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Background: The objective of this study was to investigate the role of clinical factors together with FOXO1 fusion status in patients with nonmetastatic rhabdomyosarcoma (RMS) to develop a predictive model for event‐free survival and provide a rationale for risk stratification in future trials. Methods: The authors used data from patients enrolled in the European Pediatric Soft Tissue Sarcoma Study Group (EpSSG) RMS 2005 study (EpSSG RMS 2005; EudraCT number 2005‐000217‐35). The following baseline variables were considered for the multivariable model: age at diagnosis, sex, histology, primary tumor site, Intergroup Rhabdomyosarcoma Studies group, tumor size, nodal status, and FOXO1 fusion status. Main effects and significant second‐order interactions of candidate predictors were included in a multiple Cox proportional hazards regression model. A nomogram was generated for predicting 5‐year event‐free survival (EFS) probabilities. Results: The EFS and overall survival rates at 5 years were 70.9% (95% confidence interval, 68.6%–73.1%) and 81.0% (95% confidence interval, 78.9%–82.8%), respectively. The multivariable model retained five prognostic factors, including age at diagnosis interacting with tumor size, tumor primary site, Intergroup Rhabdomyosarcoma Studies clinical group, and FOXO1 fusion status. Based on each patient's total score in the nomogram, patients were stratified into four groups. The 5‐year EFS rates were 94.1%, 78.4%, 65.2%, and 52.1% in the low‐risk, intermediate‐risk, high‐risk, and very‐high‐risk groups, respectively, and the corresponding 5‐year overall survival rates were 97.2%, 91.5%, 74.3%, and 60.8%, respectively. Conclusions: The results presented here provide the rationale to modify the EpSSG stratification, with the most significant change represented by the replacement of histology with fusion status. This classification was adopted in the new international trial launched by the EpSSG. Traditional clinical factors, together with FOXO1 fusion status, in nonmetastatic rhabdomyosarcoma were investigated to develop a predictive model for event‐free survival and provide a rationale for risk stratification in future trials. The most important result was the replacement of histology with fusion status, and this model was used for patient stratification in the new European Pediatric Soft Tissue Sarcoma Study Group Frontline and Relapse Rhabdomyosarcoma trial (ClinicalTrials.gov identifier NCT04625907). [ABSTRACT FROM AUTHOR]

Background: The aim of this study was to assess the clinical impact of indeterminate pulmonary nodules (no more than four pulmonary nodules of less than 5 mm or one nodule measuring between 5 and less than 10 mm by computed tomography [CT]) in children and adolescents with adult‐type non‐rhabdomyosarcoma soft tissue sarcoma (NRSTS) at diagnosis. Methods: Patients with NRSTS treated in 11 centers as part of the European paediatric Soft Tissue Sarcoma Study Group (EpSSG) were retrospectively assessed. Local radiologists, blinded to clinical information except for patients' age and tumor histotype, reviewed the chest CT at diagnosis and filled out a case report form. Because patients with or without indeterminate nodules in the EpSSG NRSTS 2005 study received the same type of treatment, event‐free survival (EFS) and overall survival (OS) between groups by log‐rank test were compared. Results: Overall, 206 patients were examined: 109 (52.9%) were without any nodules, 78 (38%) had at least one indeterminate nodule, and 19 (9.2%) had nodules meeting the definition of metastases, which were then considered to be misclassified and were excluded from further analyses. Five‐year EFS was 78.5% (95% CI, 69.4%–85.1%) for patients without nodules and 69.6% (95% CI, 57.9%–78.7%) for patients with indeterminate nodules (p =.135); 5‐year OS was 87.4% (95% CI, 79.3%–92.5%) and 79.0% (95% CI, 67.5%–86.8%), respectively (p =.086). Conclusions: This study suggests that survival does not differ in otherwise nonmetastatic patients with indeterminate pulmonary nodules compared to nonmetastatic patients without pulmonary nodules. Plain Language Summary: Radiologists should be aware of the classification of indeterminate pulmonary nodules in non‐rhabdomyosarcoma soft tissue sarcomas and use it in their reports.More than a third of patients with non‐rhabdomyosarcoma soft tissue sarcoma can be affected by indeterminate pulmonary nodules.Indeterminate pulmonary nodules do not significantly affect the overall survival of pediatric patients with non‐rhabdomyosarcoma soft tissue sarcoma. In pediatric patients with non‐rhabdomyosarcoma soft tissue sarcoma, indeterminate pulmonary nodules detected by computed tomography may represent a diagnostic challenge. Indeterminate pulmonary nodules seem to not influence survival in otherwise non‐metastatic children and adolescents with non‐rhabdomyosarcoma soft tissue sarcoma. [ABSTRACT FROM AUTHOR]

