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Purpose Patients with recurrent glioblastoma (rGBM) have a poor prognosis. Epidermal growth factor receptor (EGFR) gene amplification is present in ~ 50% of glioblastomas (GBMs). Depatuxizumab mafodotin (depatux-m), formerly ABT-414, is an antibody–drug conjugate that preferentially binds cells with EGFR amplification, is internalized and releases a potent antimicrotubule agent, monomethyl auristatin F (MMAF). Here we report the safety, pharmacokinetics, and efficacy of depatux-m monotherapy at the recommended Phase 2 dose (RPTD) in patients with EGFR-amplified, rGBM. Methods M12-356 (NCT01800695) is an open-label study with three escalation and expansion cohorts. Sixty-six patients with EGFR-amplified, rGBM were treated with depatux-m monotherapy at 1.25 mg/kg intravenously every 2 weeks. Adults with measurable rGBM, who were bevacizumab-naïve, with EGFR amplification were eligible. Results Among 66 patients, median age was 58 years (range 35–80). All patients were previously treated with radiotherapy/temozolomide. The most common adverse events (AEs) were eye related (91%), including blurred vision (65%), dry eye (29%), keratitis, and photophobia (27% each). Grade 3/4 AEs occurred in 42% of all patients, and ocular Grade 3/4 AEs occurred in 33% of patients overall. One patient (2%) had a Grade 4 ocular AE. Ocular AEs were manageable and usually resolved once treatment with depatux-m ceased. The objective response rate was 6.8%, the 6-month progression-free survival rate was 28.8%, and the 6-month overall survival rate was 72.5%. Conclusion Depatux-m monotherapy displayed frequent but mostly Grade 1/2 ocular toxicities. A PFS6 of 28.8% was observed in this rGBM population, warranting further study. Electronic supplementary material The online version of this article (doi:10.1007/s00280-017-3451-1) contains supplementary material, which is available to authorized users.

ABT-806 is a tumor-specific antibody targeting the epidermal growth factor receptor (EGFR). This study assessed safety, biodistribution, and pharmacokinetics of 111In-radiolabeled ABT-806 (ABT-806i) and effects of repeated doses of ABT-806 on receptor occupancy. Methods: Eligible patients had advanced tumors likely to express EGFR/EGFRvIII; adequate performance status and organ function; and measurable disease by RECIST 1.1. In cohort 1, 6 patients received a bolus administration of ABT-806i and underwent SPECT followed by whole-body planar scans. In cohort 2, 12 patients were imaged similarly as in 1 initially; thereafter, they received 3 doses of unlabeled ABT-806, before another dose of ABT-806i with associated SPECT and whole-body planar scans. At the end of both cohorts, patients who had stable or responding disease were able to enroll into an extension study (M12-326) in which they received unlabeled ABT-806 every 2 wk until disease progression, withdrawal of consent, or intolerable toxicity. Results: No toxicity related to ABT-806i infusion was observed. ABT-806i showed minimal uptake in normal tissues and cleared gradually from blood with a half-life of 6.0 ± 1.5 d. The mean effective dose of ABT-806i was 0.137 mSv/MBq for males and 0.183 mSv/MBq for females. ABT-806i tumor uptake varied and did not correlate with archived tumor EGFR expression. No change in ABT-806i uptake was observed after interval ABT-806 treatment, indicating stable EGFR expression in tumor. The patient with highest tumor uptake of ABT-806i had advanced head and neck cancer and experienced a partial response. Conclusion: ABT-806i allows for real-time imaging of EGFR conformational expression in tumors, has an acceptable radiation dosimetry, and provides important additional information about antigen expression compared with standard approaches using archival tissue. Its role to assist in patient selection for EGFR-based therapeutics and investigate treatment resistance should be further investigated.

Background: Medical students’ psychological response to societal lockdown during the covid-19 pandemic has not been studied much. Our aim was to assess levels of anxiety and depression among medical students during the initial stages of the pandemic in Nepal and relate their distress to psychosocial and other relevant situational variables.Materials and Methods: A cross-sectional study with an online questionnaire was conducted among medical students at different colleges in Nepal. Hospital Anxiety and Depression Scale (HADS) detected manifestations of anxiety and depression. The covariates were explored by logistic regression analyses.Results: A total 416 medical students [mean age: 22.2 (2.1); males 57.7%, females 42.3%] participated. HADS-anxiety scores [mean: 7.1(4.3)] were significantly and positively correlated with HADS-depression [mean: 5.9 (4.1)] (r=0.695; p22 years (AOR= 2.2, 2.5 and 4.4 respectively). HADS-cAD was almost three-times higher among those with a possible COVID-19 exposure (AOR=2.8).Conclusion: A significant number of medical students in Nepal suffered from high levels of anxiety and depression during the covid-19 shut-down. The students in the higher (>22 years) age group, those with past mental disorders, a possible covid-19 exposure, and a concurrent physical illness showed elevated levels of anxiety and/or depression.

Objective We aimed to investigate self-reported pain during screening with digital breast tomosynthesis (DBT). Methods The study was approved by the Regional Committee for Medical and Health Research Ethics in the South East of Norway (2015/424). Women completed a questionnaire about experienced pain directly after the examination, August–November 2019. A numeric rating scale (NRS, 0–10) was used. Data on compression force (N), pressure (kPa), and compressed breast thickness (mm) were obtained from the Digital Imaging and Communication in Medicine header and density assessment software. Stepwise ordinary least-squares regression was used to estimate mean self-reported pain score with 95% confidence interval (CI) for values of compression force, pressure, and compressed breast thickness. Results The mean pain score was 1.9, whereof 19.3% (822/4266) of the women reported moderate or severe pain. The mean pain score of 2.6 (95% CI: 2.4–2.7) was observed at a compression force of 60 N, decreasing to 1.3 (95% CI: 1.2–1.4) at 130 N. The mean pain score of 1.3 (95% CI: 1.1–1.4) was at a compression pressure of 6 kPa, increasing to 2.9 (95% CI: 2.7–3.1) at 16 kPa. The mean pain score was 0.6 (95% CI: 0.4–0.6) at a compressed breast thickness of 20 mm, increasing to 2.9 (95% CI: 2.7–3.1) at 90 mm. Conclusion The mean pain score was low, 1.9 on NRS, for women screened with DBT. A compression force of 60–130 N and a pressure 6–16 kPa were associated with no or mild pain.

Aims To assess if congenital foot deformity is a risk factor for developmental dysplasia of the hip (DDH). Methods Between 1996 and 2012, 60,844 children were born in Sør-Trøndelag county in Norway. In this cohort study, children with risk factors for DDH were examined using ultrasound. The risk factors evaluated were clinical hip instability, breech delivery, a family history of DDH, a foot deformity, and some syndromes. As the aim of the study was to examine the risk for DDH and foot deformity in the general population, children with syndromes were excluded. The information has been prospectively registered and retrospectively analyzed. Results Overall, 494 children (0.8%) had DDH, and 1,132 (1.9%) a foot deformity. Of the children with a foot deformity, 49 (4.3%) also demonstrated DDH. There was a statistically significant increased association between DDH and foot deformity (p < 0.001). The risk of DDH was highest for talipes calcaneovalgus (6.1%) and club foot (3.5%), whereas metatarsus adductus (1.5%) had a marginal increased risk of DDH. Conclusion Compared with the general population, children with a congenital foot deformity had a significantly increased risk for DDH and therefore we regard foot deformity as a true risk factor for DDH. Cite this article: Bone Joint J 2020;102-B(11):1582–1586.

NEW FINDINGS What is the central question of this study? Do haemoglobin mass and red blood cell volume increase in elite cyclists training in a hot environment compared to a control group training at normal temperature? What is the main finding and its importance? Five weeks of heat training increases haemoglobin mass in elite cyclists. There are small to intermediate effect sizes for exercise parameters favouring heat training. ABSTRACT In this study we tested the hypothesis that performing 1 h of regular light exercise in a heat chamber (HEAT; 37.8 ± 0.5°C; 65.4 ± 1.8% humidity) 5 times week-1 for a total of 5 weeks increases haemoglobin mass (Hbmass ) and exercise performance in elite cyclists ( VO2max = 76.2 ± 7.6 ml min-1 kg-1 ). Twenty-three male volunteers were assigned to HEAT (n = 11) or CON (n = 12; 15.5 ± 0.1°C; 25.1 ± 0.0% humidity) training groups. Hbmass was determined before and after the intervention period in conjunction with an extensive exercise test protocol (conducted at 16-19°C). HEAT increased (P

RATIONALE: Positive surgical margins for invasive breast cancer (BC) treated with breast-conserving surgery (BCS) are defined as ink on tumor. The rate of positive margins is approximately 20%, since a time- and cost-effective method for margin assessment is lacking. In this study, we investigated margin status by intra-operative imaging using high-resolution 18 F-fluoro-deoxyglucose (FDG) positron emission tomography (PET) and X-ray computed tomography (CT). METHODS: Twenty patients were enrolled and received 4 MBq/kg of FDG prior to surgery. Intra-operative imaging of the specimens was performed by the MOLECUBES β-CUBE (PET) and X-CUBE (CT). Margin status was assessed by three surgeons and compared with an algorithm. The sensitivity and specificity were calculated by using histopathological assessment as a gold standard. RESULTS: A region with high FDG uptake was visualized in all specimens. Automated analysis showed a sensitivity of 90%, a specificity of 60%, and an area under the curve (AUC) of 0.86 after ROC analysis. Margin assessment by the surgeons resulted in a mean sensitivity and specificity of 79% and 72%, respectively. CONCLUSIONS: This proof-of-concept study demonstrates that high-resolution FDG-PET/CT can facilitate intra-operative margin assessment during BCS. This technique achieves good sensitivity and specificity and may therefore reduce re-operation rates in the future.

