Search

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.

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.

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.

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.

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.

This study, performed in 2019, examined which factors influenced recognition of child abuse and the need to intervene of school staff of primary schools in Flemish rural areas. One hundred and fifty staff members of primary schools filled out the Questionnaire Assessment of Situations of Child Abuse and answered for each vignette questions regarding recognition and perceived intervention need. Although school staff recognized most of the situations of child abuse, cases of emotional abuse were recognized less often. Compared to European victims, vignettes involving non-European victims were considered as more severe, and the need to involve professional help and to call in judicial authorities was greater. School personnel’s number of years of experience in education was positively associated with recognition, but negatively with the need to involve judicial authorities. The number of students in a school was associated with lower severity assessment and more children with low socio-economic status with a decreased likelihood of referral to a Confidential Center of Child Abuse and Neglect. Awareness of the fact that characteristics of the victim, staff characteristics and context characteristics influence detection and perceived intervention need of school personnel may result in more equal treatment for all victims.

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 Youth mental health problems are a major public health concern. Anxiety and depression are among the most common psychological difficulties. The aim of this study is to evaluate an optimized version of a promising indicated group intervention for emotional problems. The program (EMOTION Coping Kids Managing Anxiety and Depression) targets school children 8–12 years with anxious and depressive symptoms and examines three factors. Factor 1 compares the standard EMOTION intervention delivered in 16 group-based sessions (Group), versus a partially-digital EMOTION intervention (DIGGI) delivered as eight group sessions and eight digital sessions. Both versions use virtual reality technology (VR) to improve behavioral experiments. Factor 2 compares parent participation in a 5-session parent group (high involvement) versus sharing information with parents via a brochure (low involvement). Factor 3 compares the use of a measurement and feedback system (MFS) designed to help group leaders tailor the intervention using feedback from children with no MFS. Methods Using a cluster-randomized factorial design, 40 schools across Norway will be randomized to eight different experimental conditions based on three, two-level factors. To assess internalizing symptoms in children, children and their parents will be given self-report questionnaires pre-, post-, and one year after intervention. Parents also report on demographics, user satisfaction, personal symptoms and perception of family related factors. Teachers report on child symptoms and school functioning. Group leaders and the head of the municipal services report on implementation issues. The primary outcomes are changes in depressive and anxious symptoms. Some secondary outcomes are changes in self-esteem, quality of life, and user satisfaction. Questions regarding the consequences of the COVID-19 pandemic are included. Treatment fidelity is based on checklists from group leaders, and on user data from the participating children. Discussion This study is a collaboration between three regional centers for child and adolescent mental health in Norway. It will provide knowledge about: (1) the effect of school-based preventive interventions on anxiety and depression in children; (2) the effect of feedback informed health systems, (3) the effect and cost of digital health interventions for children, and (4) the effect of parental involvement.

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...

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.

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.

Polyunsaturated fatty acids such as arachidonic and eicosapentaenoic acids are the precursors of eicosanoid metabolites (e.g prostaglandins and prostacyclins) which regulate inflammatory and immune response processes in fish organs. The present research studies the differential production of PGI2, PGI3, PGE2 and PGE3 by primary liver and head kidney cells isolated from salmon and challenged with single or combined ARA and/or EPA. There was a significant increase in the production of PGE2 and PGI3 in both types of cells after exposure to single and combined fatty acids. Increased production of PGE3 was only detected in liver cells after exposure to ARA+EPA. The levels of PGI2 in liver cells were significantly increased after exposure to all the tested fatty acid systems, while the production levels in head kidney cells were only significant after exposure to ARA or ARA+EPA, but not to EPA, where the production was non-significantly decreased compared to the control cells. In general, liver cells synthetized higher prostaglandin levels than prostacyclins, and the opposite was observed in head kidney cells, which synthetized highly remarkable amounts of prostacyclin compared to liver cells. The overall production for both types of cells and various fatty acid systems were characterized by a high proportion of the omega-3 fatty acid metabolites (PGE3+PGI3) compared to the omega-6 counterpart (PGE2+PGI2). Some potential production mechanisms are proposed and comprehensively discussed. The results of the present research are the first to deliver the differential production of prostacyclins and prostaglandins by liver and head kidney cells from salmon, thereby paving the way for understanding the significance of these prostanoids in fish physiology and disease.

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.

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.

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.

