous rim surrounds the tumor cells. In patients who underwent resection of BCLM, the r-HGP is associated with a worse postoperative prognosis than the d-HGP. Here, we aim at unraveling the biological differences between these HGP within ten patients presenting both HGP within the same metastasis. The transcriptomic analyses reveal overexpression of genes involved in cell cycle, DNA repair, vessel co-option and cell motility in r-HGP while angiogenesis, wound healing, and several immune processes were found overexpressed in d-HGP LM. Understanding the biology of the LM could open avenues to refine treatment of BC patients with LM. [ABSTRACT FROM AUTHOR]

As survivors of early cardiac surgery are at high risk of neurodevelopmental impairments, systematic health observations of children with critical congenital heart disease (CCHD) throughout childhood are recommended to enable early diagnosis and offer interventions to optimize neurodevelopment. A qualitative study using thematic analysis was performed to explore parents' concerns, experiences, and needs regarding the development and received developmental care of their child (0–10 years) during hospital admission and beyond. Data were collected using semi-structured online interviews with 20 parents of children with CCHD. Four major themes were identified: (1) "impact of diagnosis and disease on the family-system," (2) "parental concerns from diagnoses and beyond," (3) "the need for information," and (4) "the need for individualized and family-centered care." The main themes can be divided into 13 sub-themes as impact, concerns, and needs are influenced by various impactful moments from diagnosis and afterwards. Conclusion: This study confirms the importance of early identification of neurodevelopmental problems by experienced healthcare professionals, especially in the early years when parental expectations and concerns about their child's neurodevelopment are lower. A tailor-made family-centered follow-up program should be offered, which pays attention to both the neurodevelopment of patients with CCHD as well as the mental wellbeing of the entire family system. Furthermore, an online portal is recommended with a variety of reliable, controlled, understandable information from which parents can obtain the desired information to understand better the consequences of specific heart condition and to provide their child with the best possible guidance. What is Known: • Survivors of early cardiac surgery are at high risk of neurodevelopmental impairments; systematic health observations of children with CCHD throughout childhood are strongly recommended. What is New: • Parents need a tailor-made family-centered follow-up program, which pays attention to both the neurodevelopment of patients with CCHD as well as the mental wellbeing of the entire family system. • An online portal offering diverse, trustworthy information and sources would effectively meet parents' needs by providing accessible insights into the potential consequences of specific heart conditions and guiding them in supporting their child optimally. [ABSTRACT FROM AUTHOR]

The combination of atezolizumab plus bevacizumab (atezo/bev) has dramatically changed the treatment landscape of advanced HCC (aHCC), achieving durable responses in some patients. Using single-cell transcriptomics, we characterize the intra-tumoural and peripheral immune context of patients with aHCC treated with atezo/bev. Tumours from patients with durable responses are enriched for PDL1+ CXCL10+ macrophages and, based on cell–cell interaction analysis, express high levels of CXCL9/10/11 and are predicted to attract peripheral CXCR3+ CD8+ effector-memory T cells (CD8 TEM) into the tumour. Based on T cell receptor sharing and pseudotime trajectory analysis, we propose that CD8 TEM preferentially differentiate into clonally-expanded PD1- CD45RA+ effector-memory CD8+ T cells (CD8 TEMRA) with pronounced cytotoxicity. In contrast, in non-responders, CD8 TEM remain frozen in their effector-memory state. Finally, in responders, CD8 TEMRA display a high degree of T cell receptor sharing with blood, consistent with their patrolling activity. These findings may help understand the possible mechanisms underlying response to atezo/bev in aHCC. Although atezolizumab and bevacizumab have changed the treatment landscape of advanced hepatocellular carcinoma, the factors that determine responsiveness to treatment remain unclear. Using single-cell RNA sequencing, the authors identify specific macrophage and T cell subsets that are enriched in patients with durable responses. [ABSTRACT FROM AUTHOR]

Open-mindedness is defined as one's willingness and ability to consider opposing beliefs and perspectives and give them a serious, impartial consideration by setting aside one's commitment towards one's own beliefs and perspectives. Learning to prepare and teach open-minded lessons is a crucial skill for student teachers because it fosters an atmosphere in which pupils feel free to express their own views and to learn about the views of others. The aim of this experiment was to examine which instructional strategy best supports student teachers' learning to prepare an open-minded citizenship education lesson. Therefore, participants (n = 176) processed an instruction on how to prepare an open-minded citizenship education lesson through learning by teaching on video, preparing to teach, or re-study (control condition), and as a post-test designed a lesson plan. We examined the completeness and accuracy of the explanations of the instructional content, feelings of social presence and arousal, open-mindedness levels, the completeness and accuracy of the lesson plans, and the conceptual knowledge of the instructional content. In addition, the lesson plans were graded on overall quality. Results showed that all participants scored higher on open-mindedness as measured with the Actively Open-minded Thinking scale after the experiment than before the experiment. Participants in the control condition prepared significantly more accurate and complete open-minded lessons than participants in the other two conditions, suggesting they have gained better understanding of the instructional content. There were no significant differences between the conditions on the other outcome measures. [ABSTRACT FROM AUTHOR]