PURPOSE: Inflammatory myofibroblastic tumors (IMTs) are often driven by anaplastic lymphoma kinase fusions and less frequently by alternative fusions such as ROS1. We describe the clinical characteristics, treatment approach, and outcome for a series of young patients with IMTs and ROS1 alterations. METHODS: This was a retrospective, international, multicenter study analyzing young patients (younger than 21 years) with ROS1 -altered IMTs treated in 10 European referral centers between 2014 and 2022. Patients were included in the European pediatric Soft tissue sarcoma Study Group NRSTS-2005 protocol or registered in the Soft Tissue Sarcoma Registry. Primary surgery was recommended if a microscopic radical resection was feasible without mutilation. No standard systemic treatment protocol was available, but several medical options were recommended. RESULTS: A total of 19 patients (median age 8.3 years) were included. Most patients had a biopsy at diagnosis (Intergroup Rhabdomyosarcoma Study [IRS] I; n = 2, IRS II; n = 1, IRS III biopsy; n = 11, IRS III resection; n = 3, IRS IV; n = 2). Twelve patients received neoadjuvant systemic therapy in first line (four received multiple treatments): high-dose steroids (n = 2), vinorelbine/vinblastine with methotrexate (n = 6), or ROS1 inhibitors (n = 8). After a median follow-up of 2.8 years (range, 0.2-13.4), seven patients developed an event. The 3-year event-free survival was 41% (95% CI, 11 to 71), and the 3-year overall survival was 100%. CONCLUSION: Outcome for ROS1 -altered IMTs appears excellent. A complete resection at diagnosis was often not feasible, and most patients needed neoadjuvant therapy. Patients who developed a tumor event could be cured with reinitiation of systemic therapy and/or surgery. This approach illustrates a switch in treatment philosophy moving from immediate, often mutilating, surgery to systemic (targeted) therapy as a bridge to more conservative surgery later in the treatment course. [ABSTRACT FROM AUTHOR]

While the overall prognosis is generally quite satisfactory in children, adolescents and young adults with localised synovial sarcoma at first diagnosis, the outcome remains poor for patients after relapse. Conversely to the front-line standardised treatment options, patients with relapse generally have an individualised approach and to date, there is still a lack of consensus regarding standard treatment approaches. Studies on relapsed synovial sarcoma were able to identify some prognostic variables that influence post-relapse survival, in order to plan risk-adapted salvage protocols. Treatment proposals must consider previous first-line treatments, potential toxicities, and the possibility of achieving an adequate local treatment by new surgery and/or re-irradiation. Effective second-line drug therapies are urgently needed. Notably, experimental treatments such as adoptive engineered TCR-T cell immunotherapy seem promising in adults and are currently under validation also in paediatric patients. [ABSTRACT FROM AUTHOR]

The genomic spectrum of rhabdomyosarcoma (RMS) progression from primary to relapse is not fully understood. In this pilot study, we explore the sensitivity of various targeted and whole-genome NGS platforms in order to assess the best genomic approach of using liquid biopsy in future prospective clinical trials. Moreover, we investigate 35 paired primary/relapsed RMS from two contributing institutions, 18 fusion-positive (FP-RMS) and 17 fusion-negative RMS (FN-RMS) by either targeted DNA or whole exome sequencing (WES). In 10 cases, circulating tumor DNA (ctDNA) from multiple timepoints through clinical care and progression was analyzed for feasibility of liquid biopsy in monitoring treatment response/relapse. ctDNA alterations were evaluated using a targeted 36-gene custom RMS panel at high coverage for single-nucleotide variation and fusion detection, and a shallow whole-genome sequencing for copy number variation. FP-RMS have a stable genome with relapse, with common secondary alterations CDKN2A/B, MYCN, and CDK4 present at diagnosis and impacting survival. FP-RMS lacking major secondary events at baseline acquire recurrent MYCN and AKT1 alterations. FN-RMS acquire a higher number of new alterations, most commonly SMARCA2 missense mutations. ctDNA analyses detect pathognomonic variants in all RMS patients within our collection at diagnosis, regardless of type of alterations, and confirmed at relapse in 86% of FP-RMS and 100% FN-RMS. Moreover, a higher number of fusion reads is detected with increased disease burden and at relapse in patients following a fatal outcome. These results underscore patterns of tumor progression and provide rationale for using liquid biopsy to monitor treatment response. [ABSTRACT FROM AUTHOR]

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. This is a large cohort study reporting on pediatric metastatic non‐rhabdomyosarcoma soft tissue sarcomas (NRSTS) enrolled in two concurrent prospective European studies. The study confirmed the overall poor outcome for patients with metastatic NRSTS, whose treatment remains a challenge. [ABSTRACT FROM AUTHOR]