The concept of student partnership has attracted increased attention during the last decade, often due to an assumption that it can mitigate neo-liberal agendas and practices in teaching and learning. A review of definitions and understandings of student partnership models shows that most of the research conducted on this topic has been based on normative assumptions, with less focus on how partnership practices play out in different contexts. In this article an analytical framework for analysing student partnership is introduced and tested through an empirical analysis of collaborative practices in centres for teaching excellence in Norwegian higher education. The key findings are that the diversity and dynamics of student partnership depend on the context in which they operate, but more importantly how different practices of partnership play out in parallel in those educational contexts. The result is often a mix of hybrid practices related to different conceptualizations of student partnership.

Background Anxious and depressive symptoms in youth are highly prevalent, are often comorbid and have a high rate of relapse. Preventive interventions are promising, but follow-up results are lacking. The transdiagnostic EMOTION program is an indicated preventive cognitive behavioral therapy (CBT) intervention targeting children aged 8–12 years. Methods The present study investigates the 12 months follow-up effects of the EMOTION intervention in a cluster randomized controlled trial (RCT) with 795 children that included both child self-reports and parental reports. Results Mixed model analyses showed a larger decrease of symptoms in the intervention group than in the control group for child self-reported anxious symptoms (The Multidimensional Anxiety Scale for Children (MASC) difference 4.56, CI 1.83 to 7.29, p = .001). Parental reports for both anxious (MASC difference 2.50, CI .26 to 4.74, p = .029) and depressive (The Mood and Feelings Questionnaire-short form (SMFQ) difference 1.55, CI .83 to 2.26, p ≤ .001) symptoms in children also showed a reduction. No statistically significant difference was found for child self-reported depressive symptoms (SMFQ difference .69, CI − .22 to 1.60, p = .139). Conclusion The transdiagnostic EMOTION program has shown the potential for long-term reductions in symptoms of both anxiety and depression in school-aged children. However, results regarding depressive symptoms must be considered preliminary as only parental report indicated effect. Trial registration The regional ethics committee (REC) of Norway approved the study. Registration number: 2013/1909; Project title: Coping Kids: a randomized controlled study of a new indicated preventive intervention for children with symptoms of anxiety and depression. ClinicalTrials.gov Identifier; NCT02340637.

Background: International guidelines recommend adjuvant bone-modifying agents (BMAs) for post-menopausal women with early breast cancer (EBC) to reduce recurrence and mortality. Despite this, wide variation exists internationally in the adoption of these recommendations. BMAs are off-patent with generic formulations being manufactured. Therefore, pharmaceutical lobbying for BMAs to gain regulatory approval for this indication are lacking. This may have negative impact on promotion and education of prescribing physicians, resulting in EBC patients not receiving this intervention. In the UK, BMAs were included as a recommendation in the breast cancer CRG (Clinical Reference Group) service specification and were endorsed as a priority for implementation by the UK Breast Cancer Group (UKBCG) in November 2015, promoting national uptake, local guidance and sharing of funding arrangements through local commissioning agreements. Following these, UKBCG and Breast Cancer Now, conducted 2 surveys in March and October 2016, showing that 24% and 44% respectively, of oncologists prescribe BMAs. In November 2017, a subsequent survey was performed at the annual UKBCG meeting, showed that 77% of the attendees prescribe BMAs. From 2018, BMAs are also part of the UKs NICE (National Institute for Health and Care Excellence) recommendations for EBC treatment, with the current survey to come after the full endorsement of BMAs into UK EBC guidelines. In Australia, BMAs are still ‘off-label’ and do not receive national reimbursement or endorsement. To date there has been no formal inquiry into the prescribing habits in Australia. The aim of this international collaboration was to further evaluate this and translate the methodology for adjuvant BMA implementation in the UK to Australian practice and potentially pave a pathway for other nations struggling with similar barriers to ultimately improve outcomes for women with EBC globally. Methods: Brief, anonymous, online surveys were developed at each of our institutions using a similar template. The surveys consisted of a series of questions aimed to gather data on their respective local oncologists including demographics, knowledge of current guidelines, current prescribing habits and perceived barriers to prescribing BMAs to women with EBC. The results of the UK survey and experience were used in a collaborative manner to understand the health economics and promote the deliverability of BMAs to women with EBC in Australia. Results: Between March 2019 and June 2019, the national UK survey received 67 responses from 35 centres around the UK. 98.5% of UK respondents currently prescribe adjuvant BMAs for prevention of disease recurrence. 84.6% report they follow the UKBCG guidelines on the topic and 67.7% report it is discussed in their MDTs. Between December 2018 and April 2019, 60 responses to the Australian survey were received. 48% of Australian respondents currently prescribe adjuvant BMAs for prevention of disease recurrence. However, 83% reported that they would prescribe adjuvant BMAs if funding was available. Most respondents were aware of the international guidelines on the topic but lack of local protocol guidance was seen as a significant barrier. Only 18.3% report it is discussed in their MDTs. Conclusions: From 2016 to 2019, the number of UK oncologists who prescribe BMAs has significantly increased, demonstrating that education, pressure from national bodies, national guidelines and funding decisions have been critical to implementation. Acquiring national data on this topic for Australian medical oncologists will help to address the vital need for the development of a national consensus and to clarify the financial and educational barriers that currently limit the prescription of adjuvant BMAs to women with EBC. Citation Format: Sally Baron-Hay, Elisavet Theodoulou, Isobel Porter, Caroline Wilson, Ingunn Holen, Catherine Harper-Wynne, Janet Brown. Inclusion of adjuvant bone-modifying agents for early breast cancer into standard clinical practice: Challenges and lessons learnt from an international collaboration [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-18-08.

Background Screening that includes digital breast tomosynthesis (DBT) with two-dimensional (2D) synthetic mammography (SM) or standard 2D digital mammography (DM) results in detection of more breast cancers than does screening with DM alone. A decrease in interval breast cancer rates is anticipated but is not reported. Purpose To compare rates and characteristics of (a) interval breast cancer in women screened with DBT and SM versus those screened with DM alone and (b) screen-detected breast cancer at consecutive screenings with DM. Materials and Methods This prospective cohort study from BreastScreen Norway included women screened with DBT and SM (study group) or DM alone (control group) between February 2014 and December 2015 (baseline). All women, except nonattendees, women with breast cancer, and those who exceeded the upper age limit, were consecutively screened with DM after 2 years. Interval breast cancer, sensitivity, and specificity were estimated for women screened at baseline. Recall, screen-detected breast cancer, and positive predictive value were analyzed for consecutively screened women. A χ2 test, t test (P < .001 after Bonferroni correction indicated a significant difference), and binomial regression model were used to analyze differences across groups. Results A total of 92 404 women who underwent baseline screening (mean age, 59 years ± 6 [standard deviation]) were evaluated; 34 641 women in the study group (mean age, 59 years ± 6) were screened with DBT and SM and 57 763 women in the control group (mean age, 59 years ± 6) were screened with DM. A total of 26 474 women in the study group (mean age, 60 years ± 5) and 45 543 women in the control group (mean age, 60 years ± 5) were consecutively screened with DM. Rates of interval breast cancer were 2.0 per 1000 screened women in the study group and 1.5 per 1000 screened women in the control group (P = .12). No differences in histopathologic characteristics of interval breast cancer were observed. In the consecutive screening round, rates of screen-detected breast cancer were 3.9 per 1000 screened women (study group) and 5.6 per 1000 screened women (control group) (P = .001). Rates of histologic grade 1 invasive cancer were 0.5 per 1000 screened women (study group) and 1.3 per 1000 screened women (control group) (P = .001). Conclusion No differences in interval breast cancer rates or tumor characteristics were observed in women screened with DBT and SM compared with women screened with DM. Higher rates of low-grade screen-detected tumors were observed in the control group at consecutive screening. © RSNA, 2019 Online supplemental material is available for this article.

