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INFORM is a prospective, multinational registry gathering clinical and molecular data of relapsed, progressive, or high-risk pediatric patients with cancer. This report describes long-term follow-up of 519 patients in whom molecular alterations were evaluated according to a predefined seven-scale target prioritization algorithm. Mean turnaround time from sample receipt to report was 25.4 days. The highest target priority level was observed in 42 patients (8.1%). Of these, 20 patients received matched targeted treatment with a median progression-free survival of 204 days [95% confidence interval (CI), 99–not applicable], compared with 117 days (95% CI, 106–143; P = 0.011) in all other patients. The respective molecular targets were shown to be predictive for matched treatment response and not prognostic surrogates for improved outcome. Hereditary cancer predisposition syndromes were identified in 7.5% of patients, half of which were newly identified through the study. Integrated molecular analyses resulted in a change or refinement of diagnoses in 8.2% of cases.Significance:The pediatric precision oncology INFORM registry prospectively tested a target prioritization algorithm in a real-world, multinational setting and identified subgroups of patients benefiting from matched targeted treatment with improved progression-free survival, refinement of diagnosis, and identification of hereditary cancer predisposition syndromes.See related commentary by Eggermont et al., p. 2677.This article is highlighted in the In This Issue feature, p. 2659

Supplementary Table from The Pediatric Precision Oncology INFORM Registry: Clinical Outcome and Benefit for Patients with Very High-Evidence Targets

Supplementary Figure from The Pediatric Precision Oncology INFORM Registry: Clinical Outcome and Benefit for Patients with Very High-Evidence Targets

Supplementary Table S2. Small-molecule library.

Pediatric tumors harbor very low numbers of somatic mutations and therefore offer few targets to improve therapeutic management with targeted drugs. In particular, outcomes remain dismal for patients with metastatic alveolar rhabdomyosarcoma (aRMS), where the chimeric transcription factor PAX3/7-FOXO1 has been implicated but problematic to target. In this report, we addressed this challenge by developing a two-armed screen for druggable upstream regulatory kinases in the PAX3/7-FOXO1 pathway. Screening libraries of kinome siRNA and small molecules, we defined PLK1 as an upstream-acting regulator. Mechanistically, PLK1 interacted with and phosphorylated PAX3-FOXO1 at the novel site S503, leading to protein stabilization. Notably, PLK1 inhibition led to elevated ubiquitination and rapid proteasomal degradation of the PAX3-FOXO1 chimeric oncoprotein. On this basis, we embarked on a preclinical validation of PLK1 as a target in a xenograft mouse model of aRMS, where the PLK1 inhibitor BI 2536 reduced PAX3-FOXO1–mediated gene expression and elicited tumor regression. Clinically, analysis of human aRMS tumor biopsies documented high PLK1 expression to offer prognostic significance for both event-free survival and overall survival. Taken together, these preclinical studies validate the PLK1–PAX3-FOXO1 axis as a rational target to treat aRMS. Cancer Res; 75(1); 98–110. ©2014 AACR.

Supplementary Figure Legends. Legend for Supplementary Figures S1-S7.

Supplementary Materials and Methods. Description of additional methods and procedures used in the study.

Background The benefit of adjuvant therapy in synovial sarcoma (SS) treatment is under debate. Long-term follow-up data are missing. Methods SS patients treated in the consecutive trials CWS-81, CWS-86, CWS-91, CWS-96, CWS-2002-P, and the SoTiSaR-registry till 2013 were analyzed. Results Median age of 185 patients was 13.9 years (0.1–56)—with median follow-up of 7.4 years for 163 survivors. Most tumors (76%) were located in extremities. Size was 10 cm in 13 (7%) (13 missing). In 84 (45%) tumors, first excision was complete (R0 corresponding to IRS-I-group) and in 101 (55%) marginal (R1 corresponding to IRS-II-group). In a subsequent surgical intervention during chemotherapy, R0-status was accomplished in 23 additional IRS-II-group patients with secondary surgery. Radiotherapy was administered to 135 (73%), thereof 62 with R0-status and 67 R1-status (6 missing information). Adjuvant chemotherapy was administered to all but six patients. 5-year event-free (EFS) and overall survival (OS) was 82.9% ± 5.7 (95%CI) and 92.5% ± 3.9. Local and metastatic relapse-free survival was 91.3% ± 4.3 and 92.3% ± 4.1 at 5 years, respectively. In the multivariate analysis, tumor size and no chemotherapy were independently associated with EFS. Size and site were associated with OS. In a detailed analysis of local and metastatic events, tumor size was associated with an independent risk for developing metastases. No independent factor for suffering local recurrence could be identified. Discussion Omission of chemotherapy in a non-stratified way seems not justified. Size governs survival due to high linear association with risk of suffering metastatic recurrence in a granular classification.

In this article, we will discuss the genesis, evolution, and progress of the INternational Soft Tissue SaRcoma ConsorTium (INSTRuCT), which aims to foster international research and collaboration focused on pediatric soft tissue sarcoma. We will begin by highlighting the current state of clinical research for pediatric soft tissue sarcomas, including rhabdomyosarcoma and non-rhabdomyosarcoma soft tissue sarcoma. We will then explore challenges and research priorities, describe the development of INSTRuCT, and discuss how the consortium aims to address key research priorities.

Background: CWS/RMS-96 was an international multicenter trial with randomization between two therapy arms of the standard four-drug therapy (vincristine, ifosfamide, adriamycin, dactinomycin [VAIA]) versus an intensified six-drug regimen (carboplatin, epirubicin, vincristine, dactinomycin, ifosfamide, and etoposide [CEVAIE]) for high-risk rhabdomyosarcoma (RMS), extraskeletal Ewing sarcoma (EES), and undifferentiated sarcoma (UDS) in children, adolescents, and young adults aiming to improve their survival. Intensified chemotherapy with CEVAIE did not improve outcome. Methods: Patients younger than 21 years with a previously untreated localized HR-RMS, EES, and UDS were enrolled from Cooperative Weichteilsarkom Studiengruppe (CWS) centers in Germany, Austria, Poland, Switzerland, and from Italian Soft Tissue Sarcoma Committee (STSC) centers. Randomization (1:1) to receive either 9 x 21 days cycles of VAIA or CEVAIE was performed separately in CWS and STSC. Hyperfractionated accelerated radiotherapy (32-44.8 Gy) was added at week 9-12 according to histology and response to chemotherapy. A secondary microscopically complete nonmutilating resection was performed if possible. Primary endpoints were response to chemotherapy, event-free (EFS) and overall survival (OS). Results: Five hundred fifty-seven patients (HR-RMS: n = 416, EES and UDS: n = 141) underwent randomization: VAIA (n = 273) or CEVAIE (n = 284). Radiotherapy was given to 70% of patients in both groups. A secondary resection was performed in 47% and 48% patients, respectively. The 5-year EFS and OS for the VAIA and CEVAIE treatment arms were 59.8% and 60.8% (p = .89), and 74.2% and 68.3% (p = .16), respectively. No differences in response, toxicity, or second malignancies emerged in the two groups. Conclusion: The use of an intensified regimen failed to show a significant improvement in tumor response and outcome of patients with localized HR-RMS, EES, and UDS.

