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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.

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.

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.

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 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.

Background Epithelioid sarcoma (ES) is a rare malignant soft-tissue tumor. Little is known about the optimal treatment of primary localized (LD), metastatic (MD), and relapsed disease (RD). Methods Characteristics, treatment, and outcome of 67 patients registered within the Cooperative Weichteilsarkom Studiengruppe CWS-81, -86, -91, -96, -2002P trials and the registry SoTiSaR were analyzed (1981-2016). Results The median age was 14 years (range, 0.7-26.9); 53 patients had localized disease (LD) and 14 metastatic disease (MD). A total of 58 of 67 patients were treated with primary resection. Resection was microscopically complete (R0) in 35, microscopically incomplete (R1) in 12, macroscopically incomplete (R2) in 20 patients. Radiotherapy (RT) was administered to 33 of 67 patients and 49 of 67 patients received chemotherapy (CHT). Complete remission (CR) was achieved in 45 of 53 (85%) patients with LD. Twenty-seven of 53 patients relapsed after a median time of 0.9 years (range, 0.1-2.3). Relapse therapy consisted of resection (n = 19/27), RT (n = 10/27), CHT (n = 12/27), and limb perfusion (n = 3/27). The five-year event-free survival and overall survival of patients with LD, MD, and RD was 35% (± 12, CI 95%) and 58% (± 14, CI 95%), 7% (± 14, CI 95%), and 9% (± 16, CI 95%), 24% (± 17, CI 95%), and 40% (± 20, CI 95%), respectively. Tumor size, IRS group, tumor invasiveness, nodal status, and best resection correlated with a favorable prognosis in patients with LD while best resection was the only significant factor in patients with RD. Conclusions Complete tumor resection correlates with long-term survival in patients with ES.

BACKGROUND Low-grade fibromyxoid sarcoma (LGFMS) is a rare soft-tissue tumor with benign histologic appearance, though fully malignant behavior is possible. METHODS Patients with LGFMS 5 cm. The best surgical result was resection with free margins (R0) in 24 and microscopic residuals (R1) in seven. Five-year event-free (EFS), 5-year local-relapse-free (LRFS), and 5-year overall-survival were 71 ± 18.6% confidence interval (CI) 95%, 76 ± 17.6% CI 95%, and 100%, respectively. Six patients suffered local relapse in a median of 1 year, one combined within 1.3 year and one metastatic relapse with lesions in the lung, back muscles, and thigh discovered in whole-body imaging 6 years after the first diagnosis. In univariate analysis, T status correlated with EFS (T1 79.6 ± 18.6%, T2 50.0 ± 49.0%, P = .038). Resection with free margins tends to be associated with better LRFS (R0 82.4 ± 18.6%, R1 53.6 ± 39.4%, P = .053). Among 24 patients with R0 resection, five (21%) suffered relapse, thereof three local, one metastatic, and one combined. Among seven patients with R1-resection, three (43%) suffered local relapse. CONCLUSION Special caution is advisable in T2 tumors. The metastatic potential with lesions in unusual sites indicates that affected patients need to be informed. If long-term follow-up with whole-body imaging is beneficial, it may be addressed in larger intergroup analyses. Further research in disease biology is essential for optimal treatment and follow-up care.

// Uwe Thiel 1 , Angela Wawer 1 , Irene von Luettichau 1 , Hans-Ulrich Bender 1 , Franziska Blaeschke 1 ,Thomas G.P. Grunewald 2 , Marc Steinborn 3 , Barbara Roper 4, 10, * , Halvard Bonig 5, 6 , Thomas Klingebiel 5 , Peter Bader 5 , Ewa Koscielniak 7 , Michael Paulussen 8 , Uta Dirksen 9 , Heribert Juergens 9 , Hans-Jochem Kolb 1 , Stefan E.G. Burdach 1, 10 1 Department of Pediatrics and Pediatric Oncology Center, Kinderklinik Munchen Schwabing, Stadtisches Klinikum Munchen und Klinikum rechts der Isar, Wilhelm Sander Sarcoma Unit, Klinikum rechts der Isar, Technische Universitat Munchen, Munich, Germany 2 Laboratory for Pediatric Sarcoma Biology, Institute of Pathology, LMU, Munich, Germany 3 Department of Radiology, Klinikum Schwabing, Stadtisches Klinikum Munchen, Munich, Germany 4 Department of Radiation Oncology, Klinikum rechts der Isar, Technische Universitat Munchen, Munich, Germany 5 Department of Pediatric Hematology and Oncology, Universitatsklinikum Frankfurt, Frankfurt, Germany 6 Department of Transfusion Medicine and Immunohematology, Universitatsklinikum Frankfurt, Frankfurt, Germany 7 Department of Pediatric Oncology, Hematology and Immunology, Olgahospital, Klinikum Stuttgart, Stuttgart, Germany 8 Vestische Kinder- und Jugendklinik, Datteln, Universitat Witten/Herdecke, Datteln, Germany 9 Department of Pediatric Hematology and Oncology, Universitatsklinikum Munster, Munster, Germany 10 Munich Comprehensive Cancer Center, Munchen, Germany * Present address: Radiation Oncology Clinic, Klinikum Bogenhausen, Stadtisches Klinikum Munchen, Munich, Germany Correspondence to: Stefan E.G. Burdach, email: meta-eicess@lrz.tum.de Keywords: Ewing sarcoma, bone metastasis, bone marrow metastasis, allogeneic stem cell transplantation, high-dose chemotherapy Received: February 08, 2016 Accepted: June 30, 2016 Published: July 29, 2016 ABSTRACT Purpose: Advanced Ewing sarcomas have poor prognosis. They are defined by early relapse (

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.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.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 %.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.

Background: To evaluate optimal therapy and potential risk factors. Methods: Data of DSRCT patients

Background Synovial sarcoma of the foot/ankle is rare. Mutilating surgery is often discussed. Methods Patients registered from 1981 to 2013 were analyzed. Cooperative Weichteilsarkom Studiengruppe (CWS) protocols recommend chemotherapy for all synovial sarcoma patients. Results Thirty-two of 330 patients with localized synovial sarcoma had their tumor at the foot/ankle. Eleven of thirty-two tumors were >5 cm. Twenty were T1, 11 T2, and one TX, respectively. Eight (25%) patients underwent primary complete resection with free margins (Intergroup Rhabdomyosarcoma Study [IRS] I), 12 of 32 (38%) primary complete resection with positive margins (IRS II), and 12 of 32 (38%) had macroscopic residuals (IRS III). The best surgical result at any time was R0 in 19, R1 in 10 and R2 in one patient, and missing in two. Mutilation was documented in 14 of 32 (44%). Radiotherapy was conducted in 20 patients. All patients achieved a first complete remission. Five-year-event-free survival and overall survival rates were 80% and 86%, respectively. Four patients suffered local and four other metastatic recurrences. IRS and the best surgical result at any time did not correlate with survival. There was no prognostic difference between R0- and R1-resection. Conclusion Survival expectancies for patients with localized synovial sarcomas of the foot/ankle compare favorably to that of those with other affected sites. Discussion Further studies are needed to set the limits of minimally required aggressiveness of local therapies.