The Norwegian fish farming industry is experiencing accidents that may have serious consequences for fish-farm operators, the environment, and the farmed fish themselves. Fatalities and serious personnel injuries, mass mortality of fish during and after operations, introgression of genes from farmed salmon, the spread of disease and material damage to assets are among the consequences. The reputation of the industry and the market value of its products may also suffer as a result of such incidents. Other industries have developed regulations aimed at preventing incidents called major accidents, which are usually defined as accidents that have different characteristics than occupational accidents. A holistic and efficient risk management system needs to cover all types of incidents. In spite of serious accidents, regulators have yet to adopt a holistic approach to the prevention of major accidents in Norwegian aquaculture. Here, we describe and discuss five main risk dimensions in the aquaculture industry that provide a holistic view of the complex risk picture of fish farming; fish welfare, personnel safety, risk to the environment, economic loss and food safety. Hazards that emerge in the fish production process and in the local environment, have consequences both for the fish farm and for society as a whole. On the basis of characteristics drawn from definitions of major accident regulations in other industries and the risk dimensions of fish farming, we propose a general definition of major accidents. The definition is discussed based on the type of risks that occur in fish farming, and with an emphasis on accidents that have happened in the Norwegian aquaculture industry. The occurrence of major fish farming accidents shows that a systemic approach to safety and risk management is needed. Regulators and industry are already looking to the offshore petroleum industry in order to develop and adapt technology and risk management for aquaculture. Approaches to risk regulation in the two industries are discussed and some differences pointed out. Barrier management is one of the potentially holistic and systemic major risk management methods required in offshore regulation that is seen as a possible way forward for the fish farming industry, and we offer some reflections on adopting this method to fish farming.

Highlights • Adoption of adjuvant bisphosphonates for early breast cancer into standard clinical practice. • UK and Australian experience of adjuvant bisphosphonates in early breast cancer. • Pathway taken for adjuvant bisphosphonates implementation in the UK. • Steps to increase update of adjuvant bisphosphonates in early breast cancer. • Improve the care of women with early breast cancer., International guidelines recommend adjuvant bisphosphonates (BPs) for post-menopausal women with early breast cancer to reduce recurrence and mortality. However, globally, wide variation exists in their adoption. In the UK, adjuvant BPs were a recommendation in the breast cancer Clinical Reference Group service specification and were included as a priority for implementation by the national oncologists group UK Breast Cancer Group in November 2015, promoting national uptake, guidance and funding arrangements. In 2018, adjuvant BPs were recommended by the UKs National Institute for Health and Care Excellence. In Australia, adjuvant BPs are still ‘off-label’ and do not receive national reimbursement or endorsement. To date there has been no research into the prescribing habits of these agents in Australia. With the aim to gather data on adjuvant BPs prescribing practices, online surveys were developed and disseminated to breast oncologists in both countries between December 2018 and June 2019. Almost all of the UK oncologists prescribed adjuvant BPs, demonstrating that education, endorsement from professional bodies, presence of national guidelines and funding decisions have been critical to implementation. In contrast, only 48% of the Australian responders prescribed adjuvant BPs, while 83% reported that they would prescribe them if funding was available. Lack of local protocol guidance was also seen as a major barrier. This study was intended to assess the pathway taken for adjuvant BP implementation in the UK and how it might inform changes in Australian practice and also guide other countries with similar issues with the ultimate aim of improving the care of women with early breast cancer globally.

Background The delivery of high-quality service in nursing homes and homecare requires collaboration and shared understanding among managers, employees, users and policy makers from across the healthcare system. However, conceptualizing healthcare professionals’ perception of quality beyond hospital settings (e.g., its perspectives, defining attributes, quality dimensions, contextual factors, dilemmas) has rarely been done. This study therefore explores the meaning of “quality” among healthcare managers and staff in nursing homes and homecare. Methods The study applies a cross-sectional qualitative design with focus groups and individual interviews, to capture both depth and breadth of conceptualization of quality from healthcare professionals in nursing homes and homecare. We draw our data from 65 managers and staff in nursing homes and homecare services in Norway and the Netherlands. The participants worked as managers (n = 40), registered nurses (RNs) or assistant nurses (n = 25). Results The analysis identified the two categories and four sub-categories: “Professional issues: more than firefighting” (subcategories “professional pride” and “competence”) and “patient-centered approach: more than covering basic needs” (subcategories “dignity” and “continuity”). Quality in nursing homes and homecare is conceptualized as an ongoing process based on having the “right competence,” good cooperation across professional groups, and patient-centered care, in line with professional pride and dignity for the patients. Conclusion Based on the understanding of quality among the healthcare professionals in our study, quality should encompass the softer dimensions of professional pride and competence, as well as a patient-centered approach to care. These dimensions should be factors in improvement activities and in daily practice.

The Scandinavian welfare states are known for their universal access to healthcare; however, health inequalities affecting ethnic minority patients are prevalent. Ethnic minority patients' encounters with healthcare systems are often portrayed as part of a system that represents objectivity and neutrality. However, the Danish healthcare sector is a political apparatus that is affected by policies and conceptualisations. Health policies towards ethnic minorities are analysed using Bacchi's policy analysis, to show how implicit problem representations are translated from political and societal discourses into the Danish healthcare system. Our analysis shows that health policies are based on different ideas of who ethnic minority patients are and what kinds of challenges they entail. Two main issues are raised: First, ethnic minorities are positioned as bearers of 'culture' and 'ethnicity'. These concepts of 'othering' become both explanations for and the cause of inappropriate healthcare behaviour. Second, the Scandinavian welfare states are known for their solidarity, collectivism, equality and tolerance, also grounded in a postracial, colour-blind and noncolonial past ideology that forms the societal self-image. Combined with the ethical and legal responsibility of healthcare professionals to treat all patients equally, our findings indicate little leeway for addressing the discrimination experienced by ethnic minority patients.

Triple negative breast cancer (TNBC) cells lack expression of the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor‐2 (HER‐2). Thus, TNBC does not respond to hormone‐based therapy. TNBC is also an aggressive subtype associated with poorer prognoses compared to other breast cancers. Conventional chemotherapeutics are used to manage TNBC although systemic relapse is common with limited benefits being reported as well as adverse events being documented. Here, we discuss current therapies for TNBC in the neo‐ and adjuvant settings, as well as recent advancements in the targeting of PD‐L1‐positive tumors and inclusion of PARP inhibitors for TNBC patients with BRCA mutations. The recent development of cyclin‐dependent kinase (CDK) 4/6 inhibitors in ER‐positive breast cancers has demonstrated significant improvements in progression free survival in patients. Here, we review preclinical data of CDK 4/6 inhibitors and describe current clinical trials assessing these in TNBC disease., Triple negative breast cancer (TNBC) is an aggressive subtype associated with poorer prognoses compared to other breast cancers. Conventional chemotherapeutics are used to manage TNBC although systemic relapse is common with limited benefits being reported. The identification of alternative pathways important for the survival of cancer cells has led to the development of CDK4/6 inhibitors that have shown great promise in preliminary clinical trials in TNBC patients, in the presence of chemotherapy and alone as monotherapy. With early preclinical studies further novel agents have been identified that may lead to new strategies in treating TNBC and providing improved prognoses for patients.