Purpose: Fatigue is a distressing symptom commonly reported among pediatric patients with primary immunodeficiency (PID). However, the relationship between fatigue and disease activity is currently unknown. Methods: In this cross-sectional study, we examined the prevalence of severe fatigue, the effect of fatigue on health-related quality of life (HRQoL), and the effects of disease activity and comorbidity on fatigue severity among pediatric patients 2–18 years of age with PID. Fatigue and HRQoL were assessed using the pediatric quality of life inventory multidimensional fatigue scale (PedsQL MFS) and generic core scales (PedsQL GCS), respectively. Linear regression analyses and an analysis of covariance were used to compare the fatigue scores with the scores obtained from a healthy control group. Data were adjusted for age and sex. Results: Of the 91 eligible patients, 79 were assessed (87% participation rate), with a mean age of 10.4 ± 4.4 years. Pediatric patients with PID reported significantly higher fatigue levels compared to healthy peers, with an 18.9% prevalence of severe fatigue. Moreover, higher fatigue levels were inversely associated with HRQoL in all domains and directly associated with school absences. We found that severe fatigue was comparable between common variable immunodeficiency (CVID), combined immunodeficiency (CID), and selective immunoglobulin A deficiency (SIgAD) patients, but was not reported in the X-linked agammaglobulinemia (XLA) patients studied. Finally, fatigue severity was not significantly associated with disease activity or comorbidity. Conclusions: Nearly 20% of pediatric patients with PID reported experiencing severe fatigue, and fatigue was reported among a wide range of PID subcategories. In addition, severe fatigue negatively affected the patient's quality of life and daily functioning, but was not associated with disease activity or comorbidity. Thus, targeting severe fatigue might be a promising strategy for improving the overall well-being and quality of life of pediatric patients with PID. [ABSTRACT FROM AUTHOR]

The aim of this experiment was to examine the effect of different instructional strategies on student teachers' confirmation bias. Confirmation bias refers to the selectivity in finding and using evidence that fits one's own beliefs or hypotheses while neglecting evidence that is opposite to one's own beliefs or hypotheses (Nickerson, 1998). Dutch student teachers (n = 141) took a confirmation bias pre-test and were then randomly assigned to three conditions; teaching on video (TOV), preparing to teach (PTT) and re-study (CC). All participants received text-based instruction on confirmation bias and how it can be mitigated. They also practised with confirmation bias tasks and they received feedback on their answers. Subsequently, participants in the TOV and PTT conditions prepared a lesson about the instructional content and in the TOV condition they taught this lesson on video. After the learning phase, TOV and PTT participants completed a social presence questionnaire. All participants completed an arousal questionnaire and a confirmation bias post-test and a transfer test. The results showed that confirmation bias was reduced to a similar extent in all conditions. Results also showed that the quality of the prepared lesson was highest for TOV participants suggesting they had gained better understanding of the confirmation bias than PTT participants. Furthermore, in contrast to our expectations, PTT participants reported highest social presence scores. TOV participants experienced higher arousal levels compared to CC participants. Transfer scores did not differ between conditions. We discuss theoretical explanations of the findings from the present study. [ABSTRACT FROM AUTHOR]

Background: Telehealth modalities were introduced during the SARS-CoV-2 pandemic to assure continuation of cancer care and maintain social distance.Methods: This is a retrospective cohort analysis of our telehealth expansion programme. We adapted two existing patient-reported outcome (PRO) telemonitoring tools that register and (self-)manage toxicities to therapy, while screening for SARS-CoV-2-related symptoms. Outpatients from a tertiary cancer centre were enrolled. The adapted PRO interface allowed for uniform registration of SARS-CoV-2-related symptoms and effective triage of patients at home where we also implemented systematic throat washings, when available.Results: Three hundred and sixty patients registered to the telemonitoring systems from March 13 to May 15, 2020. Four prespecified SARS-CoV-2 alarms resulted in three patients with positive PCR testing. Other Covid-19 symptoms (fever 5× and cough 2×) led to pretreatment triage resulting in 1 seroconversion after initial negative testing. One of the 477 throat washings proved positive.Conclusions: The rapid adoption of an amended PRO (self-)registrations and toxicity management system was feasible and coordinated screening for Covid-19. Continued clinical cancer care was maintained, with significant decreased waiting time. The systemic screening with throat washings offered no real improvement. [ABSTRACT FROM AUTHOR]