The possible application of gene fusion transcripts as tumor-specific noninvasive liquid biopsy biomarkers was investigated in blood plasma from patients with alveolar rhabdomyosarcoma (ARMS) and synovial sarcoma (SS).Patients entered in the CWS Soft-Tissue Sarcoma Registry (SoTiSaR) with tumors positive for fusion genes and available blood/plasma samples were included in our analysis. Cell-free exosomal RNA was extracted and used to detect PAX-FOXO1 or SYT-SSX fusion transcripts by reverse transcription quantitative PCR (RT-qPCR).The analysis included 112 ethylene diamine tetraacetic acid blood samples from 80 patients (65 with ARMS, 15 with SS; 34 with localized, 46 with metastatic disease). For patients with metastatic ARMS, 62% (n = 18) of initial liquid biopsies were positive, and 16 (89%) of them showed initial bone marrow (BM) metastases. For all patients with primary localized ARMS, liquid biopsy was negative at diagnosis. Of the 48 plasma samples collected during therapy and follow-up, five were positive. None of the liquid biopsies from patients with SS were positive.This liquid biopsy assay based on the detection of fusion transcripts in cell-free RNA from blood exosomes is suitable for analysis of patients with ARMS. Results showed good correlation with the initial tumor status; liquid biopsy was positive in 94% of patients with metastatic ARMS and initial BM involvement, whereas biopsies from all patients with localized tumors were negative. Prospective validation and optimization of the assay, as well as its application for other markers in diagnostics and monitoring of soft-tissue sarcoma, are ongoing.

Background and objectives This study aims at examining the potential survival benefits of primary versus secondary surgery of children diagnosed with advanced infantile (iFS) and adult-type fibrosarcoma (aFS). Methods Treatment and outcome of 89 children with FS treated within prospective Cooperative Studiengruppe (CWS) trials (1981–2016) were analyzed retrospectively. Results Localized disease (LD) was diagnosed in 87 patients: 64/66 patients with iFS (≤ 2 years) and 23 with aFS (> 2 ≤ 18 years). Two patients (iFS) had metastatic disease. Resection was the mainstay of therapy of patients with LD resulting in microscopically complete (R0, IRS group I) (n = 29/87, 33%), microscopically incomplete (R1, IRS group II) (n = 17/87, 20%) and macroscopically incomplete (R2, IRS group III) (n = 41/87, 47%). Advanced LD (IRS group III) was present in 32/64 (50%) patients with iFS and in 9/23 (39%) with aFS. Chemotherapy was added predominantly in patients with advanced disease and an assessable objective response to CHT was seen in 71% iFS and 75% aFS. The 5-year event-free survival (EFS) of patients with iFS and aFS was 81% (± 10, 95% CI) and 70% (± 19, 95% CI) (p = 0.24); the 5-year overall survival (OS) was 98% (± 3, 95% CI) and 82% (± 16, 95% CI) (p = 0.02). Primary resection was no prognostic factor. Secondary R0/ R1 resection in patients with advanced disease improved 5-year EFS and OS in aFS (p = 0.002 and p = 0.000) but not in infants. Conclusions Secondary resection improves outcome in advanced aFS but not in infants. Mutilating surgery in infants should be avoided. Type of study and level of evidence Treatment study: patients were enrolled in five prospective studies and one registry, prognosis study: retrospective study. Level of evidence II/ III. Mini-abstract Fibrosarcoma is a very rare malignant tumor. Little is known about differences of local treatment of advanced infantile and adult-type. Data of 89 patients registered in five prospective trials and one registry of the Cooperative Weichteilsarkom Studiengruppe (CWS) (1981–2016) were analyzed.

BACKGROUND AND OBJECTIVES Malignant peripheral nerve sheath tumors (MPNST) are aggressive soft tissue sarcomas that present as large, invasive tumors. Our aim was to assess outcomes, identify prognostic factors, and analyze treatment strategies in a prospectively collected pediatric cohort. METHODS Patients less than 21 years with MPNST treated in the consecutive prospective European Cooperative Weichteilsarkom Studiengruppe (CWS)-trials (1981-2009) and the CWS-SoTiSaR registry (2009-2015) were analyzed. RESULTS A total of 159 patients were analyzed. Neurofibromatosis type I (NF1) was reported in thirty-eight patients (24%). Most were adolescents (67%) with large (>10 cm, 65%) tumors located at extremities (42%). Nodal involvement was documented in 15 (9%) and distant metastases in 15 (9%) upon diagnosis. Overall, event-free survival (EFS) was 40.5% at 5 and 36.3% at 10 years, and overall survival (OS) was 54.6% at 5 and 47.1% at 10 years. Age, NF1 status, tumor site, tumor size, Intergroup Rhabdomyosarcoma Study (IRS) group, metastatic disease, and achieving first complete remission (CR1) were identified as prognostic factors for EFS and/or OS in the univariate analysis. CONCLUSIONS Prognostic factors were identified and research questions for future clinical trials were addressed.

