Molecular autopsy for fetal structural anomaly: diagnostic and clinical utility of multidisciplinary team approach.

OBJECTIVES: In the West Midlands Regional Genetic Service, cases of perinatal death with a possible genetic diagnosis are evaluated by the Perinatal Pathology Genetic Multidisciplinary Team (MDT). The MDT assessed autopsy findings and considered genomic assessments. The objective of this retrospective service evaluation was to determine the clinical utility of the MDT. This is the first evaluation since the introduction of whole genome and whole exome sequencing in routine clinical care. METHOD: The outcomes for all the perinatal MDT cases from January 2021 to December 2021 were examined. All cases received a full or partial post-mortem examination (PM) and a chromosomal microarray. Demographics, phenotype, MDT recommendations, genetic testing, diagnoses, outcomes, impact of PM and impact of genetic testing were collected from patient case notes. RESULTS: One hundred and twenty-three cases were discussed at the MDT meeting in 2021. Genetic evaluation was recommended in 84 cases and accepted in 64 cases. A range of genetic tests were requested according to indication and availability. Thirty diagnoses were identified in 29 cases from 26 unrelated families. The diagnostic yield was 24% (29/123) of all cases or 45% (29/64) of the cases with a suspected genetic diagnosis who underwent genetic testing. PM examination added clinically actionable phenotype data in 79% of cases. A genetic diagnosis enabled accurate counselling of recurrence risk and provision of appropriate follow-up, including prenatal testing and preimplantation diagnosis for patients with inherited conditions. CONCLUSIONS: Genomic testing was a clinically useful addition to (but not a substitute for) PM examination in perinatal cases associated with structural anomalies. The MDT model helped assess cases and plan appropriate follow-up. Expedited whole genome sequencing or panel-agnostic analysis were most appropriate for heterogeneous presentations. This broad approach can also expand prenatal phenotypes and detect novel disease genes and should be a priority for future research. This article is protected by copyright. All rights reserved.

Prognostic value of histopathologic traits independent of stromal tumor-infiltrating lymphocyte levels in chemotherapy-naïve patients with triple-negative breast cancer.

BACKGROUND: In the absence of prognostic biomarkers, most patients with early-stage triple-negative breast cancer (eTNBC) are treated with combination chemotherapy. The identification of biomarkers to select patients for whom treatment de-escalation or escalation could be considered remains an unmet need. We evaluated the prognostic value of histopathologic traits in a unique cohort of young, (neo)adjuvant chemotherapy-naïve patients with early-stage (stage I or II), node-negative TNBC and long-term follow-up, in relation to stromal tumor-infiltrating lymphocytes (sTILs) for which the prognostic value was recently reported. MATERIALS AND METHODS: We studied all 485 patients with node-negative eTNBC from the population-based PARADIGM cohort which selected women aged <40 years diagnosed between 1989 and 2000. None of the patients had received (neo)adjuvant chemotherapy according to standard practice at the time. Associations between histopathologic traits and breast cancer-specific survival (BCSS) were analyzed with Cox proportional hazard models. RESULTS: With a median follow-up of 20.0 years, an independent prognostic value for BCSS was observed for lymphovascular invasion (LVI) [adjusted (adj.) hazard ratio (HR) 2.35, 95% confidence interval (CI) 1.49-3.69], fibrotic focus (adj. HR 1.61, 95% CI 1.09-2.37) and sTILs (per 10% increment adj. HR 0.75, 95% CI 0.69-0.82). In the sTILs <30% subgroup, the presence of LVI resulted in a higher cumulative incidence of breast cancer death (at 20 years, 58%; 95% CI 41% to 72%) compared with when LVI was absent (at 20 years, 32%; 95% CI 26% to 39%). In the ≥75% sTILs subgroup, the presence of LVI might be associated with poor survival (HR 11.45, 95% CI 0.71-182.36, two deaths). We confirm the lack of prognostic value of androgen receptor expression and human epidermal growth factor receptor 2 -low status. CONCLUSIONS: sTILs, LVI and fibrotic focus provide independent prognostic information in young women with node-negative eTNBC. Our results are of importance for the selection of patients for de-escalation and escalation trials.

Predicting response to neoadjuvant chemotherapy with liquid biopsies and multiparametric MRI in patients with breast cancer.

