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Objectives In the Cancer Core Europe Consortium (CCE), standardized biomarkers are required for therapy monitoring oncologic multicenter clinical trials. Multiparametric functional MRI and particularly diffusion-weighted MRI offer evident advantages for noninvasive characterization of tumor viability compared to CT and RECIST. A quantification of the inter- and intraindividual variation occurring in this setting using different hardware is missing. In this study, the MRI protocol including DWI was standardized and the residual variability of measurement parameters quantified. Methods Phantom and volunteer measurements (single-shot T2w and DW-EPI) were performed at the seven CCE sites using the MR hardware produced by three different vendors. Repeated measurements were performed at the sites and across the sites including a traveling volunteer, comparing qualitative and quantitative ROI-based results including an explorative radiomics analysis. Results For DWI/ADC phantom measurements using a central post-processing algorithm, the maximum deviation could be decreased to 2%. However, there is no significant difference compared to a decentralized ADC value calculation at the respective MRI devices. In volunteers, the measurement variation in 2 repeated scans did not exceed 11% for ADC and is below 20% for single-shot T2w in systematic liver ROIs. The measurement variation between sites amounted to 20% for ADC and < 25% for single-shot T2w. Explorative radiomics classification experiments yield better results for ADC than for single-shot T2w. Conclusion Harmonization of MR acquisition and post-processing parameters results in acceptable standard deviations for MR/DW imaging. MRI could be the tool in oncologic multicenter trials to overcome the limitations of RECIST-based response evaluation. Key Points • Harmonizing acquisition parameters and post-processing homogenization, standardized protocols result in acceptable standard deviations for multicenter MR–DWI studies. • Total measurement variation does not to exceed 11% for ADC in repeated measurements in repeated MR acquisitions, and below 20% for an identical volunteer travelling between sites. • Radiomic classification experiments were able to identify stable features allowing for reliable discrimination of different physiological tissue samples, even when using heterogeneous imaging data.

The thermodynamic description of pure Fe was re-assessed using updated third generation Calphad models and taking into account the most recent theoretical data. In the present re-assessment, a critical evaluation was performed for the magnetic properties of the fcc and hcp phases yielding different descriptions from those accepted in the SGTE database. The selected magnetic properties enable us to model the thermodynamic properties of fcc satisfactorily without using the magnetic two-state model. A new method was applied to extrapolate the thermodynamic data for the solid phases, i.e. a single Gibbs energy expression is used for the entire temperature range for the bcc, fcc and hcp phases. The description of the liquid phase was re-evaluated following a recent suggestion on estimating the electronic heat capacity coefficient for the liquid phase. Overall, the present Calphad description can reproduce the selected experimental and theoretical data well.

Background Most sarcomas metastasize predominantly to the lungs, and chest x-ray, or computed tomography, is the most commonly used staging investigation. Myxoid liposarcomas (MLSs) are rare tumors with a tendency to metastasize to extrapulmonary loci. The aim of this study was to assess the locations of the first metastases in MLS patients, to guide the design of effective staging and follow-up imaging protocols. Methods Patients treated for MLS between 1987 and 2017 were identified in a prospectively maintained register. Histology of the tumors was reassessed. In addition, the presence of one of the pathognomonic gene translocations was confirmed, uniquely for a retrospective series. The surgical and oncological outcomes were reviewed. A comprehensive review of the literature was performed on the metastatic pattern of MLS, including series with 10 or more MLS patients with metastatic disease. Results A total of 32 patients with genetically confirmed MLS were identified, with a median follow-up of 7.6 years. Seven patients (22%) developed metastatic disease, five initially intra-abdominally and only one to the lungs. The comprehensive review included 14 series with 1853 patients, 348 (19%) of whom had metastases. The location of the first metastases was soft tissues in 32% of patients, intra-abdominal in 26%, pulmonary in 24%, and bone in 17%. Conclusions MLSs metastasize often intra-abdominally and to extra-abdominal soft tissues. Thus, whole-body imaging may be indicated during the initial assessment and follow-up of these patients.