Objectives: To determine the frequency and discuss possible implications of early breast cancer with particularly good prognosis and defined by tumor diameter and cell proliferation. Setting: Detection of small and slowly growing tumors presents a challenge in breast cancer management, due to the risk of over-treatment. Here, we attempted to define a group of such tumors by combining small diameter (

Background Late-stage breast cancer preferentially metastasises to bone; despite advances in targeted therapies, this condition remains incurable. The lack of clinically relevant models for studying breast cancer metastasis to a human bone microenvironment has stunted the development of effective treatments for this condition. To address this problem, we have developed humanised mouse models in which breast cancer patient-derived xenografts (PDXs) metastasise to human bone implants with low variability and high frequency. Methods To model the human bone environment, bone discs from femoral heads of patients undergoing hip replacement surgery were implanted subcutaneously into NOD/SCID mice. For metastasis studies, 7 patient-derived xenograft tumours (PDX: BB3RC32, ER+ PR+ HER2−; BB2RC08, ER+ PR+ ER2−; BB6RC37, ER− PR− HER2− and BB6RC39, ER+ PR+ HER2+), MDA-MB-231-luc2, T47D-luc2 or MCF7-Luc2 cells were injected into the 4th mammary ducts and metastases monitored by luciferase imaging and confirmed on histological sections. Bone integrity, viability and vascularisation were assessed by uCT, calcein uptake and histomorphometry. Expression profiling of genes/proteins during different stages of metastasis were assessed by whole genome Affymetrix array, real-time PCR and immunohistochemistry. Importance of IL-1 was confirmed following anakinra treatment. Results Implantation of femoral bone provided a metabolically active, human-specific site for tumour cells to metastasise to. After 4 weeks, bone implants were re-vascularised and demonstrated active bone remodelling (as evidenced by the presence of osteoclasts, osteoblasts and calcein uptake). Restricting bone implants to the use of subchondral bone and introduction of cancer cells via intraductal injection maximised metastasis to human bone implants. MDA-MB-231 cells specifically metastasised to human bone (70% metastases) whereas T47D, MCF7, BB3RC32, BB2RC08, and BB6RC37 cells metastasised to both human bone and mouse bones. Importantly, human bone was the preferred metastatic site especially from ER+ PDX (100% metastasis human bone compared with 20–75% to mouse bone), whereas ER-ve PDX developed metastases in 20% of human and 20% of mouse bone. Breast cancer cells underwent a series of molecular changes as they progressed from primary tumours to bone metastasis including altered expression of IL-1B, IL-1R1, S100A4, CTSK, SPP1 and RANK. Inhibiting IL-1B signalling significantly reduced bone metastasis. Conclusions Our reliable and clinically relevant humanised mouse models provide significant advancements in modelling of breast cancer bone metastasis.

Background: Breast cancer (BC) is one of the leading causes of cancer-related deaths worldwide. Standard therapies aim to disrupt pathways that regulate the growth and survival of BC cells. Therape...

Adolescence is a sensitive period in life and a time to redefine and learn new skills. In Norway, school health services provide individual health-promoting consultations with all eighth-grade students. As an aid to support these consultations, a dialogue tool called SchoolHealth was developed using a co-creation approach. SchoolHealth consists of a web-based health information form designed to be completed by the students and generates individual feedback reports to help the school nurses to prepare for the consultation and tailor it to the individual student’s need. Our aims were to evaluate the feasibility and user experiences of SchoolHealth among students and school nurses using a mixed methods approach. A total of 79 eighth-grade students (69% of those invited) and four school nurses from three schools participated. Analyses indicated that SchoolHealth was feasible, promoted reflection among students, and helped prepare students and school nurses for the consultation.

Objective To compare breast characteristics, compression parameters, and early performance measures (rates of recall, screen-detected and interval breast cancer, and histopathologic tumour characteristics) for mammographic screening at a stationary versus mobile screening unit. Methods Results from 92,408 mammographic screening examinations performed as part of BreastScreen Norway during 2008–2017 at either a stationary ( n = 52,620) or mobile ( n = 39,788) unit in Hordaland county were compared using descriptive statistics and generalized estimating equations. A generalized estimating equation for a binary outcome was used to estimate crude and adjusted odds ratios with 95% confidence intervals for the outcomes of interest. Adjusted generalized estimating equation models included age, breast volume, and density grade as covariates. Results Screening at the stationary unit was performed on smaller breasts with higher mammographic density, using lower compression force but higher pressure than at the mobile unit. Using the stationary screening unit as reference, for women screened at the mobile unit, the adjusted odds ratio was: for recall 0.94 (95% CI: 0.87--1.01), screen-detected breast cancer 0.92 (95% CI: 0.78--1.10), and interval breast cancer 1.17 (95% CI: 0.83–1.64). Conclusions The quality of care did not differ for women screened at the stationary versus the mobile unit, but there were differences between the women who attended the two units. Sociodemographic factors should be included in future analyses to fully understand the risk of breast cancer among women residing in urban versus rural areas.

Background Several studies in Europe and the US have shown promising results favouring digital breast tomosynthesis compared to standard digital mammography (DM). However, the costs of implementing the technology in screening programmes are not yet known. Methods A randomised controlled trial comparing the results from digital breast tomosynthesis including synthetic mammograms (DBT) vs. DM was performed in Bergen during 2016 and 2017 as a part of BreastScreen Norway. The trial included 29,453 women and allowed for a detailed comparison of procedure use and screening, recall and treatment costs estimated at the individual level. Results The increased cost of equipment, examination and reading time with DBT vs. DM was €8.5 per screened woman (95% CI 8.4−8.6). Costs of DBT remained significantly higher after adding recall assessment costs, €6.2 (95% CI 4.6−7.9). Substantial reductions in either examination and reading times, price of DBT equipment or price of IT storage and connectivity did not change the conclusion. Adding treatment costs resulted in too wide confidence intervals to draw definitive conclusions (additional costs of tomosynthesis €9.8, 95% CI –56 to 74). Performing biopsy at recall, radiation therapy and chemotherapy was significantly more frequent among women screened with DBT. Conclusion The results showed lower incremental costs of DBT vs. DM, compared to what is found in previous cost analyses of DBT and DM. However, the incremental costs were still higher for DBT compared with DM after including recall costs. Further studies with long-term treatment data are needed to understand the complete costs of implementing DBT in screening.

Background No evidence-based guidelines regarding optimal breast compression in mammography exist, neither for standard digital mammography nor for digital breast tomosynthesis. Purpose To compare breast compression parameters and mean glandular dose in a randomized controlled trial with digital mammography versus digital breast tomosynthesis. Material and Methods We used information from 21,729 women aged 50–69 years, who participated in the To-Be trial, as part of BreastScreen Norway, 2016–2017. Information was obtained from the DICOM header and by assessing the images in an automated software for density estimation (VolparaDensity). Using linear regression, we investigated the effect of screening technique on breast compression parameters; compression force (N), compression pressure (kPa), and compressed breast thickness (mm), and mean glandular dose (mGy), by view (craniocaudal [CC] and mediolateral oblique [MLO]). We adjusted for age, breast volume and fibroglandular volume. Results A total of 11,056 (50.9%) women were screened with digital mammography and 10,673 (49.1%) with digital breast tomosynthesis. Adjusted regression analysis showed that women undergoing digital mammography received higher compression forces than women undergoing digital breast tomosynthesis (CC: –4.7 N; MLO: –1.1 N, P Conclusion Women undergoing digital breast tomosynthesis received lower compression force, compression pressure, and compressed breast thickness in MLO view, compared to women undergoing digital mammography. Further studies should investigate the impact of breast compression on image quality, screening outcome, and radiation dose for digital mammography and digital breast tomosynthesis in order to establish evidence-based guidelines for breast compression.

To retrospectively investigate early performance measures of digital breast tomosynthesis (DBT) versus standard digital mammography (DM) for consecutive screening rounds. We included information about 35,736 women screened in BreastScreen Norway, 2008–2016, with at least two consecutive screening examinations. The pair of two consecutive screening examinations was the unit of analysis, and results from the subsequent examination were the measure of interest. Screening technique changed during the study period, resulting in four study groups: DM after DM, DBT after DM, DM after DBT, and DBT after DBT. We compared selected early performance measures between the study groups. Recall for DM after DM was 3.6% and lower for all other study groups (p

Background: Osteoarthritis (OA) in the thumb carpometacarpal joint (CMCJ) is a prevalent disease which may lead to structural damage, severe pain and functional limitations. Evidence-based treatment recommendations state that all patients with hand OA should be offered non-pharmacological treatment. Surgery should be considered only when other treatment has proven insufficient in relieving pain. The purpose of this study was to investigate prior treatment and characteristics of patients referred to specialist health care surgical consultation due to CMCJ OA. The study includes exploring differences in pain and function between referred and non-referred hand, between men and women, and between patients with and without OA affection of other finger joints than CMCJ. Methods: Patients in this cross-sectional study reported prior non-pharmacological treatment for CMCJ OA. Patient demographics, disease and functional variables were assessed based on hand radiographs, patient-reported and observer-based outcome measures. Differences in pain and function between referred and non-referred hand, men and women, and between patients with and without additional affection of finger joints other than CMCJ, were analysed using Paired-samples T-tests, Wilcoxon Signed Rank, or Chi-Square tests. Results: One hundred and eighty patients were included. The mean age was 63 years and 79% were women. Only 21% reported having received non-pharmacological treatment before referral to surgical consultation. The results show a statistically significant worse function for referred hands, women and involvement of additional interphalangeal joints. Most patients reported no pain or mild pain in their referred hand. Conclusions: The results of this study show a non-pharmacological treatment gap in OA care. Most patients report no pain or mild pain, and that they had not received non-pharmacological treatment prior to being referred to CMCJ OA surgical consultation. The results furthermore show that CMCJ OA negatively affects all aspects of function. Strategies need to be developed to improve OA care, including educating general practitioners in evidence-based treatment recommendations and in the assessment of hand pain, and encourage the routine referral of patients with symptomatic hand OA to occupational therapy before considering surgery. This study was conducted with the financial support from The Interregional research funds (HELSEFORSK) via The Research Council of Norway, project number 243758.