Natural killer (NK) cell activity has been shown to have potential activity against Ewing's sarcoma (EWS) especially in tumors with low HLA I expression and high NKG2D expression. Two patients with metastatic relapsed and primary metastatic stage IV EWS who had received two courses of high dose chemotherapy with autologous stem cell rescue were transplanted from a haploidentical parental stem cell donor. Patients are alive in ongoing CR for 10.2 and 3.4 years now. Post transplant local second and first relapses were treated successfully in both patients. In vivo IL-2 stimulation not only increased the number and activity of effector cells in one patient but was also associated with severe GvHD. In vitro studies demonstrated high NK cell activity against K562 and relevant activity against EWS cell line A673 post transplant. NK activity was enhanced by cytokine prestimulation as well as by EWS targeting anti-GD2 Ab. Haploidentical hematopoietic stem cell transplantation (HSCT) might contribute to long-term survival by NK cell-mediated effect exerted by donor-derived NK cells. Local tumor recurrence was manageable in both high-risk patients indicating systemic immune control preventing subsequent metastasizing. The efficacy of haploidentical HSCT, cytokine application and tumor targeting antibodies for the use of Ab-dependent cellular cytotoxicity needs evaluation in clinical trials.

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.

Background Inflammatory myofibroblastic tumors (IMTs) are a rare subgroup of soft tissue tumors. The outcome of patients with IMT has been reported as favorable when the tumor is completely resected. If surgical resection is not possible, systemic therapy has to be considered. However, the best systemic treatment and response rates are currently unclear. Methods Thirty-eight patients under the age of 21, who were registered between 2000 and 2014 with a primary diagnosis of IMT, were analyzed. Results IMT was typically localized intra-abdominally or in the pelvis. In 20 patients, the tumor was resected without further therapy; 17 patients were in complete remission at last evaluation and two patients were in partial remission. Eighteen patients received systemic therapy, 15 of whom had macroscopically incomplete resection. Systemic therapy most commonly consisted of regimens with dactinomycin, ifosfamide or cyclophosphamide, and vincristine, with or without doxorubicin, and it seemed to reduce tumor extension in individual cases. Five-year event-free survival was 74 ± 14% and 5-year overall survival was 91 ± 10% for all patients. The patients who died due to the disease were those with incomplete resection (n = 3). Conclusions Surgery without further systemic therapy was a feasible and acceptable therapeutic option for every second patient with IMT. Standard chemotherapy for pediatric soft tissue sarcoma produced favorable results in individual cases and was able to shrink the tumor enough to enable resection. Superior efficacy of new targeted therapies such as anaplastic lymphoma kinase-inhibitors compared to standard chemotherapy has to be proven in the future.

The alveolar subtype of rhabdomyosarcoma (RMA) is a strong risk factor. Cases of RMA located in paratesticular sites have however been reported to have similar outcomes to those of embryonal rhabdomyosarcoma (RME). We wanted to re-evaluate the impact of subtype in paratesticular rhabdomyosarcoma (PT-RMS). Patients from a population-based cohort diagnosed with paratesticular RMA in 1990–2013 were analyzed. All tumor samples were re-reviewed using conventional morphology, immunohistochemistry, and molecular testing. Seven patients were eligible. Four tumors showed focal areas morphologically compatible with RMA (mixed RMA/RME). One case was undifferentiated, with a solid round-cell morphology which had to be reclassified as poorly differentiated RME. Two cases had a “microalveolar” morphology which is today regarded as sclerosing RME. No tumor showed the characteristic gene fusion of RMA. Five children had localized disease, one bone metastases, and another lymph-node involvement. All primaries were grossly resected. One locoregional relapse occurred. At a median follow-up of 7 years, all patients were alive disease-free. PT-RMS can show a focal alveolar histology combined with typical features of RME. In current morphological classifications, all rhabdomyosarcomas qualify for the alveolar subtype if typical features of RMA are realized at least focally. Rhabdomyosarcomas consisting of pure RMA morphology were however not found in our patients with PT-RMS. The mixed RMA/RMEs identified in our population-based study did not show a translocation typical for RMA and had a good prognosis. Further prospective studies need to evaluate if mixed RMA/RMEs have a similar favorable outcome in non-paratesticular sites as well.

Children with paratesticular rhabdomyosarcoma have a favorable prognosis. Surgical treatment problems include inadequate primary transscrotal approaches, incomplete tumor resections and the need for secondary hemiscrotectomy. We evaluated the need for hemiscrotectomy regarding local relapse and outcome.A total of 173 patients with a diagnosis of paratesticular rhabdomyosarcoma were enrolled in the Cooperative Soft Tissue Sarcoma Studies between 1986 and 2008. Of the patients 17 were excluded due to an incomplete data set and alveolar histology. Thus, a total of 156 patients with embryonal subtype were analyzed. All patients were treated according to study protocols, which included multiagent chemotherapy, tumor resection and/or radiotherapy.Mean ± SD 5-year overall survival rate was 91.5% ± 2.4% for patients with embryonal rhabdomyosarcoma. A total of 28 patients underwent transscrotal approaches initially. Of these patients 12 were treated with hemiscrotectomy (mean ± SD 5-year event-free survival 91.7% ± 8%) and 16 without hemiscrotectomy (93.8% ± 6.1%). Additionally 13 of 156 patients underwent an inguinal approach with hemiscrotectomy due to suspicious tumor infiltration of the scrotal skin (mean ± SD 5-year event-free survival 84.6% ± 10%). Relapse was observed in 3 of 12 patients after transscrotal approach with hemiscrotectomy (locoregional lymph node in 1 and metastasis in 2). One metastatic relapse was observed in the group undergoing a transscrotal approach without hemiscrotectomy. One of 13 patients treated with an inguinal approach and hemiscrotectomy had locoregional relapse and died of disease.Hemiscrotectomy seems not to be mandatory in patients after transscrotal approaches regarding outcome and local relapse. Nevertheless, hemiscrotectomy probably should be performed if the scrotal skin is infiltrated.