This study examined the warzone stressors: killing in combat, experiencing personal threats, or traumatic witnessing during deployment in relation to psychological distress, alcohol consumption and quality of life at long-term follow-up. The study was conducted in two samples of Norwegian veterans who had served in Afghanistan (Study 1, N = 4,053) or in Lebanon (Study 2, N = 10,605), respectively. Data were collected through two postdeployment mental health surveys conducted by the Norwegian Armed Forces Joint Medical Services. Using linear regressions, we investigated the impact of warzone stressors on posttraumatic stress symptoms, depression, anxiety, insomnia, alcohol use, and quality of life. In study 1 (Afghanistan veterans), killing was not a significant predictor of psychological distress, alcohol use, or quality of life, when controlling for Personal Threats and Witnessing exposure. In study 2 (Lebanon veterans) killing remained a significant predictor (p < .001) of symptoms of posttraumatic stress, depression, and anxiety, after controlling for other warzone stressors. However, killing was not a significant predictor of alcohol use or quality of life in Study 2. In summary, killing in combat may be associated with increased reports of psychological distress, but there were distinct results in the two studies. Differences in mission statements, rules of engagement, and mental states during combat could explain the diverging outcomes. The results indicate that it may be erroneous to ubiquitously regard killing in combat as a moral stressor, and highlight the importance of clear rules of engagements that accounts for the “on the ground” reality of soldiers.

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.

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

Background: Geriatric depression is a significant problem in both the developed and the developing world. To identify this condition, Geriatric Depression Scale has been used in different languages and cultural settings; it has proved to be a reliable and valid instrument. However, the Geriatric Depression Scale-15 version in Nepali has so far not been validated.Methods: The original 15-item version of the Geriatric Depression Scale-15 was translated into Nepali and administered by trained nurses to a target sample aged ?60 years at Dhulikhel Hospital (n=106). Subsequently, the participants were blindly interviewed by a consultant psychiatrist for possible geriatric depression according to the ICD-10 criteria. Cronbach’s alpha checked the reliability. Validity was assessed for three different cut-off points (4/5, 5/6, and 6/7); the related sensitivity, specificity, positive predictive value, and the negative predictive value of the scale were estimated.Results: The mean participant age was 68.1 (±7.2); males and females, 50.9% and 49.1%, respectively. Cronbach’s alpha was 0.79.The optimal cut-off point was found to be 5/6 with sensitivity and specificity 86.3% and 74.5%, respectively. Conclusions: Using a standard statistical protocol, a reliable and valid Geriatric Depression Scale-15-Nepali was developed with an adequate internal consistency and an optimal balance between sensitivity and specificity at cut-off point 5/6.The Geriatric Depression Scale-15-Nepali can serve as an appropriate instrument for assessing geriatric depression in epidemiological research as well as in primary health care settings in Nepal.Keywords: Geriatric depression; internal consistency; sensitivity; South Asia; specificity.

BACKGROUND A displaced femoral neck fracture in patients older than 70 years is a serious injury that influences the patient's quality of life and can cause serious complications or death. Previous national guidelines and a Cochrane review have recommended cemented fixation for arthroplasty to treat hip fractures in older patients, but data suggest that these guidelines are inconsistently followed in many parts of the world; the effects of that must be better characterized. QUESTIONS/PURPOSES The purpose of this study was to evaluate a large group of patients in the Norwegian Hip Fracture Register to investigate whether the fixation method in hemiarthroplasty is associated with (1) the risk of reoperation; (2) the mortality rate; and (3) patient-reported outcome measures (PROMs). METHODS Longitudinally maintained registry data from the Norwegian Hip Fracture Register with high completeness (93%) and near 100% followup of deaths were used for this report. From 2005 to 2017, 104,993 hip fractures were registered in the Norwegian Hip Fracture Register. Fractures other than intracapsular femoral neck fractures and operative methods other than bipolar hemiarthroplasty, such as osteosynthesis or THA, were excluded. The selection bias risk on using cemented or uncemented hemiarthroplasty is small in Norway because the decision is usually regulated by tender processes at each hospital and not by surgeon. A total of 7539 uncemented hemiarthroplasties (70% women, mean age, 84 years [SD 6] years) and 22,639 cemented hemiarthroplasties (72% women, mean age, 84 years [SD 6] years) were eligible for analysis. Hazard risk ratio (HRR) on reoperation and mortality was calculated in a Cox regression model adjusted for age, sex, comorbidities (according to the American Society of Anesthesiologists classification), cognitive function, surgical approach, and duration of surgery. At 12 months postoperatively, 65% of patients answered questionnaires regarding pain and quality of life, the results of which were compared between the fixation groups. RESULTS A higher overall risk of reoperation for any reason was found after uncemented hemiarthroplasty (HRR, 1.5; 95% CI, 1.4-1.7; p < 0.001) than after cemented hemiarthroplasty. When assessing reoperations for specific causes, higher risks of reoperation because of periprosthetic fracture (HRR, 5.1; 95% CI, 3.5-7.5; p < 0.001) and infection (HRR, 1.2; 95% CI, 1.0-1.5; p = 0.037) were found for uncemented hemiarthroplasty than for cemented procedures. No differences were found in the overall mortality rate after 1 year (HRR, 1.0; 95% CI, 0.9-1.0; p = 0.12). Hemiarthroplasty fixation type was not associated with differences in patients' pain (19 versus 20 for uncemented and cemented hemiarthroplasties respectively, p = 0.052) or quality of life (EuroQol [EQ]-VAS score 64 versus 64, p = 0.43, EQ5D index score 0.64 versus 0.63, p = 0.061) 1 year after surgery. CONCLUSIONS Our study found that the fixation method was not associated with differences in pain, quality of life, or the 1-year mortality rate after hemiarthroplasty. Uncemented hemiarthroplasties should not be used when treating elderly patients with hip fractures because there is an increased reoperation risk.Level of Evidence Level III, therapeutic study.

