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Patient safety incidents in paediatric radiology have profound impacts not only on the patient and their family, but also on the well-being and professional practice of healthcare professionals. These incidents, which range from procedural and diagnostic incidents to serious adverse events leading to harm or even death of the patient, may evoke feelings of distress, guilt, and anxiety among paediatric radiologists (in-training), ultimately affecting their confidence and ability to deliver high-quality care. Recognizing the importance of addressing these challenges, healthcare organizations should implement strategies to support professionals in coping with and learning from these incidents. By fostering a culture of open communication, providing access to peer support, and offering structured debriefing and educational opportunities, healthcare institutions can help mitigate the psychological toll of patient safety incidents and promote resilience among their staff. This article examines the multifaceted impacts of patient safety incidents on paediatric radiologists (in-training) and their staff and outlines effective approaches for handling these incidents to support professional well-being and enhance patient safety., (© 2024. The Author(s).)

Paediatric radiology is a challenging and intriguing subspecialty, dealing with children, guardians and non-radiological clinical colleagues. Paediatric radiologists are routinely in contact with numerous paediatric and surgical subspecialties, all having different needs, perceptions, prioritisations and expectations. Moreover, the radiologist is part of the team of radiographers, sonographers, nurses and secretaries, assisted by appropriate equipment and electronic tools. The framework of good collaboration to ensure safety and effectiveness for the imaged child is a shared responsibility among all medical practitioners involved. Communication in routine practice has many forms and includes appropriately filled radiology requests in accordance to the patient's medical records, routine and timely production of structured, problem-solving radiology reports, face-to-face or electronic-assisted communications and discussions on a pre-defined framework, mutually-agreed and evidence-based protocols adjusted to local availability, skills and national and international guidelines. Mutual understanding of advantages and limitations of imaging is paramount. Well-meant discussions, professionalism and empathy should promote soft skills, bidirectional communication and good collaboration for the benefit of added-value paediatric radiology. International societies, health authorities, medical directors and senior consultants have the responsibility to suggest and safeguard frameworks and recommendations. Regular multidisciplinary meetings and multidisciplinary research projects under openness, honesty and transparency are pathways favouring good collaboration., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: Visualization of scoliosis typically requires ionizing radiation (radiography and CT) to visualize bony anatomy. MRI is often additionally performed to screen for neural axis abnormalities. We propose a 14-minutes radiation-free scoliosis-specific MRI protocol, which combines MRI and MRI-based synthetic CT images to visualize soft and osseous structures in one examination. We assess the ability of the protocol to visualize landmarks needed to detect 3D patho-anatomical changes, screen for neural axis abnormalities, and perform surgical planning and navigation., Methods: 18 adult volunteers were scanned on 1.5 T MR-scanner using 3D T2-weighted and synthetic CT sequences. A predefined checklist of relevant landmarks was used for the parameter assessment by three readers. Parameters included Cobb angles, rotation, torsion, segmental height, area and centroids of Nucleus Pulposus and Intervertebral Disc. Precision, reliability and agreement between the readers measurements were evaluated., Results: 91 % of Likert-based questions scored ≥ 4, indicating moderate to high confidence. Precision of 3D dot positioning was 1.0 mm. Precision of angle measurement was 0.6° (ICC 0.98). Precision of vertebral and IVD height measurements was 0.4 mm (ICC 0.99). Precision of area measurement for NP was 8 mm 2 (ICC 0.55) and for IVD 18 mm 2 (ICC 0.62) for IVD. Precision of centroid measurement for NP was 1.3 mm (ICC 0.88-0.92) and for IVD 1.1 mm (ICC 0.88-91)., Conclusions: The proposed MRI protocol with synthetic CT reconstructions, has high precision, reliability and agreement between the readers for multiple scoliosis-specific measurements. It can be used to study scoliosis etiopathogenesis and to assess 3D spinal morphology., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Body composition during childhood may predispose to negative health outcomes later in life. Automatic segmentation may assist in quantifying pediatric body composition in children., Objective: To evaluate automatic segmentation for body composition on pediatric computed tomography (CT) scans and to provide normative data on muscle and fat areas throughout childhood using automatic segmentation., Materials and Methods: In this pilot study, 537 children (ages 1-17 years) who underwent abdominal CT after high-energy trauma at a Dutch tertiary center (2002-2019) were retrospectively identified. Of these, the CT images of 493 children (66% boys) were used to establish normative data. Muscle (psoas, paraspinal and abdominal wall) and fat (subcutaneous and visceral) areas were measured at the third lumbar vertebral (L3) level by automatic segmentation. A representative subset of 52 scans was also manually segmented to evaluate the performance of automatic segmentation., Results: For manually-segmented versus automatically-segmented areas (52 scans), mean Dice coefficients were high for muscle (0.87-0.90) and subcutaneous fat (0.88), but lower for visceral fat (0.60). In the control group, muscle area was comparable for both sexes until the age of 13 years, whereafter, boys developed relatively more muscle. From a young age, boys were more prone to visceral fat storage than girls. Overall, boys had significantly higher visceral-to-subcutaneous fat ratios (median 1.1 vs. 0.6, P<0.01) and girls higher fat-to-muscle ratios (median 1.0 vs. 0.7, P<0.01)., Conclusion: Automatic segmentation of L3-level muscle and fat areas allows for accurate quantification of pediatric body composition. Using automatic segmentation, the development in muscle and fat distribution during childhood (in otherwise healthy) Dutch children was demonstrated., (© 2023. The Author(s).)

18 F-fluorodeoxyglucose-positron emission tomography/computed tomography (PET/CT) imaging is currently not used in standard diagnostics for B-cell precursor lymphoblastic lymphoma (BCP-LBL), and it is unknown whether PET/CT imaging would lead to agreement between detection of lesions with the gold standard imaging methods. Therefore, we performed a retrospective cohort study in which we included 32 pediatric BCP-LBL patients and determined localizations by reviewing local imaging reports. There was a disagreement between protocol-based imaging and PET/CT in 59% of the patients, and the discrepancies mostly comprise of additional lesions detected with PET/CT, typically in lymph node and bone or the absence of bone marrow involvement with PET/CT. If PET/CT was leading in determining definite stage of disease, this would lead to a different stage and therapy branch in 31% and 28% of the patients, respectively., (© 2023 Wiley Periodicals LLC.)

Sclerosing skeletal dysplasias result from an imbalance between bone formation and resorption. We identified three homozygous, C-terminally truncating AXIN1 variants in seven individuals from four families affected by macrocephaly, cranial hyperostosis, and vertebral endplate sclerosis. Other frequent findings included hip dysplasia, heart malformations, variable developmental delay, and hematological anomalies. In line with AXIN1 being a central component of the β-catenin destruction complex, analyses of primary and genome-edited cells harboring the truncating variants revealed enhanced basal canonical Wnt pathway activity. All three AXIN1-truncating variants resulted in reduced protein levels and impaired AXIN1 polymerization mediated by its C-terminal DIX domain but partially retained Wnt-inhibitory function upon overexpression. Addition of a tankyrase inhibitor attenuated Wnt overactivity in the AXIN1-mutant model systems. Our data suggest that AXIN1 coordinates the action of osteoblasts and osteoclasts and that tankyrase inhibitors can attenuate the effects of AXIN1 hypomorphic variants., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 American Society of Human Genetics. All rights reserved.)