Accurate prediction of response to neoadjuvant chemotherapy (NAC) can help tailor treatment to individual patients' needs. Little is known about the combination of liquid biopsies and computer extracted features from multiparametric magnetic resonance imaging (MRI) for the prediction of NAC response in breast cancer. Here, we report on a prospective study with the aim to explore the predictive potential of this combination in adjunct to standard clinical and pathological information before, during and after NAC. The study was performed in four Dutch hospitals. Patients without metastases treated with NAC underwent 3 T multiparametric MRI scans before, during and after NAC. Liquid biopsies were obtained before every chemotherapy cycle and before surgery. Prediction models were developed using penalized linear regression to forecast residual cancer burden after NAC and evaluated for pathologic complete response (pCR) using leave-one-out-cross-validation (LOOCV). Sixty-one patients were included. Twenty-three patients (38%) achieved pCR. Most prediction models yielded the highest estimated LOOCV area under the curve (AUC) at the post-treatment timepoint. A clinical-only model including tumor grade, nodal status and receptor subtype yielded an estimated LOOCV AUC for pCR of 0.76, which increased to 0.82 by incorporating post-treatment radiological MRI assessment (i.e., the "clinical-radiological" model). The estimated LOOCV AUC was 0.84 after incorporation of computer-extracted MRI features, and 0.85 when liquid biopsy information was added instead of the radiological MRI assessment. Adding liquid biopsy information to the clinical-radiological resulted in an estimated LOOCV AUC of 0.86. In conclusion, inclusion of liquid biopsy-derived markers in clinical-radiological prediction models may have potential to improve prediction of pCR after NAC in breast cancer.

Lactational performance, enteric methane emission, and nutrient utilization of dairy cows supplemented with botanicals.

The objective of this study was to evaluate lactational performance, enteric gas emissions, ruminal fermentation, nutrient use efficiency, milk fatty acid profile, and energy and inflammatory markers in blood of peak-lactation dairy cows fed diets supplemented with Capsicum oleoresin or a combination of Capsicum oleoresin and clove oil. A 10-wk randomized complete block design experiment was conducted with 18 primiparous and 30 multiparous Holstein cows. Cows were blocked based on parity, days in milk, and milk yield (MY), and randomly assigned to 1 of 3 treatments (16 cows/treatment): (1) basal diet (CON); (2) basal diet supplemented with 300 mg/cow per day of Capsicum oleoresin (CAP); and (3) basal diet supplemented with 300 mg/cow per day of a combination of Capsicum oleoresin and clove oil (CAPCO). Premixes containing ground corn (CON), CAP, or CAPCO were mixed daily with the basal diet at 0.8% of dry matter intake (DMI). Supplementation of the diet with CAP or CAPCO did not affect DMI, MY, milk components, and feed efficiency of the cows. Body weight (BW) was increased during the last 2 wk of the experiment by CAP and CAPCO, compared with CON. The botanicals improved BW gain (0.85 and 0.66 kg/d for CAP and CAPCO, respectively, compared with -0.01 kg/d for CON) and CAP enhanced the efficiency of energy utilization, compared with CON (94.5% vs. 78.4%, respectively). Daily CH4 emission was not affected by treatments, but CH4 emission yield (per kg of DMI) and intensity (per kg of MY) were decreased by up to 11% by CAPCO supplementation, compared with CON and CAP. A treatment × parity interaction indicated that the CH4 mitigation effect was pronounced in primiparous but not in multiparous cows. Ruminal molar proportion of propionate was decreased by botanicals, compared with CON. Concentrations of trans-10 C18:1 and total trans fatty acids in milk fat were decreased by CAP and tended to be decreased by CAPCO, compared with CON. Total-tract apparent digestibility of nutrients was not affected by treatments, except for a tendency for decreased starch digestibility in cows supplemented with botanicals. Blood concentrations of ß-hydroxybutyrate, total fatty acids, and insulin were not affected by botanicals. Blood haptoglobin concentration was increased by CAP in multiparous but not in primiparous cows. Lactational performance of peak-lactation dairy cows was not affected by the botanicals in this study, but they appeared to improve efficiency of energy utilization and partitioned energy toward BW gain. In addition, CH4 yield and intensity were decreased in primiparous cows fed CAPCO, suggesting a potential positive environmental effect of the combination of Capsicum oleoresin and clove oil supplementation.

A retrospective cohort study of the characteristics of unsuccessful operative vaginal deliveries.