Background Symptoms of anxiety and depression are common mental health problems in children and are often referred to as internalizing symptoms. Youth with such symptoms are at greater risk for poor academic achievement, school non-completion, and future mental health problems, all of which, lead to public health consequences and costs to society. The aim of the current study was to investigate associations between young school children’s internalizing symptoms and school functioning, as assessed separately by the teachers and the children. Methods This study is a cross-sectional study including children (N = 750. 58% girls) from the ages of 8–12 years with elevated levels of self-reported symptoms of anxiety (MASC-C) and/or depression (SMFQ). Teachers reported the academic achievement, school adaptation (TRF) and internalizing symptoms (BPM-T) of the children. Associations were analyzed using linear regression analyses. Results Both teacher-reported internalizing symptoms and children’s self-reported depressive symptoms were associated with poor academic achievement and school adaptation, while self-reported symptoms of anxiety were not. Symptoms of depression as assessed by the children were associated with teacher-rated internalizing symptoms, while self-reported symptoms of anxiety were not. Conclusion We found negative associations between school functioning and internalizing symptoms, as assessed by both the teachers and the children. The dual findings strengthen the validity of these relationships. Thus, prevention of depressive and anxiety symptoms in children may lead to positive changes in school domains such as academic achievement and school adaptation. The weak and non-significant associations between teacher-rated internalizing problems and children`s self-report on depression- and anxiety symptoms respectively, indicate that teachers may have difficulties recognizing children with these symptoms. Trial registration Clinical Trials NCT02340637, Registered on June 12, 2014, Retrospectively registered.

Purpose: To compare the performance of digital breast tomosynthesis (DBT) and two-dimensional synthetic mammography (SM) with that of digital mammography (DM) in a population-based mammographic screening program. Materials and Methods: In this prospective cohort study, data from 37 185 women screened with DBT and SM and from 61 742 women screened with DM as part of a population-based screening program in 2014 and 2015 were included. Early performance measures, including recall rate due to abnormal mammographic findings, rate of screen-detected breast cancer, positive predictive value of recall, positive predictive value of needle biopsy, histopathologic type, tumor size, tumor grade, lymph node involvement, hormonal status, Ki-67 level, and human epidermal growth factor receptor 2 status were compared in women who underwent DBT and SM screening and in those who underwent DM screening by using x2 tests, two-sample unpaired t tests, and tests of proportions. Results: Recall rates were 3.4% for DBT and SM screening and 3.3% for DM screening (P = .563). DBT and SM screening showed a significantly higher rate of screen-detected cancer compared with DM screening (9.4 vs 6.1 cancers per 1000 patients screened, respectively; P , .001). The rate of detection of tumors 10 mm or smaller was 3.2 per 1000 patients screened with DBT and SM and 1.8 per 1000 patients screened with DM (P , .001), and the rate of grade 1 tumors was 3.3 per 1000 patients screened with DBT and SM versus 1.4 per 1000 patients screened with DM (P , .001). On the basis of immunohistochemical analyses, rates of lymph node involvement and tumor subtypes did not differ between women who underwent DBT and SM screening and those who underwent DM screening. Conclusion: DBT and SM screening increased the detection rate of histologically favorable tumors compared with that attained with DM screening.