Background: Childhood cancer survivors appear to be at increased risk of frailty and sarcopenia, but evidence on the occurrence of and high-risk groups for these aging phenotypes is scarce, especially in European survivors. The aim of this cross-sectional study was to assess the prevalence of and explore risk factors for pre-frailty, frailty, and sarcopenia in a national cohort of Dutch childhood cancer survivors diagnosed between 1963 and 2001., Methods: Eligible individuals (alive at the time of study, living in the Netherlands, age 18-45 years, and had not previously declined to participate in a late-effects study) from the Dutch Childhood Cancer Survivor Study (DCCSS-LATER) cohort were invited to take part in this cross-sectional study. We defined pre-frailty and frailty according to modified Fried criteria, and sarcopenia according to the European Working Group on Sarcopenia in Older People 2 definition. Associations between these conditions and demographic and treatment-related as well as endocrine and lifestyle-related factors were estimated with two separate multivariable logistic regression models in survivors with any frailty measurement or complete sarcopenia measurements., Findings: 3996 adult survivors of the DCCSS-LATER cohort were invited to participate in this cross-sectional study. 1993 non-participants were excluded due to lack of response or a decline to participate and 2003 (50·1%) childhood cancer survivors aged 18-45 years were included. 1114 (55·6%) participants had complete frailty measurements and 1472 (73·5%) participants had complete sarcopenia measurements. Mean age at participation was 33·1 years (SD  7·2). 1037 (51·8%) participants were male, 966 (48·2%) were female, and none were transgender. In survivors with complete frailty measurements or complete sarcopenia measurements, the percentage of pre-frailty was 20·3% (95% CI 18·0-22·7), frailty was 7·4% (6·0-9·0), and sarcopenia was 4·4% (3·5-5·6). In the models for pre-frailty, underweight (odds ratio [OR] 3·38 [95% CI 1·92-5·95]) and obesity (OR 1·67 [1·14-2·43]), cranial irradiation (OR 2·07 [1·47-2·93]), total body irradiation (OR 3·17 [1·77-5·70]), cisplatin dose of at least 600 mg/m 2 (OR 3·75 [1·82-7·74]), growth hormone deficiency (OR 2·25 [1·23-4·09]), hyperthyroidism (OR 3·72 [1·63-8·47]), bone mineral density (Z score ≤-1 and >-2, OR 1·80 [95% CI 1·31-2·47]; Z score ≤-2, OR 3·37 [2·20-5·15]), and folic acid deficiency (OR 1·87 [1·31-2·68]) were considered significant. For frailty, associated factors included age at diagnosis between 10-18 years (OR 1·94 [95% CI 1·19-3·16]), underweight (OR 3·09 [1·42-6·69]), cranial irradiation (OR 2·65 [1·59-4·34]), total body irradiation (OR 3·28 [1·48-7·28]), cisplatin dose of at least 600 mg/m 2 (OR 3·93 [1·45-10·67]), higher carboplatin doses (per g/m 2 ; OR 1·15 [1·02-1·31]), cyclophosphamide equivalent dose of at least 20 g/m 2 (OR 3·90 [1·65-9·24]), hyperthyroidism (OR 2·87 [1·06-7·76]), bone mineral density Z score ≤-2 (OR 2·85 [1·54-5·29]), and folic acid deficiency (OR 2·04 [1·20-3·46]). Male sex (OR 4·56 [95%CI 2·26-9·17]), lower BMI (continuous, OR 0·52 [0·45-0·60]), cranial irradiation (OR 3·87 [1·80-8·31]), total body irradiation (OR 4·52 [1·67-12·20]), hypogonadism (OR 3·96 [1·40-11·18]), growth hormone deficiency (OR 4·66 [1·44-15·15]), and vitamin B12 deficiency (OR 6·26 [2·17-1·81]) were significantly associated with sarcopenia., Interpretation: Our findings show that frailty and sarcopenia occur already at a mean age of 33 years in childhood cancer survivors. Early recognition and interventions for endocrine disorders and dietary deficiencies could be important in minimising the risk of pre-frailty, frailty, and sarcopenia in this population., Funding: Children Cancer-free Foundation, KiKaRoW, Dutch Cancer Society, ODAS Foundation., Competing Interests: Declaration of interests IH has institutional contracts with Abbott, Siemens Healthineers, and Beckman Coulter. All other authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Pediatric renal cell carcinoma (RCC) is a rare malignancy. Magnetic resonance imaging (MRI) is the preferred imaging modality for assessment of these tumors. The previous literature has suggested that cross-sectional-imaging findings differ between RCC and other pediatric renal tumors and between RCC subtypes. However, studies focusing on MRI characteristics are limited. Therefore, this study aims to identify MRI characteristics of pediatric and young-adult RCC, through a single-center case series and literature review. Six identified diagnostic MRI scans were retrospectively assessed, and an extensive literature review was conducted. The included patients had a median age of 12 years (63-193 months). Among other subtypes, 2/6 (33%) were translocation-type RCC (MiT-RCC) and 2/6 (33%) were clear-cell RCC. Median tumor volume was 393 cm 3 (29-2191 cm 3 ). Five tumors had a hypo-intense appearance on T2-weighted imaging, whereas 4/6 were iso-intense on T1-weighted imaging. Four/six tumors showed well-defined margins. The median apparent diffusion coefficient (ADC) values ranged from 0.70 to 1.20 × 10 -3 mm 2 /s. In thirteen identified articles focusing on MRI characteristics of MiT-RCC, the majority of the patients also showed T2-weighted hypo-intensity. T1-weighted hyper-intensity, irregular growth pattern and limited diffusion-restriction were also often described. Discrimination of RCC subtypes and differentiation from other pediatric renal tumors based on MRI remains difficult. Nevertheless, T2-weighted hypo-intensity of the tumor seems a potential distinctive characteristic., Competing Interests: The authors declare no conflict of interest.

While cervical lymphadenopathy is common in children, a decision model for detecting high-grade lymphoma is lacking. Previously reported individual lymphoma-predicting factors and multivariate models were not sufficiently discriminative for clinical application. To develop a diagnostic scoring tool, we collected data from all children with cervical lymphadenopathy referred to our national pediatric oncology center within 30 months ( n = 182). Thirty-nine putative lymphoma-predictive factors were investigated. The outcome groups were classical Hodgkin lymphoma (cHL), nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL), non-Hodgkin lymphoma (NHL), other malignancies, and a benign group. We integrated the best univariate predicting factors into a multivariate, machine learning model. Logistic regression allocated each variable a weighing factor. The model was tested in a different patient cohort ( n = 60). We report a 12-factor diagnostic model with a sensitivity of 95% (95% CI 89-98%) and a specificity of 88% (95% CI 77-94%) for detecting cHL and NHL. Our 12-factor diagnostic scoring model is highly sensitive and specific in detecting high-grade lymphomas in children with cervical lymphadenopathy. It may enable fast referral to a pediatric oncologist in patients with high-grade lymphoma and may reduce the number of referrals and unnecessary invasive procedures in children with benign lymphadenopathy.