INTRODUCTION: Unsuccessful operative vaginal delivery (OVD) is associated with high rates of materno-fetal morbidity. We aimed to examine institutional rates of unsuccessful OVDs (uOVD) and compare them with successful OVD (sOVD) in order to identify factors to aid patient selection and education. METHODS: A 6-month retrospective cohort study was performed on all unsuccessful and successful OVDs in a tertiary level maternity hospital in the Republic of Ireland. Maternal demographics and obstetric factors were assessed to evaluate potential underlying risk factors for unsuccessful operative vaginal delivery versus successful vaginal delivery. RESULTS: There were 4,191 births during the study period with an OVD rate of 14.2% (n = 595) with 28 (4.7% of OVDs) being unsuccessful. Unsuccessful OVD were predominately nulliparous (25; 89.2%) with a mean maternal age of 30.1 years (range 20-42), with more than half (n = 15, 53.5%) being induced. The most common indication for induction was prolonged rupture of membranes (PROM) (n = 7, 25%) which was significantly different from the successful OVD group. A senior obstetrician was significantly more likely to be the primary operator in uOVD when compared to sOVD. (82.1 % V 54.1% p < 0.01). The majority of unsuccessful OVD were vacuum deliveries (n = 17; 60.7%), with a significantly higher mean birthweight when compared to successful OVD (3.695 kg V 3.483 kg; p < 0.01). Following an unsuccessful OVD, women were more likely to have a postpartum haemorrhage (64.2 % V 31.5% p < 0.01) and their infant was more likely to require admission to the neonatal intensive care unit (NICU) (32.1 % V 5.8% p < 0.01) when compared with successful OVD. CONCLUSION: Risk factors for unsuccessful OVD were higher birth weight and induction of labour. There was a higher incidence of postpartum haemorrhage and NICU admission when compared with successful OVD.

Effect of physical exercise on the hippocampus and global grey matter volume in breast cancer patients: A randomized controlled trial (PAM study).

BACKGROUND: Physical exercise in cancer patients is a promising intervention to improve cognition and increase brain volume, including hippocampal volume. We investigated whether a 6-month exercise intervention primarily impacts total hippocampal volume and additionally hippocampal subfield volumes, cortical thickness and grey matter volume in previously physically inactive breast cancer patients. Furthermore, we evaluated associations with verbal memory. METHODS: Chemotherapy-exposed breast cancer patients (stage I-III, 2-4 years post diagnosis) with cognitive problems were included and randomized in an exercise intervention (n = 70, age = 52.5 ± 9.0 years) or control group (n = 72, age = 53.2 ± 8.6 years). The intervention consisted of 2x1 hours/week of supervised aerobic and strength training and 2x1 hours/week Nordic or power walking. At baseline and at 6-month follow-up, volumetric brain measures were derived from 3D T1-weighted 3T magnetic resonance imaging scans, including hippocampal (subfield) volume (FreeSurfer), cortical thickness (CAT12), and grey matter volume (voxel-based morphometry CAT12). Physical fitness was measured with a cardiopulmonary exercise test. Memory functioning was measured with the Hopkins Verbal Learning Test-Revised (HVLT-R total recall) and Wordlist Learning of an online cognitive test battery, the Amsterdam Cognition Scan (ACS Wordlist Learning). An explorative analysis was conducted in highly fatigued patients (score of ≥ 39 on the symptom scale 'fatigue' of the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire), as previous research in this dataset has shown that the intervention improved cognition only in these patients. RESULTS: Multiple regression analyses and voxel-based morphometry revealed no significant intervention effects on brain volume, although at baseline increased physical fitness was significantly related to larger brain volume (e.g., total hippocampal volume: R = 0.32, B = 21.7 mm3, 95 % CI = 3.0 - 40.4). Subgroup analyses showed an intervention effect in highly fatigued patients. Unexpectedly, these patients had significant reductions in hippocampal volume, compared to the control group (e.g., total hippocampal volume: B = -52.3 mm3, 95 % CI = -100.3 - -4.4)), which was related to improved memory functioning (HVLT-R total recall: B = -0.022, 95 % CI = -0.039 - -0.005; ACS Wordlist Learning: B = -0.039, 95 % CI = -0.062 - -0.015). CONCLUSIONS: No exercise intervention effects were found on hippocampal volume, hippocampal subfield volumes, cortical thickness or grey matter volume for the entire intervention group. Contrary to what we expected, in highly fatigued patients a reduction in hippocampal volume was found after the intervention, which was related to improved memory functioning. These results suggest that physical fitness may benefit cognition in specific groups and stress the importance of further research into the biological basis of this finding.

Effects of phytonutrients and yeast culture supplementation on lactational performance and nutrient use efficiency in dairy cows.