Phosphatidylcholine (PC) and phosphatidylethanolamine (PE) composition in skeletal muscle have been linked to insulin sensitivity. We evaluated the relationships between skeletal muscle PC:PE, physical exercise and insulin sensitivity. We performed lipidomics and measured PC and PE in m. vastus lateralis biopsies obtained from 13 normoglycemic normal weight men and 13 dysglycemic overweight men at rest, immediately after 45 min of cycling at 70% maximum oxygen uptake, and 2 h post-exercise, before as well as after 12 weeks of combined endurance- and strength-exercise intervention. Insulin sensitivity was monitored by euglycemic-hyperinsulinemic clamp. RNA-sequencing was performed on biopsies, and mitochondria and lipid droplets were quantified on electron microscopic images. Exercise intervention for 12 w enhanced insulin sensitivity by 33%, skeletal muscle levels of PC by 21%, PE by 42%, and reduced PC:PE by 16%. One bicycle session reduced PC:PE by 5%. PC:PE correlated negatively with insulin sensitivity (β = −1.6, P P = 0.035), and lipid droplet area (ρ = 0.55, P = 0.017) on EM pictures, and negatively with oxidative phosphorylation and mTOR based on RNA-sequencing. In conclusion, PC and PE contents of skeletal muscle respond to exercise, and PC:PE is inversely related to insulin sensitivity.

Background Epidermal growth factor receptor (EGFR) alterations are associated with multiple cancers. Current EGFR-directed therapies have led to increased efficacy but are associated with specific side effects. The antibody-drug conjugate depatuxizumab mafodotin (depatux-m) targets EGFR with a monoclonal antibody linked to a cytotoxin, and is highly tumor-specific. Methods This phase 1/2 study evaluated the safety, pharmacokinetics, and efficacy of depatux-m in patients who had advanced solid tumors with known wild-type EGFR overexpression, amplification, or mutated EGFR variant III. A 3 + 3 dose escalation was used, and 2 dosing schedules were evaluated. Depatux-m also was manufactured under an alternate process to reduce the drug load and improve the safety profile, and it was tested at the maximum tolerated dose (MTD). In another cohort, prolonged infusion time of depatux-m was evaluated; and a cohort with confirmed EGFR amplification also was evaluated at the MTD. Results Fifty-six patients were treated. The MTD and the recommended phase 2 dose for depatux-m was 3.0 mg/kg. Common adverse events (AEs) were blurred vision (48%) and fatigue (41%). A majority of patients (66%) experienced 1 or more ocular AEs. Grade 3 or 4 AEs were observed in 43% of patients. One patient with EGFR-amplified, triple-negative breast cancer had a partial response. Stable disease was observed in 23% of patients. Pharmacokinetics revealed that depatux-m exposures were approximately dose-proportional. Conclusions Depatux-m resulted in infrequent nonocular AEs but increased ocular AEs. Patient follow-up confirmed that ocular AEs were reversible. Lowering the drug-antibody ratio did not decrease the number of ocular AEs. A partial response in 1 patient with EGFR-amplified disease provides the opportunity to study depatux-m in diseases with a high incidence of EGFR amplification. Cancer 2018;124:2174-83. © 2018 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Adherence to screening may indirectly help assess whether a prior screening examination deters women from returning for a subsequent examination. We investigated whether compression force and pressure in mammography were associated with re-attendance among prevalently screened women in the organized breast cancer screening program in Norway. Data on compression force (kg) and pressure (kPa) from women's first screening examination in the program (prevalent screening) and subsequent re-attendance were available for 31,225 women aged 50-68, screened during 2007-2013. Crude re-attendance rates and log-binomial regression models estimating the prevalence ratio of re-attendance were used to identify the association between compression force or pressure and re-attendance two-years later. Age and year at prevalent screening, county of residence, screening result (negative or false positive), breast volume, and breast density were included in analyses. Overall, 27,197 (87.1%) women re-attended the program. Re-attendance was highest for women who received a compression force of 10.0-13.9 kg (87.5%) or pressure of 9.0-17.9 kPa (87.8%) and lowest for those who received a compression force of