Simple Summary: The updated results of the RMS2005 randomized study confirm that patients with non-metastatic high risk rhabdomyosarcoma have an improved survival when maintenance chemotherapy (MC) with vinorelbine and low dose cyclophosphamide is added to the standard multidisciplinary treatment. A more recent randomized study adopted the same strategy, but different drugs were used in the MC phase (trofosfamide, idarubicin and etoposide). No survival improvement was evident in the MC group, suggesting that not all types of MC are equally effective. A revision of the literature demonstrates that the role of MC in patients with metastatic or relapsed RMS may be a promising approach but need more investigations. Maintenance chemotherapy (MC) defines the administration of prolonged relatively low-intensity chemotherapy with the aim of "maintaining" tumor complete remission. This paper aims to report an update of the RMS2005 trial, which demonstrated better survival for patients with high-risk localized rhabdomyosarcoma (RMS) when MC with vinorelbine and low-dose cyclophosphamide was added to standard chemotherapy, and to discuss the published experience on MC in RMS. In the RMS2005 study, the outcome for patients receiving MC vs. those who stopped the treatment remains superior, with a 5-year disease-free survival of 78.1% vs. 70.1% (p = 0.056) and overall survival of 85.0% vs. 72.4% (p = 0.008), respectively. We found seven papers describing MC in RMS, but only one randomized trial that did not demonstrate any advantage when MC with eight courses of trofosfamide/idarubicine alternating with trofosfamide/etoposide has been employed in high-risk RMS. The use of MC showed better results in comparison to high-dose chemotherapy in non-randomized studies, including metastatic patients, and demonstrated feasibility and tolerability in relapsed RMS. Many aspects of MC in RMS need to be investigated, including the best drug combination and the optimal duration. The ongoing EpSSG trial will try to answer some of these questions. [ABSTRACT FROM AUTHOR]

The EPI VITRAKVI study is a retrospective study designed to place the results of the single-arm Phase I/II larotrectinib SCOUT trial into context by comparison with external historical controls. Its primary objective is to compare the time to medical treatment failure between larotrectinib and the historical standard of care (chemotherapy) in patients with infantile fibrosarcoma. External historical cohorts have been selected by using objective criteria. The Inverse Probability of Treatment Weighting method will be used to adjust for potential confounding. The current publication illustrates how an external control arm study can complement data from a single-arm trial and addresses uncertainties encountered in the assessment of therapies targeting rare abnormalities where randomized controlled trials are considered not feasible. Clinical Trial Registration: NCT05236257 (ClinicalTrials.gov) Infantile fibrosarcoma (IFS) is a rare type of childhood cancer that commonly affects the legs and arms. In IFS cancers, the units which carry the information that determines your traits (genes), typically have specific changes which leads to the creation of an altered fusion protein, a protein which is created by joining parts of two different genes. This altered fusion protein can cause cancer cells to survive and to grow. Larotrectinib works by blocking the altered fusion protein and is already available in Europe and in many other countries. It is approved for prescription to patients with the altered fusion protein, whose cancer has spread to nearby tissues and/or lymph nodes or to other parts of the body. Since IFSs a rare disease, previous studies did not compare larotrectinib with the standard of care, which is chemotherapy. The main purpose of our study is to collect more results on how well larotrectinib works compared with chemotherapy taken from real world evidence data. The present publication explains how such a comparison can be made and how such a study can help in the assessment of treatments that target rare diseases. [ABSTRACT FROM AUTHOR]

The aim of this study is to evaluate the prevalence, determinants and prognostic value of pain at diagnosis in patients with desmoid‐type fibromatosis (DF). We selected patients from the ALTITUDES cohort (NCT02867033), managed by surgery, active surveillance or systemic treatments, with pain assessment at diagnosis. Patients were invited to fill QLQ‐C30 questionnaire and Hospital Anxiety Depression Scale. Determinants were identified using logistic models. Prognostic value on event‐free survival (EFS) was evaluated using the Cox model. Overall, 382 patients were included in the current study (median age: 40.2 years; 117 men). The prevalence of pain was 36%, without significant difference according to first‐line treatment (P =.18). In the multivariate analysis, pain was significantly associated with tumor size >50 mm (P =.013) and tumor site (P <.001); pain was more frequent in the neck and shoulder locations (odds ratio: 3.05 [1.27‐7.29]). Pain at baseline was significantly associated with poor quality of life (P <.001), depression (P =.02), lower performance status (P =.03) and functional impairment (P =.001); we also observed a nonsignificant association with anxiety (P =.10). In the univariate analysis, baseline pain was associated with poor EFS; the 3‐year EFS was 54% in patients with pain compared to 72% in those without pain. After adjustment for sex, age, size and line of treatment, pain was still associated with poor EFS (hazard ratio: 1.82 [1.23‐2.68], P =.003). One third of recently diagnosed patients with DF experienced pain, especially those with larger tumors and neck/shoulder locations. Pain was associated with unfavorable EFS after adjustment for the confounders. [ABSTRACT FROM AUTHOR]

