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.

We profiled a large heterogeneous cohort of matched diagnostic relapse tumor tissue and paired plasma-derived cell-free DNA (cfDNA) from patients with relapsed and progressive solid tumors of childhood. Tissue and cfDNA sequencing results were concordant, with a wider spectrum of mutant alleles and higher degree of intratumor heterogeneity captured by the latter, if sufficient ctDNA was present. Serial tumor sequencing identified putative drivers of relapse, with alterations in epigenetic drivers being a common feature. In keeping with epigenetic alterations being a common driver of many childhood cancers, fragmentomic analysis of cfDNA identified tumor-specific epigenetic states and transcription factor binding sites accessible in chromatin. This study leverages a large and well-annotated genomic dataset of aggressive childhood malignancies, identifies genomic and epigenetic drivers of childhood cancer relapse, and highlights the power and practicality of cfDNA analysis to capture both intratumoral heterogeneity and the epigenetic state of cancer cells. Significance: In tumors of childhood, we identify mutations in epigenetic genes as drivers of relapse, with matched cfDNA sequencing showing significant intratumor genetic heterogeneity and cell-state specific patterns of chromatin accessibility. This highlights the power of cfDNA analysis to identify both genetic and epigenetic drivers of aggressive disease in pediatric cancers.

In addition to optimising survival of children with rhabdomyosarcoma (RMS), more attention is now focused on improving their quality of life (QOL) and reducing symptoms during treatment, palliative care or into long-term survivorship. QOL and ongoing symptoms related to the disease and its treatment are outcomes that should ideally be patient-reported (patient-reported outcomes, PROs) and can be assessed using patient-reported outcome measures (PROMS). This commentary aims to encourage PRO and PROM use in RMS by informing professionals in the field of available PROMs for utilisation in paediatric RMS and provide considerations for future use in research and clinical practice. Despite the importance of using PROMs in research and practice, PROMs have been reported scarcely in paediatric RMS literature so far. Available literature suggests lower QOL of children with RMS compared to general populations and occurrence of disease-specific symptoms, but a lack of an RMS-specific PROM. Ongoing developments in the field include the development of PROMs targeted at children with RMS specifically and expansion of PROM evaluation within clinical trials.

Background: The apparent diffusion coefficient (ADC) derived from diffusion-weighted imaging (DWI) is a potential biomarker for treatment response in pediatric rhabdomyosarcoma. Due to its rarity, investigations into this marker require multicenter approaches, which can result in variability in acquisition parameters. Objective: To evaluate the impact of different acquisition parameters on ADC estimates in a multicenter dataset of rhabdomyosarcoma patients. Materials and methods: We included 114 pediatric and adolescent rhabdomyosarcoma patients from 22 treatment centers (195 scans). Median age: 6.0 years (0.3–21.8). We evaluated the impact of voxel size, (number of) b-values, and echo time on tumor ADC values. The effect of the highest b-value was separately investigated on a subset of scans with five or more b-values. Results: We observed a large variability in key acquisition parameters in the overall cohort, and for individual imaging centers. No parameter showed a significant effect on ADC estimates of the whole cohort when corrected for multiple-comparisons. Decreasing the highest b-value within the same acquisition caused ADC to decrease on average by 2.8% per 100 s mm^-2. Differing b-values between scans at diagnosis and treatment response yielded significant changes in the longitudinal ADC for each patient (P<0.05). Conclusion: While we observed wide variation of acquisition parameters within a multicenter cohort, this did not lead to significant cross-sectional differences of tumor ADC. However, we found that modifying the highest b-value between baseline and follow-up can impact longitudinal ADC estimates. As such, we recommend the highest b-value to remain constant. This retrospective study was reviewed and approved by the Internal Review Board (UMC Utrecht, reference ID: 18-412). Graphical

The authors wish to make corrections to the authorship and title of