Background: Patients with hip fracture frequently have sarcopenia and are at great risk of loss of mobility. We have investigated if sarcopenia predicts change in mobility after hip fracture. Methods: This is a prospective, multicenter observational study with one-year follow-up. Patients with hip fracture who were community-living and capable of walking before the fracture were included at three hospitals in Norway (2011–2013). The primary outcome of the study was change in mobility, measured by the New Mobility Score (NMS). Sarcopenia was determined postoperatively by anthropometry, grip strength, and NMS. Results: We included 282 participants and sarcopenia status was determined in 201, of whom 38% (77/201) had sarcopenia, 66% (128/194) had low muscle mass, 52% (116/222) had low grip strength and 8% (20/244) had low pre-fracture mobility (NMS < 5). Sarcopenia did not predict change in mobility (effect 0.2 points; 95% CI –0.5 to 0.9, P = 0.6), but it was associated with having lower mobility at one-year (NMS 5.8 (SD 2.3) vs. 6.8 (SD 2.2), P = 0.003), becoming a resident of a nursing home (odds ratio 3.2, 95% CI 0.9 to 12.4, P = 0.048), and the combined endpoint of becoming a resident of a skilled nursing home or death (odds ratio 3.6, 95% CI 1.2 to 12.2, P = 0.02). Conclusions: Sarcopenia did not predict change in mobility in the year after hip fracture publishedVersion

Introduction Surgical treatment of head and neck malignancies relies on complete tumoral removal, while inadequate margins necessitate the use of adjuvant therapy. Therefore, intraoperative identification of margin status can help to achieve adequate surgical margins. Recent developments in molecular imaging have shown interesting results in the intraoperative visualization of the tumoral tissue, but the techniques investigated to date are limited in penetration-depth and often display the results on a two-dimensional plane. In order to solve these limitations, we investigated whether the use of high-resolution PET and CT could increase certainty about the surgical margins in all three dimensions. Materials and Methods In the current clinical trial, we used a preclinical micro-PET/CT-system (Molecubes, Ghent, Belgium) as a tool for intraoperative margin assessment. Patients planned for the resection of a pathology-proven malignancy in the head and neck were eligible. Approximately one hour prior to surgery, 4 MBq/kg 18F-FDG was administered, followed by standard of care surgical resection. The resected specimen was subsequently scanned with the micro-PET-CT imaging device, followed by pathological assessment. Results Up to date, seven patients were included in the study and intraoperative PET/CT-imaging of 10 specimens identified the 18F-FDG-distribution with a previously unprecedented spatial resolution. We were able to image malignant tissue in all scanned specimens. However, we also encountered difficulties in differentiating between inflamed and dysplastic tissue versus malignant tissue. Particularly in malignancies of the oral cavity, the increased peritumoral inflammation resulted in an increased uptake of 18F-FDG. In contrast, cutaneous malignancies displayed less peritumoral inflammation which enabled better margin assessment. Conclusions We here describe a proof of concept study allowing 3D tumor delineation in head and neck resection specimens using submillimetric PET/CT imaging. Optimization of this tool by identifying tumor types where 18F-FDG-PET has a sufficient contrast to the surrounding tissue to reduce false positives and negatives is required prior to clinical utilization. Moreover, the development of more tumor specific radiotracers, or hybrid fluorescent probes, could potentially greatly improve intraoperative margin assessment.

Objective The current scientific measures of posttraumatic changes in the wake of major stressors have mostly been unidirectional. This study is an attempt to develop a scale that will capture the continuum of positive to negative psychological changes after trauma. Method Forty-five statements were presented to a veteran sample (N = 4,053) with the request to report for each item their experiences of negative, positive, or no posttraumatic changes as a result of their deployment to Afghanistan. Results Principal component analysis brought out 4 dimensions; 26 nonoverlapping items that had correlations above .40 were selected for the final version of the scale. The 4 dimensions were given the following designations: Self-Confidence, Interpersonal Involvement, Awareness, and Social Adaptability. Most veterans reported positive changes (36.8-80.8%) whereas a minority reported negative changes (4.5-22.0%). The total scale score correlated negatively with measures of depression, anxiety, sleep disorders, and posttraumatic stress symptoms. Conclusion The posttraumatic change scale (PTCS) demonstrated acceptable psychometric properties and captured the range from negative to positive posttraumatic changes after major stress. Contrary to several previous studies, positive posttraumatic change, as measured by the PTCS, was not associated with increased symptoms of psychopathology. This underscores the heterogeneity of psychological responses to traumatic events. (PsycINFO Database Record