Background: In certain rare undifferentiated small round cell sarcomas new specific molecular CIC‐DUX4/other partner, BCOR‐CCNB3/other partner, YWHAE fusions, or BCOR‐ITD (internal tandem duplication) were identified. These new "CIC fused" (CIC‐fused/ATXN1::NUTM1) and "BCOR rearranged" (BCOR fused/ITD/ YWHAE) soft tissue sarcomas (STS) are not well described. Methods: Multi‐institutional European retrospective analysis of young patients (0–24 years) with CIC‐fused and BCOR rearranged STS. Results: Overall, out of the 60 patients selected, the fusion status was CIC‐fused (n = 29), ATXN1::NUTM1 (n = 2), BCOR::CCNB3 (n = 18), BCOR‐ITD (n = 7), and YWHAE (n = 3), MAML::BCOR STS (n = 1). The main primaries were abdomen‐pelvic (n = 23) and limbs (n = 18). Median age was 14 years (0.9–23.8) and 0.9 (0.1–19.1) for CIC‐fused and BCOR‐rearranged groups, respectively (n = 29; p < 0.001). IRS stages were I (n = 3), II (n = 7), III (n = 35), and IV (n = 15). Overall, 42 patients had large tumors (>5 cm) but only six had lymph node involvement. Patients received mainly chemotherapy (n = 57), local surgery (n = 50), and/or radiotherapy (n = 34). After a median follow‐up of 47.1 months (range, 3.4–230), 33 (52%) patients had an event and 23 patients died. Three‐year event‐free survivals were 44.0% (95% CI 28.7–67.5) and 41.2% (95% CI 25.4–67.0) for CIC and BCOR groups (p = 0.97), respectively. Three‐year overall survivals were 46.3% (95% CI 29.6–72.4) and 67.1% (95% CI 50.4–89.3; p = 0.24), respectively. Conclusions: Pediatric patients often present with large tumors and metastatic disease, especially CIC sarcomas. Overall outcome is dismal. New treatment options are needed. CIC, BCOR, and YWHAE rearranged soft tissue sarcomas are poorly characterized.Analysis of 60 young patients with these very rare sarcomas.Overall outcome is dismal and new therapies are warranted. [ABSTRACT FROM AUTHOR]

Simple Summary: Most fat-containing soft tissue tumors in children are benign, and liposarcomas are extremely rare in this age group. On the other hand, many benign fat-containing soft tissue tumors in children may demonstrate imaging features that can be reminiscent of adult liposarcoma. Although clinico-radiologic guidelines are available for adults, the diagnostic management of such tumors during childhood is still unclear. The aim of this study was to confirm the overall benignity of such tumors in a pediatric cohort and to highlight the clinical and imaging features that warrant a biopsy. Purpose: To confirm the overall benignity of fat-containing soft tissue tumors (STT) on a pediatric cohort and to define the clinical and imaging features that warrant a biopsy. Methods: A retrospective monocentric study was conducted on patients aged less than 25 years consecutively referred for fat-containing STT to our Comprehensive Cancer Center between 1998 and 2022. Tumor imaging characteristics at diagnosis (US, CT, or MRI) were correlated with pathology. Results: The database extraction identified 63 fat-containing tumors with clinical, histologic, and imaging data available for review. In total, 58 (92%) were benign tumors: 36 lipoblastomas and lipomas, 12 fibrous hamartomas of infancy (FHI), 5 lipofibromatosis, 2 lipomas arborescens, 2 lipomatosis and 1 spindle-cell lipoma. Five patients (8%) were diagnosed with liposarcoma. Factors significantly correlated with malignancy were age >10 years old (p < 0.001), having a cancer-predisposing condition (p < 0.001), a percentage of fat <25% (p = 0.002), and a presence of myxoid zones (p < 0.001) on imaging. Conclusion: Most fat-containing STT in children may be classified as benign tumors based on clinics and imaging. The indication for biopsy could be limited to patients aged 10 years or more with either a cancer-predisposing condition or imaging features demonstrating either a low-fat component (<25%) or the presence of myxoid zones. [ABSTRACT FROM AUTHOR]

Background: Margin status following surgery in children, adolescents, and young adults with soft tissue sarcomas is controversial and has been defined differently by various specialties, with definitions changing over time and by cooperative group. The International Soft Tissue Sarcoma Consortium (INSTRuCT) is a collaboration of the Children's Oncology Group (COG) Soft Tissue Sarcoma Committee, European pediatric Soft Tissue sarcoma Study Group (EpSSG), and the European Cooperative Weichteilsarkom Studiengruppe (CWS) devoted to improving patient outcomes by pooling and mining cooperative group clinical trial data. Methods: The INSTRuCT non-rhabdomyosarcoma soft tissue sarcoma (NRSTS) working group aimed to develop international harmonized recommendations regarding surgical margin assessment and definitions in children and adolescents with soft tissue tumors. Results and Conclusion: This review addresses accepted principles and areas of controversy, including the perspectives of surgeons, pathologists, radiation oncologists, and pediatric oncologists, to develop a framework for building common guidelines for future research. [ABSTRACT FROM AUTHOR]