OBJECTIVES: To analyze the clinical course, treatment, complications, outcome, and quality of life (QOL) in patients with perineal/perianal rhabdomyosarcoma (PRMS) treated within the CWS-86, -91, -96, and -2002P trials. BACKGROUND:: Although multiple international study trials exist for the treatment of rhabdomyosarcoma, only very limited information is given on treatment, outcome, and QOL in PRMS. METHODS:: A total of 35 patients suffering from PRMS were treated with neoadjuvant chemotherapy. Local therapy with radiation and/or surgery was performed, followed by adjuvant chemotherapy. Functional long-term follow-up was evaluated by a gastrointestinal/QOL survey. RESULTS: Thirty-two patients were evaluated (exclusion n = 3). Eight patients had embryonal histology, and 24 patients had alveolar histology. The median age was 108 months (median follow-up: 5.8 years). The 5-year overall survival was 47% (95% confidence interval: 29-64). Sixteen IRS (Intergroup Rhabdomyosarcoma Study) III and IV patients had locoregional lymph node involvement at diagnosis. Seven patients were treated with chemotherapy/surgery alone [5-year event-free survival (EFS): 85.7%]. Eleven patients received only radiochemotherapy (5-year EFS: 27.3%). Combined radiochemotherapy/surgery was used in 12 patients (5-year EFS: 63.6%). Two patients were treated only with chemotherapy and they died. Patients with embryonal histology had a significantly better 5-year EFS (87.5%) than patients with alveolar histology (39.1%; P = 0.013). Some patients reported symptoms of fecal incontinence. The median Wexner fecal incontinence score was 9 (possible range: 0-20), and the median QOL score was 90.5 (applicable range: 0-144). CONCLUSIONS:: The outcome of these patients remains unsatisfactory. Prognostic factors for a favorable outcome are tumor size of smaller than 5 cm, negative locoregional lymph nodes, age less than 10 years, low IRS group, and embryonal histology. Fecal incontinence seems to be a problem.

To evaluate outcome in respect to local treatment strategies in 4 prospective CWS trials in patients with paratesticular rhabdomyosarcoma (PTRMS).PTRMS patients have a high number of surgical treatment failures. Retroperitoneal lymph node (LN) involvement is common in patients more than 10 years, and the optimal treatment is unknown.A total of 173 patients with diagnosis of PTRMS were enrolled. Of these, 26 were excluded and 147 patients were finally analyzed. All patients were treated according to the Cooperative Soft Tissue Sarcoma (CWS) trial protocols.The 5-year overall survival was 95.5%, and the 5-year event-free survival (EFS) was 89.8%. Positive predictive factors for EFS were age younger than 10 years and tumor size less than 5 cm. Surgical treatment failures were observed in 34 of 135 patients undergoing primary resection. Primary inguinal/iliacal LN sampling was carried out in 15 of 147 patients with no impact on the EFS (87.5%; P = 0.666). Secondary retroperitoneal LN dissection was done in 32 of 147 patients, of which only 8 patients had viable tumor and a worse outcome (EFS: 50%; P = 0.01). Loco-regional, combined, and metastatic relapses were observed in 13 of 147 patients.The outcome of PTRMS patients is excellent and is hardly improvable. Positive predictors for outcome are age younger than 10 years and tumor size less than 5 cm. Primary LN sampling seems to have no impact on the EFS and should not be recommended. Inadequate surgery can be avoided by treatment in specialized centers. Secondary retroperitoneal LN dissection revealed a high number of unnecessary procedures, but patients with positive LN had a poor prognosis and require additional local therapy.

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.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.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 tumors10 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).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.

Purely intracranial soft tissue sarcomas (ISTS) are very rare among children. A retrospective database analysis of the Cooperative Weichteilsarkom Studiengruppe (CWS) and brain tumor (HIT) registries was conducted to describe treatment and long-term outcome of children and adolescents with ISTS. Nineteen patients from Germany, Austria and Switzerland were reported between 1988 and 2009. Median age at diagnosis was 9.7 years (range, 0.5-17.8). Central pathological review was performed in 17 patients. Eleven patients underwent a total and five a subtotal tumor resection. A biopsy was done in one patient. In two patients no data concerning extent of initial resection was available. Radiotherapy was performed in 15 patients (first-line, n = 11; following progression, n = 4). All but one patient received chemotherapy (first-line, n = 7, following progression, n = 5; first-line and following progression, n = 6). With a median follow-up of 5.8 years (range, 0.6-19.8) ten patients were alive in either first or second complete remission. Seven patients died due to relapse or progression and two were alive with progressive disease. Estimated progression-free and overall survival at 5 years were 47 % (±12 %) and 74 % (±10 %), respectively. About 50 % of patients with ISTS remain relapse-free after 5 years. Multimodality treatment including complete tumor resection and radio-/chemotherapy is required to achieve sustained tumor control in patients with ISTS. Early initiation of postoperative non-surgical treatment seems to be important to prevent recurrence. Due to the intracranial localization local therapy should follow the recommendations used in brain tumors rather than in soft tissue sarcomas, whereas chemotherapy should be guided by histological subtype.

The aim of this pilot study was to evaluate the feasibility of long-term subcutaneous application of low-dose IL-2 in children with malignancies at very high risk of relapse who underwent highly T cell and B cell depleted HLA-identical (MUD) or full haplotype mismatched related hematopoetic stem cell transplantation. We studied 11 patients with acute leukemias/myelodysplastic syndrome and juvenile myelomonocytic leukemia (active disease and/or second stem cell transplantation, n = 8; ≥CR 2, n = 2) and relapsed or progressive Ewings sarcoma ( n = 2) who received prophylactic IL-2 treatment for a high probability of disease recurrence after allo-HSCT. Toxicities from IL-2 were transient fever, fatigue and local inflammation. In one patient GvHD grade III with no clear association to IL-2 administration occurred. IL-2 administration was started at median day 57 (range 13–154) post-transplant for a mean duration of 28 days (range 15–250). IL-2 administration clearly increased NK cell activity. 3 of 11 patients (ALL, AML, multifocal Ewings sarcoma) survived with a follow-up of ten years. In conclusion, long-term low-dose IL-2 subcutaneous application is feasible in children due to a low side effect profile even after HLA mismatched transplantation and may be a strategy to prevent relapse in pediatric malignancies with extremely high risk of relapse.