Purpose This retrospective, practice-based study investigates behaviour management problems (BMPs) in dental care among Finnish children with operated congenital heart disease (CHD). Methods All the heart-operated children born between the years 1997 and 1999 were identified in the national ProCardio database (n = 570). Primary dental care records were requested from this population and were eventually received from 211 patients. Information on gender, diagnosis, number of heart operations and perioperative care were collected from the ProCardio database, and the CHDs were categorised as shunting/stenotic/complex/other defects. Data on BMP/dental fear, oral conscious sedation, dental general anaesthesia (DGA) and past and present caries indices at 6, 12 and 15 years (d/D, dmft/DMFT) were assessed. Results Notes on behaviour management problems or dental fear were found in 19% of the study population. BMPs in dental care were more frequent among boys. Children with re-operations, longer post-operative intensive care stay and hospitalisation, and complications had not more BMP than others. Those children diagnosed with syndromes had more BMP often than the rest. Past and present caries experience were significantly associated with BMP, need of oral conscious sedation and DGA. Oral conscious sedation, nitrogen oxide sedation and dental general anaesthesia were used in 17/211, 2/221 and 24/211 CHD patients, respectively. Conclusion Dental caries remains a main factor associated with BMP in the CHD population. Need for oral conscious sedation and DGA were rather common. To maintain a good oral health and to avoid development of BMP, CHD children benefit from focus in health promotion and preventive care.

Background Low-frequency variants play an important role in breast cancer (BC) susceptibility. Gene-based methods can increase power by combining multiple variants in the same gene and help identify target genes. Methods We evaluated the potential of gene-based aggregation in the Breast Cancer Association Consortium cohorts including 83,471 cases and 59,199 controls. Low-frequency variants were aggregated for individual genes’ coding and regulatory regions. Association results in European ancestry samples were compared to single-marker association results in the same cohort. Gene-based associations were also combined in meta-analysis across individuals with European, Asian, African, and Latin American and Hispanic ancestry. Results In European ancestry samples, 14 genes were significantly associated (q FMNL3 (P = 6.11 × 10−6) and AC058822.1 (P = 1.47 × 10−4), represent new associations. High FMNL3 expression has previously been linked to poor prognosis in several other cancers. Meta-analysis of samples with diverse ancestry discovered further associations including established candidate genes ESR1 and CBLB. Furthermore, literature review and database query found further support for a biologically plausible link with cancer for genes CBLB, FMNL3, FGFR2, LSP1, MAP3K1, and SRGAP2C. Conclusions Using extended gene-based aggregation tests including coding and regulatory variation, we report identification of plausible target genes for previously identified single-marker associations with BC as well as the discovery of novel genes implicated in BC development. Including multi ancestral cohorts in this study enabled the identification of otherwise missed disease associations as ESR1 (P = 1.31 × 10−5), demonstrating the importance of diversifying study cohorts.

Purpose Oral health of children with congenital heart disease (CHD) is of utmost importance. This study aimed to investigate the prevalence of dental caries and attendance to dental care in Finnish heart-operated CHD patients born in 1997–1999. Methods The cohort of children born in 1997–1999 was selected using a national register on all heart-operated children in Finland. Gender, general health problems, diagnosis, type of the heart defect (shunting, stenotic and complex defects), and number of operations were available and included in the analyses. Dental records from primary health care were collected from municipalities with their permission. The data comprised of the number of dental examinations and data on caries status (dt, DT, dmft, DMFT) at the age of 7 (grade 1), 11 (grade 5) and 15 (grade 8) years and at the most recent examination. The control group consisted of dental data on patients born in 1997–1999 provided by the City of Oulu, Finland (n = 3356). Results Oral patient records of 215/570 children were obtained. The difference between the defect types was statistically significant both for DT (p = 0.046) and DMFT (p = 0.009) at the age of 15 (grade 8). The prevalence of caries did not differ between the study population and the controls. High present and past caries experiences were not associated with higher number of visits to oral health care, especially to oral hygienist, or with oral health promotion. National obligations concerning dental visits were not implemented in all municipalities. Conclusion There seems to be a need for oral health promotion and preventive means implemented by oral hygienists among those with CHD.