Positive surgical margins represent a high risk for adverse clinical outcome in breast conserving surgery (BCS). Therefore, the goal of BCS is to avoid positive margins and hence avoid reoperation. Unfortunately, most studies currently assess the rate of positive resection margins at 20%. This is in part due to the lack of a time- and cost-effective method for intraoperative margin assessment, which would enable the prediction of positive margins during the initial surgery. We propose to address this problem by performing intraoperative high-resolution 18F-fluoro-deoxyglucose (FDG) positron emission tomography (PET) with X-ray computed tomography (CT). This method relies on the high sensitivity of FDG-PET for detecting metabolically active tumor tissue, and the delineation of the anatomical margins of the specimen using CT. In this proof-of-concept study we assess the feasibility of this technique. Twenty patients with breast cancer that were eligible to undergo BCS were enrolled in the study after providing informed consent. The study was approved by the Ethics Committee of Ghent University Hospital. Prior to surgery each patient was administered 4 MBq/kg of FDG. Surgery was performed 2-4 hours after tracer administration. Following surgical excision the breast specimen was oriented with sutures and micro-PET/CT images were obtained using the MOLECUBES β-CUBE (PET) and X-CUBE (CT). The scan time was 10 minutes on PET and 3 minutes on CT. The specimen was then sent for histopathological assessment. Micro-PET/CT images were analyzed using an automated algorithm. Briefly, this algorithm defined the contour of the tumor as the region with high FDG uptake and the contour of the specimen based on the CT image. The margin status of a specimen was positive if the distance between the contour of the tumor and specimen was 0 mm. Images were also analyzed postoperatively by two surgeons blinded to the histopathological and algorithm analysis results. The sensitivity and specificity of the proposed method were then calculated by comparing to the histopathological results, which is the gold standard for margin status assessment. In all samples a region with high FDG uptake was visualized, which corresponded to the tumor on histopathological. In one specific case a small satellite lesion with high FDG uptake, 3 mm in diameter, was detected on the micro-PET images at a distance from the main tumor. Histopathological confirmed that this previously undetected lesion was a second invasive carcinoma. For margin status, a sensitivity of 75% and specificity of 75% were obtained using automated algorithm analysis. Sensitivity and specificity obtained based on surgeons' analysis was 62,5% and 75% for surgeon A and 87,5% and 91,7% for surgeon B respectively. Taking into account the intra-operative micro-PET results could theoretically have reduced the reoperation rate by 75%. This proof-of-concept study demonstrates that high-resolution intraoperative FDG-PET/CT is a promising technique for intraoperative margin assessment in BCS that could allow to reduce re-excision rate. This technique achieves both sufficient sensitivity and specificity with minimal disruption of intraoperative workflow. Citation Format: Marcinkowski R, Keereman V, Van Holen R, Vandenberghe S, Van Bockstal M, Van Dorpe J, Brans B, Goker M, Depypere H, Van den Broecke R. 18F-FDG micro-PET/CT for intraoperative margin assessment in breast conserving surgery using: A proof-of-concept study [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-13-04.

Background: Breast cancer bone metastases are incurable and new therapeutic targets needed. After homing and colonising bone, cancer cells remain dormant, until signals from the microenvironment stimulate their proliferation to form overt metastases. We have recently identified interleukin-1B (IL-1B) as a potential marker for predicting breast cancer patients at increased risk of skeletal relapse and established a role for IL-1 signalling in tumour dormancy in bone. Here we present novel data to support that tumour cell-derived IL-1B plays major roles in breast cancer metastasis and growth in bone. Methods: Tumour/stromal IL-B and IL-1R1 expression was assessed in samples from the AZURE study following immunohistochemical staining. A humanised mouse model of MDA-MB-231 bone metastasis was used to assess effects of the IL-1R antagonist, Anakinra, on tumour growth and spontaneous metastasis. Effects of tumour cell-derived IL-1B on parameters associated with epithelial to mesenchymal transition and metastasis were measured by ELISA, QPCR, Western blot, transwell and scratch assays in MDA-MB-231, MCF7 and T47D cells transfected with IL-1B/control. Homing of breast cancer cells to bone was monitored in BALB/c nude mice intra venously injected with IL-1B overexpressing/control cells. To assess anti-tumour effects of IL-1 inhibition combined with standard of care, BALB/c or C57BL/6 mice were injected with 4T1 or E0771 cells (intra cardiac or intra ductal) 7-days prior to administration of Anakinra, doxorubicin, zoledronic acid (ZA) or placebo, alone or in combination for 14 days. Results: In tissue samples from >1300 patients with stage II/III breast cancer, active IL-1B in tumour cells correlated with relapse in bone (hazard ratio 1.85; 95% CI 1.05-3.26; P=0.02) and other sites (hazard ratio 2.09; 95% CI 1.26-3.48; P=0.0016). In a model of spontaneous human breast cancer metastasis to human bone, Anakinra significantly reduced metastasis to bone (from 80% in control animals to, 20% in Anakinra treated mice) and reduced the number of tumour cells shed into the circulation. Genetic manipulation of breast cancer cells to overexpress IL-1B demonstrated that exogenous production of IL-1B promoted EMT (decreased E-Cadherin, N-Cadherin and G-Catenin), invasion, migration and organ-specific homing in ER-ve (MDA-MB-231) and ER+ve (T47D and MCF7) cells in vitro and in vivo. Contact between tumour cells and osteoblasts or bone marrow cells increased IL-1B secretion from all three cell types. Exposure of tumour cells to IL-1B in the absence of bone cells did not stimulate tumour cell proliferation. Instead, elevated concentrations of IL-1B caused expansion of the bone metastatic niche (increased osteoblasts and blood vessels) that in turn stimulated tumour proliferation. Adding Anakinra to chemotherapy and ZA to mice injected with E0771 cells completely prevented bone metastasis formation and reduced extra-skeletal metastasis by 33%. In mice injected with 4T1 cells, the triple combination therapy reduced bone metastasis by 50% and extra-skeletal metastases by 65%. Conclusion: Our novel data demonstrate that IL-1B/IL-1R1 signalling plays an important role in breast cancer metastasis to bone. Pharmacological inhibition of IL-1B has potential as a novel treatment. Citation Format: Ottewell PD, Lefley DV, Freeman K, Gregory WM, Hanby AM, Spicer-Hadlington AR, Liu X, Bradbury SM, Hambley L, Allocca G, Cookson V, Kruithof de-Julio M, Coleman RE, Brown JE, Holen I, Tulotta C. Breast cancer cell-derived IL-1B drives metastasis and colonisation of the bone microenvironment [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-05-01.