Yeast culture and phytonutrients are dietary supplements with distinct modes of action, and they may have additive effects on the performance of dairy cattle. The objective of this study was to investigate the effects of a preparation of phytonutrients and a yeast culture from Saccharomyces cerevisiae on lactational performance, total-tract digestibility of nutrients, urinary nitrogen losses, energy metabolism markers, and blood cells in dairy cows. Thirty-six mid-lactation Holstein cows (10 primiparous and 26 multiparous) were used in an 8-wk randomized complete block design experiment with a 2-wk covariate period, 2 wk for adaptation to the diets, and a 4-wk experimental period for data and samples collection. Following a 2-wk covariate period, cows were blocked by days in milk, parity, and milk yield and randomly assigned to 1 of 3 treatments (12 cows per treatment): basal diet supplemented with 14 g/cow per day yeast culture (YC; S. cerevisiae), basal diet supplemented with 1.0 g/cow per day phytonutrients (PN; 5.5% cinnamaldehyde, 9.5% eugenol, and 3.5% capsicum oleoresin), or basal diet supplemented with a combination of YC and PN (YCPN). Treatments were top-dressed once daily on the total mixed ration at time of feeding. Dry matter intake, milk yield, and feed efficiency were not affected by treatments. Milk composition and energy-corrected milk yield were also not affected by supplementation of YC, PN, and YCPN. There were no differences in intake or total-tract digestibility of dietary nutrients among treatments. Compared with YC, the PN and YCPN treatments tended to decrease the proportion of short-chain fatty acids in milk fat. There was an additive effect of YC and PN supplementation on urinary urea nitrogen (UUN) excretion relative to total nitrogen intake. Cows fed a diet supplemented with YCPN had lower UUN excretion than cows in YC and tended to have lower UUN excretion compared with PN. Blood monocytes count and percentage were decreased in cows fed PN and YCPN diets compared with YC. Treatments did not affect concentrations of blood ß-hydroxybutyrate and total fatty acids. Overall, lactational performance, digestibility of nutrients, energy metabolism markers, and blood cells were not affected by YC, PN, or YCPN supplementation. A combination of PN and YC had an additive effect on nitrogen excretion in dairy cows.

Correlations of milk and serum element concentrations with production and management traits in dairy cows.

The present study investigated the potential consequences, positive or negative, that selection for favorable production-related traits may have on concentrations of vitamin B12 and key chemical elements in dairy cow milk and serum and the possible impact on milk healthiness, and associated benefits, for the dairy product consumer. Milk and serum samples (950 and 755, respectively) were collected from Holstein-Friesian dairy cows (n = 479) on 19 occasions over a 59-mo period, generating 34,258 individual records, and analyzed for concentrations of key trace and quantity elements, heavy metals, and milk vitamin B12. These data were then matched to economically important production data (milk, fat, and protein yield) and management data (dry matter intake, liveweight, and body condition score). Multivariate animal models, including full pedigree information, were used to analyze data and investigate relationships between traits of interest. Results highlighted negative genetic correlations between many quantity and trace elements in both milk and serum with production and management traits. Milk yield was strongly negatively correlated with the milk quantity elements Mg and Ca (genetic correlation between traits, ra = -0.58 and -0.63, respectively) as well as the trace elements Mn, Fe, Ni, Cu, Zn, and Mo (ra = -0.32, -0.58, -0.52, -0.40, -0.34, and -0.96, respectively); and in serum, Mg, Ca, Co, Fe, and Zn (ra = -0.50, -0.36, -0.68, -0.54, and -0.90, respectively). Strong genetic correlations were noted between dry matter intake with V (ra = 0.97), Fe (ra = -0.69), Ni (ra = -0.81), and Zn (ra = -0.75), and in serum, strong negative genetic correlations were observed between dry matter intake with Ca and Se (ra = -0.95 and -0.88, respectively). Body condition score was negatively correlated with serum P, Cu, Se, and Pb (ra = -0.45, -0.35, -0.51, and -0.64, respectively) and positively correlated with Mn, Fe, and Zn (ra = 0.40, 0.71, and 0.55, respectively). Our results suggest that breeding strategies aimed at improving economically important production-related traits would most likely result in a negative impact on levels of beneficial nutrients within milk for human consumption (such as Mg, Ca, Fe, Zn, and Se).

The effects of weather on beef carcass and growth traits.

To predict the impact of climate change on our beef animals and systems, we need a better understanding of how beef cattle traits are affected by varying weather and frequency of extreme events. We analysed the effect of minimum and maximum temperatures and average daily precipitation on a range of important carcass traits, including age at slaughter, cold carcass weight, carcass growth rate and conformation and fat score (N = >1.6 million), as well as calf 200-day live weight and growth rate (N = >270 000), using data from abattoirs across Britain (carcass traits) and calves in Scottish suckler beef herds (live weights and growth). Animals which experienced higher daily maximum and minimum temperatures had slower carcass and calf growth rates. Increased precipitation also led to poorer cold carcass weights, conformation scores, calf 200-day weights and calf growth. We also analysed the effect of frequency of extreme weather events, including heatwaves, cold waves, and dry and wet days. The frequency of heatwaves, dry and wet days were shown to have significant negative effects on almost all traits considered, for example, predicting that an increase in the frequency of heatwaves by 1 day per 100 days of life would reduce cold carcass weights by about 200 g and increase age at slaughter by about 3 days. Results show that varying weather and frequency of extreme weather, across the lifetime of a beef animal, influences traits which affect the potential profit for a beef farmer. These effects may be due to several factors, including direct effects on the animal, as well as feed availability and management decisions made by the farmer. However, there is potential to mitigate negative effects through a range of animal management strategies.

