Frontline and Relapsed Rhabdomyosarcoma (FAR-RMS) Clinical Trial: A Report from the European Paediatric Soft Tissue Sarcoma Study Group (EpSSG).

The Frontline and Relapsed Rhabdomyosarcoma (FaR-RMS) clinical trial is an overarching, multinational study for children and adults with rhabdomyosarcoma (RMS). The trial, developed by the European Soft Tissue Sarcoma Study Group (EpSSG), incorporates multiple different research questions within a multistage design with a focus on (i) novel regimens for poor prognostic subgroups, (ii) optimal duration of maintenance chemotherapy, and (iii) optimal use of radiotherapy for local control and widespread metastatic disease. Additional sub-studies focusing on biological risk stratification, use of imaging modalities, including [18F]FDG PET-CT and diffusion-weighted MRI imaging (DWI) as prognostic markers, and impact of therapy on quality of life are described. This paper forms part of a Special Issue on rhabdomyosarcoma and outlines the study background, rationale for randomisations and sub-studies, design, and plans for utilisation and dissemination of results.

Modeling of inflicted head injury by shaking trauma in children: what can we learn? : Update to parts I&II: A systematic review of animal, mathematical and physical models.

Inflicted shaking trauma can cause injury in infants, but exact injury mechanisms remain unclear. Controversy exists, particularly in courts, whether additional causes such as impact are required to produce injuries found in cases of (suspected) shaking. Publication rates of studies on animal and biomechanical models of inflicted head injury by shaking trauma (IHI-ST) in infants continue rising. Dissention on the topic, combined with its legal relevance, makes maintaining an up-to-date, clear and accessible overview of the current knowledge-base on IHI-ST essential. The current work reviews recent (2017-2023) studies using models of IHI-ST, serving as an update to two previously published reviews. A systematic review was conducted in Scopus and PubMed for articles using animal, physical and mathematical models for IHI-ST. Using the PRISMA methodology, two researchers independently screened the publications. Two, five, and ten publications were included on animal, physical, and mathematical models of IHI-ST, respectively. Both animal model studies used rodents. It is unknown to what degree these can accurately represent IHI-ST. Physical models were used mostly to investigate gross head-kinematics during shaking. Most mathematical models were used to study local effects on the eye and the head's internal structures. All injury thresholds and material properties used were based on scaled adult or animal data. Shaking motions used as inputs for animal, physical and mathematical models were mostly greatly simplified. Future research should focus on using more accurate shaking inputs for models, and on developing or and validating accurate injury thresholds applicable for shaking.

No Pathogenic DICER1 Gene Variants in a Cohort Study of 28 Children With Congenital Pulmonary Airway Malformation.

BACKGROUND: Distinguishing congenital pulmonary airway malformations (CPAMs) from pleuropulmonary blastoma (PPB) can be challenging. Previously diagnosed patients with CPAM may have been misdiagnosed and we may have missed DICER1-associated PPBs, a diagnosis with important clinical implications for patients and their families. To gain insight in potential misdiagnoses, we systematically assessed somatic DICER1 gene mutation status in an unselected, retrospective cohort of patients with a CPAM diagnosis. METHODS: In the Amsterdam University Medical Center (the Netherlands), it has been standard policy to resect CPAM lesions. We included all consecutive cases of children (age 0-18 years) with a diagnosis of CPAM between 2007 and 2017 at this center. Clinical and radiographic features were reviewed, and DICER1 gene sequencing was performed on DNA retrieved from CPAM tissue samples. RESULTS: Twenty-eight patients with a surgically removed CPAM were included. CPAM type 1 and type 2 were the most common subtypes (n = 12 and n = 13). For 21 patients a chest CT scan was available for reassessment by two pediatric radiologists. In 9 patients (9/21, 43%) the CPAM subtype scored by the radiologists did not correspond with the subtype given at pathology assessment. No pathogenic mutations and no copy number variations of the DICER1 gene were found in the DNA extracted from CPAM tissue (0/28). CONCLUSIONS: Our findings suggest that the initial CPAM diagnoses were correct. These findings should be validated through larger studies to draw conclusions regarding whether systematic DICER1 genetic testing is required in children with a pathological confirmed diagnosis of CPAM or not. LEVEL OF EVIDENCE: Level IV.