The Scientific Advisory Board (SAB) of the Organisation for the Prohibition of Chemical Weapons (OPCW) has provided advice in relation to the Chemical Weapons Convention on assistance and protection. We present the SAB's response to a request from the OPCW Director-General in 2014 for information on the best practices for preventing and treating the health effects from acute, prolonged, and repeated organophosphorus nerve agent (NA) exposure. The report summarises pre- and post-exposure treatments, and developments in decontaminants and adsorbing materials, that at the time of the advice, were available for NAs. The updated information provided could assist medics and emergency responders unfamiliar with treatment and decontamination options related to exposure to NAs. The SAB recommended that developments in research on medical countermeasures and decontaminants for NAs should be monitored by the OPCW, and used in assistance and protection training courses and workshops organised through its capacity building programmes. Fil: Timperley, Christopher M.. Defence Science and Technology Laboratory; Reino Unido Fil: Abdollahi, Mohammad. Tehran University of Medical Sciences; Irán Fil: Al-Amri, Abdullah Saeed. Saudi Basic Industries Corporation; Arabia Saudita Fil: Baulig, Augustin. Secrétariat Général de la Défense Et de la Sécurité Nationale; Francia Fil: Benachour, Djafer. Université Ferhat Abbas Sétif 1; Argelia Fil: Borrett, Veronica. Bai Scientific; Australia. University of Melbourne; Australia Fil: Cariño, Flerida A.. University Of The Philippines Diliman; Filipinas Fil: Geist, Michael. Basf Se; Alemania Fil: Gonzalez, David. Universidad de la República Facultad de Química; Uruguay Fil: Kane, William. Monsanto Company; Estados Unidos Fil: Kovarik, Zrinka. Institut Za Medicinska Istrazivanja I Medicinu Rada; Croacia Fil: Martínez Álvarez, Roberto. Universidad Complutense de Madrid; España Fil: Mourão, Nicia Maria Fusaro. ABIQUIM; Brasil Fil: Neffe, Slawomir. Military University of Technology; Polonia Fil: Raza, Syed K.. Institute of Pesticides Formulation Technology; India Fil: Rubaylo, Valentin. State Scientific Research Institute of Organic Chemistry and Technology; Rusia Fil: Suarez, Alejandra Graciela. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Química Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Química Rosario; Argentina Fil: Takeuchi, Koji. National Institute of Advanced Industrial Science and Technology; Japón Fil: Tang, Cheng. National Defence University; China Fil: Trifirò, Ferruccio. Universidad de Bologna; Italia Fil: van Straten, Francois Mauritz. South African Nuclear Energy Corporation SOC Ltd.; Sudáfrica Fil: Vanninen, Paula S.. University of Helsinki; Finlandia Fil: Vucinic, Slavica. Vojnomedicinska Akademija; Serbia Fil: Zaitsev, Volodymyr. Pontifícia Universidade Católica do Rio de Janeiro; Brasil. Taras Shevchenko National University Of Kyiv; Ucrania Fil: Zafar Uz Zaman, Muhammad. National Engineering and Scientific Commission; Pakistán Fil: Zina, Mongia Saïd. Université de Tunis El Manar. Faculté Des Sciences de Tunis; Túnez Fil: Holen, Stian. Opcw Scientific Advisory Board Secretary; Países Bajos Fil: Forman, Jonathan E.. Opcw Scientific Advisory Board Secretary And Science Policy Adviser; Países Bajos. Organisation for The Prohibition of Chemical Weapons; Países Bajos Fil: Alwan, Wesam S.. Monash University Victorian College Of Pharmacy; Australia. OPCW Office of Strategy and Policy; Países Bajos Fil: Suri, Vivek. Opcw Office Of Strategy And Policy; Países Bajos

Background Patients with glioblastoma (GBM) have a dismal prognosis. Nearly all will relapse with no clear standard of care for recurrent disease (rGBM). Approximately 50% of patients have tumors harboring epidermal growth factor receptor (EGFR) amplification. The antibody–drug conjugate depatuxizumab mafodotin (depatux-m) binds cells with EGFR amplification, is internalized, and releases a microtubule toxin, killing the cell. Here we report efficacy, safety and pharmacokinetics (PK) of depatux-m + temozolomide (TMZ) in patients with EGFR-amplified rGBM. Methods M12-356 (NCT01800695) was an open-label study encompassing patients with newly diagnosed or rGBM across 3 treatment arms. Results are reported for adults with EGFR-amplified, measurable rGBM who received depatux-m (0.5–1.5 mg/kg) on days 1 and 15, and TMZ (150–200 mg/m2) on days 1–5 in a 28-day cycle. Patients were bevacizumab and nitrosourea naïve. Results There were 60 patients, median age 56 years (range, 20–79). Fifty-nine patients previously received TMZ. Common adverse events (AEs) were blurred vision (63%), fatigue (38%), and photophobia (35%). Grades 3/4 AEs were split between ocular and non-ocular AEs, occurring in 22% of patients each. Systemic PK exposure of depatux-m was dose proportional. The objective response rate was 14.3%, the 6-month progression-free survival rate was 25.2%, and the 6-month overall survival rate was 69.1%. Conclusions Depatux-m + TMZ displayed an AE profile similar to what was described previously. Antitumor activity in this TMZ-refractory population was encouraging. Continued study of depatux-m in patients with EGFR-amplified, newly diagnosed, or recurrent GBM is ongoing in 2 global, randomized trials (NCT02573324, NCT02343406).

Prevalent digital breast tomosynthesis (DBT) has shown higher cancer detection rates and lower recall rates compared with those of digital mammography (DM). However, data are limited on rates and histopathologic tumor characteristics of interval and subsequent round screen-detected cancers for DBT. Purpose To follow women randomized to screening with DBT or DM and to investigate rates and tumor characteristics of interval and subsequent round screen-detected cancers. Materials and Methods To-Be is a randomized controlled trial comparing the outcome of DBT and DM in organized breast cancer screening. The trial included 28 749 women, with 22 306 women returning for subsequent DBT screening 2 years later (11 201 and 11 105 originally screened with DBT and DM, respectively). Differences in rates, means, and distribution of histopathologic tumor characteristics between women prevalently screened with DBT versus DM were evaluated with Z tests, t tests, and χ2 tests. Relative risk (RR) with 95% CIs was calculated for the cancer rates. Results Interval cancer rates were 1.4 per 1000 screens (20 of 14 380; 95% CI: 0.9, 2.1) for DBT versus 2.0 per 1000 screens (29 of 14 369; 95% CI: 1.4, 2.9; P = .20) for DM. The rates of subsequent round screen-detected cancer were 8.1 per 1000 (95% CI: 6.6, 10.0) for women originally screened with DBT and 9.1 per 1000 (95% CI: 7.4, 11.0; P = .43) for women screened with DM. The distribution of tumor characteristics did not differ between groups for either interval or subsequent screen-detected cancer. The RR of interval cancer was 0.69 (95% CI: 0.39, 1.22; P = .20) for DBT versus DM, whereas RR of subsequent screen-detected cancer for women prevalently screened with DBT versus DM was 0.89 (95% CI: 0.67, 1.19; P = .43). Conclusion Rates of interval or subsequent round screen-detected cancers and their tumor characteristics did not differ between women originally screened with digital breast tomosynthesis (DBT) versus digital mammography. The analysis suggests that the benefits of prevalent DBT screening did not come at the expense of worse downstream screening performance measures in a population-based screening program.

Objectives To determine the agreement between artificial intelligence software (AI) and radiographers in assessing breast positioning criteria for mammograms from standard digital mammography and digital breast tomosynthesis. Methods Assessment of breast positioning was performed by AI and by four radiographers in pairs of two on 156 examinations of women screened in Bergen, April to September 2019, as part of BreastScreen Norway. Ten criteria were used; three for craniocaudal and seven for mediolateral-oblique view. The criteria evaluated the appearance of the nipple, breast rotation, pectoral muscle, inframammary fold and pectoral nipple line. Intraclass correlation and Cohen’s kappa coefficient (κ) were used to investigate the correlation and agreement between the radiographer’s assessments and AI. Results The intraclass correlation for the pectoral nipple line between the radiographers and AI was >0.92. A substantial to almost perfect agreement (κ > 0.69) was observed between the radiographers and AI on the nipple in profile criterion. We observed a slight to moderate agreement for the other criteria (κ = 0.06–0.52) and generally a higher agreement between the two pairs of radiographers (mean κ = 0.70) than between the radiographers and AI (mean κ = 0.41). Conclusions AI has great potential in evaluating breast position criteria in mammography by reducing subjectivity. However, varying agreement between radiographers and AI was observed. Standardized and evidence-based criteria for definitions, understandings and assessment methods are needed to reach optimal image quality in mammography.

Background Disability is a vital public health issue for health care programs. Affluent countries usually prioritize disability-related research, while often it remains neglected in resource-poor countries like Nepal. The aim of this study was to make available a translated and culturally adapted version of the World Health Organization Disability Assessment Schedule 2.0 (WHODAS 2.0) for measuring disability in the Nepalese population. Methods WHODAS 2.0 (12-items version) was translated into Nepali using a standard forward–backward translation protocol. Purposive and convenience recruitment of participants with psychiatric disabilities was done at the Psychiatry services in a tertiary care hospital. Age and gender-matched participants with physical disabilities were selected from the Internal Medicine department, and participants with no disability were recruited from their accompanying persons. A structured interview in Nepali including the translated WHODAS 2.0 was administered to all participants. Exploratory factor analysis and parallel analysis assessed the construct validity. Content validity was explored, and a quality of life instrument was used for establishing criterion validity. Reliability was measured via Cronbach alpha. Mann–Whitney test explored score differences between the disabled and non-disabled. Results In total, 149 persons [mean age: 40.6 (12.8); 43.6% males, 56.4% females; 61.7% disabled, 38.3% non-disabled] consented to participate. Parallel analysis indicated that a single factor was adequate for the Nepali WHODAS version that captured 45.4% of the total variance. The translated scale got a good Cronbach alpha (= 0.89). Satisfactory construct, content and criterion validity was found. The WHODAS total scores showed a significant difference between the disabled and non-disabled (U = 2002.5; p = 0.015). However, the difference between psychiatric and physical disabilities was not significant, which underscores that the scale is rating disability in general. Conclusion The one-factor structure of the translated and culturally adapted Nepali-version of WHODAS 2.0 showed acceptable validity and an adequate reliability. For epidemiological research purposes, this version of WHODAS 2.0 is now available for measuring global disability in Nepal.