In Flanders, family foster care is increasingly the option of choice for children in need of out-of-home care. Foster care is however an assailable intervention as is shown by the high number of placement disruptions. Knowledge regarding breakdown in Flanders remains scant. This study aimed at investigating the incidence of placement breakdown in Flemish long-term foster care and exploring the association of breakdown with foster child, foster family and case characteristics. Case files of 309 Flemish foster children were analysed. After 6 years, 208 placements had terminated: 90 placements broke down and 118 placements ended positively. Foster child's behavioural problems, conflicts between birth and foster parents and parenting problems of the foster parents were the main causes of placement disruption. Foster children with behavioural problems at admission, older foster children and foster children who denied treatment were more at risk of breakdown. Consideration of these factors is important in view of the appropriateness of family foster care placements.

Summary Background Further optimisation of present standard chemoradiation is needed in patients with locally advanced rectal cancer. Veliparib, an oral poly(ADP-ribose) polymerase inhibitor, has been shown to enhance the antitumour activity of chemotherapy and radiotherapy in preclinical models. We aimed to establish the maximum tolerated dose and establish the recommended phase 2 dose of veliparib combined with neoadjuvant capecitabine and radiotherapy. Methods This phase 1b, open-label, multicentre, dose-escalation study was done at six hospitals (one in Australia and five in the USA). Patients were eligible if they were aged 18 years or more and were newly diagnosed with stage II to III locally advanced, resectable adenocarcinoma of the rectum with a distal tumour border of less than 12 cm from anal verge. Patients were ineligible if they had received anticancer therapy or surgery (except colostomy or ileostomy) 28 days or less before the first dose of study drug, previous pelvic radiotherapy, or previous treatment with poly (ADP-ribose) polymerase inhibitors. Enrolled patients received capecitabine (825 mg/m 2 orally twice daily) with radiotherapy (50·4 Gy in 1·8 Gy fractions daily, approximately 5 days consecutively per week for about 5·5 weeks). Veliparib (20–400 mg orally twice daily) was administered daily starting on day 2 of week 1 and continuing until 2 days after radiotherapy completion. Patients underwent total mesorectal excision 5–10 weeks after radiotherapy completion. The primary objectives were to establish the maximum tolerated dose and recommended phase 2 dose of veliparib plus capecitabine and radiotherapy, with an exposure-adjusted continual reassessment methodology. Efficacy and safety analyses were done per protocol. The reported study has completed accrual and all analyses are final. This trial is registered with ClinicalTrials.gov, number NCT01589419. Findings Between June 12, 2012, and Jan 13, 2015, 32 patients received veliparib (22 in the dose-escalation group; ten in the safety expansion group); 31 were assessable for efficacy ( Interpretation Veliparib plus capecitabine and radiotherapy had an acceptable safety profile and showed a dose-proportional pharmacokinetic profile with no effect on the pharmacokinetics of capecitabine. Preliminary antitumour activity warrants further evaluation. Funding AbbVie Inc.

ABT-414 is an antibody-drug conjugate (ADC) being developed for the treatment of tumors harboring amplification of the epidermal growth factor receptor (EGFR). This study evaluated the potential of ABT-414 to prolong the QT interval as part of the initial phase 1 study (NCT01741727). Data from patients who received ABT-414 monotherapy at a dose of 1–4 mg/kg once every 3 weeks or 1 or 1.5 mg/kg weekly for 2 out of every 3 weeks (alternate schedule) by intravenous infusion were included in the analysis of triplicate 12-lead ECGs obtained before dosing and through 168 h after dosing. Data from time-matched pharmacokinetic samples and QT interval assessments were evaluated using linear mixed-effects modeling to determine the effects of ABT-414, total ABT-806, and cysteine-maleimidocaproyl monomethyl auristatin F (Cys-mcMMAF) on the QT interval corrected using Fridericia’s formula (QTcF). Fifty-one patients were included in the analyses. ABT-414 had no clinically meaningful effect on QTcF. Using pooled data from doses ≥2 mg/kg, the estimated mean ∆QTcF reached a maximum of 4.30 ms after dosing, with a one-sided 95% upper confidence bound of 8.32 ms. The exposure–response analysis showed no statistically significant relationship between ΔQTcF and the concentration of any analyte (P > 0.05). No patient had a QTcF value >480 ms or a ∆QTcF value >30 ms. ABT-414 had no clinically meaningful effect on the QTcF interval at doses being evaluated for treatment of patients with solid tumors.