Quantitative diffusion-weighted MRI response assessment in rhabdomyosarcoma: an international retrospective study on behalf of the European paediatric Soft tissue sarcoma Study Group Imaging Committee.

OBJECTIVE: To investigate the feasibility of diffusion-weighted magnetic resonance imaging (DW-MRI) as a predictive imaging marker after neoadjuvant chemotherapy in patients with rhabdomyosarcoma. MATERIAL AND METHODS: We performed a multicenter retrospective study including pediatric, adolescent and young adult patients with rhabdomyosarcoma, Intergroup Rhabdomyosarcoma Study group III/IV, treated according to the European paediatric Soft tissue sarcoma Study Group (EpSSG) RMS2005 or MTS2008 studies. DW-MRI was performed according to institutional protocols. We performed two-dimensional single-slice tumor delineation. Areas of necrosis or hemorrhage were delineated to be excluded in the primary analysis. Mean, median and 5th and 95th apparent diffusion coefficient (ADC) were extracted. RESULTS: Of 134 included patients, 82 had measurable tumor at diagnosis and response and DW-MRI scans of adequate quality and were included in the analysis. Technical heterogeneity in scan acquisition protocols and scanners was observed. Mean ADC at diagnosis was 1.1 (95% confidence interval [CI]: 1.1-1.2) (all ADC expressed in * 10-3 mm2/s), versus 1.6 (1.5-1.6) at response assessment. The 5th percentile ADC was 0.8 (0.7-0.9) at diagnosis and 1.1 (1.0-1.2) at response. Absolute change in mean ADC after neoadjuvant chemotherapy was 0.4 (0.3-0.5). Exploratory analyses for association between ADC and clinical parameters showed a significant difference in mean ADC at diagnosis for alveolar versus embryonal histology. Landmark analysis at nine weeks after the date of diagnosis showed no significant association (hazard ratio 1.3 [0.6-3.2]) between the mean ADC change and event-free survival. CONCLUSION: A significant change in the 5th percentile and the mean ADC after chemotherapy was observed. Strong heterogeneity was identified in DW-MRI acquisition protocols between centers and in individual patients.

INternational Soft Tissue saRcoma ConsorTium (INSTRuCT) consensus statement: Imaging recommendations for the management of rhabdomyosarcoma.

Rhabdomyosarcoma is the most common soft-tissue neoplasm in the pediatric population. The survival of children with rhabdomyosarcoma has only marginally improved over the past 25 years and remains poor for those with metastatic disease. A significant challenge to advances in treatment of rhabdomyosarcoma is the relative rarity of this disease, necessitating years to complete clinical trials. Progress can be accelerated by international cooperation and sharing national experiences. This necessitates agreement on a common language to describe patient cohorts and consensus standards to guide diagnosis, treatment, and response assessment. These goals formed the premise for creating the INternational Soft Tissue saRcoma ConsorTium (INSTRuCT) in 2017. Multidisciplinary members of this consortium have since developed international consensus statements on the diagnosis, treatment, and management of pediatric soft-tissue sarcomas. Herein, members of the INSTRuCT Diagnostic Imaging Working Group present international consensus recommendations for imaging of patients with rhabdomyosarcoma at diagnosis, at staging, and during and after completion of therapy. The intent is to promote a standardized imaging approach to pediatric patients with this malignancy to create more-reliable comparisons of results of clinical trials internationally, thereby accelerating progress in managing rhabdomyosarcoma and improving survival.

Metastatic adult-type non-rhabdomyosarcoma soft tissue sarcomas in children and adolescents: A cohort study from the European paediatric Soft tissue sarcoma Study Group.