Effects of a combination of Capsicum oleoresin and clove essential oil on metabolic status, lactational performance, and enteric methane emissions in dairy cows.

Botanical extracts have a potential to modify ruminal fermentation while enhancing metabolism and immunity in dairy cows. The objective of this study was to investigate the effects of a combination of Capsicum oleoresin and clove essential oil (botanicals; BTC) on lactational performance, nutrient utilization, enteric methane (CH4) emissions, and blood parameters in dairy cows. Twenty Holstein cows (12 multiparous and 8 primiparous) averaging (±SD) 77 ± 28 d in milk in the beginning of the study were used in a replicated 4 × 4 Latin square design experiment with 4 periods of 28 d each. Cows were grouped into squares based on parity, milk yield and days in milk, and assigned to 1 of 4 treatments: control (CON), 150, 300, or 600 mg/cow per day of BTC. Cows received the same basal diet and BTC were top-dressed on the total mixed ration once daily. Dry matter intake, milk production, and milk composition were not affected by BTC supplementation, except for milk fat content that tended to be increased in BTC, compared with CON. Daily CH4 emission (measured using the GreenFeed system) was linearly decreased by up to 7.5% with increasing doses of BTC. Treatment decreased CH4 yield (kg of CH4 ÷ kg of DMI) and tended to decrease CH4 intensity (kg of CH4 ÷ kg of milk or energy-corrected milk yields) by 5% in BTC, compared with CON. Supplementation of BTC resulted in a quadratic decrease of serum ß-hydroxybutyrate in all cows, and a linear decrease of serum insulin concentration in primiparous but not in multiparous cows. Nutrient utilization and other blood parameters (e.g., blood cells count) were not affected by BTC in the current study. The reduction of enteric CH4 emission demonstrates a moderate mitigation effect on carbon footprint of milk by BTC supplementation. These results must be further investigated and confirmed in longer-term experiments.

MRI to assess response after neoadjuvant chemotherapy in breast cancer subtypes: a systematic review and meta-analysis.

This meta-analysis aimed to estimate and compare sensitivity, specificity, positive- (PPV) and negative predictive value (NPV) of magnetic resonance imaging (MRI) for predicting pathological complete remission (pCR) after neoadjuvant chemotherapy (NAC) in patients with early-stage breast cancer. We stratified for molecular subtype by immunohistochemistry (IHC) and explored the impact of other factors. Two researchers systematically searched PUBMED and EMBASE to select relevant studies and extract data. For meta-analysis of sensitivity and specificity, we used bivariate random-effects models. Twenty-six included studies contained 4497 patients. There was a significant impact of IHC subtype on post-NAC MRI accuracy (p = 0.0082) for pCR. The pooled sensitivity was 0.67 [95% CI 0.58-0.74] for the HR-/HER2-, 0.65 [95% CI 0.56-0.73] for the HR-/HER2+, 0.55 [95% CI 0.45-0.64] for the HR+/HER2- and 0.60 [95% CI 0.50-0.70] for the HR+/HER2+ subtype. The pooled specificity was 0.85 [95% CI 0.81-0.88] for the HR-/HER2-, 0.81 [95% CI 0.74-0.86] for the HR-/HER2+, 0.88[95% CI 0.84-0.91] for the HR+/HER2- and 0.74 [95% CI 0.63-0.83] for the HR+/HER2+ subtype. The PPV was highest in the HR-/HER2- subtype and lowest in the HR+/HER2- subtype. MRI field strength of 3.0 T was associated with a higher sensitivity compared to 1.5 T (p = 0.00063). The accuracy of MRI for predicting pCR depends on molecular subtype, which should be taken into account in clinical practice. Higher MRI field strength positively impacts accuracy. When intervention trials based on MRI response evaluation are designed, the impact of IHC subtype and field strength on MR accuracy should be considered.

Possible alleviation of symptoms and side effects through clinicians' nocebo information and empathy in an experimental video vignette study.

To alleviate anti-cancer treatment burden in advanced breast cancer, patient-clinician communication strategies based on nocebo-effect mechanisms are promising. We assessed distinct/combined effects on psychological outcomes (e.g. anxiety; main outcome) and side-effect expectations of (1) nocebo information about the (non)pharmacological origin of side effects, and (2) clinician-expressed empathy through reassurance of continuing support. Furthermore, we explored whether information and empathy effects on side-effect expectations were mediated by decreased anxiety. In a two-by-two experimental video-vignette design, 160 cancer patients/survivors and healthy women watched one of four videos differing in level of nocebo information (±) and empathy (±). Regression and mediation analysis were used to determine effects of information/empathy and explore anxiety's mediating role. Anxiety was not influenced by empathy or information (Stai-state: p = 0.295; p = 0.390, VAS p = 0.399; p = 0.823). Information improved (specific) side-effect coping expectations (p < 0.01). Empathy improved side-effect intensity expectations (p < 0.01 = specific; p < 0.05 = non-specific/partial) and specific side-effect probability expectations (p < 0.01), and increased satisfaction, trust, and self-efficacy (p < 0.001). No mediating effects were found of anxiety on expectations. Mainly empathy, but also nocebo information improved psychological outcomes and-mainly specific-side-effect expectations. Exploring the power of these communication elements in clinical practice is essential to diminish the anti-cancer treatment burden in advanced breast cancer.