Background: Childhood cancer survivors are at risk of developing skeletal comorbidities later in life. We aimed to assess risk factors for low and very low bone mineral density (BMD), and the risk of and risk factors for any fractures and vertebral fractures in a national cohort of Dutch adult childhood cancer survivors., Methods: In this cross-sectional study, we used data from the DCCSS LATER cohort, which comprised individuals who were alive for at least 5 years after diagnosis of childhood cancer (ie, histologically confirmed malignancies or Langerhans cell histiocytosis), were diagnosed before the age of 19 years, and who had been treated at one of seven Dutch paediatric oncology centres between 1963 and 2002 (hereafter referred to as survivors). For this study, we invited survivors aged 18-45 years, who were alive as of Oct 10, 2016, living in the Netherlands, and who were deemed eligible by their treating physician to participate. We assessed BMD using dual-energy x-ray absorptiometry (DXA). Self-reported fractures that occurred at least 5 years after cancer diagnosis were assessed using available medical history and compared with population-level data from the Swedish national registry. We assessed vertebral fractures in a subset of participants using a vertebral fracture assessment. We assessed associations between the occurrence of low (Z-score of ≤-1) or very low (Z-score of ≤-2) BMD, fractures, and vertebral fractures and demographic, treatment-related, endocrine, and lifestyle-related factors using logistic regression analysis., Findings: Between April 29, 2016, and Jan 22, 2020, 3996 (64·8%) of 6165 individuals from the DCCSS LATER cohort were invited to participate, of whom 2003 (50·1%) were enrolled (mean age at participation was 33·1 years [SD 7·2], 966 [48·2%] were female, and 1037 [51·8%] were male [data on ethnicity and race were not available due to national policies]). 1548 (77·3%) had evaluable DXA scans for assessment of BMD, 1892 (94·5%) provided medical history of fractures, and 249 (12·4%) were assessed for vertebral fractures. 559 (36·1%) of 1548 had low BMD at any site, and 149 (9·6%) had very low BMD at any site. The standardised incidence ratio of any first fracture was 3·53 (95% CI 3·06-4·06) for male participants and 5·35 (4·46-6·52) for female participants. 33 (13·3%) of 249 participants had vertebral fractures. Male sex, underweight, high carboplatin dose, any dose of cranial radiotherapy, hypogonadism, hyperthyroidism, low physical activity, and severe vitamin D deficiency were associated with low BMD at any site and male sex, underweight, cranial radiotherapy, growth hormone deficiency, and severe vitamin D deficiency were associated with very low BMD at any site. Additionally, male sex, former and current smoking, and very low lumbar spine BMD were associated with any fractures, whereas older age at follow-up, previous treatment with platinum compounds, growth hormone deficiency, and low physical activity were specifically associated with vertebral fractures., Interpretation: Survivors of childhood cancer are at increased risk of any first fracture. Very low lumbar spine BMD was associated with fractures, highlighting the importance of active BMD surveillance in high-risk survivors (ie, those treated with cranial, craniospinal, or total body irradiation). Moreover, our results indicate that intensive surveillance and timely interventions for endocrine disorders and vitamin deficiencies might improve bone health in childhood cancer survivors, but this needs to be assessed in future studies., Funding: Children Cancer-free Foundation (KiKa), KiKaRoW, and ODAS foundation., Competing Interests: Declaration of interests IH declares institutional contracts from Abbott, Siemens Healthineers, and Beckman Coulter. CMR declares a non-commercial charity grant funding, and a personal grant for Jr Group Leaders 2013–2018 (Dutch Cancer Society). All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Spinal muscular atrophy (SMA) is a hereditary motor neuron disorder, characterized by the degeneration of motor neurons and progressive muscle weakness. There is a large variability of disease severity, reflected by the classification of SMA types 1-4., Objective: The aim of this cross-sectional study was to determine the nature of swallowing problems and underlying mechanisms in patients with SMA types 2 and 3, and the relationship between swallowing and mastication problems., Methods: We enrolled patients (aged 13-67 years) with self-reported swallowing and/or mastication problems. We used a questionnaire, the functional oral intake scale, clinical tests (dysphagia limit, and timed test swallowing, the test of mastication and swallowing solids), a videofluoroscopic swallowing study (VFSS), and muscle ultrasound of the bulbar muscles (i.e. digastric, geniohyoid and tongue muscles)., Results: Non-ambulant patients (n = 24) had a reduced dysphagia limit (median 13 ml (3-45), and a swallowing rate at the limit of normal (median 10 ml/sec (range 4-25 ml). VFSS revealed piecemeal deglutition and pharyngeal residue. We found pharyngo-oral regurgitation in fourteen patients (58%), i.e. they transported the residue from the hypopharynx back into the oral cavity and re-swallowed it. Six patients (25%) demonstrated impaired swallowing safety (i.e. penetration aspiration scale > 3). Muscle ultrasound revealed an abnormal muscle structure of the submental and tongue muscles. Ambulant patients (n = 3), had a normal dysphagia limit and swallowing rate, but VFSS showed pharyngeal residue, and muscle ultrasound demonstrated an abnormal echogenicity of the tongue. Swallowing problems were associated with mastication problems (p = 0.001).

Mastication problems can have a negative impact on the intake of food and quality of life. This cross-sectional study characterizes mastication problems using clinical and instrumental assessments in patients with spinal muscular atrophy (SMA) types 2 and 3 with self-reported bulbar problems. We included 27 patients (aged 13-67 years), 18 with SMA type 2 and 9 patients with SMA type 3 (of whom three were still ambulant) and applied a questionnaire, clinical mastication tests (TOMASS and 6-min mastication test), and muscle ultrasound of the mastication muscles. Non-ambulant patients demonstrated inefficient mastication as reflected by median z scores for masticatory cycles (z = 1.8), number of swallows (z = 4.3) and time needed to finish the cracker (z = 3.4), and limited endurance of continuous mastication as demonstrated by the median z scores of the 6-min mastication test (z = - 1.5). Patients reported increased fatigue directly after the 6-min mastication test as well as 5 min after completing the test (p < 0.001; p = 0.003). Reduced maximal mouth opening was associated with mastication problems (p < 0.001). Muscle ultrasound of the mastication muscles showed an abnormal muscle structure in 90% of both ambulant and non-ambulant patients. This study aims to understand the nature and underlying mechanisms of mastication problems in patients with SMA types 2 and 3 with reported bulbar problems., (© 2021. The Author(s).)

Ultrasound shear wave elastography is a radiation-free and low-cost technique for evaluating the mechanical properties of different tissues. This study systematically reviewed all relevant literature on shear wave elastography of the intervertebral disc. The purpose was twofold: first, to determine the validity of the elastography method, that is, the correlation between elastographically measured shear wave speed and disc mechanical properties, and inter-/intra-operator reliability; and second, to explore if disc elastography is potentially useful in identifying children at risk for idiopathic scoliosis. This systematic review was performed according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) guidelines. A comprehensive search was performed in PubMed and Embase, and study quality was assessed using the AXIS (Appraisal Tool for Cross-sectional Studies) critical appraisal instrument. Seven articles were included. Three animal ex vivo studies reported moderate-to-good correlations between shear wave speed and disc mechanical properties (r = 0.45-0.81). Three studies reported high intra-operator repeatability (intra-class correlation coefficient [ICC] 0.94-0.99) and inter-operator reproducibility (ICC 0.97-0.98). Four clinical studies measured shear wave speed in asymptomatic children. Two studies reported significantly higher shear wave speeds in scoliosis patients compared with healthy controls, measured in discs both inside and outside the scoliotic curve. In conclusion, shear wave elastography appears reliable in assessing intervertebral disc mechanical characteristics. Despite its promising capabilities to distinguish patients with asymptomatic from those with pathological discs, the exact correlation between disc mechanical properties and shear wave speed remains unclear., Competing Interests: Conflict of interest disclosure S.D.R reports a Scoliosis Research Society and Fondation Yves Cotrel research grant. All other authors have no disclosures to declare., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The SIOP-Renal Tumor Study Group (RTSG) does not advocate invasive procedures to determine histology before the start of therapy. This may induce misdiagnosis-based treatment initiation, but only for a relatively small percentage of approximately 10% of non-Wilms tumors (non-WTs). MRI could be useful for reducing misdiagnosis, but there is no global consensus on differentiating characteristics., Purpose: To identify MRI characteristics that may be used for discrimination of newly diagnosed pediatric renal tumors., Study Type: Consensus process using a Delphi method., Population: Not applicable., Field Strength/sequence: Abdominal MRI including T1- and T2-weighted imaging, contrast-enhanced MRI, and diffusion-weighted imaging at 1.5 or 3 T., Assessment: Twenty-three radiologists from the SIOP-RTSG radiology panel with ≥5 years of experience in MRI of pediatric renal tumors and/or who had assessed ≥50 MRI scans of pediatric renal tumors in the past 5 years identified potentially discriminatory characteristics in the first questionnaire. These characteristics were scored in the subsequent second round, consisting of 5-point Likert scales, ranking- and multiple choice questions., Statistical Tests: The cut-off value for consensus and agreement among the majority was ≥75% and ≥60%, respectively, with a median of ≥4 on the Likert scale., Results: Consensus on specific characteristics mainly concerned the discrimination between WTs and non-WTs, and WTs and nephrogenic rest(s) (NR)/nephroblastomatosis. The presence of bilateral lesions (75.0%) and NR/nephroblastomatosis (65.0%) were MRI characteristics indicated as specific for the diagnosis of a WT, and 91.3% of the participants agreed that MRI is useful to distinguish NR/nephroblastomatosis from WT. Furthermore, all participants agreed that age influenced their prediction in the discrimination of pediatric renal tumors., Data Conclusion: Although the discrimination of pediatric renal tumors based on MRI remains challenging, this study identified some specific characteristics for tumor subtypes, based on the shared opinion of experts. These results may guide future validation studies and innovative efforts., Level of Evidence: 3 Technical Efficacy Stage: 3., (© 2021 The Authors. Journal of Magnetic Resonance Imaging published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

