Explore the vast range of titles available.

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.

Background The histologic classification of rhabdomyosarcoma (RMS) as alveolar (aRMS) or embryonal (eRMS) is of prognostic importance, with the aRMS being associated with a worse outcome. Specific gene fusions (PAX3/7::FOXO1) found in the majority of aRMS have been recognized as markers associated with poor prognosis and are included in current risk stratification instead of histologic subtypes in localized disease. In metastatic disease, the independent prognostic significance of fusion status has not been definitively established. The objective of this analysis was to evaluate survival outcomes of patients with localized and metastatic aRMS and its association with fusion status and subtype (PAX3/7::FOXO1, FOXO1 break), and clinical prognostic factors. Methods A total of 470 patients with aRMS ≤21 years of age enrolled in two CWS‐trials and two registries was eligible for the analysis. Results The 5‐year event‐free survival (EFS) and overall survival (OS) rates for all patients with localized vs. metastatic tumors were: 56% and 65% vs. 18% and 22%, respectively. Of the 368 (78%) tumors tested, specific fusion was found in 330 (90%), considered “fusion positive” FP (PAX3::FOXO1 in 280, PAX7::FOXO1 in 49, FOXO1 break in 59 tumors). In patients with localized tumors, univariate analysis revealed that clinical group, tumor invasiveness (T1 vs.T2), regional lymph node involvement (N0 vs. N1) and FOXO1 fusion were significantly associated with EFS and OS, tumor size and PAX variant with OS only. In patients with metastatic aRMS, age, bone/marrow (B/BM) metastases, FOXO1 fusion and PAX variant were associated with EFS and OS, T status with OS only. Multivariate analysis identified PAX3::FOXO1 fusion as an independent adverse prognostic factor for EFS in patients with localized disease and for EFS and OS in patients with metastatic disease, B/BM metastases for EFS. Conclusion PAX3::FOXO1 fusion should replace FOXO1 fusion as an adverse prognostic factor in risk stratification. The prognostic relevance of PAX7::FOXO1‐positive and FOXO1 fusion negative aRMS, along with the clinical factors described in this report, allows further refinement of risk assessment of patients with localized and metastatic aRMS. PAX3::FOXO1 fusion should replace FOXO1 fusion as an adverse prognostic factor in risk stratification of patients with rhabdomyosarcoma. The prognostic relevance of PAX7::FOXO1‐positive and FN alveolar rhabdomyosarcoma (aRMS), along with the clinical factors described in this report, allows further refinement of risk assessment of patients with localized and metastatic (aRMS).

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. Surgical margin assessment following surgery in children, adolescents, and young adults with soft tissue sarcomas is not standardized, making comparisons of different therapeutic approaches difficult. The International Soft Tissue Sarcoma Consortium (INSTRuCT) addresses accepted principles and areas of controversy, including the perspectives of surgeons, pathologists, radiation oncologists, and pediatric oncologists, to develop a framework for building harmonized margin status guidelines for future protocols.

Background To evaluate optimal therapy and potential risk factors. Methods Data of DSRCT patients <40 years treated in prospective CWS trials 1997‐2015 were analyzed. Results Median age of 60 patients was 14.5 years. Male:female ratio was 4:1. Tumors were abdominal/retroperitoneal in 56/60 (93%). 6/60 (10%) presented with a localized mass, 16/60 (27%) regionally disseminated nodes, and 38/60 (63%) with extraperitoneal metastases. At diagnosis, 23/60 (38%) patients had effusions, 4/60 (7%) a thrombosis, and 37/54 (69%) elevated CRP. 40/60 (67%) patients underwent tumor resection, 21/60 (35%) macroscopically complete. 37/60 (62%) received chemotherapy according to CEVAIE (ifosfamide, vincristine, actinomycin D, carboplatin, epirubicin, etoposide), 15/60 (25%) VAIA (ifosfamide, vincristine, adriamycin, actinomycin D) and, 5/60 (8%) P6 (cyclophosphamide, doxorubicin, vincristine, ifosfamide, etoposide). Nine received high‐dose chemotherapy, 6 received regional hyperthermia, and 20 received radiotherapy. Among 25 patients achieving complete remission, 18 (72%) received metronomic therapies. Three‐year event‐free (EFS) and overall survival (OS) were 11% (±8 confidence interval [CI] 95%) and 30% (±12 CI 95%), respectively, for all patients and 26.7% (±18.0 CI 95%) and 56.9% (±20.4 CI 95%) for 25 patients achieving remission. Extra‐abdominal site, localized disease, no effusion or ascites only, absence of thrombosis, normal CRP, complete tumor resection, and chemotherapy with VAIA correlated with EFS in univariate analysis. In multivariate analysis, significant factors were no thrombosis and chemotherapy with VAIA. In patients achieving complete remission, metronomic therapy with cyclophosphamide/vinblastine correlated with prolonged time to relapse. Conclusion Pleural effusions, venous thrombosis, and CRP elevation were identified as potential risk factors. The VAIA scheme showed best outcome. Maintenance therapy should be investigated further. To evaluate optimal therapy and potential risk factors, data of DSRCT patients <40 years treated in prospective CWS trials 1997‐2015 were analyzed. Pleural effusions, venous thrombosis, and CRP elevation were identified as novel potential risk factors. The VAIA scheme (ifosfamide, vincristine, adriamycin, actinomycin D) showed best outcome in a multivariable model. Maintenance therapy should be investigated further.