Genomic copy number alterations as biomarkers for triple negative pregnancy-associated breast cancer.

BACKGROUND: PABC, commonly defined as breast cancer diagnosed during or ≤ 1 year after pregnancy, accounts for 7% of all breast cancers in women ≤ 45 years. Compared to age-matched non-PABC patients, PABC is characterized by a particularly aggressive histopathologic profile with poorly differentiated and estrogen- and progesterone receptor negative tumors and associated high mortality rates. This study assessed the genomic background of triple-negative PABC tumors by detection of copy number alterations (CNAs). METHODS: MLPA was used to compare CNAs in breast cancer-associated chromosomal loci between triple-negative PABC- and subtype-matched non-PABC patients. Both CNA patterns were evaluated by cluster analysis; associations between individual gene CNAs, pathological characteristics and survival were explored. RESULTS: Triple-negative PABC tumors exhibited unique CNAs compared to non-PABC tumors, including enrichment for TOP2A copy number loss, an independent predictor of worse overall survival (HR 8.96, p = 0.020). Cluster analysis based on CNA profiles identified a triple-negative PABC-subgroup with a particularly poor prognosis, characterized by chromosome 8p copy number loss. Individual gene CNAs analysis revealed that FGFR1 copy number loss on chromosome 8p11.23 was an independent predictor of poor outcome in multivariate analysis (HR 3.59, p = 0.053) and predicted the development of distant metastases (p = 0.048). CONCLUSION: This study provides novel insights into the biology of triple-negative PABC tumors suggesting that CNAs, particularly 8p loss and TOP2A loss, are involved in the development of breast cancer during pregnancy. FGFR1 loss and TOP2A loss seem to be promising new biomarkers that independently identify subgroups of PABC patients with poor prognosis. These genomic biomarkers may provide clues for personalized therapy.

Effects of structured involvement of the primary care team versus standard care after a cancer diagnosis on patient satisfaction and healthcare use: the GRIP randomised controlled trial.

BACKGROUND: The growing number of cancer survivors and treatment possibilities call for more personalised and integrated cancer care. Primary care seems well positioned to support this. We aimed to assess the effects of structured follow-up of a primary care team after a cancer diagnosis. METHODS: We performed a multicentre randomised controlled trial enrolling patients curatively treated for breast, lung, colorectal, gynaecologic cancer or melanoma. In addition to usual cancer care in the control group, patients randomized to intervention were offered a "Time Out consultation" (TOC) with the general practitioner (GP) after diagnosis, and subsequent follow-up during and after treatment by a home care oncology nurse (HON). Primary outcomes were patient satisfaction with care (questionnaire: EORTC-INPATSAT-32) and healthcare utilisation. Intention-to-treat linear mixed regression analyses were used for satisfaction with care and other continuous outcome variables. The difference in healthcare utilisation for categorical data was calculated with a Pearson Chi-Square or a Fisher exact test and count data (none versus any) with a log-binomial regression. RESULTS: We included 154 patients (control n = 77, intervention n = 77) who were mostly female (75%), mainly diagnosed with breast cancer (51%), and had a mean age of 61 (SD ± 11.9) years. 81% of the intervention patients had a TOC and 68% had HON contact. Satisfaction with care was high (8 out of 10) in both study groups. At 3 months after treatment, GP satisfaction was significantly lower in the intervention group on 3 of 6 subscales, i.e., quality (- 14.2 (95%CI -27.0;-1.3)), availability (- 15,9 (- 29.1;-2.6)) and information provision (- 15.2 (- 29.1;-1.4)). Patients in the intervention group visited the GP practice and the emergency department more often ((RR 1.3 (1.0;1.7) and 1.70 (1.0;2.8)), respectively). CONCLUSIONS: In conclusion, the GRIP intervention, which was designed to involve the primary care team during and after cancer treatment, increased the number of primary healthcare contacts. However, it did not improve patient satisfaction with care and it increased emergency department visits. As the high uptake of the intervention suggests a need of patients, future research should focus on optimizing the design and implementation of the intervention. TRIAL REGISTRATION: GRIP is retrospectively (21/06/2016) registered in the 'Netherlands Trial Register' (NTR5909).