BACKGROUND: Limited data exist on the clinical behavior of pediatric non-rhabdomyosarcoma soft tissue sarcomas (NRSTS) with distant metastases at onset, and a clear standard of care has not yet been defined. METHODS: This cohort study reports on pediatric adult-type metastatic NRSTS enrolled in two concurrent prospective European studies, i.e., the randomized BERNIE study and the single-arm MTS 2008 study developed by the European paediatric Soft tissue sarcoma Study Group. Treatment programs were originally designed for patients with metastatic rhabdomyosarcoma, i.e., nine courses of multidrug chemotherapy (with or without bevacizumab in the BERNIE study), followed by 12 cycles of maintenance therapy, whereas radiotherapy and/or surgery (on primary tumor and/or metastases) were delayed until after seven courses of chemotherapy had been administered. RESULTS: The study included 61 patients <21 years old treated from July 2008 to December 2016. The lung was the site of metastases in 75% of the cases. All patients received multi-agent chemotherapy, 44% had local therapy to primary tumor, and 18% had treatment of metastases. Median time to progression/relapse was 6 months. A high rate of tumor progression was observed during the initial part of the chemotherapy program. With a median follow-up of 41.5 months (range, 2-111 months), 3-year event-free survival and overall survival were 15.4% (95% confidence interval [CI], 7.6-25.7) and 34.9% (95% CI, 22.7-47.5), respectively. There were no statistically significant differences in outcome depending on the type of treatment administered. CONCLUSIONS: The study confirmed the overall poor outcome for patients with metastatic NRSTS, whose treatment remains a challenge. PLAIN LANGUAGE SUMMARY: Pediatric non-rhabdomyosarcoma soft tissue sarcomas form a heterogeneous group of rare tumors. Although recent international studies have defined the standard of care for patients with localized disease, limited data are available on the clinical behavior of patients with distant metastases. This study on 61 metastatic cases treated on two prospective European protocols confirms that the chances of survival of such patients are often dismal and a standard treatment is still lacking.

Benign enlargement of the subarachnoid spaces and subdural collections-when to evaluate for abuse.

In infants without a history of trauma, subdural haemorrhages should raise the concern for an abusive head injury, particularly when they are associated with bridging vein clotting/rupture or with septations. However, non-haemorrhagic, fluid-appearing subdural collections (also called hygromas) may also be the result of abuse. Subdural collections have also been uncommonly observed in patients with benign enlargement of the subarachnoid spaces (BESS) and a few large-scale studies accurately investigate the incidence and the significance. Currently, there is a wide variation of practices in children with BESS and subdural collections. Due to the social risks associated with abuse evaluation and the perceived risk of radiation exposure, there might be a reluctance to fully evaluate these children in some centres. The diagnosis of physical abuse cannot be substantiated nor safely excluded in infants with BESS and subdural collection(s), without investigation for concomitant traumatic findings. The exact prevalence of occult injuries and abuse in these infants is unknown. In macrocephalic infants with subdural collections and imaging features of BESS, thorough investigations for abuse are warranted and paediatricians should consider performing full skeletal surveys even when fundoscopy, social work consult, and detailed clinical evaluation are unremarkable.

International Consensus Statement on the Radiological Screening of Contact Children in the Context of Suspected Child Physical Abuse.

Importance: Physical abuse is a common but preventable cause of long-term childhood morbidity and mortality. Despite the strong association between abuse in an index child and abuse in contact children, there is no guidance outlining how to screen the latter, significantly more vulnerable group, for abusive injuries. Consequently, the radiological assessment of contact children is often omitted, or variably performed, allowing occult injuries to go undetected and increasing the risk of further abuse. Objective: To report an evidence-based and consensus-derived set of best practices for the radiological screening of contact children in the context of suspected child physical abuse. Evidence Review: This consensus statement is supported by a systematic review of the literature and the clinical opinion of an internationally recognized group of 26 experts. The modified Delphi consensus process comprised 3 meetings of the International Consensus Group on Contact Screening in Suspected Child Physical Abuse held between February and June 2021. Findings: Contacts are defined as the asymptomatic siblings, cohabiting children, or children under the same care as an index child with suspected child physical abuse. All contact children should undergo a thorough physical examination and a history elicited prior to imaging. Contact children younger than 12 months should have neuroimaging, the preferred modality for which is magnetic resonance imaging, and skeletal survey. Contact children aged 12 to 24 months should undergo skeletal survey. No routine imaging is indicated in asymptomatic children older than 24 months. Follow-up skeletal survey with limited views should be performed if abnormal or equivocal at presentation. Contacts with positive findings should be investigated as an index child. Conclusions and Relevance: This Special Communication reports consensus recommendations for the radiological screening of contact children in the context of suspected child physical abuse, establishing a recognized baseline for the stringent evaluation of these at-risk children and providing clinicians with a more resilient platform from which to advocate for them.