BackgroundFew studies have focused on patient-related factors in analyzing long-term functional outcome and health-related quality of life (HRQoL) in patients with postoperative lower extremity soft tissue sarcoma (STS).ObjectiveThe purpose of this study was to investigate factors associated with postoperative functional outcome and HRQoL in patients with lower extremity STS.MethodsThis cross-sectional study was performed in a tertiary referral center using the Toronto Extremity Salvage Score (TESS), Quality-of-Life Questionnaire (QLQ)-C30 and 15 Dimension (15D) measures. Functional outcome and HRQoL data were collected prospectively. All patients were treated by a multidisciplinary team according to a written treatment protocol.ResultsA total of 141 patients who had undergone limb-salvage surgery were included. Depending on the outcome measure used, 19–51% of patients were completely asymptomatic and 13–14% of patients had an unimpaired HRQoL. The mean score for TESS, 15D mobility score, and QLQ-C30 Physical Functioning scale were 86, 0.83, and 75, respectively, while the mean score for 15D was 0.88, and 73 for QLQ-C30 QoL. Lower functional outcome was statistically significantly associated with higher age, higher body mass index (BMI), and the need for reconstructive surgery and radiotherapy, while lower HRQoL was statistically significantly associated with higher age, higher BMI, and reconstructive surgery.ConclusionFunctional outcome and HRQoL were generally high in this cross-sectional study of patients with STS in the lower extremity. Both tumor- and treatment-related factors had an impact but patient-related factors such as age and BMI were the major determinants of both functional outcome and HRQoL.

To analyze whether monitoring serum estradiol (E2) levels using a highly sensitive and specific liquid chromatography tandem mass spectrometry (LC–MS/MS) method may identify patients with AI failure with E2 levels below the lower limit of quantification (LLOQ) after schwitching from tamoxifen to letrozole. In a prospective study of breast cancer patients switching to letrozole treatment after previous tamoxifen, plasma estrogen levels were measured at baseline and after 3- and 12-months using LC–MS/MS. Forty-six patients were classified postmenopausal and entered into the final analysis. Thirty-nine (85%) patients had three- and 12-month E2 concentrations below the LLOQ (5 pmol/L). In the seven patients classified as AI-failures during letrozole treatment, serum E2-MS level rose above 5 pmol/L at 3 months with a mean E2-MS 77.5 pmol/L or 12 months with a mean E2-MS 21 pmol/L. None of the baseline variables i.e., age at diagnosis, age at study entry, age at menarche, BMI, endometrial thickness, total ovarian volume, baseline FSH, E2-IA, or E2-MS were significantly associated with the risk of AI failure in logistic regression. E2 levels at baseline measured by E2-IA did not significantly correlate to the levels measured by E2-MS. There is a relatively high risk of inadequate estrogen suppression in patients who switch from tamoxifen treatment to AIs. The use of sensitive and specific assays, such as LC–MS/MS methods, to monitor estrogen levels during AI treatment is essential to minimize the risk of a proceeding inefficient endocrine therapy.