Review: Preference elicitation methods for appropriate breeding objectives.

Breeding objectives of livestock and other agricultural species are usually profit maximising. The selection emphasis placed on specific traits to achieve a breeding objective is often informed by the financial value of a trait to a farm system. However, there are alternative, and complementary approaches to defining both the breeding objective and the selection emphasis placed on traits that are included in associated selection tools. These are based on the preferences of stakeholders, which are often heterogeneous and include broader values and motivations than profit. In this regard, stated preference methods are useful when considering traits that have either no discernible market value or whose value is not fully transferred via the market. Such approaches can guide more appropriate breeding decisions that are amenable to changing societal values, for example with reduced negative environmental externalities. However, while stated preference methods offer promising conceptualisations of value in genetic improvement programmes, there is still a substantial knowledge gap in terms of the current state of research and a catalogue of publications to date. This paper reviews publications of stated preference approaches in the field of livestock breeding (and some relevant crop breeding examples), providing a knowledge base of published applications and promoting their continued development and implementation towards the formulation of appropriate breeding objectives and selection indices. A systematic review of 84 peer-reviewed publications and an aggregate ranking of traits for the most commonly studied subject (cattle) reveals uncertainty in preference estimates which may be driven by (i) a diverse set of non-standardised methodologies, (ii) common oversights in the selection, inclusion and description of traits, and (iii) inaccurate representations of the respondent population. We discuss key considerations to help overcome these limitations, including avoiding methodological confinement to a disciplinary silo and reducing complexity so that the values of broader respondent groups may be accounted for.

Effect of physical exercise on cognitive function after chemotherapy in patients with breast cancer: a randomized controlled trial (PAM study).

BACKGROUND: Up to 60% of breast cancer patients treated with chemotherapy is confronted with cognitive problems, which can have a significant impact on daily activities and quality of life (QoL). We investigated whether exercise training improves cognition in chemotherapy-exposed breast cancer patients 2-4 years after diagnosis. METHODS: Chemotherapy-exposed breast cancer patients, with both self-reported cognitive problems and lower than expected performance on neuropsychological tests, were randomized to an exercise or control group. The 6-month exercise intervention consisted of supervised aerobic and strength training (2 h/week), and Nordic/power walking (2 h/week). Our primary outcome was memory functioning (Hopkins Verbal Learning Test-Revised; HVLT-R). Secondary outcomes included online neuropsychological tests (Amsterdam Cognition Scan; ACS), self-reported cognition (MD Anderson Symptom Inventory for multiple myeloma; MDASI-MM), physical fitness (relative maximum oxygen uptake; VO2peak), fatigue (Multidimensional Fatigue Inventory), QoL (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire; EORTC QLQ C-30), depression (Patient Health Questionnaire-9, Hospital Anxiety and Depression Scale; HADS), and anxiety (HADS). HVLT-R total recall was analyzed with a Fisher exact test for clinically relevant improvement (≥ 5 words). Other outcomes were analyzed using multiple regression analyses adjusted for baseline and stratification factors. RESULTS: We randomized 181 patients to the exercise (n = 91) or control group (n = 90). Two-third of the patients attended ≥ 80% of the exercise sessions, and physical fitness significantly improved compared to control patients (B VO2peak 1.4 ml/min/kg, 95%CI:0.6;2.2). No difference in favor of the intervention group was seen on the primary outcome. Significant beneficial intervention effects were found for self-reported cognitive functioning [MDASI-MM severity (B-0.7, 95% CI - 1.2; - 0.1)], fatigue, QoL, and depression. A hypothesis-driven analysis in highly fatigued patients showed positive exercise effects on tested cognitive functioning [ACS Reaction Time (B-26.8, 95% CI - 52.9; - 0.6) and ACS Wordlist Learning (B4.4, 95% CI 0.5; 8.3)]. CONCLUSIONS: A 6-month exercise intervention improved self-reported cognitive functioning, physical fitness, fatigue, QoL, and depression in chemotherapy-exposed breast cancer patients with cognitive problems. Tested cognitive functioning was not affected. However, subgroup analysis indicated a positive effect of exercise on tested cognitive functioning in highly fatigued patients. Trial Registration Netherlands Trial Registry: Trial NL5924 (NTR6104). Registered 24 October 2016, https://www.trialregister.nl/trial/5924 .

Population-based estimates of overtreatment with adjuvant systemic therapy in early breast cancer patients with data from the Netherlands and the USA.