Controversial aspects of imaging in child abuse: a second roundtable discussion from the ESPR child abuse taskforce.

This second roundtable discussion was convened at the 56th European Society of Paediatric Radiology (ESPR) 2022 Annual Meeting in Marseille, France, to discuss controversial aspects of imaging in child abuse. The following topics were discussed: Fracture dating-the published literature is broadly similar with respect to the identification of the radiographic stages of bony healing. The non-expert/general radiologist is encouraged to use broad descriptors of fracture healing (acute, healing or old) within their reports, rather than attempting to date fractures. The more experienced/expert radiologist, who may provide a timeframe/range to assist the courts, should be aware that any published timeframes are not absolute and that recent research indicates that the rate of healing may differ according to the bone affected and the age of the patient. Whole spine imaging in suspected abusive head trauma-this is recommended to enable a complete assessment of the neuraxis when abusive head trauma is suspected or diagnosed, particularly in the presence of intracranial and cervical subdural haemorrhage and cervical ligamentous injury. Cranial imaging in suspected physical abuse-both computed tomography (CT) and magnetic resonance imaging (MRI) remain complimentary depending on the clinical context in which they are used with CT remaining first-line in the assessment of children with (suspected abusive) head trauma prior to an early MRI. MRI is superior in its assessment of parenchymal injury and may be employed as first-line in age appropriate asymptomatic siblings of a child with suspected physical abuse.

Imaging in rhabdomyosarcoma: a patient journey.

Rhabdomyosarcoma, although rare, is the most frequent soft tissue sarcoma in children and adolescents. It can present as a mass at nearly any site in the body, with most common presentations in the head and neck, genitourinary tract and extremities. The optimal diagnostic approach and management of rhabdomyosarcoma require a multidisciplinary team with multimodal treatment, including chemotherapy and local therapy. Survival has improved over the last decades; however, further improvement in management is essential with current 5-year overall survival ranging from 35% to 100%, depending on disease and patient characteristics. In the full patient journey, from diagnosis, staging, management to follow-up after therapy, the paediatric radiologist and nuclear physician are essential members of the multidisciplinary team. Recently, guidelines of the European paediatric Soft tissue sarcoma Study Group, the Cooperative Weichteilsarkom Studiengruppe and the Oncology Task Force of the European Society of Paediatric Radiology (ESPR), in an ongoing collaboration with the International Soft-Tissue Sarcoma Database Consortium, provided guidance for high-quality imaging. In this educational paper, given as a lecture during the 2022 postgraduate ESPR course, the multi-disciplinary team of our national paediatric oncology centre presents the journey of two patients with rhabdomyosarcoma and discusses the impact on and considerations for the clinical (paediatric) radiologist and nuclear physician. The key learning points of the guidelines and their implementation in clinical practice are highlighted and up-to-date insights provided for all aspects from clinical suspicion of rhabdomyosarcoma and its differential diagnosis, to biopsy, staging, risk stratification, treatment response assessment and follow-up.

Assessing Disease Activity in Pediatric Crohn's Disease Using Ultrasound: The Pediatric Crohn Disease Intestinal Ultrasound Score.

OBJECTIVES: Currently, there is no consensus on how to score Crohn disease (CD) activity assessed by intestinal ultrasound (IUS) in children. This study aimed to design an easy-to-use IUS score for disease activity in pediatric CD. METHODS: Children undergoing ileo-colonoscopy for CD assessment underwent IUS the day before ileo-colonoscopy, assessed with simple endoscopic score for CD (SES-CD). IUS features were compared to the SES-CD on segmental level. Multiple regression analyses, separately for terminal ileum (TI) and colon, were done to assess predictors of disease activity and to develop a model. RESULTS: In 74 CD patients (median 15 years, 48% female), 67 TI and 364 colon segments were assessed. Based on receiver operating characteristics curves, bowel wall thickness (BWT) was categorized into low [1 point: 2-3 mm (TI) and 1.6-2 mm (colon)], medium [2 points: 3.0-3.7 mm (TI) and 2.0-2.7 mm (colon)], and high [3 points: >3.7 mm (TI) and >2.7 mm (colon)]. In TI, only BWT was retained in the model [high BWT: odds ratio (OR) 11.50, P < 0.001]. In colon, BWT (high BWT: OR 8.63, P < 0.001) and mesenteric fat (1 point: OR 3.02, P < 0.001) were independent predictors. A pediatric Crohn disease IUS score (PCD-US) cut-off of 1 resulted in a sensitivity of 82% (95% confidence interval, CI: 65%-93%) and 85% (95% CI: 80%-89%) and a cut-off of 3 in a specificity of 88% (72%-97%) and 92% (87%-96%) for TI and colon, respectively. Inter-observer agreement was moderate for TI and colon ( K : 0.42, K : 0.49, respectively). CONCLUSIONS: The PCD-US score is an easy-to-use and reliable score to detect or rule out CD activity on segmental level in children. External validation is needed before applying this score in clinical practice.