BACKGROUND Dermatofibrosarcoma protuberans (DFSP) is a rare low-grade tumor. Little is known about best treatment of primary and relapsed disease (RD). METHODS Treatment and outcome of 40 patients with DFSP prospectively registered within the CWS-96 and -2002P trials and the registry SoTiSaR (1996-2016) were analysed. RESULTS Median age was 8 years (range, 0.64-17.77). Fluorescence in situ hybridization analysis to detect COL1A1-PDGFB fusion genes was positive in 86% (12/14) of evaluated patients. Primary resection was performed in all patients. Patients had IRS group I (n = 28), II (n = 9), and III (n = 2); not available (n = 1). To achieve complete remission (CR), a secondary resection was performed in 18 patients resulting in microscopically complete (R0, n = 34/40) and microscopically incomplete (R1, n = 5/40) resection. All patients achieved CR. The 5-year event-free survival (EFS) and overall survival was 86% (±12; CI, 95%) and 100% (±0; CI, 95%), respectively. R0 resection/IRS I was significantly favorable for the 5-year EFS. Local relapse occurred after a median time of 1.1 years (range, 0.04-5.1) in 15% (6/40) after CR. All patients with RD underwent resection and achieved CR. Three patients had fibrosarcomatous DFSP, two were alive after R0 resection. CONCLUSION Complete surgical resection is mandatory to prevent relapse of DFSP.

Optimization of local therapies in synovial sarcoma (SS) considered unresectable at diagnosis is needed. We evaluated the effects of neoadjuvant versus adjuvant radiation versus surgery only on long-term outcomes.Patients with macroscopic SS tumors before chemotherapy (IRS-group-III) in the trials CWS-81, CWS-86, CWS-91, CWS-96, CWS-2002-P and SoTiSaR-registry were analyzed. Local therapies were scheduled after 3 neoadjuvant chemotherapy cycles.Median age of 145 patients was 14.5 years. 106 survivors had median follow-up of 7.0 years. Tumor site was 96 extremities, 19 head-neck, 16 shoulder/hip, 14 trunk. Tumors were 3 cm in 16, 3-5 cm in 28, 5-10 cm in 55, 10 cm in 34 patients. In a secondary resection during chemotherapy, R0-status was accomplished in 82, R1 in 30, R2 in 21 (12 missing). Radiotherapy was administered to 115 (R0 61, R1 29, R2 20, missing 5), thereof 57 before and 52 after tumor resection. 23 were treated with surgery only. For all patients, 5 year event-free (EFS) and overall survival (OS) was 68.9% ± 7.6 (95%CI) and 79.1% ± 6.9. To establish independent significance, tumor site, size, surgical results and sequencing of local therapies were analyzed in a Cox regression analysis. Variables associated with EFS and OS are site, size and sequencing of local therapies. Variables associated with local recurrence are site, surgical results and sequencing of local therapies. The only variable associated with suffering metastatic recurrence is tumor size.Differences in sequencing of local therapy procedures are independently associated with outcomes. Best local control is achieved when tumors are irradiated pre-operatively and undergo R0 or R1 resection thereafter.

We report here the results of the prospective, non-randomized, historically controlled CWS-2002P study in patients ≤ 21 years with localized RMS developed with the aim to improve the long-term outcome by adapting the burden of therapy to risk profile and to investigate the feasibility and relation to the outcome of maintenance therapy (MT) in the high-risk groups. Patients were allocated into low-risk (LR), standard-risk (SR), high-risk (HR), and very high-risk (VHR) groups. Chemotherapy consisted of vincristine (VCR) and dactinomycin (ACTO-D) for all patients with the addition of ifosfamide (IFO) in the SR, HR, and VHR and doxorubicin (DOX) in the HR and VHR groups. Low-dose cyclophosphamide and vinblastine maintenance therapy (MT) over 6 months was recommended in the HR and VHR groups. A total of 444 patients have been included in this analysis. With a median follow-up of 9·6 years (IQR 7·6–10·9) for patients alive, the 5-year EFS and OS for the whole group was 73% (95% CI 69–77) and 80% (95% CI 76–84), respectively. The 5-year EFS by risk group was 100% in the LR, 79% (95% CI 72–84) in the SR, 69% (95% CI 63–75) in the HR, and 42% (95% CI 23–61) in the VHR (log-rank p = 0.000). The 5-year EFS was 77% (95% CI 70–84) for 155 patients in the HR group who received MT as compared to 63% (95% CI 50–76) for 49 patients who did not (log-rank p = 0.015). Neither the reduction in the IFO dose in the SR nor the increased dose intensity of DOX in HR groups influenced the outcome when compared to the previous CWS and other European studies. MT was feasible, seemed to have an impact on prognosis, and should be studied in a well-controlled prospective trial in this patient population. The weighting of risk factors used for therapy stratification needs to be reevaluated.

Rhabdomyosarcomas (RMSs) are the most common soft tissue sarcomas in children/adolescents less than 18 years of age with an annual incidence of 1-2/million. Inter/intra-tumour heterogeneity raise challenges in clinical, pathological and biological research studies. Risk stratification in European and North American clinical trials previously relied on clinico-pathological features, but now, incorporates PAX3/7-FOXO1-fusion gene status in the place of alveolar histology. International working groups propose a coordinated approach through the INternational Soft Tissue SaRcoma ConsorTium to evaluate the specific genetic abnormalities and generate and integrate molecular and clinical data related to patients with RMS across different trial settings. We review relevant data and present a consensus view on what molecular features should be assessed. In particular, we recommend the assessment of the MYOD1-LR122R mutation for risk escalation, as it has been associated with poor outcomes in spindle/sclerosing RMS and rare RMS with classic embryonal histopathology. The prospective analyses of rare fusion genes beyond PAX3/7-FOXO1 will generate new data linked to outcomes and assessment of TP53 mutations and CDK4 amplification may confirm their prognostic value. Pathogenic/likely pathogenic germline variants in TP53 and other cancer predisposition genes should also be assessed. DNA/RNA profiling of tumours at diagnosis/relapse and serial analyses of plasma samples is recommended where possible to validate potential molecular biomarkers, identify new biomarkers and assess how liquid biopsy analyses can have the greatest benefit. Together with the development of new molecularly-derived therapeutic strategies that we review, a synchronised international approach is expected to enhance progress towards improved treatment assignment, management and outcomes for patients with RMS.