Background Rhabdomyosarcoma (RMS) diagnosed during the first year of life is reported to have poor outcome. Little is known about treatment and outcome data of relapsed disease (RD). Methods Characteristics, treatment, and outcome of 155 patients ≤ 12 months registered within the Cooperative Weichteilsarkom Studiengruppe (CWS) between 1981 and 2016 were evaluated. Results Localized disease (LD) was diagnosed in 144 patients and metastatic disease (MD) in 11. The histological diagnosis was alveolar (RMA) (n = 38, 23/25 examined patients PAX7/3:FOXO1-positive), embryonal (RME) (n = 100), botryoid (n = 10), anaplastic (n = 1), and spindle-cell RMS (n = 6). Multimodal treatment including conventional (age-adjusted) chemotherapy (CHT) (n = 150), resection (n = 137), and radiotherapy (RT) (n = 37) was administered. Complete remission was achieved in 129 of 144 patients with LD. RD occurred in 51 infants at a median age of 1.7 years (range, 0.3-8.8). Sixty-three percent of patients with RMA suffered RD, in contrast to 28% of patients with RME. Relapse treatment consisted of conventional CHT (n = 48), resection (n = 28), and RT (n = 21). The pattern of relapse and best resection were significant prognostic factors for patients with RD (P = 0.000 and P = 0.002). Late effects occurred as secondary malignancies in 6%, long-term toxicity in 21%, and resection-related impairment in 33% of the 105 surviving patients. The 5-year event-free survival and overall survival for infants with initial LD were 51% and 69%, 14% and 14% for patients with initial MD and 39% and 41% for relapsed patients, respectively. Conclusion Multimodal treatment including microscopically complete resection is strongly recommended to achieve a good prognosis in LD and RD of infants with RMS.

BACKGROUND Ewing tumors are the most frequent malignant tumors of the chest wall in children and young adults. Surgical management of these tumors can be challenging. Optimal local control remains controversial. The aim of this study was to analyze treatment, outcome, and surgical procedures in patients with thoracic tumors of the Ewing sarcoma family (TES) treated within four Cooperative Soft-Tissue Sarcoma (CWS) trials and one registry. PATIENTS AND METHODS Sixty-two patients from 0 to 21 years treated between 1981 and 2014 were selected for this analysis. A retrospective chart analysis was carried out. Institutional review board approval was obtained for all trials. RESULTS The median age of the patients was 7 years. The 5-year overall (OS) and event-free survival (EFS) rates were 58.7% (52.7-64.7) and 52.8% (46.8-58.8). Patients with intrathoracic tumor localization (n = 24) had a worse outcome (EFS: 37.5%; 27.5-37.5) compared with those with chest wall tumors (n = 38; EFS: 62.3%; 54.3-70.3, P = 0.008). Patients ≤10 years (n = 38) had a better survival compared with those > 10 years (EFS: 65.7%; 57.7-73.7 vs 31.3%; 21.3-41.3, P = 0.01). Tumor size ≤5 cm (n = 15) was associated with significantly better survival compared with a size > 5 cm (n = 47, EFS: 93.3%; 87.3-99.3 vs 40%; 33-47, P = 0.002). Primary resections were carried out in 36 patients, of which 75% were incomplete resulting in inferior EFS (P = 0.006). Complete secondary resections were performed in 22 of 40. CONCLUSIONS Positive predictive factors for outcome are age ≤10 years, size ≤5 cm, and localization at the chest wall. Diverse IRS groups require individual treatment.

BACKGROUND Patients with metastatic alveolar soft-part sarcoma (ASPS) are known to have a very poor prognosis. Little is known about best treatment of primary metastatic disease (MD) or relapsed metastatic disease (rMD). PATIENTS AND METHODS Patients with localized disease (LD), primary MD, and metastatic recurrence after complete remission (CR) treated within the CWS-86, -91, -96, -2002P trials and the recent registry SoTiSaR (1985-2016) were analyzed. RESULTS Fifteen of 61 patients had primary metastases at initial diagnosis at the age of 14.6 years (range, 7.8-19.7). Nine of 46 patients with initial LD suffered of rMD at a median age of 9.9 years (range, 3.5-30), 3.75 years (0.75-21) after CR of primary disease. Complete resection (microscopically or macroscopically) was possible in 2 of 15 patients with MD and in 5 of 9 with rMD. RT was administered in 4 of 15 MD and 1 of 9 rMD. Chemotherapy was administered to 11 of 15 MD and 3 of 9 rMD, targeted therapy to 3 of 15 MD and 1 of 9 rMD. Median time to progression of patients treated with targeted therapy (n = 4), CHT (n = 14), and resection only (n = 6) was 56, 17, and 23 months, respectively. The 5-year event-free survival and overall survival (OS) rates were 19.8% and 61%, respectively, for patients with MD compared with 79% and 98% for patients with LD. The 5-year progression-free survival and OS were 67% and 100% for patients with rMD. CONCLUSIONS Complete tumor resection correlates with long-term survival in patients with primary and relapsed MD.

The purpose of this study was to determine patient characteristics and outcomes for bladder/prostate (BP) rhabdomyosarcoma (RMS) using an international cohort of prospectively treated patients comparing different treatment algorithms. Data were collected from 379 patients (1979-1998) treated on protocol; Intergroup Rhabdomyosarcoma Study, IRS-IV (n = 239 patients), International Society of Pediatric Oncology Malignant Mesenchymal Tumors (MMT) Committee MMT-84 and -89 (n = 74), Italian Cooperative Group, RMS-79 and RMS-88 Studies (n = 37) or German Cooperative Soft Tissue Sarcoma Study CWS-91 protocols (n = 29). A total of 322 (85%) patients had localized embryonal RMS (ERMS) and 27 had metastatic disease. Thirty patients (21 local disease; 9 metastatic) had nonembryonal BP RMS. Patients with localized ERMS had large tumors (64% >5 cm) that were invasive (54%) with uninvolved regional lymph nodes (N0, 93%). The 5-year failure-free survival (FFS) was 75% and the overall survival (OS) was 84%, with 89% of deaths attributed to disease. Treatment failures were usually local disease recurrence (60%). Predictors of FFS included T-stage (invasiveness), size, and histology. FFS was decreased for patients not receiving initial radiotherapy but this did not translate into a decreased OS. The 21 patients with localized nonembryonal BP RMS had a FFS and OS of 47%. The 36 patients with metastatic disease were more likely to be older and had large tumors that were invasive with alveolar histology and regional lymph node involvement. The 5-year FFS and OS were 41 and 44%, respectively. In conclusion, the majority of BP RMS patients had localized ERMS with a resultant good prognosis using current treatment algorithms. There were differences in FFS between treatment protocols but this did not result in an altered OS.