Background: Computed tomography (CT) is often used to investigate muscle and fat mass in adult patients with cancer. However, this method has rarely been used in the pediatric cancer population. The present retrospective study aimed to investigate changes in body composition using CT during treatment in children with neuroblastoma., Procedure: CT images of 29 patients with high-risk neuroblastoma were retrospectively analyzed at diagnosis and longitudinally during treatment. The cross-sectional area of skeletal muscle, intermuscular adipose tissue (IMAT), visceral adipose tissue (VAT), and subcutaneous adipose tissue (SAT) and skeletal muscle density at the level of the third lumbar vertebra were examined. To correct for height, cross-sectional areas were divided by height in meters squared. A linear mixed model was estimated to investigate changes in body composition over time., Results: A small increase in skeletal muscle (p = .029), skeletal muscle density (p = .002), and IMAT (p < .001) was found. Furthermore, a rapid increase in VAT (p < .001) and SAT (p = .001) was seen early during treatment with the highest volumes after six cycles of chemotherapy., Conclusions: CT scans obtained during standard care provide insight into the direction and timing of changes in skeletal muscle and different types of adipose tissue in childhood cancer patients. Future research is needed regarding the consequences of the rapid increase of VAT and SAT early during treatment., (© 2021 The Authors. Pediatric Blood & Cancer published by Wiley Periodicals LLC.)

Objectives: To compare WB-MRI with an [ 18 F]FDG-PET/CT-based reference for early response assessment and restaging in children with Hodgkin's lymphoma (HL)., Methods: Fifty-one children (ages 10-17) with HL were included in this prospective, multicentre study. All participants underwent WB-MRI and [ 18 F]FDG-PET/CT at early response assessment. Thirteen of the 51 patients also underwent both WB-MRI and [ 18 F]FDG-PET/CT at restaging. Two radiologists independently evaluated all WB-MR images in two separate readings: without and with DWI. The [ 18 F]FDG-PET/CT examinations were evaluated by a nuclear medicine physician. An expert panel assessed all discrepancies between WB-MRI and [ 18 F]FDG-PET/CT to derive the [ 18 F]FDG-PET/CT-based reference standard. Inter-observer agreement for WB-MRI was calculated using kappa statistics. Concordance, PPV, NPV, sensitivity and specificity for a correct assessment of the response between WB-MRI and the reference standard were calculated for both nodal and extra-nodal disease presence and total response evaluation., Results: Inter-observer agreement of WB-MRI including DWI between both readers was moderate (κ 0.46-0.60). For early response assessment, WB-MRI DWI agreed with the reference standard in 33/51 patients (65%, 95% CI 51-77%) versus 15/51 (29%, 95% CI 19-43%) for WB-MRI without DWI. For restaging, WB-MRI including DWI agreed with the reference standard in 9/13 patients (69%, 95% CI 42-87%) versus 5/13 patients (38%, 95% CI 18-64%) for WB-MRI without DWI., Conclusions: The addition of DWI to the WB-MRI protocol in early response assessment and restaging of paediatric HL improved agreement with the [ 18 F]FDG-PET/CT-based reference standard. However, WB-MRI remained discordant in 30% of the patients compared to standard imaging for assessing residual disease presence., Key Points: • Inter-observer agreement of WB-MRI including DWI between both readers was moderate for (early) response assessment of paediatric Hodgkin's lymphoma. • The addition of DWI to the WB-MRI protocol in early response assessment and restaging of paediatric Hodgkin's lymphoma improved agreement with the [18F]FDG-PET/CT-based reference standard. • WB-MRI including DWI agreed with the reference standard in respectively 65% and 69% of the patients for early response assessment and restaging., (© 2021. The Author(s).)

Background and Aims: Core needle biopsies (CNB) are less invasive, cause less morbidity, and have lower costs than open biopsies (OB). However, the number of studies reporting CNB accuracy in pediatric tumors is limited and series are small. The aim of this study is to investigate if CNB diagnosis is concordant with the final diagnosis in pediatric solid non-central nervous system (CNS) tumors., Methods: Data from all patients treated in a single center between November 2014 and December 2019 were collected from the national pathology database and from local medical records. Data collection included age, sex, CNB diagnosis, final diagnosis, number of cores obtained, number of cores used for histology, cumulative core length, greatest dimension of the lesion, lesion volume, and complications., Results: Out of 361 CNB, 95.6% (345/361) provided a diagnosis. A resection or follow-up biopsy was performed in 201 cases. The final diagnosis was concordant with the CNB in 100% (201/201) of cases. The age, number of cores used for histology, and the greatest dimension of the lesion did not significantly differ between diagnostic and nondiagnostic CNB. The cumulative core length of diagnostic CNB was significantly higher than in the nondiagnostic group (24.72 mm vs. 13.37 mm, p-value .022). Complications occurred in 2.1% (7/337) of CNB procedures. Molecular analysis was successful in 228/233 (98%) of cases in which it was performed., Conclusions: CNB diagnosis is highly concordant with the final diagnosis and the diagnostic rate is high. The complication rate in CNB is low., (© 2021 The Authors. Pediatric Blood & Cancer published by Wiley Periodicals LLC.)

Hypomagnesemia, seizures, and intellectual disability (HSMR) syndrome is a rare disorder caused by mutations in the cyclin M2 (CNNM2) gene. Due to the limited number of cases, extensive phenotype analyses of these patients have not been performed, hindering early recognition of patients. In this study, we established the largest cohort of HSMR to date, aiming to improve recognition and diagnosis of this complex disorder. Eleven novel variants in CNNM2 were identified in nine single sporadic cases and in two families with suspected HSMR syndrome. 25 Mg 2+ uptake assays demonstrated loss-of-function in seven out of nine variants in CNNM2. Interestingly, the pathogenic mutations resulted in decreased plasma membrane expression. The phenotype of those affected by pathogenic CNNM2 mutations was compared with five previously reported cases of HSMR. All patients suffered from hypomagnesemia (0.44-0.72 mmol/L), which could not be fully corrected by Mg 2+ supplementation. The majority of patients (77%) experienced generalized seizures and exhibited mild to moderate intellectual disability and speech delay. Moreover, severe obesity was present in most patients (89%). Our data establish hypomagnesemia, seizures, intellectual disability, and obesity as hallmarks of HSMR syndrome. The assessment of these major features offers a straightforward tool for the clinical diagnosis of HSMR., (© 2021 The Authors. Human Mutation published by Wiley Periodicals LLC.)

Objectives: To assess the concordance of whole-body MRI (WB-MRI) and an FDG-PET/CT-based reference standard for the initial staging in children with Hodgkin lymphoma (HL) METHODS: Children with newly diagnosed HL were included in this prospective, multicentre, international study and underwent WB-MRI and FDG-PET/CT at staging. Two radiologists and a nuclear medicine physician independently evaluated all images. Discrepancies between WB-MRI and FDG-PET/CT were assessed by an expert panel. All FDG-PET/CT errors were corrected to derive the FDG-PET/CT-based reference standard. The expert panel corrected all reader errors in the WB-MRI DWI dataset to form the intrinsic MRI data. Inter-observer agreement for WB-MRI DWI was calculated using overall agreement, specific agreements and kappa statistics. Concordance for correct classification of all disease sites and disease stage between WB-MRI (without DWI, with DWI and intrinsic WB-MRI DWI) and the reference standard was calculated as primary outcome. Secondary outcomes included positive predictive value, negative predictive value and kappa statistics. Clustering within patients was accounted for using a mixed-effect logistic regression model with random intercepts and a multilevel kappa analysis., Results: Sixty-eight children were included. Inter-observer agreement between WB-MRI DWI readers was good for disease stage (κ = 0.74). WB-MRI DWI agreed with the FDG-PET/CT-based reference standard for determining disease stage in 96% of the patients versus 88% for WB-MRI without DWI. Agreement between WB-MRI DWI and the reference standard was excellent for both nodal (98%) and extra-nodal (100%) staging., Conclusions: WB-MRI DWI showed excellent agreement with the FDG-PET/CT-based reference standard. The addition of DWI to the WB-MRI protocol improved the staging agreement., Key Points: • This study showed excellent agreement between WB-MRI DWI and an FDG-PET/CT-based reference standard for staging paediatric HL. • Diffusion-weighted imaging is a useful addition to WB-MRI in staging paediatric HL. • Inter-observer agreement for WB-MRI DWI was good for both nodal and extra-nodal staging and determining disease stage.