We report here the results of the prospective, non-randomized, historically controlled CWS-2002P study in patients ≤ 21 years with localized RMS developed with the aim to improve the long-term outcome by adapting the burden of therapy to risk profile and to investigate the feasibility and relation to the outcome of maintenance therapy (MT) in the high-risk groups. Patients were allocated into low-risk (LR), standard-risk (SR), high-risk (HR), and very high-risk (VHR) groups. Chemotherapy consisted of vincristine (VCR) and dactinomycin (ACTO-D) for all patients with the addition of ifosfamide (IFO) in the SR, HR, and VHR and doxorubicin (DOX) in the HR and VHR groups. Low-dose cyclophosphamide and vinblastine maintenance therapy (MT) over 6 months was recommended in the HR and VHR groups. A total of 444 patients have been included in this analysis. With a median follow-up of 9·6 years (IQR 7·6-10·9) for patients alive, the 5-year EFS and OS for the whole group was 73% (95% CI 69-77) and 80% (95% CI 76-84), respectively. The 5-year EFS by risk group was 100% in the LR, 79% (95% CI 72-84) in the SR, 69% (95% CI 63-75) in the HR, and 42% (95% CI 23-61) in the VHR (log-rank

Background: Infantile myofibromatosis (IM) is a rare benign soft tissue tumor and often a self-limiting disease but rarely includes life-threatening complications. Little is known about optimal treatment of primary localized (LD) and multifocal disease (MFD). Methods: Treatment and outcome of 95 children with IM registered within five Cooperative Weichteilsarkom Studiengruppe (CWS) trials and one registry (1981-2016) were evaluated. Results: LD was diagnosed in 71 patients at a median age of 0.4 years (range 0.0-17.7). MFD was present in 24 patients. The mainstay of treatment was watch-and-wait strategy (w&w) after initial biopsy or resection. Low-dose chemotherapy (CHT) was administered to 16/71 (23%) patients with LD and eight of 24 (33%) patients with MFD, imatinib was added in two. A delayed resection was possible in eight of 71 (11%) and five of 24 (21%) patients with LD and MFD, respectively. Overall, patients were alive in complete remission (n = 77) and partial remission (n = 10) at a median follow-up time of 3.4 years after diagnosis (range 0.01-19.4); no data available (n = 5). Three patients died of progressive disease (PD) despite CHT. Gender, tumor size, and location correlated with a favorable event-free survival (EFS) in patients with LD. The 5-year EFS and overall survival of patients with LD were 73% (±12, confidence interval [CI] 95%) and 95% (±6, CI 95%), respectively; for MFD 51% (±22, CI 95%) and 95% (±10, CI 95%). Cconclusion: Prognosis is excellent in patients with LD and MFD. Targeted treatment needs to be evaluated for rare fatal PD.

The international pediatric oncology community has a long history of research collaboration. In the United States, the 2019 launch of the Children's Cancer Data Initiative puts the focus on developing a rich and robust data ecosystem for pediatric oncology. In this spirit, we present here our experience in constructing the Pediatric Cancer Data Commons (PCDC) to highlight the significance of this effort in fighting pediatric cancer and improving outcomes and to provide essential information to those creating resources in other disease areas. The University of Chicago's PCDC team has worked with the international research community since 2015 to build data commons for children's cancers. We identified six critical features of successful data commons design and implementation: (1) establish the need for a data commons, (2) develop and deploy the technical infrastructure, (3) establish and implement governance, (4) make the data commons platform easy and intuitive for researchers, (5) socialize the data commons and create working knowledge and expertise in the research community, and (6) plan for longevity and sustainability. Data commons are critical to conducting research on large patient cohorts that will ultimately lead to improved outcomes for children with cancer. There is value in connecting high-quality clinical and phenotype data to external sources of data such as genomic, proteomics, and imaging data. Next steps for the PCDC include creating an informed and invested data-sharing culture, developing sustainable methods of data collection and sharing, standardizing genetic biomarker reporting, incorporating radiologic and molecular analysis data, and building models for electronic patient consent. The methods and processes described here can be extended to any clinical area and provide a blueprint for others wishing to develop similar resources.

Background Children with progressive (PD) or relapsed disease (RD) of pleuropulmonary blastoma (PPB) type II/III are known to have a very poor outcome. Methods A retrospective review of children registered in national and European databases and trials (2000-2018) with diagnosis of PPB type II/III and PD or RD was performed. Results A total of 35 patients with PPB were analysed: patients with PD (n = 9) and RD (n = 26). Patients experienced PD at the median age of 3.9 years [range, 0.5-17.8] despite surgery, chemotherapy (CHT, n = 9) and radiotherapy (RT, n = 1) with a median time to progression of 0.58 years [range, 0.02-1.27] from diagnosis. All of them died. Patients suffered from RD at the median age of 4.3 years [1.7-15.1], median delay to relapse 1.03 years [range, 0.03-2.95]. RD occurred locally (n = 12), combined (n = 1) and in metastatic sites (n = 13): central nervous system (n = 11) and unspecified site (n = 2). Patients were treated with salvage CHT (n = 20), surgery (n = 10) ± RT (n = 10). After a median follow-up of 4.2 years [range, 2.1-14.6], a second complete remission (CR) was achieved in nine out of 26 patients. Patients were alive in the second CR (n = 6), in the third CR (n = 1), in partial remission (n = 2) and lost of follow-up (n = 1). Five-year event-free survival (EFS) and overall survival (OS) for patients with RD were both 37% (±19, CI 95%). Local therapy (surgery, RT) had a favourable impact on OS (p = 0.03 and 0.02, respectively). Conclusions Cure of patients with RD of PPB type II/III with multimodal treatment is possible but rare. Progressive PPB is fatal and patients need new treatment options.