Background: Oestrogen receptor (ER) expression is a prognostic biomarker in endometrial cancer (EC). However, expression does not provide information about the functional activity of the ER pathway. We evaluated a model to quantify ER pathway activity in EC, and determined the prognostic relevance of ER pathway activity.Methods: ER pathway activity was measured in two publicly available datasets with endometrial and EC tissue, and one clinical cohort with 107 samples from proliferative and hyperplastic endometrium and endometrioid-type EC (EEC) and uterine serous cancer (USC). ER pathway activity scores were inferred from ER target gene mRNA levels from Affymetrix microarray data (public datasets), or measured by qPCR on formalin-fixed paraffin-embedded samples (clinical cohort) and related to ER expression and outcome.Results: ER pathway activity scores differed significantly throughout the menstrual cycle supporting the validity of the pathway test. The highest ER pathway scores were found in proliferative and hyperplastic endometrium and stage I EEC, whereas stage II-IV EEC and USCs had significantly lower levels. Low ER pathway activity was associated with recurrent disease, and added prognostic value in patients with low ER expression.Conclusion: The ER pathway test reflects activity of the ER pathway, and may improve prediction of outcome in EC patients. [ABSTRACT FROM AUTHOR]

Background: Catheter-based renal sympathetic denervation (RDN) has been considered a potential treatment for therapy resistant hypertension (RHT). However, in a randomized placebo-controlled trial, RDN did not lead to a substantial blood pressure (BP) reduction. We hypothesized that variation in the reported RDN efficacy might be explained by incomplete nerve disruption as assessed by renal I- meta-iodobenzylguanidine (I- mIBG) scintigraphy. Methods: In 21 RHT patients (median age 60 years), we performed I- mIBG scintigraphy before and 6 weeks after RDN. Additionally, we assessed changes in BP (24 h day, night, and average), plasma- and urinary-catecholamines and plasma renin activity (PRA) before and after RDN. Planar scintigraphy was performed at 15 min and 4 h after I- mIBG administration. The ratio of the mean renal (specific) counts vs. muscle (non-specific) counts represented I- mIBG uptake. Renal I- mIBG washout was calculated between 15 min and 4 h. Results: After RDN office-based systolic BP decreased from 172 to 153 mmHg ( p = 0.036), while diastolic office BP ( p = 0.531), mean 24 h systolic and diastolic BP ( p = 0.602, p = 0.369, respectively), PRA ( p = 0.409) and plasma catecholamines ( p = 0.324) did not significantly change post-RDN. Following RDN, I- mIBG renal uptake at 15 min was 3.47 (IQR 2.26-5.53) compared to 3.08 (IQR 2.79-4.95) before RDN ( p = 0.289). Renal I- mIBG washout did not change post-RDN ( p = 0.230). In addition, there was no significant correlation between the number of denervations and the renal I- mIBG parameters. Conclusions: No changes were observed in renal I- mIBG uptake or washout at 6 weeks post-RDN. These observations support incomplete renal denervation as a possible explanation for the lack of RDN efficacy. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this work was to develop a CAIX-specific nanobody conjugated to IRDye800CW for molecular imaging of pre-invasive breast cancer.Procedures: CAIX-specific nanobodies were selected using a modified phage display technology, conjugated site-specifically to IRDye800CW and evaluated in a xenograft breast cancer mouse model using ductal carcinoma in situ cells (DCIS).Results: Specific anti-CAIX nanobodies were obtained. Administration of a CAIX-specific nanobody into mice with DCIS xenografts overexpressing CAIX showed after 2 h a mean tumor-to-normal tissue ratio (TNR) of 4.3 ± 0.6, compared to a TNR of 1.4 ± 0.2 in mice injected with the negative control nanobody R2-IR. In DCIS mice, a TNR of 1.8 ± 0.1 was obtained. Biodistribution studies demonstrated an uptake of 14.0 ± 1.1 %I.D./g in DCIS + CAIX tumors, 4.6 ± 0.8 %I.D./g in DCIS tumors, while 2.0 ± 0.2 %I.D./g was obtained with R2-IR.Conclusions: These results demonstrate the successful generation of a CAIX-specific nanobody-IRDye800CW conjugate that can be used for rapid imaging of (pre-)invasive breast cancer. [ABSTRACT FROM AUTHOR]