Purpose: To compare the distribution of mammographic features among women recalled for further assessment after screening with digital breast tomosynthesis (DBT) versus digital mammography (DM), and to assess associations between features and final outcome of the screening, including immunohistochemical subtypes of the tumour. Methods: This randomized controlled trial was performed in Bergen, Norway, and included 28,749 women, of which 1015 were recalled due to mammographic findings. Mammographic features were classified according to a modified BI-RADS-scale. The distribution were compared using 95 % confidence intervals (CI). Results: Asymmetry was the most common feature of all recalls, 24.3 % (108/444) for DBT and 38.9 % (222/571) for DM. Spiculated mass was most common for breast cancer after screening with DBT (36.8 %, 35/95, 95 %CI: 27.2− 47.4) while calcifications (23.0 %, 20/87, 95 %CI: 14.6− 33.2) was the most frequent after DM. Among women screened with DBT, 0.13 % (95 %CI: 0.08− 0.21) had benign outcome after recall due to indistinct mass while the percentage was 0.28 % (95 %CI: 0.20− 0.38) for DM. The distributions were 0.70 % (95 %CI: 0.57− 0.85) versus 1.46 % (95 %CI: 1.27− 1.67) for asymmetry and 0.24 % (95 %CI: 0.16− 0.33) versus 0.54 % (95 %CI: 0.43− 0.68) for obscured mass, among women screened with DBT versus DM, respectively. Spiculated mass was the most common feature among women diagnosed with non-luminal A-like cancer after DBT and after DM. Conclusions: Spiculated mass was the dominant feature for breast cancer among women screened with DBT while calcifications was the most frequent feature for DM. Further studies exploring the clinical relevance of mammographic features visible particularly on DBT are warranted. This study was funded by the Research Council of Norway (the To-Be trial; project number 247941/H10), the Cancer Registry of Norway, and the Department of Radiology at Haukeland University Hospital.

Skeletal metastases are frequent complications of many cancers, causing bone complications (fractures, bone pain, disability) that negatively affect the patient’s quality of life. Here, we first discuss the burden of skeletal complications in cancer bone metastasis. We then describe the pathophysiology of bone metastasis. Bone metastasis is a multistage process: long before the development of clinically detectable metastases, circulating tumor cells settle and enter a dormant state in normal vascular and endosteal niches present in the bone marrow, which provide immediate attachment and shelter, and only become active years later as they proliferate and alter the functions of bone-resorbing (osteoclasts) and bone-forming (osteoblasts) cells, promoting skeletal destruction. The molecular mechanisms involved in mediating each of these steps are described, and we also explain how tumor cells interact with a myriad of interconnected cell populations in the bone marrow, including a rich vascular network, immune cells, adipocytes, and nerves. We discuss metabolic programs that tumor cells could engage with to specifically grow in bone. We also describe the progress and future directions of existing bone-targeted agents and report emerging therapies that have arisen from recent advances in our understanding of the pathophysiology of bone metastases. Finally, we discuss the value of bone turnover biomarkers in detection and monitoring of progression and therapeutic effects in patients with bone metastasis.

Objective To investigate whether having the nipple imaged in profile was associated with breast characteristics or compression parameters, and whether it affected selected outcomes in screening with standard digital mammography or digital breast tomosynthesis. Methods In this IRB-approved retrospective study, results from 87 450 examinations (174 900 breasts) performed as part of BreastScreen Norway, 2016–2019, were compared by nipple in profile status and screening technique using descriptive statistics and generalized estimating equations. Unadjusted and adjusted odds ratios with 95% confidence intervals (95% CIs) were estimated for outcomes of interest, including age, breast volume, volumetric breast density, and compression force as covariates. Results Achieving the nipple in profile versus not in profile was associated with lower breast volume (845.1 cm3 versus 1059.9 cm3, P < 0.01) and higher mammographic density (5.6% versus 4.4%, P < 0.01). Lower compression force and higher compression pressure were applied to breasts with the nipple in profile (106.6 N and 11.5 kPa) compared to the nipple not in profile (110.8 N and 10.5 kPa, P < 0.01 for both). The adjusted odds ratio was 0.95 (95% CI: 0.88–1.02; P = 0.15) for recall and 0.92 (95% CI: 0.77–1.10; P = 0.36) for screen-detected cancer for nipple in profile versus not in profile. Conclusion Breast characteristics and compression parameters might hamper imaging of the nipple in profile. However, whether the nipple was in profile or not on the screening mammograms did not influence the odds of recall or screen-detected cancer, regardless of screening technique.

A whey protein/guar gum preload reduces postprandial glycaemia in type 2 diabetes through slowing gastric emptying. However, gastric emptying has previously been assessed using a stable isotope breath test technique, which cannot discriminate between slowing of gastric emptying and small intestinal absorption. This preload also may be useful in the management of postprandial hypotension. We evaluated the effects of a whey protein/guar preload on gastric emptying, glucose absorption, glycaemic/insulinaemic and blood pressure (BP) responses to an oral glucose load. Eighteen healthy older participants underwent measurements of gastric emptying (scintigraphy), plasma glucose and insulin, glucose absorption, superior mesenteric artery (SMA) flow, BP and heart rate (HR) after ingesting a 50 g glucose drink, with or without the preload. The preload reduced plasma glucose (p = 0.02) and serum 3-O-methylglucose (3-OMG) (p = 0.003), and increased plasma insulin (p = 0.03). There was no difference in gastric emptying or BP between the two days. The reduction in plasma glucose on the preload day was related to the reduction in glucose absorption (r = 0.71, p = 0.002). In conclusion, the glucose-lowering effect of the preload may relate to delayed small intestinal glucose absorption and insulin stimulation, rather than slowing of gastric emptying.

We aimed to determine if compression force or pressure could be associated with early performance measures for women screened with digital breast tomosynthesis (DBT) in BreastScreen Norway. Early performance measures included rates of consensus, recall, and screen-detected breast cancer.Data on compression force and pressure, compressed breast thickness and breast characteristics were extracted from an automated software for density assessment of DBT screening examinations for 25,286 women. For descriptive analyses, force (Newton, N) and pressure (kilopascal, kPa) were categorized into quartiles. Analyses were stratified by mammographic view, craniocaudal (CC) and mediolateral oblique (MLO). Logistic regression with restricted cubic splines was used to investigate the association between force and pressure as continuous exposures and early performance measures adjusted for age, compressed breast thickness and fibroglandular volume.Mean age of the screened women was 60.7 (SD = 5.2) years. Mean compression force was 90.8 (SD = 14.2) N for CC and 106.3 (SD = 20.6) N for MLO, and pressure was 11.3 (SD = 3.6) kPa for CC and 8.7 (SD = 2.0) kPa for MLO. The highest rates of screen-detected cancer were observed for low force (1.04 % for82.5 N for CC and 1.07 % for92.0 N for MLO) and low pressure (1.07 % for7.2 kPa for MLO). No association was found between force or pressure as continuous exposures and early performance measures in adjusted regression analyses.We found the highest rates of screen-detected cancer for low force and pressure, but no significant association between continuous values of force or pressure and early performance measures in DBT. The findings might indicate that the levels of force and pressure in DBT are of lower significance for screening performance than reported in standard digital mammography.

To detect gamma rays with good spatial, timing and energy resolution while maintaining high sensitivity we need accurate and efficient algorithms to estimate the first gamma interaction position from the measured light distribution. Furthermore, monolithic detectors are investigated as an alternative to pixelated detectors due to increased sensitivity, resolution and intrinsic DOI encoding. Monolithic detectors, however, are challenging because of complicated calibration setups and edge effects. In this work, we evaluate the use of neural networks to estimate the 3D first (Compton or photoelectric) interaction position. Using optical simulation data of a 50 × 50 × 16 mm3 LYSO crystal, performance is evaluated as a function of network complexity (two to five hidden layers with 64 to 1024 neurons) and amount of training data (1000−8000 training events per calibration position). We identify and address the potential pitfall of overfitting on the training grid through evaluation on intermediate positions that are not in the training set. Additionally, the performance of neural networks is directly compared with nearest neighbour positioning. Optimal performance was achieved with a network containing three hidden layers of 256 neurons trained on 1000 events/position. For more complex networks, the performance degrades at intermediate positions and overfitting starts to occur. A median 3D positioning error of 0.77 mm and a 2D FWHM of 0.46 mm is obtained. This is a 17% improvement in terms of FWHM compared to the nearest neighbour algorithm. Evaluation only on events that are not Compton scattered results in a 3D positioning error of 0.40 mm and 2D FWHM of 0.42 mm. This reveals that Compton scatter results in a considerable increase of 93% in positioning error. This study demonstrates that very good spatial resolutions can be achieved with neural networks, superior to nearest neighbour positioning. However, potential overfitting on the training grid should be carefully evaluated.