10033 Background: Low dose maintenance therapy as consolidation after multimodal standard therapy has been shown to improve survival in patients with sarcoma. It is however unclear which drugs and how long would be optimal. We investigated whether adding oral maintenance chemotherapy after standard multimodal therapy (ST) in patients with localized RMS and RMS-like sarcoma defined as high and very-high risk (HR and VHR), according to CWS stratification, would improve survival. Methods: Patients (pts) age > 6 months < 21 years, with 1. embryonal RMS N0, incompletely resected, (Group II or III), tumor size > 5cm and/or ≥10 years, in unfavorable primary sites and all N1 (HR RMS Group), 2. alveolar RMS N0/N1 (VHR RMS Group) 3.Unidfferentiated sarcoma (UDS), extraskeletal Ewing sarcoma (EES) and primary non resectable (Group III) synovial sarcoma (SS) (HR RMS-like Group) in complete remission after ST including 9 cycles of ifosfamide, vincristine and actinomycin D +/- doxorubicin, surgery and/or radiotherapy were eligible for randomization to stop treatment (S-arm) or receive maintenance chemotherapy (M-arm) with eight 10-days courses consisting of trofosfamide (2x 75mg/m²/day) and idarubicine (1 x 5mg/m²/day 1,4,7,10) alternating with trofosfamide and etoposide (2x 25mg/m²/day). The study was designed with 80% power and a two-sided alpha level of 5% to detect an increase in 3 yr EFS from 60 to 75%. Randomisation was stratified according to risk groups. To reduce possible imbalances in the number of treatment assignments, a permuted block design was used. The initial calculated sample size was 145 pts in each group (recruitment period six years). Due to the lower than planned recruitement rate, the accrual was extended to 10 years and sample size recalculated to 98 pts in each group. Results: Between 1.7.2009 and 30.6.2019, 441 pts were eligible at diagnosis and 337 at the end of ST. 195 pts were randomized: 99 were assigned to the S-arm and 96 to M-arm. The distribution of the following clinical features:age, gender, tumor size, IRS-Group, T-Status, N-Status, histology and localisation showed no significant difference between the treatment groups. In the intent to treat population, with a median follow up of 4.9 years (IQR 3.0-5.7) in surviving pts, 3yr EFS and OS in M-arm vs S-arm were respectively: EFS 66.2% (95% IC 57.1-76.79) vs 75.0% (95% IC 66.8-84.3) (p 0.07) and OS 81.9% (95% IC 74.2-90.4) vs 84.6 (95% IC 77.5-92.4) (p 0.15). Toxicity grade 3 (no grade 4) in the M-arm was: hematological in 51 %, febrile infection 5%, sensory neuropathy in 1% pts. Conclusions: The addition of maintenance therapy with trofosfamide, etoposide and idarubicine after ST does not improve EFS and OS in patients with high risk RMS and RMS-like sarcomas. Clinical trial information: 2007-0001478-10.

Purpose Treatment recommendations for localized paratesticular rhabdomyosarcoma (PT RMS) differ in North America and Europe. We conducted a pooled analysis to identify demographic features and treatment choices that affect outcome. Patients and Methods We retrospectively analyzed the effect of nine demographic variables and four treatment choices on event-free survival (EFS) and overall survival (OS) from 12 studies conducted by five cooperative groups. Results Eight hundred forty-two patients with localized PT RMS who enrolled from 1988 to 2013 were included. Patients age ≥ 10 years were more likely than younger patients to have tumors that were > 5 cm, enlarged nodes (N1), or pathologically involved nodes ( P ≤ .05 each). With a median follow-up of 7.5 years, Kaplan-Meier estimates for 5-year EFS and OS were 87.7% and 94.8%, respectively. Of demographic variables, cooperative group, era of enrollment, age category, tumor size, Intergroup Rhabdomyosarcoma Study group, and T stage affected EFS ( P ≤ .05 each). Surgical assessment of regional nodes, which was performed in 23.5% of patients—usually in those age ≥ 10 years or with suspicious or N1 nodes—was the only treatment variable associated with EFS by univariable and multivariable analyses ( P ≤ .05 each) in patients age ≥ 1 year. A variable selection procedure on a proportional hazards regression model selected era of enrollment, age, tumor size, and surgical assessment of regional nodes as significant ( P ≤ .05 each) in the EFS model, and era of enrollment, age, tumor size, and histology ( P ≤ .05 each) in the OS model. Conclusion Localized PT RMS has a favorable prognosis. Age ≥ 10 years at diagnosis and tumor size larger than 5 cm are unfavorable prognostic features. Surgical assessment of regional nodes is important in patients age ≥ 10 years and in those with N1 nodes as it affects EFS.

Pleuropulmonary blastoma (PPB) is a rare cancer occurring mainly during early childhood and often associated with germline DICER1 mutations. It is classified by the macroscopic appearance into three interrelated clinico-pathologic entities on a developmental continuum. Complete tumor resection is a main prognostic factor and can be performed at diagnosis or after neoadjuvant treatment that includes chemotherapy and in some cases radiotherapy. Optimal modalities of neo- or adjuvant treatments can be challenging taking into account potential long-term toxicities in this young population. This paper presents the recommendations for diagnosis and treatment of children and adolescents with PPB elaborated by the European Cooperative Study Group for Pediatric Rare Tumors (EXPeRT) within the European Union-funded project PARTNER (Paediatric Rare Tumours Network - European Registry).

INFORM is a prospective, multinational registry gathering clinical and molecular data of relapsed, progressive, or high-risk pediatric patients with cancer. This report describes long-term follow-up of 519 patients in whom molecular alterations were evaluated according to a predefined seven-scale target prioritization algorithm. Mean turnaround time from sample receipt to report was 25.4 days. The highest target priority level was observed in 42 patients (8.1%). Of these, 20 patients received matched targeted treatment with a median progression-free survival of 204 days [95% confidence interval (CI), 99–not applicable], compared with 117 days (95% CI, 106–143; P = 0.011) in all other patients. The respective molecular targets were shown to be predictive for matched treatment response and not prognostic surrogates for improved outcome. Hereditary cancer predisposition syndromes were identified in 7.5% of patients, half of which were newly identified through the study. Integrated molecular analyses resulted in a change or refinement of diagnoses in 8.2% of cases. Significance: The pediatric precision oncology INFORM registry prospectively tested a target prioritization algorithm in a real-world, multinational setting and identified subgroups of patients benefiting from matched targeted treatment with improved progression-free survival, refinement of diagnosis, and identification of hereditary cancer predisposition syndromes. See related commentary by Eggermont et al., p. 2677 . This article is highlighted in the In This Issue feature, p. 2659

Background Rhabdomyosarcoma (RMS) of the female genitourinary tract (FGU-RMS) located at the vagina or uterus is one of the most favorable RMS sites. Little is known about treatment and outcome in infants and relapsed disease (RD). Methods Characteristics, treatment, and outcome of 71 children with FGU-RMS registered within five Cooperative Weichteilsarkom Studiengruppe (CWS) trials and one registry (1981-2019) were evaluated. Results FGU-RMS was diagnosed in 67 patients with localized disease (LD) at a median age of 2.89 years (0.09-18.08). Multimodal treatment consisted of chemotherapy (CHT) (n = 66), secondary surgery (n = 32), and radiotherapy (n = 11). Age at diagnosis ≤12 months was the only significant negative prognostic factor influencing the event-free survival (EFS). Ten-year EFS and overall survival (OS) for infants ≤12 months were 50% and 81%, respectively. In contrast, children with LD >1 year and ≤10 years had a 10-year EFS and OS of 78% and 94% (P = .038), and >10 years of 82% and 88%, respectively (P = .53). Metastatic disease was observed in four patients of which three are alive. RD occurred in five of 12 infants ≤1 year and 10/55 children at a median of 1.38 years (0.53-2.97) after initial diagnosis. Treatment of patients with RD consisted of multimodal treatment (n = 13) or resection only (n = 2). Nine patients (60%) were alive in clinical remission at a median of 7.02 years (1.23-16.72) after diagnosis of RD. Conclusion Infants with FGU-RMS have a higher relapse rate than older children with FGU-RMS, but prognosis is fair.