Complex I deficiency is the most common pediatric mitochondrial disease. It can cause a wide range of clinical disorders, including Leigh syndrome. TIMMDC1 encodes an assembly protein of complex I and has been recently associated with early onset mitochondrial disease in three unrelated families. In all three families the same homozygous deep intronic variant was identified leading to inclusion of a new exon resulting in a frameshift and premature stop codon (c.596 + 2146A > G, p.Gly199&#95;Thr200ins5*). Herein, we describe two brothers of Dutch descent, presenting in infancy with hypotonia and respiratory insufficiency and a rapidly progressive and fatal disease course. Laboratory findings and metabolic investigations revealed no specific abnormalities, notably no raised plasma lactate. MRI showed transient lesions in the basal ganglia of brother 1. A muscle biopsy demonstrated complex I deficiency in brother 2. Exome sequencing yielded a novel heterozygous TIMMDC1 variant: c.385C > T, p.(Arg129*). Targeted sequencing revealed the previously published deep intronic variant c.596 + 2146A > G, p.(Gly199&#95;Thr200ins5*) on the second allele which is not detected by exome sequencing. In summary, we present the fourth family with TIMMDC1-related disease, with a novel nonsense variant. This report illustrates the importance of considering mitochondrial disease even when laboratory findings are normal, and the added value of targeted sequencing of introns., (Copyright © 2020 The Author(s). Published by Elsevier Masson SAS.. All rights reserved.)

Background: Conjoined twinning is a rare congenital malformation with an incidence of about 1.5 per 100,000 births. Because no consensus has been reached regarding the dysmorphology, thorough descriptions of conjoined twins as part of teratological collections can be useful to increase knowledge of this congenital malformation. In this case report, we describe a parapagus dicephalus twin from the collection of the Department of Anatomy of the University Medical Center Utrecht in the Netherlands. External anatomical characteristics were assessed through a detailed macroscopic examination and internal characteristics by means of whole-body computed tomography and magnetic resonance imaging (3 Tesla)., Case Presentation: Macroscopic examination showed a Caucasian male parapagus dicephalus tripus tribrachius conjoined twin a type of conjoined twinning in which there are two heads side by side, one rump, and three upper and three lower limbs. In addition, anencephaly was observed in the left twin. Radiological imaging showed a normal central nervous system in the right twin and absence of the calvaria, cerebrum, diencephalon, and mesencephalon in the left twin. There was clear duplication of the vertebral column, rib cage, respiratory system, and gastrointestinal system at least up to and including the first part of the duodenum. The heart consisted of a monoatrium with two separate ventricles. There was a fused liver with a single gallbladder, a single spleen, three kidneys, two bladders, and duplication of the penis. The third upper and lower extremities were articulating with a fused glenoid and acetabulum, respectively. The third foot showed both polydactyly and syndactyly of the toes., Conclusion: This case report describes a unique case of a male dicephalus parapagus tripus tribrachus conjoined twin discordant for anencephaly. Radiological imaging proved to be an adequate noninvasive method to provide insights into the internal (dys)morphology of this specific specimen, improving its scientific and educational value. This approach could be generally applied to other teratological specimens, thereby strengthening arguments regarding pathogenetic hypotheses, which may lead to new or improved insights into both normal and abnormal embryonic development.

Background: Currently, there are no European recommendations for the management of pediatric thyroid cancer. Other current international guidelines are not completely concordant. In addition, medical regulations differ between, for instance, the US and Europe. We aimed to develop new, easily accessible national recommendations for differentiated thyroid carcinoma (DTC) patients <18 years of age in the Netherlands as a first step toward a harmonized European Recommendation., Methods: A multidisciplinary working group was formed including pediatric and adult endocrinologists, a pediatric radiologist, a pathologist, endocrine surgeons, pediatric surgeons, pediatric oncologists, nuclear medicine physicians, a clinical geneticist and a patient representative. A systematic literature search was conducted for all existing guidelines and review articles for pediatric DTC from 2000 until February 2019. The Appraisal of Guidelines, Research and Evaluation (AGREE) instrument was used for assessing quality of the articles. All were compared to determine dis- and concordances. The American Thyroid Association (ATA) pediatric guideline 2015 was used as framework to develop specific Dutch recommendations. Discussion points based upon expert opinion and current treatment management of DTC in children in the Netherlands were identified and elaborated., Results: Based on the most recent evidence combined with expert opinion, a 2020 Dutch recommendation for pediatric DTC was written and published as an online interactive decision tree (www.oncoguide.nl)., Conclusion: Pediatric DTC requires a multidisciplinary approach. The 2020 Dutch Pediatric DTC Recommendation can be used as a starting point for the development of a collaborative European recommendation for treatment of pediatric DTC.

Background: PTEN hamartoma tumor syndrome (PHTS) represents a group of syndromes caused by a mutation in the PTEN gene. Children with a germline PTEN mutation have an increased risk of developing differentiated thyroid carcinoma (DTC). Several guidelines have focused on thyroid surveillance in these children, but studies substantiating these recommendations are lacking., Objective: The present study intends to provide the available evidence for a thyroid carcinoma surveillance program in children with PHTS., Methods: An extensive literature search was performed to identify all studies on DTC in pediatric PHTS patients. Two pediatric cases are presented to illustrate the pros and cons of thyroid carcinoma surveillance. Recommendations for other patient groups at risk for DTC were evaluated. Consensus within the study team on recommendations for children with PHTS was reached by balancing the incidence and behavior of DTC with the pros and cons of thyroid surveillance, and the different surveillance methods., Results: In 5 cohort studies the incidence of DTC in childhood ranged from 4 to 12%. In total 57 cases of DTC and/or benign nodular disease in pediatric PHTS patients were identified, of which 27 had proven DTC, with a median age of 12 years (range 4-17). Follicular thyroid carcinoma (FTC) was diagnosed in 52% of the pediatric DTC patients. No evidence was found for a different clinical behavior of DTC in PHTS patients compared to sporadic DTC., Conclusions: Children with PHTS are at increased risk for developing DTC, with 4 years being the youngest age reported at presentation and FTC being overrepresented. DTC in pediatric PHTS patients does not seem to be more aggressive than sporadic DTC., Recommendations: Surveillance for DTC in pediatric PHTS patients seems justified, as early diagnosis may decrease morbidity. Consensus within the study team was reached to recommend surveillance from the age of 10 years onwards, since at that age the incidence of DTC seems to reach 5%. Surveillance for DTC should consist of yearly neck palpation and triennial thyroid ultrasound. Surveillance in children with PHTS should be performed in a center of excellence for pediatric thyroid disease or PHTS., Competing Interests: The authors have nothing to disclose., (Copyright © 2020 by S. Karger AG, Basel.)