Desmoplastic small round cell tumor (DSRCT) is an extremely rare and highly aggressive soft tissue sarcoma, presenting mainly in male adolescents and young adults with multiple nodules disseminated within the abdominopelvic cavity. Despite a multimodal approach including aggressive cytoreductive surgery, intensive multi-agent chemotherapy, and postoperative whole abdominopelvic radiotherapy, the prognosis for DSRCT remains dismal. Median progression-free survival ranges between 4 and 21 months, and overall survival between 17 and 60 months, with the 5-year overall survival rate in the range of 10–20%. This review discusses the treatment strategies used for DSRCT over the years, the state of the art of current treatments, and future clinical prospects. The unsatisfactory outcomes for patients with DSRCT warrant investigations into innovative treatment combinations. An international multidisciplinary and multi-stakeholder collaboration, involving both pediatric and adult sarcoma communities, is needed to propel preclinical model generation and drug development, and innovative clinical trial designs to enable the timely testing of treatments involving novel agents guided by biology to boost the chances of survival for patients with this devastating disease. [ABSTRACT FROM AUTHOR]

Background: The initial management of patients with sarcoma is a critical issue. We used the nationwide French National Cancer Institute-funded prospective sarcoma database NETSARC to report the management and oncologic outcomes in adolescents and young adults (AYAs) patients with sarcoma at the national level. Patients and methods: NETSARC database gathers regularly monitored and updated data from patients with sarcoma. NETSARC was queried for patients (15–30 years) with sarcoma diagnosed from 2010 to 2017 for whom tumor resection had been performed. We reported management, locoregional recurrence-free survival (LRFS), progression-free survival (PFS), and overall survival (OS) in AYA treated in French reference sarcoma centers (RSC) and outside RSC (non-RSC) and conducted multivariable survival analyses adjusted for classical prognostic factors. Results: Among 3,227 patients aged 15–30 years with sarcoma diagnosed between 2010 and 2017, the study included 2,227 patients with surgery data available, among whom 1,290 AYAs had been operated in RSC, and 937 AYAs in non-RSC. Significant differences in compliance to guidelines were observed including pre-treatment biopsy (RSC: 85.9%; non-RSC 48.1%), pre-treatment imaging (RSC: 86.8%; non-RSC: 56.5%) and R0 margins (RSC 57.6%; non-RSC: 20.2%) (p < 0.001). 3y-OS rates were 81.1% (95%CI 78.3–83.6) in AYA in RSC and 82.7% (95%CI 79.4–85.5) in AYA in non-RSC, respectively. Whereas no significant differences in OS was observed in AYAs treated in RSC and in non-RSC, LRFS and PFS were improved in AYAs treated in RSC compared to AYAs treated in non-RSC (Hazard Ratios (HR): 0.58 and 0.83, respectively). Conclusions: This study highlights the importance for AYA patients with sarcoma to be managed in national sarcoma reference centers involving multidisciplinary medical teams with paediatric and adult oncologists. [ABSTRACT FROM AUTHOR]

Simple Summary: Rhabdomyosarcoma is the most frequent soft tissue sarcoma of childhood, but can occur at any age. Adolescent and young adult patients with rhabdomyosarcoma often have poorer outcomes than do children. This survival gap may be related to differences in clinical management or differences in tumor biology and intrinsic aggressiveness. Various studies have suggested that young adults may have better outcomes when treated with multidisciplinary treatment in line with the pediatric approach. However, treatment results seem to remain worse in young adults when compared with children, even when they were treated in the same way, and this suggest that part of the prognostic gap between children and adults may be attributable to biological differences in rhabdomyosarcoma arising in different age groups. A multifaced strategy is needed to further improve outcome of adults with rhabdomyosarcoma, including a trans-age academic societies and national/international cooperation, the definition of integrated biologic and genomic approach, and the development of collaborative rhabdomyosarcoma clinical trials without upper age limit. Rhabdomyosarcoma (RMS) is a typical tumour of childhood but can occur at any age. Several studies have reported that adolescent and young adult (AYA) patients with RMS have poorer survival than do younger patients. This review discusses the specific challenges in AYA patients with pediatric-type RMS, exploring possible underlying factors which may influence different outcomes. Reasons for AYA survival gap are likely multifactorial, and might be related to differences in tumor biology and intrinsic aggressiveness, or differences in clinical management (that could include patient referral patterns, time to diagnosis, enrolment into clinical trials, the adequacy and intensity of treatment), as well as patient factors (including physiology and comorbidity that may influence treatment tolerability, drug pharmacokinetics and efficacy). However, improved survival has been reported in the most recent studies for AYA patients treated on pediatric RMS protocols. Different strategies may help to further improve outcome, such as supporting trans-age academic societies and national/international collaborations; developing specific clinical trials without upper age limit; defining integrated and comprehensive approach to AYA patients, including the genomic aspects; establishing multidisciplinary tumor boards with involvement of both pediatric and adult oncologists to discuss all pediatric-type RMS patients; developing dedicated projects with specific treatment recommendations and registry/database. [ABSTRACT FROM AUTHOR]