The rarity of malignant and intermediate vascular tumors in children means that little is known about their clinical course, optimal treatment, and variables predicting survival. A total of 32 children with malignant vascular tumors (14 angiosarcomas [AS], 5 epithelioid hemangioendotheliomas, and 13 intermediate vascular tumors, including other hemangioendotheliomas plus adult-type hemangiopericytomas), registered in the German and Polish Paediatric Soft Tissue Sarcomas Study Groups, were treated following the Cooperative Weichteilsarkom Studiengruppe (CWS)-81, -86, -91, and -96 protocols. Male sex, AS histology, tumor size >5 cm, and T2 invasiveness were independent predictors of inferior 5-year overall survival, while AS histology and T2 invasiveness were predictors of inferior 5-year event-free survival. AS histology was the most important negative prognostic factor for overall survival and event-free survival. Completeness of primary tumor excision was a good prognostic factor for survival in univariate, but not multivariate, analysis. Local therapy (radiotherapy and delayed surgery) were provided to the minority of patients (28% and 38%, respectively) late in the course of disease (after a mean of 9 and 6 months, respectively) and did not prevent local relapses. Response to systemic treatment was poor (44%) and did not prevent local and distant relapses. The clinical course and outcome in childhood epithelioid HE seems to be similar to intravascular tumors and less aggressive than AS. RTX and delayed surgery should be performed more frequently and earlier in the disease course. An urgent need for modification of systemic therapy is needed because of the development of many metastatic and/or combined relapses and poor response to classic chemotherapy. The problem of effective therapy for childhood AS is the most appaling: 13 of 14 patients died of progression despite multimodal treatment.

Background: Childhood rhabdomyosarcoma (RMS), a soft tissue malignant tumor of skeletal muscle origin, accounts for approximately 3.5% of the cases of cancer among children 0–14 years and 2% of the cases among adolescents and young adults 15–19 years of age. Procedure: We evaluated survival (SUR) after first relapse depending on the time to relapse (TTR) in RMSs of childhood and adolescence. Early, intermediate, and late relapsing patients were evaluated for prognostic risk factors. Results: Two hundred thirty‐four patients with RMS enrolled in the German sarcoma trial CWS‐81, CWS‐86, CWS‐91, and CWS‐96 met selection criteria. Of the 234 patients, 35%, 32%, and 33% relapsed within 6 (early), 6–12 (intermediate), and more than 12 (late) months respectively after the end of primary therapy. Four‐year SUR was 12%, 21%, and 41% for early, intermediate, and late relapse respectively (P

Purpose To improve risk-adapted therapy for localized childhood soft tissue sarcoma within an international multicenter setting. Patients and Methods Four hundred forty-one patients younger than 21 years with localized rhabdomyosarcoma and rhabdomyosarcoma-like tumors (ie, extraosseous tumors of the Ewing family, synovial sarcoma, and undifferentiated sarcoma) were eligible. Therapy was stratified according to postsurgical stage, histology, and tumor site. In unresectable tumors, treatment was further adapted depending on response to induction chemotherapy, TN classification, tumor size and second-look surgery. A novel five-drug combination of etoposide, vincristine, dactinomycin, ifosfamide, and doxorubicin (EVAIA) was evaluated for high-risk patients, but cumulative chemotherapy dosage and treatment duration were reduced for the remaining individuals as compared with that of the previous trial CWS-86. Hyperfractionated accelerated radiotherapy (HART) was recommended at doses of either 32 or 48 Gy. Results At a median follow-up of 8 years, 5-year event-free survival (EFS) and overall (OS) survival for the entire cohort was 63% ± 4% and 73% ± 4%, respectively (all survival rates in this abstract are calculated and displayed with ±95% CI). EFS/OS rates by histology were 60% ± 5%/72% ± 5% in rhabdomyosarcoma, 62% ± 10%/69% ± 10% for Ewing tumors of soft tissues, 84% ± 12%/90% ± 10% for synovial sarcoma, and 67% ± 38%/83% ± 30% for undifferentiated sarcoma, respectively. Response to one cycle of the five-drug combination EVAIA was similar to that of the four-drug combination VAIA used in CWS-86. Two hundred twelve patients with rhabdomyosarcoma underwent radiation (EFS, 66% ± 6%); 53 of those patients had a favorable risk profile and received 32 Gy of HART (EFS, 73% ± 12%). TN classification, tumor site, tumor size, histology, and age were prognostic in univariate analysis. Conclusion Improved risk stratification enabled decreased therapy intensity for selected patients without compromising survival. Intensified chemotherapy with EVAIA did not improve outcome of localized high-risk rhabdomyosarcoma.

Purpose Evaluation of primary tumor-, treatment-, and patient-related factors predicting relapse pattern, risk, and survival after relapse with the aim to design a risk-adapted, tumor-directed surveillance program for patients with localized rhabdomyosarcoma (RMS). Patients and Methods One thousand one hundred sixty-four patients with nonmetastatic RMS achieved complete remission at the end of multimodal therapy in the consecutive trials of the Cooperative Weichteilsarkom Studiengruppe (CWS)-81, CWS-86, CWS-91, and CWS-96 between 1980 and 2002 (median follow-up, 5 years). Three hundred thirty-seven of these individuals developed either locoregional, metastatic, or combined relapses. Predictive factors for relapse, its pattern, and postrelapse survival were analyzed. Results Age, histology, tumor size, tumor site, postsurgical stage, and omission of radiotherapy were identified as factors associated with an increased relapse risk in multivariate analyses. Relapse rates did not differ among the CWS trials. Median time to relapse was 1.43 years from first diagnosis (range, 0.13 to 13.5 years). There were 217 locoregional, 72 metastatic, and 48 combined recurrences. Only two patients developed metastases more than 4 years after diagnosis, and both had combined recurrences. Five-year postrelapse survival was 24%. Patient subsets with consistent relapse pattern, risk, and postrelapse survival rates were identified on the basis of histologic subtype and tumor size. Conclusion Initial patient and tumor characteristics predict pattern and risk of relapse and also correlate with postrelapse survival probabilities. In localized RMS, tumor-directed follow-up should focus on the primary site. Screening for metastatic relapse may not be necessary more than 4 years after diagnosis. The identification of subgroups with distinctive pattern and risk of relapse may be used to develop risk-adapted, tumor-directed guidance for detection of recurrent disease in localized RMS.