Methodological considerations on segmenting rhabdomyosarcoma with diffusion-weighted imaging-What can we do better?

PURPOSE: Diffusion-weighted MRI is a promising technique to monitor response to treatment in pediatric rhabdomyosarcoma. However, its validation in clinical practice remains challenging. This study aims to investigate how the tumor segmentation strategy can affect the apparent diffusion coefficient (ADC) measured in pediatric rhabdomyosarcoma. MATERIALS AND METHODS: A literature review was performed in PubMed using search terms relating to MRI and sarcomas to identify commonly applied segmentation strategies. Seventy-six articles were included, and their presented segmentation methods were evaluated. Commonly reported segmentation strategies were then evaluated on diffusion-weighted imaging of five pediatric rhabdomyosarcoma patients to assess their impact on ADC. RESULTS: We found that studies applied different segmentation strategies to define the shape of the region of interest (ROI)(outline 60%, circular ROI 27%), to define the segmentation volume (2D 44%, multislice 9%, 3D 21%), and to define the segmentation area (excludes edge 7%, excludes other region 19%, specific area 27%, whole tumor 48%). In addition, details of the segmentation strategy are often unreported. When implementing and comparing these strategies on in-house data, we found that excluding necrotic, cystic, and hemorrhagic areas from segmentations resulted in on average 5.6% lower mean ADC. Additionally, the slice location used in 2D segmentation methods could affect ADC by as much as 66%. CONCLUSION: Diffusion-weighted MRI studies in pediatric sarcoma currently employ a variety of segmentation methods. Our study shows that different segmentation strategies can result in vastly different ADC measurements, highlighting the importance to further investigate and standardize segmentation.

Intestinal Ultrasound to Assess Ulcerative Colitis Disease Activity in Children: External Validation and Comparison of 2 Intestinal Ultrasound Activity Indices.

BACKGROUND: There is currently no consensus on the definition of an abnormal intestinal ultrasound (IUS) for children with ulcerative colitis (UC). This cross-sectional study aimed to externally validate and compare 2 existing IUS indices in children with UC. METHODS: Children undergoing colonoscopy for UC assessment underwent IUS the day before colonoscopy, assessed with the Mayo endoscopic subscore. The UC-IUS index and the Civitelli index were compared with the Mayo endoscopic score in the ascending, transverse, and descending colon. The area under the receiver-operating characteristic curve for detecting a Mayo endoscopic score ≥2 of both scores was compared and sensitivity and specificity were calculated. RESULTS: A total of 35 UC patients were included (median age 15 years, 39% female). The area under the receiver-operating characteristic curve was higher for the UC-IUS index in the ascending colon (0.82 [95% confidence interval (CI), 0.67-0.97] vs 0.76 [95% CI, 0.59-0.93]; P = .046) and transverse colon (0.88 [95% CI, 0.76-1.00] vs 0.77 [95% CI, 0.60-0.93]; P = .01). In the descending colon, there was no difference (0.84 [95% CI, 0.70-0.99] vs 0.84 [95% CI, 0.70-0.98]). The optimal cutoff for the UC-IUS was <1 point to rule out a Mayo endoscopic score ≥2 (sensitivity: 88%, 100%, and 90% in the ascending, transverse, and descending colon, respectively) and a Mayo endoscopic score ≥2 could be detected using a cutoff of >1 (specificity: 84%, 83%, and 87%, respectively). For the Civitelli index, in our cohort, the optimal cutoff was <1 to rule out a Mayo endoscopic score ≥2 (sensitivity 75%, 65%, and 80%, respectively) and a cutoff >1 to detect a Mayo endoscopic score ≥2 (specificity 89%, 89%, and 93%, respectively). CONCLUSIONS: In this cohort, the UC-IUS index performed better than the Civitelli index. The UC-IUS index had both a high sensitivity and specificity in this cohort, when using 1 point as cutoff for a Mayo endoscopic score ≥2.