Novel therapeutic strategies to eliminate chemo-resistant tumour cells responsible for the development of secondary lesions are essential in order to prevent breast cancer relapse. We have developed an in vitro model system enabling isolation of a putative metastasis-initiating breast cancer cell sub-population with a mitotically quiescent, drug-resistant phenotype. We hypothesise that this population is able to utilise oestrogen-related receptor-alpha (ERR-α)-regulated oxidative lactate metabolism and that inhibition of this critical survival pathway will result in elimination of tumour cells that have survived anti-cancer therapies. Flow cytofluormetric monitoring of Vybrant® DiD retention identified a mitotically quiescent sub-population (~0.05%) in MDA-MB-231 human breast cancer cells grown under high glucose (11mM) conditions. DiD-retaining cells accumulated in the G2/M phase of the cell cycle and were shown to be non-senescent following cytochemical analysis of β-galactosidase activity. Cytotoxicity assays with doxorubicin (0.40μM for 72 hours) demonstrated increased survival in the quiescent fraction (40.76%) compared with the rapidly dividing bulk cell population (1.63%, P ≤ 0.0001). Isolated drug-resistant cells contained a sub-fraction (~1%) that was able to form new clonal populations following cessation of treatment. Mitotically quiescent cells were cultured under high glucose (11mM) or glucose-depleted conditions with high lactate (22mM) in the presence of ERR-α inhibitors Cpd29 (10μM) or XCT790 (10μM). Colony formation was completely eliminated in Cpd29- and XCT790-treated samples compared to untreated controls. Drug-resistant sub-clones were isolated from the quiescent population following 72 hours treatment with doxorubicin (0.40μM) and were cultured under glucose-depleted conditions with high lactate (22mM) in the presence of ERR-α inhibitors Cpd29 (10μM) or XCT790 (10μM). In both instances, colony formation was completely prevented. We provide the first evidence that blocking cellular energy production through inhibition of ERR-α regulated oxidative lactate metabolism can eradicate a chemo-resistant, quiescent breast cancer cell population. Our data suggest that ERR-α inhibitors may be used in combination with chemotherapy to eliminate minimal residual disease and reduce breast cancer recurrence. Citation Format: Quayle L, Park S, McDonnell DP, Ottewell PD, Holen I. Targeting ERR-α regulated lactate metabolism eliminates drug-resistant breast cancer cells [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P3-07-14.

Introduction Bioelectrical impedance analysis (BIA) is in widespread use, but there is uncertainty about its validity in patients with metal implants or after acute hip fracture and surgery. We aimed to investigate the use of single frequency tetrapolar BIA in patients with hip fracture by answering the following questions: 1) Are BIA measurements affected by recent hip fracture and surgical repair? 2) Are BIA measurements affected by the presence of metal implants used in hip fracture surgery? Setting Two hospitals in Bergen, Norway. Participants A convenience sample of 203 acute hip fracture patients. Methods Participants had their body composition measured by single frequency, tetrapolar BIA on the fractured and unfractured side of the body in the immediate postoperative period and at follow-up three months after hip fracture. Measurements from fractured and unfractured side and measurements in hospital and at follow-up were compared. BIA readings for hips treated with cannulated screws, compression hip screw and hip arthroplasty were compared. Results Resistance was lower on the side of the fractured hip compared to the unfractured side postoperatively, but not at follow-up. BIA readings did not differ by type of surgical implant. Conclusion Recent fracture and surgery influences single frequency tetrapolar BIA resistance. The presence of surgical implants in the hip do not affect BIA measurements. If BIA is used in acute hip fracture patients, the contralateral side to the fracture should be measured.

