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BackgroundSurvival after childhood cancer has improved to more than 80% during the last few years, leading to an increased number of childhood cancer survivors. Cancer itself, or its treatment, may cause chronic health conditions, including somatic and mental sequelae, which may affect survivors’ health-related quality of life (HRQoL). ObjectiveThe project PanCareLIFE aims to establish a large database with comprehensive data on childhood cancer survivors from different European countries, including data on HRQoL. Within PanCareLIFE, this study aims to describe HRQoL in survivors, investigate predictors of HRQoL, and describe the association of HRQoL with hearing and female fertility impairment. This paper describes the design of the HRQoL study, the origin of data, strategies for data collection, and sampling characteristics of survivors from each contributing country. MethodsA total of 6 institutions from 5 European countries (the Czech Republic, France, Germany, the Netherlands, and Switzerland) provided data on HRQoL assessed with the Short Form 36 and on relevant predictors. The central PanCareLIFE data center aggregated the data and harmonized the variables between the institutions. Survivors were eligible if they received a diagnosis of cancer according to the 12 main groups of the International Classification of Childhood Cancer, 3rd edition, or Langerhans cell histiocytosis; were aged ≤18 years at the time of diagnosis; were residents of the respective country at the time of diagnosis; had survived ≥5 years after cancer diagnosis; were aged ≥18 years at the time of the questionnaire survey; and did not refuse to registration in the national or local childhood cancer cohort. ResultsWe identified 24,993 eligible survivors. Of those, 19,268 survivors received a questionnaire and 9871 survivors participated, resulting in response rates of 9871/24,993 (39.50%) of eligible survivors and of 9871/19,268 (51.23%) invited survivors. Most participants were diagnosed with cancer between the ages of 10 and 14 years (3448/9871, 34.93%) or

Objectives: To evaluate the value of virtual monoenergetic images (VMI) from photon-counting detector CT (PCD-CT) for discriminability of severe lung injury and atelectasis in polytraumatized patients. Materials & Methods: Contrast-enhanced PCD-CT examinations of 20 polytraumatized patients with severe thoracic trauma were included in this retrospective study. Spectral PCD-CT data were reconstructed using a noise-optimized virtual monoenergetic imaging (VMI) algorithm with calculated VMIs ranging from 40 to 120 keV at 10 keV increments. Injury-to-atelectasis contrast-to-noise ratio (CNR) was calculated and compared at each energy level based on CT number measurements in severely injured as well as atelectatic lung areas. Three radiologists assessed subjective discriminability, noise perception, and overall image quality. Results: CT values for atelectasis decreased as photon energy increased from 40 keV to 120 keV (mean Hounsfield units (HU): 69 at 40 keV; 342 at 120 keV), whereas CT values for severe lung injury remained near-constant from 40 keV to 120 keV (mean HU: 42 at 40 keV; 44 at 120 keV) with significant differences at each keV level (p < 0.001). The optimal injury-to-atelectasis CNR was observed at 40 keV in comparison with the remaining energy levels (p < 0.001) except for 50 keV (p > 0.05). In line with this, VMIs at 40 keV were rated best regarding subjective discriminability. VMIs at 60–70 keV, however, provided the highest subjective observer parameters regarding subjective image noise as well as image quality. Conclusions: Discriminability between severely injured and atelectatic lung areas after thoracic trauma can be substantially improved by virtual monoenergetic imaging from PCD-CT with superior contrast and visual discriminability at 40–50 keV.

Objectives: The aim of this study was to analyze the extent of dental metal artifacts in virtual monoenergetic (VME) images, as they often compromise image quality by obscuring soft tissue affecting vascular attenuation reducing sensitivity in the detection of dissections. Methods: Neck photon-counting CT datasets of 50 patients undergoing contrast-enhanced trauma CT were analyzed. Hyperattenuation and hypoattenuation artifacts, muscle with and without artifacts and vessels with and without artifacts were measured at energy levels from 40 keV to 190 keV. The corrected artifact burden, corrected image noise and artifact index were calculated. We also assessed subjective image quality on a Likert-scale. Results: Our study showed a lower artifact burden and less noise in artifact-affected areas above the energy levels of 70 keV for hyperattenuation artifacts (conventional polychromatic CT images 1123 ± 625 HU vs. 70 keV VME 1089 ± 733 HU, p = 0.125) and above of 80 keV for hypoattenuation artifacts (conventional CT images −1166 ± 779 HU vs. 80 keV VME −1170 ± 851 HU, p = 0.927). Vascular structures were less hampered by metal artifacts than muscles (e.g., corrected artifact burden at 40 keV muscle 158 ± 125 HU vs. vessels −63 ± 158 HU p < 0.001), which was also reflected in the subjective image assessment, which showed better ratings at higher keV values and overall better ratings for vascular structures than for the overall artifact burden. Conclusions: Our research suggests 70 keV might be the best compromise for reducing metal artifacts affecting vascular structures and preventing vascular contrast if solely using VME reconstructions. VME imaging shows only significant effects on the general artifact burden. Vascular structures generally experience fewer metal artifacts than soft tissue due to their greater distance from the teeth, which are a common source of such artifacts.