In this prospective study, we validated and compared 2 intestinal ultrasound indices to score pediatric ulcerative colitis: the UC-IUS index and the Civitelli index. In our cohort, the UC-IUS index was more accurate.

Current and future funding streams for paediatric postmortem imaging: European Society of Paediatric Radiology survey results.

BACKGROUND: Perinatal and childhood postmortem imaging has been accepted as a noninvasive alternative or adjunct to autopsy. However, the variation in funding models from institution to institution is a major factor prohibiting uniform provision of this service. OBJECTIVE: To describe current funding models employed in European and non-European institutions offering paediatric postmortem imaging services and to discuss the perceived barriers to future postmortem imaging service provision. MATERIALS AND METHODS: A web-based 16-question survey was distributed to members of the European Society of Paediatric Radiology (ESPR) and ESPR postmortem imaging task force over a 6-month period (March-August 2021). Survey questions related to the radiologic and autopsy services being offered and how each was funded within the respondent's institute. RESULTS: Eighteen individual responses were received (13/18, 72.2% from Europe). Only one-third of the institutions (6/18, 33.3%) have fully funded postmortem imaging services, with the remainder receiving partial (6/18, 33.3%) or no funding (5/18, 27.8%). Funding (full or partial) was more commonly available for forensic work (13/18, 72%), particularly where this was nationally provided. Where funding was not provided, the imaging and reporting costs were absorbed by the institute. CONCLUSION: Increased access is required for the expansion of postmortem imaging into routine clinical use. This can only be achieved with formal funding on a national level, potentially through health care commissioning and acknowledgement by health care policy makers and pathology services of the value the service provides following the death of a fetus or child. Funding should include the costs involved in training, equipment, reporting and image acquisition.

Diagnostic accuracy of palpation and ultrasonography for diagnosing infantile hypertrophic pyloric stenosis: a systematic review and meta-analysis.

OBJECTIVE: Although infantile hypertrophic pyloric stenosis (IHPS) is a well-known disease, there is no systematic review regarding the optimal diagnostic strategy. We conducted a systematic review and meta-analysis to obtain diagnostic accuracy of all methods to diagnose IHPS. METHODS: According to the Preferred Reported Items for Systematic Reviews and Meta-Analysis guidelines, we searched MEDLINE and Embase to identify studies reporting sensitivity and specificity of all methods used to diagnose IHPS. Inclusion criteria were infants with suspicion of/or diagnosed with IHPS who underwent pyloromyotomy or had clinical follow-up. A random-effects model was used to obtain pooled estimates of sensitivity, specificity and area under the receiver operating characteristic curve. RESULTS: After screening 5364 studies, we included 43 studies with in total 6085 infants (n = 4241 IHPS; n = 1844 controls). The diagnostic sensitivity of palpation ranged from 10.0 to 93.4% and decreased over time. Different parameters for ultrasonography were found. Most used parameters were pyloric muscle thickness (PMT) ≥ 3 mm (pooled sensitivity 97.6% and specificity 98.8%), PMT ≥ 4 mm (pooled sensitivity 94.0% and specificity 98.0%) or a combination of PMT ≥ 4 mm and/or pyloric canal length ≥16 mm (pooled sensitivity 94.0% and specificity 91.7%). The AUC showed high diagnostic accuracy (0.997, 0.966 and 0.981 respectively), but large heterogeneity exists. Due to the large differences in cut-off values no meta-analysis could be conducted for pyloric canal length and pyloric diameter. CONCLUSION: Palpation has limited sensitivity in diagnosing IHPS. We showed that ultrasonography has highest diagnostic accuracy to diagnose IHPS and we advise to use PMT ≥ 3 mm as cut-off. ADVANCES IN KNOWLEDGE: This is the first systematic review and meta-analysis on diagnosing IHPS, which summarizes the available literature and may be used as a guideline.