In a typical monolithic PET detector setup, scintillation light is captured by an array of photodetectors from which the first interaction position is estimated. This is necessary to draw an accurate line of response. However, a majority of gamma rays undergo one or more Compton interactions before photoelectric interaction. For these events, it is more difficult to recover the first interaction position. In this study we use optical simulation data and neural networks to understand and mitigate the degrading effect of Compton scatter on positioning accuracy. A neural network was trained to predict the 3D first interaction position. Additionally, a network was trained to classify events into three classes: events scattered over a 2D distance smaller than 1 mm (class 0), between 1 mm and 5 mm (class 1) and further than 5 mm (class 2). Finally, a pipeline was designed where events are first classified with the scatter detection network and subsequently discarded (class 2) or positioned with separate networks trained for class 0 and 1. With one neural network trained for all events, an average 3D positioning error of 1.5 mm and FWHM of 0.49 mm is achieved. The scatter detection network achieves an overall accuracy of 65%. Through the combination of scatter detection and separate positioning neural networks for class 0 and 1, the average 3D positioning error reduces with 0.29 mm. Hence, we show that an improvement of about 20% can be achieved through the inclusion of Compton scatter detection. The ultimate goal is to apply the presented methodology to experimental data.

Background: Knowledge is lacking on patient goals and motivation for carpometacarpal joint osteoarthritis (CMCJ OA) surgery. The objective of this study was to explore patient goals and motivation for surgery, whether patient goals were reflected in self-reports of pain and function, and factors characterizing patients highly motivated for surgery. Methods: This cross-sectional study included 180 patients referred from their general practitioner for CMCJ surgical consultation. Goals for surgery were collected with an open-ended question, categorized with the International Classification of Functioning, Disability and Health coding system, and compared to self-reports of pain and function. Motivation for surgery was rated with a Numeric Rating Scale (NRS, 0-10, 0 = not motivated). Factors characterizing patients highly motivated for surgery (NRS ≥ 8) were explored with multivariate regression analyses. Results: The mean age of the participants was 63 years (SD = 7.6), and 142 (79%) were women. The most common goals for surgery were to reduce pain and improve arm and hand use, but these were not reflected in self-reports of pain and function. Fifty-six (31%) of the patients were characterized as highly motivated for surgery. High motivation for surgery was strongly associated with reporting more activity limitations (odds ratio [OR] = 4.00, P = .008), living alone (OR = 3.18, P = .007), and a young age (OR = 0.94, P = .002). Conclusions: Decisions on CMCJ OA surgery should be based on assessment and discussion of patients’ life situation, hand pain, activity limitations for, and goals and motivation for surgery. According to the european league against rheumatism (EULAR) recommendations, previously received conservative and pharmacological treatment should also be evaluated.

We studied the quality of life (QoL) of the elderly in Nepal and their special needs. Nepal is a low- and middle-income country where the elderly population is growing significantly. A random selection of informants from the Kavre district was carried out in this cross-sectional, population-based, door-to-door survey. The district has a mixture of urban and rural communities. In Nepal, families generally take care of their elderly. Hardly any placement is made in institutions. A validated Nepali version of World Health Organization Quality of Life 8-question scale (WHOQoL-8) estimated QoL among the elderly (≥ 60 years; N = 439). Other variables of interest were socio-demographics, substance use, physical and psychological health, and family support. Depression was measured by Geriatric Depression Scale short form [GDS-15]. Due to a high illiteracy rate, a structured and culturally adapted questionnaire was presented in an interview format. The relationships between the variables and QoL were analyzed using independent sample t tests, linear regression and Pearson’s correlations. The mean QoL score was 25.7 (± 4.2); 49.2% rated their QoL as good. Positive predictors of QoL were: urban residence (p = 0.03); employment (p = 0.02); absence of chronic physical health problems (p = 0.02); absence of depression (p

In the WHO glioma classification guidelines grade (glioblastoma versus lower-grade glioma), IDH mutation and 1p/19q co-deletion status play a central role as they are important markers for prognosis and optimal therapy planning. Currently, diagnosis requires invasive surgical procedures. Therefore, we propose an automatic segmentation and classification pipeline based on routinely acquired pre-operative MRI (T1, T1 postcontrast, T2 and/or FLAIR). A 3D U-Net was designed for segmentation and trained on the BraTS 2019 training dataset. After segmentation, the 3D tumor region of interest is extracted from the MRI and fed into a CNN to simultaneously predict grade, IDH mutation and 1p19q co-deletion. Multi-task learning allowed to handle missing labels and train one network on a large dataset of 628 patients, collected from The Cancer Imaging Archive and BraTS databases. Additionally, the network was validated on an independent dataset of 110 patients retrospectively acquired at the Ghent University Hospital (GUH). Segmentation performance calculated on the BraTS validation set shows an average whole tumor dice score of 90% and increased robustness to missing image modalities by randomly excluding input MRI during training. Classification area under the curve scores are 93%, 94% and 82% on the TCIA test data and 94%, 86% and 87% on the GUH data for grade, IDH and 1p19q status respectively. We developed a fast, automatic pipeline to segment glioma and accurately predict important (molecular) markers based on pre-therapy MRI.

Human mistakes in traffic often have terrible consequences. The long-awaited introduction of self-driving vehicles may solve many of the problems with traffic, but much research is still needed before cars are fully autonomous.In this paper, we propose a new Road Detection algorithm using online supervised learning based on a Neural Network architecture. This algorithm is designed to support a Reinforcement Learning algorithm (for example, the standard Proximal Policy Optimization or PPO) by detecting when the car is in an adverse condition. Specifically, the PPO gets a penalty whenever the virtual automobile gets stuck or drives off the road with any of its four wheels.Initial experiments show significantly improved results for PPO when using our Road Detection algorithm, as compared to not using any form of Road Detection.In fact, without this detection algorithm, the vehicle often gets into non-terminating loops (for example, driving into the dividers, getting stuck, or driving into a pit).

The military has become one of many actors operating in conflict settings where the objective is to protect civilians. This has spurred a debate on how military means can be utilized more successfully to combat violence against populations. A key part of this debate concerns threat analysis, since in order to protect civilians, one needs to know whom to protect and what to protect them from. The ‘threat’ concept is used repetitively in conversations concerning conflict resolution. Yet, professions and disciplines understand threats in different ways, indicative of the numerous perspectives that exist on how to manage conflict. This chapter explores two different understandings of threats to civilians: a context-oriented threat as understood by the peace and security field and an actor-oriented threat as understood in military operations. The chapter discusses what the conceptual understandings can learn from each other and what cultural competencies are needed to further strengthen the threat perspectives to improve civilian protection in practice.

Background and purpose — About one-fourth of hip fracture patients have cognitive impairment. We investigated whether patients’ cognitive function affects surgical treatment, risk of reoperation, and mortality after hip fracture, based on data in the Norwegian Hip Fracture Register (NHFR). Patients and methods — This prospective cohort study included 87,573 hip fractures reported to the NHFR in 2005–2017. Hazard rate ratios (HRRs) for risk of reoperation and mortality were calculated using Cox regression adjusted for sex, age, ASA class, fracture type, and surgical method. Results — Cognitive impairment was reported in 27% of patients. They were older (86 vs. 82 years) and had higher ASA class than non-impaired patients. There were no differences in fracture type or operation methods. Cognitively impaired patients had a lower overall reoperation rate (4.7% vs. 8.9%, HRR 0.71; 95% CI 0.66–0.76) and lower risk of reoperation after osteosynthesis (HRR 0.58; CI 0.53–0.63) than non-impaired patients. Cognitively impaired hip fracture patients had an increased reoperation risk after hemiarthroplasty (HRR 1.2; CI 1.1–1.4), mainly due to dislocations (1.5% vs. 1.0%, HRR 1.7; CI 1.3–2.1). Risk of dislocation was particularly high following the posterior approach (4.7% vs. 2.8%, HRR 1.8; CI 1.2–2.7). Further, they had a higher risk of reoperation due to periprosthetic fracture after uncemented hemiarthroplasty (HRR 1.6; CI 1.0–2.6). Cognitively impaired hip fracture patients had higher 1-year mortality than those without cognitive impairment (38% vs. 16%, HRR 2.1; CI 2.1–2.2). Interpretation — Our findings support giving cognitively impaired patients the same surgical treatment as non-impaired patients. But since the risk of hemiprosthesis dislocation and periprosthetic fracture was higher in cognitively impaired patients, they should probably not have posterior approach surgery or uncemented implants. publishedVersion