Advice from multiple stakeholders is required to design the optimal pediatric clinical trial. We present recommendations for acquiring advice from trial experts and patients/caregivers, derived from advice meetings that were performed through a collaboration of the Collaborative Network for European Clinical Trials for Children (c4c) and the European Patient‐CEntric ClinicAl TRial PLatforms (EU‐PEARL). Three advice meetings were performed: (1) an advice meeting for clinical and methodology experts, (2) an advice meeting for patients/caregivers, and (3) a combined meeting with both experts and patients/caregivers. Trial experts were recruited from c4c database. Patients/caregivers were recruited through a patient organization. Participants were asked to provide input on a trial protocol, including endpoints, outcomes, and the assessment schedule. Ten experts, 10 patients, and 13 caregivers participated. The advice meetings resulted in modification of eligibility criteria and outcome measures. We have provided recommendations for the most effective meeting type per protocol topic. Topics with limited options for patient input were most efficiently discussed in expert advice meetings. Other topics benefit from patient/caregiver input, either through a combined meeting with experts or a patients/caregivers‐only advice meeting. Some topics, such as endpoints and outcome measures, are suitable for all meeting types. Combined sessions profit from synergy between experts and patients/caregivers, balancing input on protocol scientific feasibility and acceptability. Both experts and patients/caregivers provided critical input on the presented protocol. The combined meeting was the most effective methodology for most protocol topics. The presented methodology can be used effectively to acquire expert and patient feedback.

Soft tissue tumors of infancy encompass an overlapping spectrum of diseases that pose unique diagnostic and clinical challenges. We studied genomes and transcriptomes of cryptogenic congenital mesoblastic nephroma (CMN), and extended our findings to five anatomically or histologically related soft tissue tumors: infantile fibrosarcoma (IFS), nephroblastomatosis, Wilms tumor, malignant rhabdoid tumor, and clear cell sarcoma of the kidney. A key finding is recurrent mutation of EGFR in CMN by internal tandem duplication of the kinase domain, thus delineating CMN from other childhood renal tumors. Furthermore, we identify BRAF intragenic rearrangements in CMN and IFS. Collectively these findings reveal novel diagnostic markers and therapeutic strategies and highlight a prominent role of isolated intragenic rearrangements as drivers of infant tumors. Soft tissue tumors in infants encompass an overlapping spectrum of diseases posing unique diagnostic and clinical challenges. Here, the authors investigate the genetic basis of cryptogenic congenital mesoblastic nephroma and infantile fibrosarcoma lacking the canonical NTRK3-ETV6 fusion gene, and identify therapeutically tractable intragenic rearrangements in EGFR and BRAF .

Background Biliary rhabdomyosarcoma (RMS) is the most common biliary tumor in children. The management of affected patients contains unique challenges because of the rarity of this tumor entity and its critical location at the porta hepatis, which can make achievement of a radical resection very difficult. Methods In a retrospective chart analysis we analysed children suffering from biliary RMS who were registered in three different CWS trials (CWS-96, CWS-2002P, and SoTiSaR registry). Results Seventeen patients (12 female, 5 male) with a median age of 4.3 years were assessed. The median follow-up was 42.2 months (10.7–202.5). The 5-year overall (OS) and event free survival (EFS) rates were 58% (45–71) and 47% (34–50), respectively. Patients > 10 years of age and those with alveolar histology had the worst prognosis (OS 0%). Patients with botryoid histology had an excellent survival (OS 100%) compared to those with non-botryoid histology (OS 38%, 22–54, p  = 0.047). Microscopic complete tumor resection was achieved in almost all patients who received initial tumor biopsy followed by chemotherapy and delayed surgery. Conclusion Positive predictive factors for survival of children with biliary RMS are age ≤ 10 years and botryoid tumor histology. Primary surgery with intention of tumor resection should be avoided.

Purpose Modern treatment concepts for bladder/prostate rhabdomyosarcoma (BPRMS) are designed to improve survival, to reduce therapy intensity, and to increase bladder preservation rates. Nevertheless, treatment is not optimal. The purpose of this study was to analyze BPRMS patients treated within the CWS-2002P trial regarding outcome, treatment modalities, complications, and to compare the data with the precursor trial CWS-96. Methods Fifty children with localized embryonal BPRMS were analyzed. Eight patients were excluded. Patients received neoadjuvant chemotherapy. At week 9, reassessment using MRI scan was performed. Depending on tumor size, age, and response, local therapy consisting of radiotherapy and/or surgery was initiated. After local therapy, systemic therapy was continued. Results Patients’ median age was 35.6 months. Median follow-up was 59 months. The 5-year OS was 84.5 % and the 5-year ES 79.9 %. Ten patients underwent combined radiochemotherapy and tumor resection (5-year ES: 87.5 %). Six patients were treated solely with radiochemotherapy (5-year ES: 60 %). Twenty-six patients received preoperative chemotherapy followed by tumor resection (ES: 80.8). One patient was treated with chemotherapy only and survived. The bladder preservation rate was 80.9 %. Conclusions The outcome within the CWS-2002P trial regarding OS and ES seemed to be better than in the precursor trial CWS-96 due to a reduction of protocol violations, but there was no statistical significant difference possibly due to low numbers. Radiotherapy was used less frequently, and the bladder preservation rate was slightly higher. Novel concepts will be required in the future to improve bladder preservation rates.