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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]

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]

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]

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]

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]

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]

Objective: Localized orbital rhabdomyosarcoma (oRMS) has an overall favourable prognosis with more than 90% of survival. Little is known about the best strategy in recurrent/refractory (R/R) cases. The purpose is to examine the characteristics of patients with R/R‐oRMS, focusing on local therapy. Methods: This is bicentric retrospective study. Analysis is of young patients (<30 years) with R/R‐oRMS who were treated from 1989 to 2018 at the Institut Curie and Gustave Roussy Cancer Campus, France. Results: Twenty‐seven out of 162 patients (17%) with oRMS presented with R/R disease. 6 of these patients had alveolar RMS (22%), 3 of whom had initial parameningeal extension (11%). During first‐line treatment, 18 patients (67%) had orbital radiotherapy. Median age at R/R was 10 years (ranges: 4–28) after a delay of 19 months from diagnosis (ranges: 3–40). Tumoral events were local relapses (22 cases), local progression (3 cases) or regional relapses (2 cases). Second‐line treatments included chemotherapy (27 cases), radiotherapy (16 cases), surgery (exenteration; 8 cases) and metastasis/ nodal removal (3 cases). After a median follow‐up of 99 months (range: 10–306), 4 patients died and 23 are in complete remission (CR) without treatment. One patient had subsequent relapse treated with exenteration and brachytherapy until a new tumour remission. Five‐year event‐free and overall survivals after first tumour event are, respectively, 84.4% (95% confidence interval: 71.5%–98.8%) and 85.8% (95% confidence interval: 72.1%–100.0%) Conclusion: R/R‐oRMS is a rare situation. Second‐line therapy is efficient in this location, sometime at the cost of lifesaving mutilating surgery. Second‐line local therapy needs therefore to consider local radiotherapy if possible or complete wide surgery. [ABSTRACT FROM AUTHOR]

Fibrosarcomatous transformation of dermatofibrosarcoma protuberans is associated with a significantly worse prognosis in adults, but is a very rare feature in the pediatric population. Here, we report a case that occurred in a child. The diagnosis of fibrosarcomatous transformation of dermatofibrosarcoma protuberans was confirmed by a histopathological assessment and fluorescence in situ hybridization. A comparison with eleven other patients reported in the literature revealed that the local recurrence and mortality rates in children are similar to those observed in adults. [ABSTRACT FROM AUTHOR]

Rhabdomyosarcoma of the extremities present with two main challenges: correct evaluation of initial regional nodal involvement and define adequate local treatment. Methods: Pediatric patients with localized rhabdomyosarcoma of the extremity included in the EpSSG‐RMS2005 study between 2005 and 2014 were evaluated for staging, treatment, and survival. The outcome was compared to the preceding European SIOP‐MMT studies. Results: Of the 162 patients included, histology was unfavorable in 113 (70%), 124 (77%) were younger than 10 years, 128 (79%) were IRS III, and 47 (29%) were node‐positive. A regional node biopsy was performed in 97 patients (60%) and modified the lymph node stage in 15/97 (16%). Primary and delayed surgery was performed in 155 (96%) and radiotherapy delivered in 118 (73%) patients. Relapse occurred in 61 cases (38%), local in 14 (23%), regional in 13 (21%), distant in 22 (36%), and combined relapse in 12 (20%) with five progressive diseases (8%) and four secondary tumors (7%). Five‐year event free (EFS) and overall survival (OS) were 58.4% (95%CI, 50.3‐65.7) and 71.7% (63.6‐78.4), respectively. In the previous studies MMT89 and MMT95, tumor surgery was performed in 32/53 (60%) and 74/82(90%), respectively, and radiotherapy delivered in 13/53 (25%) and 26/82 (30%), respectively. Five‐year EFS and OS were 35.6%, and 50.3% in MMT89 and 54.3% and 68.2% in the MMT95 study. Conclusions: Even if the lymph node staging was not always complete according to the RMS2005 protocol, node sampling changed lymph node status in a significant number of patients. Despite the higher rate of patients treated with locoregional radiotherapy, survival in RMS2005 did not improve compared to the previous European SIOP‐MMT95 study. [ABSTRACT FROM AUTHOR]