Background: Lymph node enlargement is commonly used to indicate abnormality., Objective: To evaluate the normal size and prevalence of abdominal lymph nodes in children at CT., Materials and Methods: In this retrospective study, we included a total of 152 children ages 1-17 years who underwent abdominal CT examination after high-energy trauma. We measured abdominal lymph nodes in five lymph node stations (inguinal, iliac, para-aortic, hepatic and mesenteric). For the largest lymph node in each level, we measured long- and short-axis diameters in both the axial and coronal planes. We then calculated distribution parameters, correlation coefficients between lymph node size and age, and reference intervals., Results: The prevalence of detectable lymph nodes was high for the inguinal (100%), iliac (98%), para-aortic (97%) and mesenteric (99%) stations and lower for the hepatic station (32%). Lymph node size showed small to medium significant correlations (ranging from 0.21 to 0.50) with age. When applying the Lugano criteria and RECIST (Response Criteria in Solid Tumors), 29 children (19%) would have had one or more enlarged abdominal lymph nodes., Conclusion: The results of this study provide normative data of abdominal lymph node size in children. The current adult guidelines for enlarged lymph nodes seem adequate for most children with the exception of young adolescents, in which larger lymph nodes were relatively common, particularly in the inguinal region.

The purpose of this recommendation of the Oncology Task Force of the European Society of Paediatric Radiology (ESPR) is to indicate reasonable applications of whole-body MRI in children with cancer and to address useful protocols to optimize workflow and diagnostic performance. Whole-body MRI as a radiation-free modality has been increasingly performed over the last two decades, and newer applications, as in screening of children with germ-line mutation cancer-related gene defects, are now widely accepted. We aim to provide a comprehensive outline of the diagnostic value for use in daily practice. Based on the results of our task force session in 2018 and the revision in 2019 during the ESPR meeting, we summarized our group's experiences in whole-body MRI. The lack of large evidence by clinical studies is challenging when focusing on a balanced view regarding the impact of whole-body MRI in pediatric oncology. Therefore, the final version of this recommendation was supported by the members of Oncology Task Force.

Background: No normal measurements or specific size criteria have been described for cervical lymph nodes in children., Objective: To determine the normal measurements of cervical lymph nodes in children on CT., Materials and Methods: We included 142 children (ages 1-17 years) who underwent cervical CT examination after high-energy trauma. We evaluated axial and coronal 2-mm reconstructions for lymph nodes at six cervical levels. For the largest lymph node at each level, we measured diameters in both the long and short axial axes and the long coronal axis., Results: A total of 733 lymph nodes were measured in 142 children (62% boys, 38% girls). The greatest measured diameters were 14 mm for the short axis in the axial plane, 24 mm for the long axis in the axial plane and 28 mm for the long axis in the coronal plane. The Pearson correlation coefficient for age and lymph node size at Levels IV-VI was in the range of 0.19-0.47., Conclusion: Lymph nodes with an axial short-axis diameter exceeding 15 mm for Level II and 10 mm for all other cervical levels are uncommon in otherwise healthy children.

RNA polymerase III (Pol III) is an essential 17-subunit complex responsible for the transcription of small housekeeping RNAs such as transfer RNAs and 5S ribosomal RNA. Biallelic variants in four genes (POLR3A, POLR3B, and POLR1C and POLR3K) encoding Pol III subunits have previously been found in individuals with (neuro-) developmental disorders. In this report, we describe three individuals with biallelic variants in POLR3GL, a gene encoding a Pol III subunit that has not been associated with disease before. Using whole exome sequencing in a monozygotic twin and an unrelated individual, we detected homozygous and compound heterozygous POLR3GL splice acceptor site variants. RNA sequencing confirmed the loss of full-length POLR3GL RNA transcripts in blood samples of the individuals. The phenotypes of the described individuals are mainly characterized by axial endosteal hyperostosis, oligodontia, short stature, and mild facial dysmorphisms. These features largely fit within the spectrum of phenotypes caused by previously described biallelic variants in POLR3A, POLR3B, POLR1C, and POLR3K. These findings further expand the spectrum of POLR3-related disorders and implicate that POLR3GL should be included in genetic testing if such disorders are suspected.

Purpose: To evaluate the value of fused high b-value diffusion weighted and T2-weighted MRI compared to T1-weighted imaging, T2-weighted imaging and DWI for staging pediatric Hodgkin's lymphoma., Method: 21 consecutive pediatric patients who underwent whole-body MRI at Hodgkin's lymphoma staging were included. Fused, colorized DWI/T2-weighted images were created. Image sets consisting of (a) T1-weighted, T2-weighted and DWI images and (b) T1-weighted, T2-weighted, DWI and DWI/T2-weighted fused images were reviewed by a radiologist using a cross-over design with blinding and randomization. Scoring was performed using a standardized form, based on detection, characterization and reading time, using a FDG-PET/CT based reference standard. Test characteristics, test agreement to a FDG-PET/CT based reference standard and reading times were calculated., Results: Agreement for whole-body MRI without fused images and FDG-PET/CT was very good for nodal staging (κ = 0.86, 95% CI 0.78-0.93) and extra-nodal staging (κ = 0.90, 95% CI 0.71-1.09). Agreement improved with the addition of the fused DWI/T2-weighted images (κ = 0.92 95% CI 0.87-0.97 (nodal staging), κ = 0.92 95% CI 0.76-1.08 (extra-nodal staging). Sensitivity and specificity for staging nodal disease were 99 % and 95% respectively for whole-body MRI including DWI/T2-weighted fused images (versus 88 % and 97 % without fused images) and 100 % and 99 % for extra-nodal disease (83 % and 100 % without fused images). Disease stage for MRI including fused DWI/T2-weighted images agreed with the reference standard in 18 out of 21 patients., Conclusions: The addition of DWI/T2-weighted fusion images to T1-weighted, T2-weighted and DWI whole-body MRI might shorten reading times and might improve the diagnostic performance of whole-body MRI in staging pediatric Hodgkin's lymphoma., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Objectives: To compare the total number of adverse events (AEs) before and after mesenchymal stromal cell (MSC) infusion in refractory JIA and to evaluate its effectiveness., Methods: Single-centre Proof of Mechanism Phase Ib, open label intervention study in JIA patients previously failing all biologicals registered for their diagnosis. Six patients received 2 million/kg intravenous infusions of allogeneic bone-marrow derived MSC. In case of ACR-Ped30-response but subsequent loss of response one and maximal two repeated infusions are allowed., Results: Six JIA patients with 9.2 years median disease duration, still active arthritis and damage were included. All had failed methotrexate, corticosteroids and median five different biologicals. MSC were administered twice in three patients. No acute infusion reactions were observed and a lower post-treatment than pre-treatment incidence in AEs was found. The one systemic onset JIA (sJIA) patient had again an evolving macrophage activation syndrome, 9 weeks after tocilizumab discontinuation and 7 weeks post-MSC infusion. Statistically significant decreases were found 8 weeks after one MSC infusion in VAS well-being (75-56), the JADAS-71 (24.5-11.0) and the cJADAS10 (18.0-10.6)., Conclusion: MSC infusions in six refractory JIA patients were safe, although in sJIA stopping the 'failing' biologic treatment carries a risk of a MAS flare, as the drug might still suppress the systemic features., Trial Registration: Trial register.nl, http://https://www.trialregister.nl, NTR4146., (© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Background: Computed tomography (CT), a strong diagnostic tool, delivers higher radiation doses than most imaging modalities. As CT use has increased rapidly, radiation protection is important, particularly among children. We evaluate leukemia and brain tumor risk following exposure to low-dose ionizing radiation from CT scans in childhood., Methods: For a nationwide retrospective cohort of 168 394 children who received one or more CT scans in a Dutch hospital between 1979 and 2012 who were younger than age 18 years, we obtained cancer incidence, vital status, and confounder information by record linkage with external registries. Standardized incidence ratios were calculated using cancer incidence rates from the general Dutch population. Excess relative risks (ERRs) per 100 mGy organ dose were calculated with Poisson regression. All statistical tests were two-sided., Results: Standardized incidence ratios were elevated for all cancer sites. Mean cumulative bone marrow doses were 9.5 mGy at the end of follow-up, and leukemia risk (excluding myelodysplastic syndrome) was not associated with cumulative bone marrow dose (44 cases). Cumulative brain dose was on average 38.5 mGy and was statistically significantly associated with risk for malignant and nonmalignant brain tumors combined (ERR/100 mGy: 0.86, 95% confidence interval = 0.20 to 2.22, P = .002, 84 cases). Excluding tuberous sclerosis complex patients did not substantially change the risk., Conclusions: We found evidence that CT-related radiation exposure increases brain tumor risk. No association was observed for leukemia. Compared with the general population, incidence of brain tumors was higher in the cohort of children with CT scans, requiring cautious interpretation of the findings., (© The Author(s) 2018. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Detecting extranodal disease in paediatric Hodgkin lymphoma is of great importance for both treatment and prognosis. Different imaging techniques can be used to identify these extranodal sites. This pictorial essay provides an overview of imaging features of extranodal disease manifestation in paediatric Hodgkin lymphoma.