Background The aim of our analysis was the evaluation of the prognostic impact of SYT-SSX fusion status and histological grading in synovial sarcoma (SS) of children and adolescents in the context of the consistent multimodal treatment strategy of the CWS (Cooperative Weichteilsarkom Studie; Cooperative Soft Tissue Sarcoma Study Group) and in comparison with other risk factors. Procedure Between 1986 and 2006, out of 243 patients with SS, tumor samples from 84 patients with localized disease were available for RT-PCR analysis. Outcome depending on fusion status in the context with known clinical risk factors was analyzed. Results No prognostic significance was shown for SYT-SSX fusion status and for histological grade. Highest significance of negative prognostic impact was found for large tumor size in uni- and multivariate analysis (P < 0.01). Furthermore, male gender was shown to be an adverse prognostic factor in multivariate analysis (P = 0.01). Conclusions Based on our results, neither histological grading nor SYT-SSX fusion status seems to be suitable for outcome prediction and risk stratification in localized SS treated according to the CWS. This is in contrast to several other publications concerning more heterogeneous age groups including children and adults, and this indicates that prognostic factors should not be interpreted apart from the particular study population and the therapeutic context.

The 'Individualized Therapy for Relapsed Malignancies in Childhood' (INFORM) precision medicine study is a nationwide German program for children with high-risk relapsed/refractory malignancies, which aims to identify therapeutic targets on an individualised basis. In a pilot phase, reported here, we developed the logistical and analytical pipelines necessary for rapid and comprehensive molecular profiling in a clinical setting. Fifty-seven patients from 20 centers were prospectively recruited. Malignancies investigated included sarcomas (n = 25), brain tumours (n = 23), and others (n = 9). Whole-exome, low-coverage whole-genome, and RNA sequencing were complemented with methylation and expression microarray analyses. Alterations were assessed for potential targetability according to a customised prioritisation algorithm and subsequently discussed in an interdisciplinary molecular tumour board. Next-generation sequencing data were generated for 52 patients, with the full analysis possible in 46 of 52. Turnaround time from sample receipt until first report averaged 28 d. Twenty-six patients (50%) harbored a potentially druggable alteration with a prioritisation score of 'intermediate' or higher (level 4 of 7). Common targets included receptor tyrosine kinases, phosphoinositide 3-kinase-mammalian target of rapamycin pathway, mitogen-activated protein kinase pathway, and cell cycle control. Ten patients received a targeted therapy based on these findings, with responses observed in some previously treatment-refractory tumours. Comparative primary relapse analysis revealed substantial tumour evolution as well as one case of unsuspected secondary malignancy, highlighting the importance of re-biopsy at relapse. This study demonstrates the feasibility of comprehensive, real-time molecular profiling for high-risk paediatric cancer patients. This extended proof-of-concept, with examples of treatment consequences, expands upon previous personalised oncology endeavors, and presents a model with considerable interest and practical relevance in the burgeoning era of personalised medicine.

Rhabdomyosarcoma is a highly malignant embryonic tumor of childhood. Two specific translocations t(2;13)(q35;q14) and t(1;13)(p36;q14) have been identified in about 75-80% of ARMS cells. The aim of this multicenter study was to analyze the relationships between the identified fusion transcripts and survival including some selected clinical parameters. The extent of disease was graded according to clinical staging system with following distribution: 3 children with stage I, 4 with stage II, 23 with stage III, and 18 with stage IV spread disease having distant metastases. PAX3-FKHR fusion genes were detected in 28 and PAX7-FKHR fusion genes in 7 tumor biopsy specimens. Children with PAX3-FKHR fusion gene had often distant metastases at presentation (p = 0.03). PAX3-FKHR positive patients with locoregional disease had significantly poorer outcome compared with the ones with PAX7-FKHR positive tumors (p = 0.04). Although analyzed groups were small, significant differences in survival and clinical characteristics between PAX3-FKHR and PAX7-FKHR positive tumors were stated indicating their role in carcinogenesis. In addition, fusion gene analysis is a helpful tool in differential diagnosis of poorly differentiated soft tissue tumors.

Prognostic factors for localized synovial sarcoma are well defined. However, few data exist regarding patients with metastases at diagnosis. Poor outcome is described but the optimal therapeutic regimen remains unclear. Our aim was to assess the outcome, identify prognostic factors, and analyze treatment strategies.Patients21 years with synovial sarcoma and primary distant metastases treated in the consecutive prospective European Cooperative Weichteilsarkom Studiengruppe trials 1980-2010 were analyzed.Twenty-nine of 296 patients had primary metastases. Twenty-seven could be included. Median age was 16.7 years. Primaries were mainly located in the limbs (78%) and 74% were ≥10 cm. Metastases involved the lungs in all patients. Two patients presented with synchronous bone metastases. Sixty-three percent of patients achieved a first remission, whereas only 26% maintained it. Relapses were metastatic with pulmonary metastases in nearly all patients. Five-year event-free survival and overall survival (OS) rates were 26% and 30%, respectively. Prognosis was best for patients with oligometastatic lung metastases (5-year OS probability 85%). Prognosis was worse for patients with multiple bilateral lung metastases (5-year OS 13%) and even poorer for those with concurrent bone metastases. Treatment elements associated with superior survival were adequate local therapy of the primary tumor and, if feasible, for metastases, chemotherapy with an ifosfamide/doxorubicin-based regimen. The use of whole lung irradiation was not correlated with better outcomes.The overall prognosis of primary metastatic synovial sarcoma is poor. However, individuals with oligometastatic lung metastases had very good chance for long-term survival when treated with adequate multimodal therapy.