Background Clinical research has shown that therapeutic hypothermia after neonatal hypoxic-ischemic injury improves survival without disability. There is no consensus regarding pain relief or sedation during therapeutic hypothermia in newborns; however, therapeutic hypothermia seems to be associated with pain and stress, and adequate analgesia and sedation are central to maximize the effect of therapeutic hypothermia. Pain needs to be adequately managed in all patients, especially the newborn infant due to the potential short- and long-term negative effects of inadequately treated pain in this population. Methods We will perform a systematic review of pharmacological and non-pharmacological interventions for the management of pain and sedation in newborn infants undergoing therapeutic hypothermia for hypoxic-ischemic encephalopathy. We will include randomized, quasi-randomized controlled trials and observational studies. The use of pharmacological or non-pharmacological interventions will be compared to other pharmacological and or non-pharmacological interventions or no intervention/placebo. The primary outcomes for this review will be analgesia and sedation assessed with validated pain scales, circulatory instability, mortality to discharge, and moderate-to-severe neurodevelopmental disability. We will search the following databases: CINAHL, ClinicalTrials.gov, Cochrane Library, Embase, PubMed, Scopus, and Web of Science. Two independent researchers will screen the records for inclusion, extract data using a data extraction form, and assess the risk of bias in the included trials. Discussion The result of this review will summarize the knowledge regarding the management of pain and sedation in infants treated with therapeutic hypothermia and potentially provide clinicians with guidance on the effective and safe methods. Systematic review registration PROSPERO CRD42020205755

The declines in wet-grassland breeding shorebird populations are considered to mainly result from changes in reproduction. While there is plenty of information on nest survival, little reliable information exists on local recruitment due to confounding effects of permanent emigration. Furthermore, few studies have been able to study the roles of pre- and post-fledging survival on local recruitment. Therefore, it is unclear whether local recruitment of young reflects conditions at the breeding sites or at non-breeding sites. We studied an isolated population of the endangered Southern Dunlin (Calidris alpina schinzii) breeding on the west coast of Sweden to examine (1) brood survival (probability of at least one chick fledging) by following broods fates and (2) local recruitment (survival from hatching to 1 year old) using capture-recapture data. We then examined how much of the annual variation in juvenile survival was explained by variation in brood survival. Brood survival was on average 0.58 (annual range 0.08–1.00) and explained 64% of variation in annual local recruitment. Still local recruitment was rather high for a shorebird (0.17, SE = 0.023), which reflects the isolated nature of the study population. Our results suggest that local recruitment seems to be mainly constrained by chick survival during the pre-fledging period. Therefore, management of breeding sites leading to increased brood survival, e.g., reducing predation on chicks, should have strong impacts on local recruitment and local population growth.

Adjuvant radiotherapy (RT) for breast cancer (BC) has been associated with an increased risk of later radiation-induced lung cancer (LC). We examined the risk of primary LC in a population-based cohort of 52300 women treated for BC during 1992 to 2012, and 253796 age-matched women without BC. Cumulative incidence of LC was calculated by the Kaplan–Meier method, and the risk of LC after BC treatment was estimated by Cox proportional hazards regression analyses. Women with BC receiving RT had a higher cumulative incidence of LC compared to women with BC not receiving RT and women without BC. This became apparent 5 years after RT and increased with longer follow-up. Women with BC receiving RT had a Hazard ratio of 1.59 (95% confidence interval 1.37–1.84) for LC compared to women without BC. RT techniques that lower the incidental lung doses, e.g breathing adaption techniques, may lower this risk. Originally included in thesis in manuscript form.

BackgroundRadiation-associated angiosarcoma of the breast (RAASB) is an aggressive malignancy that is increasing in incidence. Only a few previous population-based studies have reported the results of RAASB treatment.MethodsA search for RAASB patients was carried out in the Finnish Cancer Registry, and treatment data were collected to identify prognostic factors for survival.ResultsOverall, 50 RAASB patients were identified. The median follow-up time was 5.4 years (range 0.4–15.6), and the 5-year overall survival rate was 69%. Forty-seven (94%) patients were operated on with curative intent. Among these patients, the 5-year local recurrence-free survival, distant recurrence-free survival, and overall survival rates were 62%, 75%, and 74%, respectively. A larger planned surgical margin was associated with improved survival.ConclusionsWe found that the majority of RAASB patients were eligible for radical surgical management in this population-based analysis. With radical surgery, the prognosis is relatively good.