Background: Photon-counting detector (PCD) computed tomography (CT) allows for the reconstruction of virtual monoenergetic images (VMI) at different thresholds. Objective: The aim of our study was to evaluate the optimal arterial contrast in portal venous (pv) scans regarding objective parameters and subjective image quality for different virtual keV levels. Methods: We identified 40 patients that underwent a CT scan with an arterial and pv phase on a PCD-CT (NAEOTOM alpha, Siemens Healthineers, Forchheim, Germany). The attenuation of abdominal arteries on pv phases was measured for different virtual keV levels in a monoenergetic+ application profile and for polychromatic (pc) arterial images. Two independent readers assessed subjective image quality, including vascular contrast in pv scans at different energy levels. Additionally, signal- and contrast-to-noise ratios (SNR and CNR) were measured. Results: Our results showed increasing arterial attenuation levels with decreasing energy levels in virtual monoenergetic imaging on pv scans with the highest attenuation at 40 keV, significantly higher than in the pc arterial phase (439 ± 97 HU vs. 360 ± 97, p < 0.001). Noise, SNR, and CNR were worse at this energy level (p < 0.001). Pv VMI showed less noise at energy levels above 70 keV (all p < 0.001). Subjective image quality was rated best at 70 keV, vascular contrast was best at 40 keV. Conclusions: Our research suggests that virtual monoenergetic images at 40 keV in Mono+ mode derived from a PCD-CT can be a feasible alternative to a true arterial phase for assessment of vessels with worse CNR and SNR.

Abstract In children with cancer, the heterogeneity in ototoxicity occurrence after similar treatment suggests a role for genetic susceptibility. Using a genome-wide association study (GWAS) approach, we identified a genetic variant in TCERG1L (rs893507) to be associated with hearing loss in 390 non-cranial irradiated, cisplatin-treated children with cancer. These results were replicated in two independent, similarly treated cohorts (n = 192 and 188, respectively) (combined cohort: P = 5.3 × 10−10, OR 3.11, 95% CI 2.2–4.5). Modulating TCERG1L expression in cultured human cells revealed significantly altered cellular responses to cisplatin-induced cytokine secretion and toxicity. These results contribute to insights into the genetic and pathophysiological basis of cisplatin-induced ototoxicity.

Abstract Dual-energy CT provides enhanced diagnostic power with similar or even reduced radiation dose as compared to single-energy CT. Its principle is based on the distinct physical properties of low and high energetic photons, which, however, may also affect the biological effectiveness and hence the extent of CT-induced cellular damage. Therefore, a comparative analysis of biological effectiveness of dual- and single-energy CT scans with focus on early gene regulation and frequency of radiation-induced DNA double strand breaks (DSBs) was performed. Blood samples from three healthy individuals were irradiated ex vivo with single-energy (80 kV and 150 kV) and dual-energy tube voltages (80 kV/Sn150kV) employing a modern dual source CT scanner resulting in Volume Computed Tomography Dose Index (CTDIvol) of 15.79–18.26 mGy and dose length product (DLP) of 606.7–613.8 mGy*cm. Non-irradiated samples served as a control. Differential gene expression in peripheral blood mononuclear cells was analyzed 6 h after irradiation using whole transcriptome sequencing. DSB frequency was studied by 53BP1 + γH2AX co-immunostaining and microscopic evaluation of their focal accumulation at DSBs. Neither the analysis of gene expression nor DSB frequency provided any evidence for significantly increased biological effectiveness of dual-energy CT in comparison to samples irradiated with particular single-energy CT spectra. Relative to control, irradiated samples were characterized by a significantly higher rate of DSBs (p