This paper describes the standard of care for patients with non-rhabdomyosarcoma soft tissue sarcomas (NRSTS) and the therapeutic recommendations developed by the European paediatric Soft tissue sarcoma Study Group (EpSSG). NRSTS form a very mixed group of mesenchymal extraskeletal malignancies. Their rarity, heterogeneity, and aggressiveness make the management of children and adolescents with these tumors complex and challenging. The overall cure rate for patients with NRSTS is around 70%, but survival depends on several prognostic variables, such as histotype and tumor grade, extent of disease and stage, tumor size, and tumor site. While surgery remains the mainstay of treatment for most of these tumors, a multimodal therapeutic approach including radiotherapy and chemotherapy is required in many cases. The EpSSG NRSTS 2005 study was the first prospective protocol tailored specifically to NRSTS. Together with the ARST0332 study developed by the North-American Soft Tissue Sarcoma Committee of the Children's Oncology Group (COG), the EpSSG NRSTS 2005 study currently represents the benchmark for these tumors, establishing risk-adapted standards of care. The EpSSG has developed common treatment recommendations for the large group of adult-type NRSTS (including synovial sarcoma), and specific treatment recommendations for other particular adult-type histologies (ie, alveolar soft-part sarcoma, clear cell sarcoma and dermatofibrosarcoma protuberans); other highly malignant tumors with a biology and clinical behavior differing from those of adult-type NRSTS (ie, rhabdoid tumors and desmoplastic small round cell tumor); and soft tissue tumors of intermediate malignancy (ie desmoid-type fibromatosis, inflammatory myofibroblastic tumors, and infantile fibrosarcoma). New effective drugs are needed for patients whose NRSTS carries the worst prognosis, ie, those with unresectable tumors, metastases at diagnosis, or relapsing disease. Progress in this area relies on our ability to develop international integrated prospective collaborations, both within existing pediatric oncology networks and, importantly, between the communities of specialists treating pediatric and adult sarcoma. [ABSTRACT FROM AUTHOR]

Simple Summary: As patients with rare cancers face specific problems, reference networks have been developed in several European countries and then at the European level to improve their management. In some cases, the specialized centers belonging to reference networks provide remote services (specialized diagnosis review, discussion in the Multidisciplinary Tumour Board, etc.) to increase access to these services. Using data from the national sarcoma reference network implemented in France (NETSARC+), the IGéAS research program assesses the potential of its organization to address the geographical inequalities in cancer management. We analyze the individual, clinical, and geographical determinants of the overall survival of sarcoma patients in France. We found no association between the overall survival of sarcoma patients and variables measuring their social deprivation, remoteness from reference centers, and geographical context. Following previous results from the research program, this study suggests that reference network organization should be considered to reduce cancer inequalities. The national reference network NETSARC+ provides remote access to specialized diagnosis and the Multidisciplinary Tumour Board (MTB) to improve the management and survival of sarcoma patients in France. The IGéAS research program aims to assess the potential of this innovative organization to address geographical inequalities in cancer management. Using the IGéAS cohort built from the nationwide NETSARC+ database, the individual, clinical, and geographical determinants of the 3-year overall survival of sarcoma patients in France were analyzed. The survival analysis was focused on patients diagnosed in 2013 (n = 2281) to ensure sufficient hindsight to collect patient follow-up. Our study included patients with bone (16.8%), soft-tissue (69%), and visceral (14.2%) sarcomas, with a median age of 61.8 years. The overall survival was not associated with geographical variables after adjustment for individual and clinical factors. The lower survival in precarious population districts [HR 1.23, 95% CI 1.02 to 1.48] in comparison to wealthy metropolitan areas (HR = 1) found in univariable analysis was due to the worst clinical presentation at diagnosis of patients. The place of residence had no impact on sarcoma patients' survival, in the context of the national organization driven by the reference network. Following previous findings, this suggests the ability of this organization to go through geographical barriers usually impeding the optimal management of cancer patients. [ABSTRACT FROM AUTHOR]