Background: The introduction of oral anti-cancer agents provides a convenient administration route for chronic cancer treatment to outpatients. Health information technology through web-based applications or other electronic tools can offer a platform to improve treatment compliance, symptom management, and patient-provider communication.Purpose: The purposes of this study were to test the feasibility and clinical utility of an electronic self-report device (RemeCoach) for patients or their caregivers and to register and prospectively evaluate the quality of data generated.Patients and Methods: Patients using Teysuno® (S-1) for advanced gastrointestinal carcinoma used a pre-programmed device in order to register compliance to treatment and six clinical parameters. Real-time data were collected onto a central platform, which processed the data by an algorithm. This algorithm stratified the data into different grades based on the Common Terminology Criteria for Adverse Events (CTCAE v4.0).Results: From December 2013 to March 2014, 11 patients (5 men, 6 women) were enrolled. Compliance to the device was high, six patients (55 %) registered timely intake of medication (demonstrating >95 % treatment compliance). Agreement between patients' and clinicians' reported toxicity was substantial for nausea, but discrepant for fatigue, hand-foot syndrome, and mucositis.Conclusion: The use of an interactive self-report tool is feasible, reliable, and acceptable to outpatients. The RemeCoach and the algorithm devised will be further developed as an interactive patient-reported outcome (PRO) system, to improve early detection of side effects in an outpatient setting. Further studies are needed to confirm these data and to explore the relationship between optimal patient support and efficacy of treatment. [ABSTRACT FROM AUTHOR]

Introduction: Hormone-refractory disseminated prostate cancer is a major oncological problem. Preclinical studies with temozolomide, an oral alkylating agent, in prostate cancer have shown encouraging results. In phase I studies the safety of temozolomide in non-prostate cancer patients has been demonstrated. Based on these results, a phase II study of temozolomide in patients with metastatic disease who had developed progressive symptomatic disease while on antiandrogen therapy, was initiated.Methods: A group of 18 patients started a 5-day temozolomide regimen, with a 28-day treatment cycle. Response parameters (prostate-specific antigen, bone scan, quality of life questionnaire) and toxicity (common toxicity criteria for international studies) were recorded at regular intervals.Results: Of the 18 patients, 16 were evaluable by completing two or three cycles. All patients developed progressive disease within two cycles, except one who had progressive disease at the end of cycle 3. Of the 16 evaluable patients, 11 developed new bone metastases (bone scan), 1 developed lung metastases, 4 had progressive disease as reflected by a 25% increase in serum PSA together with subjective progression, and 7 and 5 had progressive disease as reflected by decreased quality of life and increased pain score, respectively. Toxicity was limited to nausea and vomiting, which was effectively treated with antiemetic medication, and anemia and thrombocytopenia, which returned to normal values within 1 week.Discussion: Treatment with temozolomide was generally well tolerated, with occasionally moderate toxicity. As all patients developed progressive disease the results are rather discouraging. Temozolomide is ineffective for the treatment of patients with symptomatic progressive hormone-refractory prostate cancer. [ABSTRACT FROM AUTHOR]

Traumatic tattoos can result from accidental deposition of foreign particles in the dermis. These pigmented particles become permanently lodged in the dermis after re-epithelialization of the wound and can give rise to irregular black or blue discoloration of the skin. Different methods for tattoo removal exist. The best strategy is to prevent traumatic tattooing by immediate removal of the foreign bodies before the healing process has begun. We present a fine-tuned debridement method to selectively debride the wound and preserve as much viable tissue as possible. Level of Evidence V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors . [ABSTRACT FROM AUTHOR]

This paper presents a decision-making pattern that uses trust mechanisms. It comprises an expectation module that performs two functions. First, it infers-based on past performance-how information is to be understood (e.g. consider the expected outcome of a promise to deliver tomorrow, morgen, mañana or domani). Second, it infers-based on past performance-the uncertainty on the expected behavior. This pattern makes a key contribution by enabling cooperation in large systems of systems without requiring conventional integration, which typically results in rigidity and monolithic system designs. It contributes to the development of holonic systems or nearly decomposable systems that deliver most of the advantages of integration without the disadvantages. [ABSTRACT FROM AUTHOR]

With this analysis we would like to raise some issues that emerge as a result of recent evolutions in the burgeoning field of human cells, tissues, and cellular and tissue-based product (HCT/P) transplantation, and this in the light of the current EU regulatory framework. This paper is intended as an open letter addressed to the EU policy makers, who will be charged with the review and revision of the current legislation. We propose some urgent corrections or additions to cope with the rapid advances in biomedical science, an extensive commercialization of HCT/Ps, and the growing expectation of the general public regarding the ethical use of altruistically donated cells and tissues. Without a sound wake-up call, the diverging interests of this newly established 'healthcare' industry and the wellbeing of humanity will likely lead to totally unacceptable situations, like some of which we are reporting here. [ABSTRACT FROM AUTHOR]

In this paper, we present a framework for the classification of images in surface inspection tasks and address several key aspects of the processing chain from the original image to the final classification result. A major contribution of this paper is a quantitative assessment of how incorporating adaptivity into the feature calculation, the feature pre-processing, and into the classifiers themselves, influences the final image classification performance. Hereby, results achieved on a range of artificial and real-world test data from applications in printing, die-casting, metal processing and food production are presented. [ABSTRACT FROM AUTHOR]