The aim of the study was to assess morphological predictors for lymph node metastases (Stage III disease) in colon cancer on computed tomography. Ninety-four patients with histology-proven colon cancer (adenocarcinoma) who underwent elective primary curative resection between the years 2012 and 2014 were included. Contrast-enhanced CT examinations were independently reviewed by two blinded observers regarding tumor location, depth of tumor invasion, and presence of lymph node metastases. Ocular presence of internal heterogeneity and presence of irregular outer border were used as morphological criteria for lymph node involvement. Protocol-based histopathology after curative surgery served as reference standard. Sensitivity, specificity, positive (PPV) and negative (NPV) predictive values, and accuracy for each morphological criterion for prediction of stage III disease were calculated. Inter-observer agreement was compared using Kappa statistics. According to histopathology, 59 patients were staged as I–II disease and 35 patients were staged as stage III disease. The presence of internal heterogeneity in a lymph node on CT resulted in moderate sensitivity (66–77%) but high specificity (95–95%) for prediction of Stage III disease by both observers. The presence of irregular outer border also resulted in poor sensitivity (49–54%) but high specificity (97–97%). The combination of either internal heterogeneity and/or irregular outer border per patient resulted in a moderate sensitivity (67–77%) and high specificity (95–95%), PPV (89–96%), and NPV (84–88%). Inter-observer agreement (Cohens Kappa) was 0.72. Consensus reading for the combined criteria resulted in sensitivity and specificity of 69% and 100%, respectively. Using morphological criteria for lymph node metastases on CT examination in patients with colon cancer results in high specificity but moderate sensitivity in predicting stage III disease.

Background Microbial oils, generated from lignocellulosic material, have great potential as renewable and sustainable alternatives to fossil-based fuels and chemicals. By unravelling the diversity of lipid accumulation physiology in different oleaginous yeasts grown on the various carbon sources present in lignocellulose hydrolysate (LH), new targets for optimisation of lipid accumulation can be identified. Monitoring lipid formation over time is essential for understanding lipid accumulation physiology. This study investigated lipid accumulation in a variety of oleaginous ascomycetous and basidiomycetous strains grown in glucose and xylose and followed lipid formation kinetics of selected strains in wheat straw hydrolysate (WSH). Results Twenty-nine oleaginous yeast strains were tested for their ability to utilise glucose and xylose, the main sugars present in WSH. Evaluation of sugar consumption and lipid accumulation revealed marked differences in xylose utilisation capacity between the yeast strains, even between those belonging to the same species. Five different promising strains, belonging to the species Lipomyces starkeyi, Rhodotorula glutinis, Rhodotorula babjevae and Rhodotorula toruloides, were grown on undiluted wheat straw hydrolysate and lipid accumulation was followed over time, using Fourier transform-infrared (FTIR) spectroscopy. All five strains were able to grow on undiluted WSH and to accumulate lipids, but to different extents and with different productivities. R. babjevae DVBPG 8058 was the best-performing strain, accumulating 64.8% of cell dry weight (CDW) as lipids. It reached a culture density of 28 g/L CDW in batch cultivation, resulting in a lipid content of 18.1 g/L and yield of 0.24 g lipids per g carbon source. This strain formed lipids from the major carbon sources in hydrolysate, glucose, acetate and xylose. R. glutinis CBS 2367 also consumed these carbon sources, but when assimilating xylose it consumed intracellular lipids simultaneously. Rhodotorula strains contained a higher proportion of polyunsaturated fatty acids than the two tested Lipomyces starkeyi strains. Conclusions There is considerable metabolic diversity among oleaginous yeasts, even between closely related species and strains, especially when converting xylose to biomass and lipids. Monitoring the kinetics of lipid accumulation and identifying the molecular basis of this diversity are keys to selecting suitable strains for high lipid production from lignocellulose.