BCOR‐ITD tumours form an emerging family of aggressive entities with an internal tandem duplication (ITD) in the last exon of the BCOR gene. The family includes cerebral tumours, termed central nervous system BCOR‐ITD (CNS BCOR‐ITD), and sarcomatous types described in the kidney as clear cell sarcoma of the kidney (CCSK), in the endometrium as high‐grade endometrial stromal sarcoma, and in the bone and soft tissue as undifferentiated round cell sarcoma or primitive myxoid mesenchymal tumour of infancy. Based on a series of 33 retrospective cases, including 10 CNS BCOR‐ITD and 23 BCOR‐ITD sarcomas, we interrogated the homogeneity of the entity regarding clinical, radiological, and histopathological findings, and molecular signatures. Whole‐transcriptomic sequencing and DNA methylation profiling were used for unsupervised clustering. BCOR‐ITD tumours mostly affected young children with a median age at diagnosis of 2.1 years (range 0–62.4). Median overall survival was 3.9 years and progression‐free survival was 1.4 years. This dismal prognosis is shared among tumours in all locations except CCSK. Histopathological review revealed marked differences between CNS BCOR‐ITD and BCOR‐ITD sarcomas. These two groups were consistently segregated by unsupervised clustering of expression (n = 22) and DNA methylation (n = 21) data. Proximity between the two groups may result from common somatic changes within key pathways directly related to the novel activity of the ITD itself. Conversely, comparison of gene signatures with single‐cell RNA‐Seq atlases suggests that the distinction between BCOR‐ITD sarcomas and CNS BCOR‐ITD may result from differences in cells of origin. [ABSTRACT FROM AUTHOR]

DICER1 syndrome is a rare paediatric autosomal dominant inherited disorder predisposing to various benign and malignant tumours. It is caused by a germline pathogenic variant in DICER1, and the second hit for tumour development is usually a missense hotspot pathogenic variant in the DICER1 ribonuclease IIIb domain. While DICER1 predisposing variants account for about 60% of ovarian Sertoli-Leydig cell tumours, no DICER1-related testicular stromal tumours have been described. Here we report the first two cases of testicular stromal tumours in children carrying a DICER1 germline pathogenic variant: a case of Sertoli cell tumour and a case of Leydig cell tumour diagnosed at 2 and 12 years of age, respectively. A somatic DICER1 hotspot pathogenic variant was detected in the Sertoli cell tumour. This report extends the spectrum of DICER1-related tumours to include testicular Sertoli cell tumour and potentially testicular Leydig cell tumour. Diagnosis of a testicular Sertoli cell tumour should prompt DICER1 genetic testing so that patients with a DICER1 germline pathogenic variant can benefit from established surveillance guidelines. DICER1 genetic evaluation may be considered for testicular Leydig cell tumour. Our findings suggest that miRNA dysregulation underlies the aetiology of some testicular stromal tumours. [ABSTRACT FROM AUTHOR]

Background: While robotics has become commonplace in adult oncology, it remains rare in pediatric oncology due to the rarity of childhood cancers. We present the results of a large nationwide experience with robotic oncology, with the aim of providing practical and feasible guidelines for child selection. Methods: This was a prospective analysis performed over a period of 4 years. Treatment was delivered according to the Société Internationale d'Oncologie Pédiatrique/International Society of Paediatric Oncology Europe Neuroblastoma Group (SIOP/SIOPEN) protocols. Indications were approved by a certified tumor board. Results: Overall, 100 tumors were resected during 93 procedures (abdomen, 67%; thorax, 17%; pelvis, 10%; retroperitoneum, 6%) in 89 children (56 girls). The median age at surgery was 8.2 years (range 3.6–13); 19 children (21%) harbored germinal genetic alterations predisposing to cancer. No intraoperative tumor ruptures occurred. Seven conversions (8%) to an open approach were performed. Neuroblastic tumors (n = 31) comprised the main group (18 neuroblastomas, 4 ganglioneuroblastomas, 9 ganglioneuromas) and renal tumors comprised the second largest group (n = 24, including 20 Wilms' tumors). The remaining 45 tumors included neuroendocrine (n = 12), adrenal (n = 9), germ-cell (n = 7), pancreatic (n = 4), thymic (n = 4), inflammatory myofibroblastic (n = 4), and different rare tumors (n = 5). Overall, 51 tumors were malignant, 2 were borderline, and 47 were benign. The median hospital stay was 3 days (2–4), and five postoperative complications occurred within the first 30 days. During a median follow-up of 2.4 years, one child (Wilms' tumor) presented with pleural recurrence. One girl with Wilms' tumor died of central nervous system metastasis. Conclusions: Robotic surgery for pediatric tumors is a safe option in highly selected cases. Indications should be discussed by tumor boards to avoid widespread and uncontrolled application. [ABSTRACT FROM AUTHOR]