Purpose: Diffuse large B-cell lymphoma (DLBCL) represents the most common subtype of non-Hodgkin lymphoma. Most relapses occur in the first 2 years after diagnosis. Early response assessment with 18 F-fluoro-2-deoxy-D-glucose ( 18 F-FDG) positron emission tomography (PET) may facilitate early change of treatment, thereby preventing ineffective treatment and unnecessary side effects. We aimed to assess the predictive value of visually-assessed interim 18 F-FDG PET on progression-free survival (PFS) or event-free survival (EFS) in DLBCL patients treated with first-line immuno-chemotherapy regimens., Methods: For this systematic review and meta-analysis Pubmed, Embase, and the Cochrane Library were searched until July 11, 2017. Prospective and retrospective studies investigating qualitative interim PET response assessment without treatment adaptation based on the interim PET result were eligible. The primary outcome was two-year PFS or EFS. Prognostic and diagnostic measures were extracted and analysed with pooled hazard ratios and Hierarchical Summary Receiver Operator Characteristic Curves, respectively. Meta-regression was used to study covariate effects., Results: The pooled hazard ratio for 18 studies comprising 2,255 patients was 3.13 (95%CI 2.52-3.89) with a 95% prediction interval of 1.68-5.83. In 19 studies with 2,366 patients, the negative predictive value for progression generally exceeded 80% (64-95), but sensitivity (33-87), specificity (49-94), and positive predictive values (20-74) ranged widely., Conclusions: These findings showed that interim 18 F-FDG PET has predictive value in DLBCL patients. However, (subgroup) analyses were limited by lack of information and small sample sizes. Some diagnostic test characteristics were not satisfactory, especially the positive predictive value should be improved, before a successful risk stratified treatment approach can be implemented in clinical practice.

Autosomal-dominant hypertension and brachydactyly syndrome (HTNB; Bilginturan syndrome) is known to cause stroke before age 50 when untreated. We report a novel PDE3A gene mutation in a mother and daughter affected with dominant brachydactyly of the hands and feet, a short stature, and hypertension. The hypertension was medically responsive to anti-hypertensive treatment. The 3-bp deletion in the PDE3A gene presented de novo in the mother. Here, we expand the list of PDE3A mutations identified in Bilginturan syndrome and emphasize the importance of standardized genetic testing of HTNB patients to improve diagnostics at an early age. We recommend extended phenotyping in patients with brachydactyly, a short stature or hypertension in clinical practice.

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Objectives: Neonates with congenital heart disease may have an increased risk of cerebral sinovenous thrombosis, but incidence rates are lacking. This study describes the clinical and neuroimaging characteristics of cerebral sinovenous thrombosis in neonates undergoing cardiac surgery., Methods: Forty neonates (78% male) requiring neonatal univentricular or biventricular cardiac repair using cardiopulmonary bypass were included. All underwent preoperative (median postnatal day 7) and postoperative (median postoperative day 7) magnetic resonance imaging of the brain, including venography, to detect cerebral sinovenous thrombosis. Clinical characteristics were compared between cerebral sinovenous thrombosis positive and cerebral sinovenous thrombosis negative neonates., Results: Postoperatively, cerebral sinovenous thrombosis was diagnosed in 11 neonates (28%), with the transverse sinus affected in all, and involvement of multiple sinuses in 10 (91%). Preoperatively, signs of thrombosis were seen in 3 cases (8%). Focal infarction of the basal ganglia was significantly more common in cerebral sinovenous thrombosis positive than cerebral sinovenous thrombosis negative neonates (P = .025). Cerebral sinovenous thrombosis positive neonates spent more time in the intensive care unit preoperatively (P = .001), had lower weight (P = .024) and lower postmenstrual age (P = .030) at surgery, and had prolonged use of a central venous catheter (P = .023) and a catheter placed in the internal jugular vein more often (P = .039). Surgical and postoperative factors were not different between new postoperative cerebral sinovenous thrombosis positive and cerebral sinovenous thrombosis negative neonates., Conclusions: Cerebral sinovenous thrombosis might be more common than previously understood in neonates undergoing cardiac surgery. In our study, cerebral sinovenous thrombosis was associated with a higher risk of additional intra-parenchymal brain injury., (Copyright © 2017 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Background: Normative data on pulmonary nodules in children without malignancy are limited. Knowledge of the frequency and characteristics of pulmonary nodules in healthy children can influence care decisions in children with malignant disease., Objective: To provide normative data concerning the frequency and characteristics of pulmonary nodules on computed tomography (CT) in young children., Materials and Methods: All children ages 1 year-12 years who underwent chest CT after high-energy trauma were retrospectively investigated. Exclusion criteria were a history of malignancy, thick image slices, motion artefacts and extensive post-traumatic pulmonary changes. Two radiologists were asked to independently identify all nodules and to characterize each nodule with respect to location, size, perifissural location and calcification. Discrepancies were adjudicated by a third reader, who set the reference standard in this study. Interobserver agreement in detection and characterization was assessed using the kappa coefficient (κ)., Results: Identified were 120 patients, of whom 72 (75% male; median age: 8.0 years [interquartile range: 4-11]) were included. A total of 59 pulmonary nodules were present in 27 patients (38%; 95% confidence interval: 26-49%; range: 1-5 nodules per patient, with a mean diameter of 3.2 mm [standard deviation: 0.9 mm]). For nodule detection, the per-patient interobserver agreement was substantial (κ=0.78) and per-lobe agreement was moderate (κ=0.40). For characterization, there was fair to substantial agreement (κ=0.36-0.74)., Conclusion: Small pulmonary nodules on chest CT are a common finding in otherwise healthy children, but detection and characterization have only moderate interobserver agreement.

Background: Hydrostatic or pneumatic reduction of intussusception is an invasive procedure that is stressful and may be painful for a child. Resistance of the child may increase the duration of the procedure and decrease success rate of reduction. Analgesia can help to reduce pain, but not necessarily resistance. General anesthesia increases success rate of reduction. However, it requires the presence of an anesthesiologist, and may lead to anesthesia-related complications. Procedural sedation with esketamine could be a safe alternative., Aim: The aim of this study was to compare hydrostatic reduction using morphine analgesia compared to procedural sedation with esketamine in terms of success rate, adverse events, and duration of reduction., Methods: A retrospective case-cohort comparison study was performed with two groups of patients who had undergone hydrostatic reduction for ileocolic intussusception and received morphine analgesia (n = 37) or esketamine sedation (n = 20). Until July 2013, reduction was performed after intravenously administered morphine. Hereafter, a new protocol for procedural sedation was implemented and reduction was performed after administration of esketamine. Cases were matched for age and duration of symptoms., Results: No adverse events requiring intervention other than administration of oxygen were reported for either group. Success rate of reduction using esketamine sedation was 90% vs 70% using morphine analgesia, risk ratio (RR) 1.29, 95% CI[0.93-1.77]. Recurrence rate using esketamine sedation was 10% vs 15% using morphine analgesia, RR 0.67, 95% CI[0.12-3.57]. Reduction time was shorter using esketamine sedation (Median 5 minutes, IQR 9 minutes) vs morphine analgesia (Median 8 minutes, IQR 16 minutes, P = .04, Median difference 3, 95% CI[-1.50-8.75]). Median hospital stay in the esketamine group was 1.5 days (IQR 1.8) vs 2 days (IQR 5.3) in the morphine group., Conclusion: No serious adverse events were recorded. In comparison to morphine analgesia, with esketamine there was weak evidence for a higher success rate, lower recurrence rate, shorter duration, and shorter length of hospital stay., (© 2017 John Wiley & Sons Ltd.)