Background: Rhabdomyosarcoma (RMS) in infants is a particular entity with various clinical presentations and outcomes. To better understand the clinical heterogeneity of RMS in infants, an integrative clinical, histological, and molecular analysis was performed. Methods: From 1989 to 2015, 37 infants aged less than 6 months with a diagnosis of RMS and archival tumor materials were identified in France. Clinical data, central pathologic review, and molecular profile including RNA sequencing were analyzed. Results: Nineteen patients (51%) had embryonal RMS (ERMS) (including three highly differentiated ERMS with PTCH deletion), eight (22%) had spindle cell RMS (SRMS) (three VGLL2‐, one NTRK‐, and two (B)RAF‐fusions), six (16%) had alveolar RMS (ARMS) (all FOXO1‐ or PAX3‐fusion), two had unclassified RMS, and two poorly differentiated RMS were retrospectively diagnosed as rhabdoid tumors (RT) with loss of INI1 expression. The two RT patients died of rapid disease progression. Five‐year event‐free (EFS) and overall survival (OS) for RMS were 62% (95%CI, 47‐82) and 52% (95%CI, 37‐72). Eleven patients (31%) relapsed and four (11%) had primary refractory disease (all ERMS). In univariate analysis, EFS and OS were only associated with histology subtype, with 100% survival of known fusion‐positive SRMS. RNA cluster expression showed three main clusters: ARMS, ERMS, and "VGLL2‐fusion" cluster, consisting of SRMS and ERMS. Conclusions: Biopathology findings from this study support the different prognosis of infantile RMS. New fusion‐positive SRMS has a very good outcome which may allow more conservative treatment in the future. [ABSTRACT FROM AUTHOR]

Background: After the completion of therapy, patients with localized rhabdomyosarcoma (RMS) are subjected to intensive radiological tumor surveillance. However, the clinical benefit of this surveillance is unclear. This study retrospectively analyzed the value of off-therapy surveillance by comparing the survival of patients in whom relapse was detected by routine imaging (the imaging group) and patients in whom relapse was first suspected by symptoms (the symptom group).Methods: This study included patients with relapsed RMS after the completion of therapy for localized RMS who were treated in large pediatric oncology hospitals in France, the United Kingdom, Italy, and the Netherlands and who were enrolled in the International Society of Paediatric Oncology Malignant Mesenchymal Tumor 95 (1995-2004) study, the Italian Paediatric Soft Tissue Sarcoma Committee Rhabdomyosarcoma 96 (1996-2004) study, or the European Paediatric Soft Tissue Sarcoma Study Group Rhabdomyosarcoma 2005 (2005-2013) study. The survival times after relapse were compared with a log-rank test between patients in the imaging group and patients in the symptom group.Results: In total, 199 patients with relapsed RMS were included: 78 patients (39.2%) in the imaging group and 121 patients (60.8%) in the symptom group. The median follow-up time after relapse was 7.4 years (interquartile range, 3.9-11.5 years) for survivors (n = 86); the 3-year postrelapse survival rate was 50% (95% confidence interval [CI], 38%-61%) for the imaging group and 46% (95% CI, 37%-55%) for the symptom group (P = .7).Conclusions: Although systematic routine imaging is the standard of care after RMS therapy, the majority of relapses were detected as a result of clinical symptoms. This study found no survival advantage for patients whose relapse was detected before the emergence of clinical symptoms. These results show that the value of off-therapy surveillance is controversial, particularly because repeated imaging may also entail potential harm. [ABSTRACT FROM AUTHOR]

Background: Alveolar rhabdomyosarcoma (aRMS) with lymph node involvement (N1 classification) accounts for up to 10% of all cases of RMS. The prognosis is poor, and is comparable to that of distant metastatic disease. In the European Paediatric Soft Tissue Sarcoma Study Group (EpSSG) RMS2005 protocol, patients with a histologic diagnosis of aRMS/N1 received intensified chemotherapy with systematic locoregional treatment.Methods: Patients with aRMS/N1 were enrolled prospectively after primary surgery/biopsy and fusion status was assessed in tumor samples. All patients received 9 cycles of induction chemotherapy and 6 months of maintenance therapy. Local treatment included radiotherapy to the primary site and lymph nodes with or without secondary surgical resection.Results: A total of 103 patients were enrolled. The clinical characteristics of the patients were predominantly unfavorable: 90% had macroscopic residual disease after initial surgery/biopsy, 63% had locally invasive tumors, 77% had a tumor measuring >5 cm, and 81% had disease at unfavorable sites. Fusion genes involving forkhead box protein O1 (FOXO1) were detected in 56 of 84 patients. Events occurred in 52 patients: 43 developed disease recurrence, 7 had disease that was refractory to treatment, and 2 patients developed second neoplasms. On univariate analysis, unfavorable disease site, tumor invasiveness, Intergroup Rhabdomyosarcoma Study group III, and fusion-positive status correlated with worse prognosis. The 5-year event-free survival rate of patients with fusion-positive tumors was 43% compared with 74% in patients with fusion-negative tumors (P = .01). On multivariate analysis, fusion positivity and tumor invasiveness proved to be unfavorable prognostic markers.Conclusions: Fusion status and tumor invasiveness appear to have a strong impact on prognosis in patients with aRMS/N1. Fusion status will be used to stratify these patients in the next EpSSG RMS study, and treatment will be intensified in patients with fusion-positive tumors. Cancer 2018. © 2018 American Cancer Society. [ABSTRACT FROM AUTHOR]