OBJECTIVE: The aim of the CWS 96 Study was to achieve an optimal treatment in children and adolescents with soft tissue sarcoma (STS) implementing a further refinement of risk-adapted allocation to chemotherapy, surgery and radiotherapy. METHODS: Treatment stratification was based on tumour histology, TNM status, postsurgical stage, localisation and age. Local tumour control was ensured by surgery and risk-adapted radiotherapy. RESULTS: From 1995 to 2002, 89 patients were registered in Austria. The 3-year event-free survival (EFS) and overall survival rates (OS) were 63% ± 6% and 71% ± 6%, respectively. 59/89 patients had localised RMS-like (rhabdomayosarcoma) STS (EFS 73% ± 7%), 14 had localised Non-RMS STS (EFS, 54% ± 16%) and 15 patients had metastatic disease at diagnosis (EFS, 33% ± 12%), 1 patient had fibromatosis. The EFS rates at 3 years in patients with localised RMS-like tumours according to risk group were 92% ± 8% for low and standard risk (12 patients) and 67% ± 8% for high risk (47 patients). Favourable primary tumour sites of nonmetastatic RMS-like STS i.e. orbit, head/neck nonparameningeal or genitourinary non-bladder/prostate were diagnosed in 15 patients (1 of 15 patients died). In 44 patients with unfavourable localisation such as parameningeal, genitourinary bladder/prostate, extremity and others, 7 deceased. The 3-year EFS according to histology in patients with RMS-like STS was 61% ± 11% for RME (embryonal RMS ) (28 patients) and 71% ± 15% for RMA (alveolar RMS) (10 patients). The most common treatment failure was local relapse occurring in 21% of patients in the high-risk group. CONCLUSION: Risk-adapted individualisation of treatment led to a reduction of chemotherapy in the low- and standard-risk group without compromising survival. The outcome of RME and RMA was similar in this cohort of patients. These preliminary results after a median observation time of 2.5 years confirm the CWS 96 strategy.

Objectives To evaluate the outcome of hematopoietic stem cell transplantation (HSCT) in a series of patients with inherited complete IFN-γ receptor 1 (IFNγR1) deficiency. Study design We report 8 patients who received altogether 11 HSCT from family donors, including 10 HLA-identical (5 siblings and 5 relatives) and 1 HLA-haplo-identical donors. Five grafts were T-cell depleted, and conditioning regimens varied in intensity. Results Four patients died within 8 months after HSCT. Two of these deaths were due to specific complications related to mycobacterial infection. There was no or very low (2%) donor cell engraftment in 2 survivors. Only 2 patients are in full remission of mycobacterial disease 5 years after HSCT. These are the only patients who received non–T-cell–depleted grafts from an HLA-identical sibling after a fully myeloablative conditioning regimen. Conclusions HSCT can lead to prolonged remission of mycobacterial disease in children with complete IFNγR1 deficiency. However, optimal control of mycobacterial infection before HSCT and the use of a non–T-cell–depleted transplant from an HLA-identical sibling after a fully myeloablative conditioning regimen are recommended.

Treatment algorithms for patients with aggressive fibromatosis (AF) are challenging. There are limited data available about the use of systemic therapy (ST) in pediatric patients with AF.Patient-, tumor-, and treatment-related factors of 90 children and adolescents with AF treated on multiple prospective trials of the Cooperative Weichteilsarkom Studiengruppe (1981-2015) were analyzed with focus on response and outcome of ST.Median age was 9.48 years (0.02-18.05). Primary resection was performed in 54 patients and ST was administered in 29 of 54 patients because of disease progression or relapse. In 35 patients, ST was the initial treatment modality. A secondary resection was performed in 21 of 35 patients after ST. A total of 64 patients received ST, mainly methotrexate and vinblastine (40%) with a median duration of 380 days. The most frequent radiological response to ST was stable disease at 3 months (39%) and partial response at 6 months (53%). Radiotherapy was administered to 15 of 90 patients. One patient remained on observation only. The 5-year overall survival was 100% and the 5-year event-free survival (EFS) was 44%. Patients who had a primary resection showed a 5-year EFS of 35% versus 59% in patients who had received primary ST (P = 0.08). Functional deficiencies as long-term sequelae following resection occurred in 11 patients. At a median follow-up of 5.05 years (0.25-14.88), complete remission was achieved in 51 patients and partial remission in 28 patients.ST seems appropriate if a primary complete resection is not feasible and at relapse/progression after resection.

Epithelioid hemangioendothelioma (EHE) is a rare, vascular sarcoma. Visceral forms arise in the liver/ lungs. We review the clinical and molecular phenotype of pediatric visceral EHE based on the case of a 9-year-old male child with EHE of the liver/lungs. His tumor expressed the EHE-specific fusion oncogene WWTR1-CAMTA1. Molecular characterization revealed a low somatic mutation rate and activated interferon signaling, angiogenesis regulation, and blood vessel remodeling. After polychemotherapy and resection of lung tumors, residual disease remained stable on oral lenalidomide. Literature review identified another 24 children with EHE of the liver/lungs. Most presented with multifocal, systemic disease. Only those who underwent complete resection achieved complete remission. Four children experienced rapid progression and died. In six children, disease remained stable for years without therapy. Two patients died from progressive EHE 21 and 24 years after first diagnosis. Natural evolution of pediatric visceral EHE is variable, and long-term prognosis remains unclear.

Background Patients with metastatic rhabdomyosarcoma (RMS) have a poor prognosis apart from children with embryonal RMS whose metastases are confined to the lungs (PRME). The prognostic significance of response in patients with metastatic disease is still unknown and optimal treatment remains to be defined. Methods Patient-, tumor- and treatment-related factors of patients with PRME treated on multiple prospective trials of the Cooperative Weichteilsarkom Studiengruppe (CWS) (1981-2013) were analyzed with a focus on response to induction chemotherapy. Response at week 7-10 was based on anatomic imaging and determined (1) for the primary tumor as complete response (CR), good response (GR), partial response (PR) and no response (NR) and (2) for pulmonary metastases as either complete lack of residual lesions (pCR) or no complete response (no-pCR). Event-free (EFS) and overall survival (OS) were the endpoints. Results EFS and OS of all 53 eligible patients was 41% (±13 confidence interval [CI] 95%) and 52% (±11 CI 95%), respectively. pCR at week 7-10 and maintenance therapy (MT) were favorable prognostic factors. Interestingly, response of primary tumor at week 7-10 and number of metastases were not prognostic factors. The 5-year OS was 68% (±18 CI 95%) for 26 patients in pCR, but only 36% (±18 CI 95%) for 27 patients not in pCR at week 7-10 (P = 0.004) despite achieving pCR under continuation of chemotherapy or local therapy. Conclusion Achievement of pCR at week 7-10 by induction chemotherapy is a prognostic factor.