Fouad MF Elshaghabee,1 Darab Ghadimi,1 Diana Habermann,1 Michael de Vrese,1 Wilhelm Bockelmann,1 Hans-Jürgen Kaatsch,2 Knut J Heller,1 Jürgen Schrezenmeir3,4 1Max Rubner-Institute, Federal Research Institute of Nutrition and Food, Department of Microbiology and Biotechnology, Kiel, Germany; 2Institute of Legal Medicine, University Hospital of Schleswig-Holstein, Kiel, Germany; 3Max Rubner-Institute, Federal Research Institute of Nutrition and Food, Department of Physiology and Biochemistry of Nutrition, Karlsruhe, Germany; 4Clinical Research Center, Kiel Innovation and Technology Center, Kiel, GermanyCorrespondence: Darab Ghadimi Tel +49 4316092512Fax +49 4316092472Email darab.ghadimi@mri.bund.deBackground and Purpose: In previous investigations, Weissella confusa was shown to lack the metabolic pathway from fructose to mannitol and to produce ethanol when cultivated in the presence of fructose. Hence, we assessed the effect of oral administration of W. confusa (strain NRRL-B-14171) on blood and fecal ethanol concentrations, glucose and lipid metabolism and traits of the metabolic syndrome in Wistar rats (n=27) fed diets with two different fat and fructose levels and with or without the addition of W. confusa during a total intervention time of 15 weeks (105 days).Materials and Methods: From week 1 to 6, rats were given a medium fructose and fat (MFru-MF) diet containing 28% fructose and 10% fat without the addition of W. confusa (control group, n=13) or mixed with 30 g per kg diet of lyophilized W. confusa (10.56 ± 0.20 log CFU/g; W. confusa group, n=14). From week 7 to 15, the percentage of dietary fructose and fat in the control and W. confusa group was increased to 56% and 16%, respectively (high fructose-high fat (HFru-HF) diet).Results: In HFru-HF-fed rats, W. confusa was detected in feces, regardless of whether W. confusa was added to the diet or not, but not in rats receiving the MFru-MF diet without added W. confusa or in an additional control group (n=10) fed standard rat food without fructose, increased fat content and W. confusa. This indicates that fecal W. confusa may be derived from orally administered W. confusa as well as – in the case of high fructose and fat intake and obesity of rats – from the intestinal microbiota. As shown by multifactorial ANOVA, blood ethanol, the relative liver weight, serum triglycerides, and serum cholesterol as well as fecal ethanol, ADH, acetate, propionate and butyrate, but not lactate, were significantly higher in the W. confusa – compared to the control group.Discussion: This is the first in vivo trial demonstrating that heterofermentative lactic acid bacteria lacking the mannitol pathway (like W. confusa) can increase fecal and blood ethanol concentrations in mammals on a high fructose-high fat diet. This may explain why W. confusa resulted in hyperlipidemia and may promote development of NAFLD in the host.Keywords: high fructose-high fat diet, fecal ethanol, fecal short-chain fatty acids, lipidemia, glycemia, NAFLD

Genetic association studies suggest a genetic predisposition for cisplatin-induced ototoxicity. Among other candidate genes, thiopurine methyltransferase (TPMT) is considered a critical gene for susceptibility to cisplatin-induced hearing loss in a pharmacogenetic guideline. The PanCareLIFE cross-sectional cohort study evaluated the genetic associations in a large pan-European population and assessed the diagnostic accuracy of the genetic markers. 1,112 pediatric cancer survivors who had provided biomaterial for genotyping were screened for participation in the pharmacogenetic association study. 900 participants qualified for inclusion. Based on the assessment of original audiograms, patients were assigned to three phenotype categories: no, minor, and clinically relevant hearing loss. Fourteen variants in eleven candidate genes (ABCC3, OTOS, TPMT, SLC22A2, NFE2L2, SLC16A5, LRP2, GSTP1, SOD2, WFS1, and ACYP2) were genotyped. The genotype and phenotype data represent a resource for conducting meta-analyses to derive a more precise pooled estimate of the effects of genes on the risk of hearing loss due to platinum treatment.

Abstract Background Improved risk stratification, more effective therapy and better supportive care have resulted in survival rates after childhood cancer of around 80% in developed countries. Treatment however can be harsh, and three in every four childhood cancer survivors (CCS) develop at least one late effect, such as gonadal impairment. Gonadal impairment can cause involuntary childlessness, with serious consequences for the well-being of CCS. In addition, early menopause increases the risk of comorbidities such as cardiovascular disease and osteoporosis. Inter-individual variability in susceptibility to therapy related gonadal impairment suggests a role for genetic variation. Currently, only one candidate gene study investigated genetic determinants in relation to gonadal impairment in female CCS; it yielded one single nucleotide polymorphism (SNP) that was previously linked with the predicted age at menopause in the general population of women, now associated with gonadal impairment in CCS. Additionally, one genome wide association study (GWAS) evaluated an association with premature menopause, but no GWAS has been performed using endocrine measurements for gonadal impairment as the primary outcome in CCS. Methods As part of the PanCareLIFE study, the genetic variability of chemotherapy induced gonadal impairment among CCS will be addressed. Gonadal impairment will be determined by anti-Müllerian hormone (AMH) levels or alternatively by fertility and reproductive medical history retrieved by questionnaire. Clinical and genetic data from 837 non-brain or non-bilateral gonadal irradiated long-term CCS will result in the largest clinical European cohort assembled for this late-effect study to date. A candidate gene study will examine SNPs that have already been associated with age at natural menopause and DNA maintenance in the general population. In addition, a GWAS will be performed to identify novel allelic variants. The results will be validated in an independent CCS cohort. Discussion This international collaboration aims to enhance knowledge of genetic variation which may be included in risk prediction models for gonadal impairment in CCS.