Background We have analyzed the outcome of patients with localized extraskeletal Ewing sarcoma (EES) treated in three consecutive Cooperative Weichteilsarkomstudiengruppe (CWS) soft tissue sarcoma (STS) studies: CWS-91, CWS-96, and CWS-2002P. Methods Patients were treated in CWS-91 with four- (vincristine, dactinomycin, doxorubicin, and ifosfamide [VAIA] or cyclophosphamide [VACA II]) or five-drug (+etoposide [EVAIA]) cycles, in CWS-96 they were randomly assigned to receive VAIA or CEVAIE (+carboplatin and etoposide), and in CWS-2002P with VAIA III plus optional maintenance therapy (MT) with cyclophosphamide and vinblastine. Local therapy consisted of resection and/or radiotherapy (RT). Results Two hundred forty-three patients fulfilled the eligibility criteria. The 5-year event-free survival (EFS) and overall survival (OS) were 63% (95% confidence interval [CI] 57-69) and 73% (95% CI 67-79), respectively. The 5-year EFS by study was 64% (95% CI 54-74) in CWS-91, 57% (95% CI 48-66) in CWS-96, and 79% (95% CI 67-91) in CWS-2002P (n.s.). The 5-year OS was 72% (95% CI 62-82) in CWS-91, 70% (95% CI 61-79) in CWS-96, and 86% (95% CI 76-96) in CWS-2002P (n.s.). In CWS-96, 5-year EFS and OS in the VAIA arm versus the CEVAIE were 65% (95% CI 52-81) versus 55% (95% CI 39-76) log-rank p = .13, and 85% (95% CI 75-96) versus 61% (95% CI 45-82), log-rank p = .09. Conclusion Our analysis provides interesting information on the treatment and specificities of EES, which can be useful for a better understanding of this rare entity and should be considered in the development of future clinical trials for Ewing sarcoma defined as FET-ETS fusion positive tumors.

The treatment of paratesticular rhabdomyosarcoma (PT-RMS) has varied over time and by cooperative group. The International Soft Tissue Sarcoma Database 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 Cooperative Weichteilsarkom Studiengruppe (CWS). The INSTRuCT surgical committee has been given charge of the development of internationally applicable consensus guidelines for the surgical treatment of rhabdomyosarcoma. This clinical consensus opinion document addresses accepted principles and areas of controversy, such as scrotal violation and retroperitoneal nodal evaluation, providing an evidence-based guideline for the surgical treatment for PT-RMS.

The diagnosis and classification of rhabdomyosarcoma (RMS) has undergone several shifts over the last 30 years. While the main diagnostic categories remained the same, changes in the histologic criteria necessary for diagnosis, as well as varied reliance on immunohistochemical and molecular data over time, have created confusion, particularly regarding how these shifts impacted risk stratification and enrollment onto clinical trials. The goal of this report is to review the evolution and current status of RMS diagnosis, focusing on diagnostic criteria in the Children's Oncology Group (COG), the European Paediatric Soft Tissue Sarcoma Group (EpSSG), and the Cooperative Weichteilsarkom Studiengruppe (CWS). In addition, we emphasize research tools used to classify RMS and address biological questions within current clinical trials run by each group. The INternational Soft Tissue SaRcoma ConsorTium (INSTRuCT) initiative will maximize potential to optimize risk stratification by recognizing and accounting for differences in historical data and current practices.

Soft tissue sarcoma comprises 7.4% of childhood soft tissue malignancies with rhabdomyosarcoma (RMS) being the most common soft tissue sarcoma in children. RMS can arise in virtually any site in the body. Presenting symptoms depend on the site of origin of the tumor and can range from urinary obstruction or constipation in patients with pelvic or bladder/prostate tumors to proptosis in patients with orbital RMS, sinusitis symptoms in patients with parameningeal/sinus tumors, or a painless mass in extremity tumors. In North America there are about 350 new cases of RMS in children annually, with a similar number of new cases in Europe. The staging system for rhabdomyosarcoma has already been discussed in Chap. 5 and will not be repeated here. Risk stratification has evolved over the past several decades. Meza and colleagues analyzed patient and disease characteristics of patients with nonmetastatic RMS treated on the third and fourth Intergroup Rhabdomyosarcoma Studies and identified the prognostic significance of histology (alveolar (ARMS) and embryonal RMS (ERMS)), stage, group, and primary site (Meza et al. 2006) and resulted in stratification of patients into two low risk, one intermediate risk, and one high risk group for North American studies from 1997 to 2004. In Europe ongoing protocols use IRS Group, histology, patient age, primary tumor site, and size and nodal involvement to assign patients into four groups: low risk, standard risk, high risk, and very high risk. A multivariate analysis of risk factors in 788 patients with metastatic RMS treated in nine studies in Europe and North America from 1984 to 2000 identified age under 1 year or older than 10, unfavorable site of primary tumor, presence of three or more sites of metastatic disease, and presence of bone or bone marrow involvement as being correlated with inferior event-free survival (EFS) (Oberlin et al. 2008).Risk group assignment for therapy differs between European and North American trials, so comparison of outcomes for clinical trials needs to take this into consideration. For example, in the European trials, positive lymph nodes in patients with unfavorable histology and Group III tumors result in assignment of patients to very high-risk therapy, whereas they are treated as intermediate risk on Children’s Oncology Group (COG) trials. Many other COG “intermediate-risk” patients on the “D” series of studies were considered in European Pediatric Soft Tissue Sarcoma Group (EpSSG) or Cooperative Weichteilsarkom Studie (CWS) to be “high risk” (Sultan and Ferrari 2010).