Response (tumour volume reduction) to induction chemotherapy has been used to stratify secondary local and systemic treatment of Intergroup Rhabdomyosarcoma Study Group III (IRSG-III) embryonal rhabdomyosarcoma (RME) in consecutive CWS-trials. To evaluate its actual impact we studied response-related treatment and outcomes.Patients with IRSG-III RME21 years and non-response (NR,33% volume reduction) in five consecutive CWS-trials were analysed and compared with partial responders (PAR, ≥ 33% reduction). The NR was reviewed and sub-classified as Objective Response (OR,0%-33% reduction) or Stable/Progressive Disease (SPD).Fifty-nine of 529 patients had NR (n = 34 OR, n = 25 SPD). Primary risk-factors including age, tumour size, and TN-classification did not differ between NR and PAR groups but NR had more patients with unfavourable sites comparatively (P = 0.04). There were no differences in primary risk-factors between OR and SPD. Significant factors associated with poor outcome in multivariate analysis were NR, TN-classification, age10 years, tumour size5 cm and therapy in older trials. After response assessment n = 24 NR continued to receive induction chemotherapy, n = 32 received other combinations and n = 3 no further chemotherapy. Forty-two non-responders were irradiated, and the tumours were completely resected in n = 20. After a median follow-up of 8 years, 34 NR are alive. Seventeen of 21 failures leading to disease-related deaths were locoregional. The five-year overall survival rate (OS) was 76 ± 4% for PAR, 79 ± 14% for OR, but only 40 ± 19% for SPD (P0.001).Response to induction chemotherapy appears to be an important surrogate marker of poor outcome in patients with SPD largely due to ineffective local control.

Rhabdomyosarcomas (RMS) of the urinary bladder and vagina vary in their biologic and clinical behavior and require different types of treatment. Anatomically the two organs are close, and the reason for these differences in behavior is unknown. We investigated tumor specimens of 51 urinary bladder RMS and 14 vaginal RMS with regard to histologic subtype, growth pattern, differentiation, and proliferation morphologically and immunohistochemically. Recurrences and/or "second look" specimens from 15 patients after chemotherapy were compared with the primary tumors. Within the 65 specimens we found 31 "classical" embryonal RMS, 26 embryonal RMS of botryoid subtype (BRMS), 3 embryonal RMS of spindle cell subtype, and 5 alveolar RMS. BRMS is more common in the vagina (11 BRMS of 14 cases) than in the urinary bladder RMS (15 BRMS of 54 cases). Classical embryonal RMS with a polypoid (exophytic) growth pattern is associated with a more favorable prognosis (92% 10-year survival) than the same type with a diffuse intramural (endophytic) growth pattern (68% 10-year survival, p = 0.02). The proliferation rate was associated with the degree of differentiation, but neither showed a correlation with prognosis. A marked maturation after chemotherapy was seen in the majority of recurrences and SL specimens, associated with lowered proliferation activity. Two of 12 patients with recurrences showing chemotherapy-induced maturation died of the disease. In conclusion, we determined that polypoid embryonal RMS of both the urinary bladder and the vagina have a comparably good prognosis. This includes all botryoid RMS. The poorer prognosis of the group of urinary bladder RMS as a whole was caused by a high incidence of diffusely growing RMS, which have a less favorable prognosis than polypoid RMS. Maturation after chemotherapy occurs frequently in RMS. In contrast to the excellent prognosis reported in other studies, we had two patients with fatal outcome despite chemotherapy-induced maturation in the recurrences.

Humoral angiogenesis stimulators including vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) have been implicated in the pathogenesis of solid malignancies. However, it has remained unclear whether both stimulators contribute to the development and progression of solid malignancies of children. The aim of the present study was to determine whether VEGF and bFGF are elevated in body fluids of children with solid malignancies and, if so, whether these elevated levels correlate with clinical parameters. Using enzyme-linked immunosorbent assays (ELISAs), we quantified VEGF and bFGF in serum (n = 107) and urine (n = 57) of healthy children and of children with solid malignancies (serum: nVEGF = 69, nbFGF = 60; urine: nVEGF or nbFGF = 13). Finally, we compared patients' pre-therapeutic and post-therapeutic levels. Serum VEGF was elevated in children with several solid tumors (Ewing's sarcoma, primitive neuroectodermal tumours, malignant lymphoma, Langerhans cell histiocytosis and medulloblastoma). In contrast, serum bFGF, urinary bFGF or urinary VEGF were not significantly elevated. Upon successful therapy, elevated pre-therapeutic serum VEGF levels declined to levels present in healthy children. VEGF could contribute to the progression of pediatric solid malignancies, and serum VEGF could be used to monitor therapeutic response. Furthermore, the determination of angiogenesis stimulators could identify patients eligible for anti-angiogenic therapy. © 2001 Wiley-Liss, Inc.

Background The present study was performed to evaluate the possibilities of relapse treatment in patients heavily pretreated for a soft tissue sarcoma. Patients and Methods Prospective, multicenter study in 44 soft tissue sarcoma (STS) patients with first relapse. Primary diagnosis was embryonal rhabdomyosarcoma (RME) in 17 patients, alveolar rhabdomyosarcoma (RMA) in 13, primitive neuroectodermal tumor (PNET) in 6, and miscellaneous soft tissue sarcomas in 8 patients. Initial chemotherapy consisted of carboplatin/etoposide combination (150 mg/m2 each, days 1 to 4) followed by local therapy including surgical treatment and, whenever possible, radiotherapy. Results In 11/17 patients without primary tumor resection, CR or PR was achieved following the initial two cycles of chemotherapy (61%). The probability of event-free survival (pEFS) for RME patients was 0.41 ± 0.12 at 5 years, and 0.25 ± 0.12 for RMA patients. But, in contrast no PNET patient or patient with another soft-tissue sarcoma achieved long-term remission. Additional local radiotherapy significantly (P = 0.002) improved pEFS (3-year estimates of 0.23 ± 0.2 vs. 0.1 ± 0.1 in patients without radiotherapy). Conclusions In patients with RME, relapse treatment employing a carboplatin/etoposide combination may induce a second remission in approximately 40% of patients. Surgical excission and additional local radiotherapy seem to be essential to maintain a stable remission. In patients with RMA or PNET, however, this treatment strategy is of no long-term benefit. Med. Pediatr. Oncol. 30:269–275, 1998. © 1998 Wiley-Liss, Inc.

We report two unrelated patients with infantile spinal muscular atrophy (SMA) types II and IIIa who developed alveolar rhabdomyosarcoma (ARMS) at 15 and 19 years, respectively. The tumours were located in the forearm, within severely atrophic flexor muscles. They displayed a similar histology and shared the most common translocation, t(2;13)(q35;14) in ARMS. Since cell proliferation is increased in de- and regenerating muscle and the PAX3/FKHR fusion protein activates myogenic transcription, it is tempting to speculate whether severe muscle atrophy in SMA might predispose to malignant transformation in long-standing disease.