PURPOSE: Although adjuvant systemic therapy (AST) helps increase breast cancer-specific survival (BCSS), there is a growing concern for overtreatment. By estimating the expected BCSS of AST using PREDICT, this study aims to quantify the number of patients treated with AST without benefit to provide estimates of overtreatment. METHODS: Data of all non-metastatic unilateral breast cancer patients diagnosed in 2015 were retrieved from cancer registries from The Netherlands and the USA. The PREDICT tool was used to estimate AST survival benefit. Overtreatment was defined as the proportion of patients that would have survived regardless of or died despite AST within 10 years. Three scenarios were evaluated: actual treatment, and recommendations by the Dutch or USA guidelines. RESULTS: 59.5% of Dutch patients were treated with AST. 6.4% (interquartile interval [IQI] = 2.5, 8.2%) was expected to survive at least 10 years due to AST, leaving 93.6% (IQI = 91.8, 97.5%) without AST benefit (overtreatment). The lowest expected amount of overtreatment was in the targeted and chemotherapy subgroup, with 86.5% (IQI = 83.4, 89.6%) overtreatment, and highest in the only endocrine treatment subgroup, with 96.7% (IQI = 96.0, 98.1%) overtreatment. Similar results were obtained using data from the USA, and guideline recommendations. CONCLUSION: Based on PREDICT, AST prevents 10-year breast cancer death in 6.4% of the patients treated with AST. Consequently, AST yields no survival benefit to many treated patients. Especially improved personalization of endocrine therapy is relevant, as this therapy is widely used and is associated with the highest amount of overtreatment.

Prognosis of pregnancy-associated breast cancer: inferior outcome in patients diagnosed during second and third gestational trimesters and lactation.

PURPOSE: Pregnancy-associated breast cancer, although most commonly defined as breast cancer diagnosed during pregnancy or ≤1 year following delivery, knows a variety of definitions, likely related to the diversity of reported clinicopathological features and prognosis. More insight into the different breast cancer subgroups during pregnancy, time after delivery and the postpartum period is therefore warranted. METHODS: Patients with breast cancer diagnosed during pregnancy or ≤6 months postdelivery were included, and subdivided according to gestational trimester, and postpartum patients according to lactational status. Subgroups were compared to matched non-PABC patients, to investigate the influence of pregnancy and lactation on clinical course and outcome. RESULTS: Overall, 662 PABC patients were included (median age 34 years, median follow-up 6.5 years). PABC patients showed an advanced stage at diagnosis and an inferior 5-years-OS (75.4% vs. 83.2%, p = 0.000) compared to 1392 matched non-PABC patients. In subgroup analysis, first trimester PABC patients showed a significantly lower tumor size and stage as compared to other trimesters. Patients diagnosed during the first trimester and postpartum non-lactating patients had a relatively good OS (81.3% and 77.9%, respectively) versus patients diagnosed during the second and third trimesters and during lactation (OS 60.0%, 64.9% and 65.6%, respectively, p = 0.003). CONCLUSION: In this large (uniquely specified) PABC cohort, an inferior outcome was found for patients diagnosed within the second and third gestational trimesters and during lactation. These findings indicate that PABC is clinically a heterogeneous group of breast cancer patients that should be redefined based on trimester of diagnosis and lactational status.

Preferences of European dairy stakeholders in breeding for resilient and efficient cattle: A best-worst scaling approach.

Including resilience in the breeding objective of dairy cattle is gaining increasing attention, primarily as anticipated challenges to production systems, such as climate change, may make some perturbations more difficult to moderate at the farm level. Consequently, the underlying biological mechanisms by which resilience is achieved are likely to become an important part of the system itself, increasing value on the animal's ability to be unperturbed by variable production circumstances, or to quickly return to pre-perturbed levels of productivity and health. However, because the value of improving genetic traits to a system is usually based on known profit functions or bioeconomic models linked to current production conditions, it can be difficult to define longer-term value, especially under uncertain future production circumstances and where nonmonetary values may be progressively more important. We present the novel application of a discrete choice experiment, used to investigate potential antagonisms in the values of genetic improvements for 8 traits to dairy cattle system stakeholders in Europe when the production goal was either efficiency or resilience. A latent class model was used to identify heterogeneous preferences within each production goal, and postestimation was used to identify associations between these preferences and sociodemographic characteristics of respondents. Results suggested 3 distinct latent preference classes for each production goal. For the efficiency goal, yield and feed efficiency traits were generally highly valued, whereas for the resilience goal, health and robustness traits were generally highly valued. In both cases, these traits generally carried a low value in the other production scenario. Overall, in both scenarios, longevity was highly valued; however, the value of this trait in terms of resilience will depend on phenotyping across diverse environments to sufficiently capture performance under various anticipated system challenges. Additionally, results showed significant associations between membership of latent preference classes with education level and profession. In conclusion, as resilience becomes increasingly important, it is likely that a continued reliance on the short-term economic value of traits alone will lead decision makers to misrepresent the importance of some traits, including those with substantial contextual values in terms of resilience.