Targeted neurotrophic tropomyosin receptor kinase (TRK) inhibitors offer a highly specific therapeutic option for patients with infantile fibrosarcoma (IFS) carrying the NTRK gene translocation. International recommendations are needed to define the role of TRK inhibitors (TRKI) for infants with IFS. We analysed retrospective data for all published patients with IFS in the European Paediatric Soft tissue sarcoma Study Group and Cooperative Weichteilsarkomstudiengruppe (CWS) experience and developed a consensus strategy with the Children's Oncology Group. Therapies consisted of tumour resection and/or perioperative chemotherapy for extensive tumours. Among the 172 European patients treated, 162 were alive at the end of the follow-up. Sixty-five patients (40% of all survivors) were treated with surgery alone and 64 patients (39%) with surgery combined with chemotherapy. Radiotherapy was delivered to 3% of survivors (five patients). In addition, 28 survivors (17%) exclusively received chemotherapy. Among the 129 patients treated with surgery, 91% had conservative surgery (118 cases). Overall, nine patients died of disease, one from toxicity (6%) and 20 patients (12%) survived with major functional deficits or had mutilating surgery. Overall, conventional conservative strategies before the era of targeted therapy, even in the case of extensive tumours, demonstrate efficacy in IFS, but are associated with acute and some chronic side effects. TRKI have demonstrated very rapid responses in the vast majority of children with IFS with limited acute toxicity. With the current state of our knowledge, both conventional chemotherapy and TRKI should be regarded as options for patients with localised disease at the physician’s and parent's discretion. TRKI should be considered in patients with metastatic disease, and before mutilating surgery when conventional chemotherapy fails. Outside a clinical trial, additional data are needed to resolve the lack of consensus about front-line use of conventional chemotherapy versus TRKI in patients with localised disease.

Background The occurrence of prior, concurrent and subsequent neoplasms (SN) represents a serious problem in children and adolescents with soft tissue sarcomas. Pathogenic germline variants contribute to the diagnosis of multiple neoplasms in sarcoma survivors. Materials and methods The records of 748 children and adolescents, diagnosed with soft tissue sarcomas and registered in trials/registries by the cooperative soft tissue sarcoma (Cooperative Weichteilsarkom Studie) group, were reviewed for the occurrence of SNs. Reference histology review was available for all cases; the presence of oncogenic fusions known at the time of diagnosis was confirmed for fusion-positive (F+) entities. Results Concurrent or subsequent SNs developed in 13 of 473 survivors of fusion-negative (F-) sarcomas, for an 8-year cumulative SN incidence of 5% in survivors of F- sarcomas. In contrast, only 1 of 278 survivors of F+ sarcoma developed an SN. Twenty of 748 patients with soft tissue sarcomas had a history of prior neoplasms. Six of 14 patients who developed SNs after their index sarcomas met Chompret criteria for Li-Fraumeni syndrome. Nine of 20 patients who had tumors before their index sarcoma diagnosis had neurofibromatosis type 1 or neurofibromatosis type 1 spectrum tumors. Conclusion Sarcoma phenotype/genotype and the sequence and nature of prior and subsequent neoplasms provide a window into underlying germline genetic susceptibilities in children and adolescents with soft tissue sarcomas.

The International Soft-Tissue Sarcoma Consortium (INSTRuCT) was founded as an international collaboration between different pediatric soft-tissue sarcoma cooperative groups (Children's Oncology Group, European Pediatric Soft-Tissue Sarcoma Group, and Cooperative Weichteilsarkom Studiengruppe). Besides other tasks, a major goal of INSTRuCT is to develop consensus expert opinions for best clinical treatment. This consensus paper for patients with rhabdomyosarcoma of the female genital tract (FGU-RMS) provides treatment recommendations for local treatment, long-term follow-up, and fertility preservation. Therefore, a review of the current literature was combined with recommendations of the treatment protocols of the appropriate clinical trials. Additionally, opinions of international FGU-RMS experts were incorporated into recommendations. Results were that the prognosis of FGU-RMS is favorable with an excellent response to chemotherapy. Initial complete surgical resection is not indicated, but diagnosis should be established properly. In patients with tumors localized at the vagina or cervix demonstrating incomplete response after induction chemotherapy, local radiotherapy (brachytherapy) should be carried out. In patients with persistent tumors at the corpus uteri, hysterectomy should be performed. Fertility preservation should be considered in all patients. In conclusion, for the first time, an international consensus for the treatment of FGU-RMS patients could be achieved, which will help to harmonize the treatment of these patients in different study groups.

BACKGROUND Endothelial cell malignancies are extremely rare in childhood. New identification of genetic abnormalities (WWTR1:CAMTA1 translocation) helps to recognize potential therapeutic targets. Little is known about treatment and outcome of these patients. METHODS Clinical course, treatment, and outcome in patients with endothelial cell malignancies treated within the Cooperative Weichteilsarkom Studiengruppe (CWS) trials CWS-91, -96, -2002P, and the Soft-Tissue Sarcoma Registry (SoTiSaR) were analyzed (1991-2019). RESULTS Patients had angiosarcoma (AS) (n = 12), malignant epithelioid hemangioendothelioma (EHE) (n = 16), and kaposiform hemangioendothelioma (KHE) (n = 13). The median age was 5.39 years (range, 0.8-17.34); 33 patients had localized disease (LD), and 8 patients had metastatic disease. Therapy consisted of chemotherapy (CHT) (AS n = 8, EHE n = 9, KHE n = 5), interferon or new agent therapy (EHE n = 5, 2 KHE n = 2), microscopically or macroscopically complete resection (AS n = 3, EHE n = 6, KHE n = 3), and radiotherapy (AS n = 6, EHE n = 2, KHE n = 1). Two patients (KHE) had watch-and-wait strategy resulting in stable disease. Complete remission (CR) was achieved in AS (10/12; 83%), EHE (10/16; 63%), and KHE (5/13; 38%). The five-year EFS and OS for patients with AS was 64% (± 29 CI 95%) and 80% (± 25, CI 95%), with EHE 62% (± 24, CI 95%) and 78% (± 23, CI 95%), with KHE 33% (± 34, CI 95%) and 92% (± 15, CI 95%), respectively. Complete resection was a significant prognostic factor for AS, LD for EHE. CONCLUSIONS Endothelial cell malignancies in childhood have a fair outcome with multimodal treatment. New treatment options are needed for metastic disease.