Objective: To evaluate trends and patterns in CT usage among children (aged 0-17 years) in The Netherlands during the period 1990-2012., Methods: Lists of electronically archived paediatric CT scans were requested from the Radiology Information Systems (RIS) of Dutch hospitals which reported >10 paediatric CT scans annually in a survey conducted in 2010. Data included patient identification, birth date, gender, scan date and body part scanned. For non-participating hospitals and for years prior to electronic archiving in some participating hospitals, data were imputed by calendar year and hospital type (academic, general with <500 beds, general with ≥ 500 beds)., Results: Based on 236,066 CT scans among 146,368 patients performed between 1990 and 2012, estimated annual numbers of paediatric CT scans in The Netherlands increased from 7,731 in 1990 to 26,023 in 2012. More than 70 % of all scans were of the head and neck. During the last decade, substantial increases of more than 5 % per year were observed in general hospitals with fewer than 500 beds and among children aged 10 years or older., Conclusion: The estimated number of paediatric CT scans has more than tripled in The Netherlands during the last two decades., Key Points: • Paediatric CT in The Netherlands has tripled during the last two decades. • The number of paediatric CTs increased through 2012 in general hospitals. • Paediatric CTs continued to increase among children aged 10 years or older.

This study aimed to systematically review and meta-analyze the prognostic value of complete remission status at 18F-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) in Hodgkin lymphoma after completion of first-line therapy. A systematic literature search was performed in the MEDLINE database for suitable original articles. The included studies were methodologically assessed using the Quality In Prognosis Studies tool. The proportion of patients who developed disease relapse during follow-up, among those patients who were in complete remission according to FDG-PET at the completion of first-line therapy, was calculated for each included study. Heterogeneity in disease relapse proportions across individual studies was assessed using the I2 statistic, with heterogeneity regarded present if I2<50 %. Weighted summary disease relapse proportion was calculated using either a random effects model (if I2>50) or a fixed effects model (if I2≤50). Ten studies comprising a total number of 1137 Hodgkin lymphoma patients with complete remission status according to FDG-PET after completion of first-line therapy were included. Overall methodological quality of included studies was reasonably good. The disease relapse rate during follow-up among all patients with complete remission status at end-of-treatment FDG-PET ranged from 0 to 26.7 %, with a weighted summary proportion of 7.5 % (95 % confidence interval 3.9–13.8 %) using the random effects model (I2=88.3 %). In conclusion, although the disease relapse rate in Hodgkin lymphoma patients who achieve an FDG-PET-based complete remission after first-line therapy is low from an absolute point of view, it is actually high when considering the generally favorable outcome of Hodgkin lymphoma.

Purpose: To determine the prognostic performance of tumor necrosis at FDG-PET in patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) who are treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) therapy., Materials and Methods: 108 patients with newly diagnosed DLBCL who underwent FDG-PET before R-CHOP therapy were retrospectively included. Lymphomatous sites at FDG-PET were assessed for the presence of a photopenic area, in keeping with tumor necrosis. Univariate and multivariate Cox regression analyses were performed to determine the associations of tumor necrosis and National Comprehensive Cancer Network International Prognostic Index (NCCN-IPI) with progression-free survival (PFS) and overall survival (OS)., Results: On univariate Cox regression analysis, both tumor necrosis and higher NCCN-IPI risk groups were significantly associated with PFS (P=0.024 and P<0.001, respectively) and OS (P=0.034 and P<0.001, respectively). On multivariate Cox regression analysis, both tumor necrosis and the NCCN-IPI were independent significant predictors for PFS (P=0.007, hazard ratio: 2.723 [95% confidence interval: 1.324-5.597] and P<0.001, hazard ratio: 2.952 [95% confidence interval: 1.876-4.646], respectively) and OS (P=0.009, hazard ratio: 2.794 [95% confidence interval: 1.305-5.985] and P<0.001, hazard ratio: 2.813 [95% confidence interval: 1.724-4.587], respectively)., Conclusion: Tumor necrosis at FDG-PET is an NCCN-IPI-independent predictor of outcome in DLBCL., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

This study aimed to systematically review the prognostic value of interim and end-of-treatment (18)F-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) in follicular lymphoma during and after first-line therapy. The PubMed/MEDLINE database was searched for relevant original studies. Included studies were methodologically assessed, and their results were extracted and descriptively analyzed. Three studies on the prognostic value of interim FDG-PET and eight studies on the prognostic value of end-of-treatment FDG-PET were included. Overall, studies were of poor methodological quality. In addition, there was incomplete reporting of progression-free survival (PFS) and overall survival (OS) data by several studies, and none of the studies incorporated the Follicular Lymphoma International Prognostic Index (FLIPI) in the OS analyses. Two studies reported no significant difference in PFS between interim FDG-PET positive and negative patients, whereas one study reported a significant difference in PFS between the two groups. Two studies reported no significant difference in OS between interim FDG-PET positive and negative patients. Five studies reported end-of-treatment FDG-PET positive patients to have a significantly worse PFS than end-of-treatment FDG-PET negative patients, and one study reported a non-significant trend towards a worse PFS for end-of-treatment FDG-PET positive patients. Three studies reported end-of-treatment FDG-PET positive patients to have a significantly worse OS than end-of-treatment FDG-PET negative patients. In conclusion, the available evidence does not support the use of interim FDG-PET in follicular lymphoma. Although published studies suggest end-of-treatment FDG-PET to be predictive of PFS and OS, they suffer from numerous biases and failure to correct OS prediction for the FLIPI.

Objective: To determine the prognostic value of tumor necrosis at computed tomography (CT) in newly diagnosed diffuse large B-cell lymphoma (DLBCL)., Materials and Methods: This retrospective study included 51 patients with newly diagnosed DLBCL who had undergone both unenhanced and intravenous contrast-enhanced CT before R-CHOP (rituximab, cyclophosphamide, hydroxydaunorubicin, oncovin and prednisolone) chemo-immunotherapy. Presence of tumor necrosis was visually and quantitatively assessed at CT. Associations between tumor necrosis status at CT and the National Comprehensive Cancer Network (NCCN) International Prognostic Index (IPI) factors were assessed. Cox regression analysis was used to determine the prognostic impact of NCCN-IPI scores and tumor necrosis status at CT., Results: There were no correlations between tumor necrosis status at CT and the NCCN-IPI factors categorized age (ρ=-0.042, P=0.765), categorized lactate dehydrogenase (LDH) ratio (ρ=0.201, P=0.156), extranodal disease in major organs (φ=-0.245, P=0.083), Ann Arbor stage III/IV disease (φ=-0.208, P=0.141), and Eastern Cooperative Oncology Group (ECOG) performance status (φ=0.015, P=0.914). In the multivariate Cox proportional hazards model, only tumor necrosis status at CT was an independent predictive factor of progression-free survival (P=0.003) and overall survival (P=0.004)., Conclusion: The findings of this study indicate the prognostic potential of tumor necrosis at CT in newly diagnosed DLBCL., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

We describe two patients with severe developmental delay, hypotonia and breathing abnormalities initially diagnosed with the autosomal recessive Joubert syndrome (JBS) who at a later stage appeared to carry chromosomal abnormalities. One case was due to a 4.8 Mb terminal 1q44 deletion, and the other due to a 15.5 Mb duplication of Xq27.2-qter containing the MECP2 gene. Critical evaluation of the clinical data showed that, retrospectively, the cases did not fulfil the diagnostic criteria for JBS, and that the diagnosis of JBS was incorrectly made. We discuss the diagnostic pitfalls and recommend adhering strictly to the JBS diagnostic criteria in the case of a negative molecular diagnosis. Critical assessment of the MRI findings by a specialized neuroradiologist is imperative. As chromosomal abnormalities may give rise to symptoms resembling JBS, we recommend array-based screening for segmental aneuploidies as an initial genetic test in all cases with a JBS-like phenotype.