BACKGROUND One of the objectives in the action plan to reduce antimicrobial resistance in the health services in Norway is to reduce the use of broad-spectrum antibiotics in Norwegian hospitals. This study describes the use of certain broad-spectrum antibiotics mentioned in the action plan in Norwegian hospitals, and assesses prescribing practices in relation to the Norwegian guidelines for antibiotic use in hospitals.MATERIAL AND METHOD Data were analysed from a nationwide non-identifiable point prevalence survey in May 2016 where all systemic use of antibiotics was recorded.RESULTS Broad-spectrum antibiotics accounted for 33 % of all antibiotics prescribed. Altogether 84 % of all broad-spectrum antibiotics were prescribed as treatment, 8 % were for prophylactic use, and 8 % were classified as other/unknown. Lower respiratory tract infections were the most frequent indication for treatment with broad-spectrum antibiotics, involving 30 % of all broad-spectrum treatment.INTERPRETATION This point prevalence survey in Norwegian hospitals in spring 2016 indicates a possibility for reducing the use of broad-spectrum antibiotics in the treatment of lower respiratory tract infections and for prophylactic use. Reduction of healthcare-associated infections may also contribute.

Objective Skeletal muscle is an important secretory organ, producing and releasing numerous myokines, which may be involved in mediating beneficial health effects of physical activity. More than 100 myokines have been identified by different proteomics approaches, but these techniques may not detect all myokines. We used mRNA sequencing as an untargeted approach to study gene expression of secreted proteins in skeletal muscle upon acute as well as long-term exercise. Methods Twenty-six middle-aged, sedentary men underwent combined endurance and strength training for 12 weeks. Skeletal muscle biopsies from m. vastus lateralis and blood samples were taken before and after an acute bicycle test, performed at baseline as well as after 12 weeks of training intervention. We identified transcripts encoding secretory proteins that were changed more than 1.5-fold in muscle after exercise. Secretory proteins were defined based on either curated UniProt annotations or predictions made by multiple bioinformatics methods. Results This approach led to the identification of 161 candidate secretory transcripts that were up-regulated after acute exercise and 99 that where increased after 12 weeks exercise training. Furthermore, 92 secretory transcripts were decreased after acute and/or long-term physical activity. From these responsive transcripts, we selected 17 candidate myokines sensitive to short- and/or long-term exercise that have not been described as myokines before. The expression of these transcripts was confirmed in primary human skeletal muscle cells during in vitro differentiation and electrical pulse stimulation (EPS). One of the candidates we identified was macrophage colony-stimulating factor-1 (CSF1), which influences macrophage homeostasis. CSF1 mRNA increased in skeletal muscle after acute and long-term exercise, which was accompanied by a rise in circulating CSF1 protein. In cultured muscle cells, EPS promoted a significant increase in the expression and secretion of CSF1. Conclusion We identified 17 new, exercise-responsive transcripts encoding secretory proteins. We further identified CSF1 as a novel myokine, which is secreted from cultured muscle cells and up-regulated in muscle and plasma after acute exercise., Highlights • Numerous transcripts were identified that were regulated in human skeletal muscle after acute and/or long-term exercise. • These transcripts encode potential myokines, which may play key roles in local and systemic adaptations to exercise. • CSF1 was identified as a novel myokine. CSF1 was increased after acute exercise, and secreted from cultured human myotubes in response to EPS.

Aims and objectives This paper explores the conditions for the possibilities of recovery in a Danish mental healthcare practice, expressed from the perspective of nurses. The results and discussion of the study help to make visible and explore the muddle of conceptualisations of recovery in mental healthcare practice. Background Few studies examine the possibilities of recovery for inpatients and outpatients in mental health centres from a nursing perspective. Design A qualitative design using a critical social constructionist frame of understanding, in which the real world is considered as a series of social constructions. Method A Fairclough-inspired critical discourse analysis was chosen as the analytical strategy. The analysis is comprised of ten interviews in mental health care and notes, written by nurses, in medical records of ten patients with a mental illness admitted to a mental healthcare centre in 2016-2017. The Consolidated Criteria for Reporting Qualitative Research checklist was used as a guideline to secure accurate and complete reporting of the study (See Appendix S1). Results From the findings of the textual analysis and the analysis of the discourse practice, it seems clear that the social relations and structures relating to recovery in Danish psychiatry are steered and controlled by discourses that reflect, in general terms, the essence of the core of neoliberal ideology. Conclusion Recovery is generally articulated from an overall discourse of neoliberalism with its embedded discourses of paternalism, biomedicine, self-care and holism. All these discourses coexist in nursing practice, but the paternalistic discourse becomes the framework for the conditions for the possibility of how recovery is expressed in practice. Relevance to clinical practice Nurses need to be supported to seek clarity in the understanding and operationalisation of a recovery-oriented approach, if the agenda is to be truly adopted and strengthened.