Kaposiform hemangioendothelioma (KHE) is a rare vascular tumor affecting infants and young children. Although benign, it can be associated with an aggressive locally growing tumor and/or a life-threatening Kasabach–Merritt phenomenon (KMP). To date, only reviews of limited cases have been performed. We, therefore, conducted a comprehensive literature search to collect relevant data and make recommendations for future treatment trials. Review of the available literature between 1993 and 2017 revealed a total of 105 publications involving 215 patients of less than 21 years of age. To this, we added 12 from our department and 4 from the Cooperative Weichteilsarkomstudie database. We found that KMP was present in 79% of the infants, in 47% of the 1–5-year olds, in 43% of the 6–12-year olds, and in 10% of the 13–21-year-old patients. KMP was present in nearly all (94%) patients with retroperitoneal tumors and in all patients with extra-regional tumors. The median size of a KHE without KMP was 12 cm2 as compared to 49 cm2 when associated with a KMP. With complete (not further classifiable if R0 or R1) resection, all patients were cured. If inoperable, response regarding KMP/regression of tumor size was seen in 29/28% with steroid-, 47/39% with vincristine-, 44/43% with interferon alpha-, 65/61% with anti-platelet agents-, and in 97/100% with sirolimus-containing therapies. Patients with progressive KHE should undergo resection whenever it is considered a safe option. If inoperable, sirolimus should be the first choice for treating KMP and reducing tumor size.

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.

Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma. In 7% of the cases it is localized at the chest wall or intrathoracically. The aim of this study was to analyze the multimodal treatment concepts and outcomes of children suffering from intrathoracic and chest wall RMS treated within three different Cooperative Soft Tissue Sarcoma (CWS) trials and one registry (Soft Tissue Sarcoma Registry, SoTiSaR). Data of 51 patients with thoracic RMS enrolled in three different CWS trials (CWS-86, -91, -2002P) and one registry (SoTiSaR) were analyzed retrospectively. Surgery and its influence on outcome were assessed. Median follow-up was 37.5 months (0.9–152.5). Median age of the patients was 8.8 years (range 0–19 years). The 5-year overall survival rate (OS) was 57% (95%-CI 49–65) and the 5-year event–free survival rate (EFS) was 45% (38–52). Thirty-five patients had tumors located at the chest wall (EFS: 51%, 43–59), and 16 patients had intrathoracic tumors (EFS: 26%, 13–39). Seventeen patients with tumors ≤ 5 cm had a better outcome (EFS: 64%, 52–76) compared to patients with tumors larger than 5 cm (EFS: 36%, 27–45). Radiotherapy (RT) significantly improved the survival of patients with alveolar RMS compared to patients with embryonal histology (EFS: 66%, 52–80 vs. 32%, 21–43 p = 0.02). Complete tumor excision during delayed surgery was the main prognostic factor for survival (p = 0.045). Thoracic RMS is a rare tumor entity. Completeness of tumor resection significantly improved survival of the patients.

Alveolar rhabdomyosarcoma commonly arises in the extremities and is characterized by aggressive biology and high frequency of metastases. Whole-body imaging is increasingly employed in pediatric oncology but not recommended as standard in the staging of soft-tissue sarcomas. After observing patients with a large symptomatic alveolar rhabdomyosarcoma lesion and a smaller silent lesion in the more distal part of an extremity we sought to estimate the frequency of this constellation. We retrospectively evaluated the data of prospectively registered paediatric patients (age

The prognosis in children with refractory or relapsed (r/r) T-cell acute lymphoblastic leukaemia (T-ALL) or lymphoblastic lymphoma (T-LBL) is poor. Nelarabine (Ara-G) has successfully been used as salvage therapy in these children, but has been associated with significant, even fatal, neurotoxicities. We retrospectively analysed 52 patients with r/r T-ALL/T-LBL aged ≤19 years who were treated with Ara-G alone (n = 25) or in combination with cyclophosphamide and etoposide (n = 27). The majority of patients (45/52) received 1-2 cycles of Ara-G. Seventeen patients (32·7%) had refractory disease, 28 (53·8%) were in first relapse and 7 (13·5%) were in second relapse. A response to Ara-G was achieved in 20 patients and 15 (28·8%) were in remission at last follow-up. Twelve patients (23·1%) had neurotoxic adverse effects (neuro-AE) of any grade, of whom 7 (13·5%) developed neurotoxicity ≥ grade III. The most frequent neuro-AEs were peripheral motor neuropathy (19·2%), peripheral sensory neuropathy (11·5%) and seizures (9·6%). Three patients died of central neuro-AE after 1-2 cycles of combination therapy. Patients with neurotoxicity were significantly older (median 15·17 years) than those without (10·34 years, P = 0·017). No differences were observed between mono- and combination therapy concerning outcome and neuro-AE. The incidence of neuro-AE was not associated with concurrent intrathecal therapy or prior central nervous system irradiation.

Background and objectives This study aims at examining the potential survival benefits of primary versus secondary surgery in the management of children diagnosed with pleuropulmonary blastoma (PPB) type II/III. Patients and methods Disease characteristics, treatment, and survival of 29 children with localized PPB type II/III, treated in six prospective Cooperative Weichteilsarkom Studiengruppe (CWS) trials, were reviewed retrospectively. Results Five year event free survival (EFS) and overall survival (OS) of children treated according to CWS protocols was 72%. Patients with tumors ≤10 cm had a 5 year OS of 91% versus 57% in patients with tumors >10 cm (P = 0.025). Five year OS of patients with macroscopically incomplete upfront resections was 44% as opposed to 68% in patients with delayed/secondary microscopically or macroscopically complete resection after an initial biopsy (P = 0.476). Ten patients died of disease, one patient died of second malignancy. Tumor size and complete tumor resection at any time were significant prognostic factors (P = 0.025/0.003) for EFS. EFS for microscopically complete, microscopically incomplete, and macroscopically incomplete resection at any time was 91%, 90%, and 25%, respectively (P = 0.01). Conclusions Primary or secondary microscopically/macroscopically complete tumor resections in combination with chemotherapy correlates with long term survival in children with PPB. J. Surg. Oncol. 2017;115:164-172. © 2017 Wiley Periodicals, Inc.