Purpose: Childhood RMS is a rare malignant disease in which evaluation of tumour spread at diagnosis is essential for therapeutic management. F-18 FDG-PET imaging is currently used for initial RMS disease staging. Materials and methods: This multicentre retrospective study in six French university hospitals was designed to analyse the prognostic accuracy of MTV at diagnosis for patients with RMS between 1 January 2007 and 31 October 2017, for overall (OS) and progression-free survival (PFS). MTV was defined as the sum of the primitive tumour and the largest metastasis, where relevant, with a 40% threshold of the primary tumour SUVmax. Additional aims were to define the prognostic value of SUVmax, SUVpeak, and bone lysis at diagnosis. Results: Participants were 101 patients with a median age of 7.4 years (IQR [4.0-12.5], 62 boys), with localized disease (35 cases), regional nodal spread (43 cases), or distant metastases (23). 44 patients had alveolar subtypes. In a univariate analysis, a MTV greater than 200 cm3 was associated with OS (HR = 3.47 [1.79;6.74], p<0.001) and PFS (HR = 3.03 [1.51;6.07], p = 0.002). SUVmax, SUVpeak, and bone lysis also influenced OS (respectively p = 0.005, p = 0.004 and p = 0.007) and PFS (p = 0.029, p = 0.019 and p = 0.015). In a multivariate analysis, a MTV greater than 200 cm3 was associated with OS (HR = 2.642 [1.272;5.486], p = 0.009) and PFS (HR = 2.707 [1.322;5.547], p = 0.006) after adjustment for confounding factors, including SUVmax, SUVpeak, and bone lysis. Conclusion: A metabolic tumor volume greater than 200 cm3, SUVmax, SUVpeak, and bone lysis in the pre-treatment assessment were unfavourable for outcome. [ABSTRACT FROM AUTHOR]

Extracranial rhabdoid tumours (ECRTs) are an aggressive malignancy of infancy and early childhood. The vast majority of cases demonstrate inactivation of SMARCB1 (ECRTSMARCB1) on a background of a remarkably stable genome, a low mutational burden, and no other recurrent mutations. Rarely, ECRTs can harbour the alternative inactivation of SMARCA4 (ECRTSMARCA4) instead of SMARCB1. However, very few ECRTSMARCA4 cases have been published to date, and a systematic characterization of ECRTSMARCA4 is missing from the literature. In this study, we report the clinical, pathological, and genomic features of additional cases of ECRTSMARCA4 and show that they are comparable to those of ECRTSMARCB1. We also assess whether ECRTSMARCB1, ECRTSMARCA4, and small cell carcinomas of the ovary, hypercalcaemic type (SCCOHT) represent distinct or overlapping entities at a molecular level. Using DNA methylation and transcriptomics‐based tumour classification approaches, we demonstrate that ECRTSMARCA4 display molecular features intermediate between SCCOHT and ECRTSMARCB1; however, ECRTSMARCA4 appear to be more closely related to SCCOHT by DNA methylation. Conversely, both transcriptomics and DNA methylation show a larger gap between SCCOHT and ECRTSMARCB1, potentially supporting their continuous separate classification. Lastly, we show that ECRTSMARCA4 display concomitant lack of SMARCA4 (BRG1) and SMARCA2 (BRM) expression at the protein level, similar to what is seen in SCCOHT. Overall, these results expand our knowledge on this rare tumour type and explore the similarities and differences among entities from the 'rhabdoid tumour' spectrum. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Background: Treatment of extremity rhabdomyosarcomas (RMS) includes chemotherapy, surgery, and radiotherapy. Lymph node irradiation is recommended in the presence of regional node involvement at diagnosis. The aim of this study was to analyze the correlation between the pattern of relapse of non-metastatic extremity RMS and the initial therapies delivered. Methods: All patients with localized extremity RMS prospectively treated in France in the MMT-95 and RMS-05 protocols were selected. Extent of disease and pattern of relapse were evaluated by clinical examination and imaging. Results: We identified 59 patients with clinical characteristics corresponding to unfavorable prognostic factors. Twenty patients (34%) were considered to have lymph node involvement at diagnosis. Regional node biopsy was performed in 32 patients (54%) and modified the lymph node stage in 8 of the 59 patients (14%). Seventy-three percent of patients received radiotherapy. Fifty-two patients achieved first remission. Overall, 26 patients underwent complete tumor resection, 17 had R1 margins, and 5 were not operated due to early tumor progression. With a median follow-up of 82 months (range: 5–287), 18 relapses had occurred, at least locoregional in 12 cases. The 5‑year local and nodal control rates were 73% (63–86%) and 86% (77–95%), respectively. Five-year progression-free and overall survival were 57% (95%CI [45–72%]) and 70% (95%CI [58–84%]), respectively. Conclusion: The main sites of extremity RMS relapse are locoregional. Nodal failures in non-irradiated fields are not uncommon. We recommend systematic biopsy of in-transit nodes, especially in alveolar RMS and/or RMS with regional positive nodes at diagnosis to ensure their negativity. [ABSTRACT FROM AUTHOR]