Publications by authors named "Stefan Bielack"

139 Publications

Extraskeletal Ewing sarcoma in children, adolescents, and young adults. An analysis of three prospective studies of the Cooperative Weichteilsarkomstudiengruppe (CWS).

Pediatr Blood Cancer 2021 Jun 5:e29145. Epub 2021 Jun 5.

Department for Children and Adolescents, University Hospital, Goethe University, Frankfurt, Germany.

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.
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http://dx.doi.org/10.1002/pbc.29145DOI Listing
June 2021

Outcome in dedifferentiated chondrosarcoma for patients treated with multimodal therapy: Results from the EUROpean Bone Over 40 Sarcoma Study.

Eur J Cancer 2021 Jul 11;151:150-158. Epub 2021 May 11.

Department of Orthopaedics and Orthopaedic Oncology, University of Padova, Padova, Italy.

Introduction: The role of chemotherapy for patients with dedifferentiated chondrosarcoma (DDCS) is still under discussion. Here, we present the outcome in patients with DDCS treated with intensive chemotherapy from the EUROpean Bone Over 40 Sarcoma Study.

Materials And Methods: The chemotherapy regimen included doxorubicin, ifosfamide and cisplatin. Postoperative methotrexate was added in case of poor histological response. Toxicity was graded based on the National Cancer Institute expanded common toxicity criteria, version 2.0, and survival was analysed using Kaplan-Meier curves, log-rank tests and univariate Cox regression models.

Results: Fifty-seven patients with DDCS (localised, 34 [60%]; metastatic, 23 [40%]) aged 42-65 years were included. Surgical complete remission (SCR) was achieved in 36 (63%) patients. The median overall survival (OS) was 24 months (95% confidence interval, 22-25), and the 5-year OS was 39%. Patients with extremity localisation had a 5-year OS of 49% compared with 29% in patients with a central tumour (P = 0.08). Patients with localised disease had a 5-year OS of 46%, whereas patients with metastatic disease had a 5-year OS of 29% (P = 0.12). Patients in SCR had a 5-year OS of 49%, whereas patients not in SCR had a 5-year OS of 23% (P = 0.004). Chemotherapy toxicity was considerable but manageable. There was no treatment-related death, and 39 (70%) patients received ≥6 cycles of the planned nine chemotherapy cycles.

Conclusions: Adding intensive chemotherapy to surgery for treatment of DDCS is feasible and shows favourable survival data compared with previous reports. With the limitations of data from a non-controlled trial, we conclude that chemotherapy could be considered in the management of patients aged >40 years.
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http://dx.doi.org/10.1016/j.ejca.2021.04.017DOI Listing
July 2021

The early evolutionary landscape of osteosarcoma provides clues for targeted treatment strategies.

J Pathol 2021 Aug 25;254(5):556-566. Epub 2021 May 25.

Bone Tumor Reference Centre, Institute of Medical Genetics and Pathology, University Hospital Basel, University of Basel, Basel, Switzerland.

Osteosarcomas are aggressive primary tumors of bone that are typically detected in locally advanced stages; however, which genetic mutations drive the cancer before its clinical detection remain unknown. To identify these events, we performed longitudinal genome-sequencing analysis of 12 patients with metastatic or refractory osteosarcoma. Phylogenetic and molecular clock analyses were carried out next to identify actionable mutations, and these were validated by integrating data from additional 153 osteosarcomas and pre-existing functional evidence from mouse PDX models. We found that the earliest and thus clinically most promising mutations affect the cell cycle G1 transition, which is guarded by cyclins D3, E1, and cyclin-dependent kinases 2, 4, and 6. Cell cycle G1 alterations originate no more than a year before the primary tumor is clinically detected and occur in >90% and 50% of patients of the discovery and validation cohorts, respectively. In comparison, other cancer driver mutations could be acquired at any evolutionary stage and often do not become pervasive. Consequently, our data support that the repertoire of actionable mutations present in every osteosarcoma cell is largely limited to cell cycle G1 mutations. Since they occur in mutually exclusive combinations favoring either CDK2 or CDK4/6 pathway activation, we propose a new genomically-based algorithm to direct patients to correct clinical trial options. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.
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http://dx.doi.org/10.1002/path.5699DOI Listing
August 2021

Supratentorial ependymoma in childhood: more than just RELA or YAP.

Acta Neuropathol 2021 03 22;141(3):455-466. Epub 2021 Jan 22.

Department of Neuropathology, DGNN Brain Tumor Reference Center, University of Bonn Medical Center, Venusberg-Campus 1, 53127, Bonn, Germany.

Two distinct genetically defined entities of ependymoma arising in the supratentorial compartment are characterized by the presence of either a C11orf95-RELA or a YAP-MAMLD1 fusion, respectively. There is growing evidence that supratentorial ependymomas without these genetic features exist. In this study, we report on 18 pediatric non-RELA/non-YAP supratentorial ependymomas that were systematically characterized by means of their histology, immunophenotype, genetics, and epigenomics. Comprehensive molecular analyses included high-resolution copy number analysis, methylation profiling, analysis of fusion transcripts by Nanostring technology, and RNA sequencing. Based upon histological and immunohistochemical features two main patterns were identified-RELA-like (n = 9) and tanycytic ependymomas (n = 6). In the RELA-like group histologically assigned to WHO grade III and resembling RELA-fused ependymomas, tumors lacked nuclear expression of p65-RelA as a surrogate marker for a pathological activation of the NF-κB pathway. Three tumors showed alternative C11orf95 fusions to MAML2 or NCOA1. A methylation-based brain tumor classifier assigned two RELA-like tumors to the methylation class "EP, RELA-fusion"; the others demonstrated no significant similarity score. Of the tanycytic group, 5/6 tumors were assigned a WHO grade II. No gene fusions were detected. Methylation profiling did not show any association with an established methylation class. We additionally identified two astroblastoma-like tumors that both presented with chromothripsis of chromosome 22 but lacked MN1 breaks according to FISH analysis. They revealed novel fusion events involving genes in chromosome 22. One further tumor with polyploid cytogenetics was interpreted as PFB ependymoma by the brain tumor methylation classifier but had no relation to the posterior fossa. Clinical follow-up was available for 16/18 patients. Patients with tanycytic and astroblastoma-like tumors had no relapse, while 2 patients with RELA-like ependymomas died. Our data indicate that in addition to ependymomas discovered so far, at least two more supratentorial ependymoma types (RELA-like and tanycytic) exist.
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http://dx.doi.org/10.1007/s00401-020-02260-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7882569PMC
March 2021

Rhabdomyosarcoma of the female genitourinary tract: Primary and relapsed disease in infants and older children. Treatment results of five Cooperative Weichteilsarkom Studiengruppe (CWS) trials and one registry.

Pediatr Blood Cancer 2021 04 12;68(4):e28889. Epub 2021 Jan 12.

Pediatrics 5 (Oncology, Hematology, Immunology), Klinikum Stuttgart - Olgahospital, Stuttgart Cancer Center, Zentrum für Kinder-, Jugend- und Frauenmedizin, Stuttgart, Germany.

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.
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http://dx.doi.org/10.1002/pbc.28889DOI Listing
April 2021

[Diagnosis and therapy of tumors with NTRK gene fusion].

Pathologe 2021 Feb;42(1):103-115

Klinik für Innere Medizin I, Universitätsklinikum Ulm, Ulm, Deutschland.

NTRK gene fusions are sporadic genetic alterations that can occur across tumor entities. Whereas they are quite rare in most solid tumors they are present at much higher frequencies in certain rare tumors such as infantile fibrosarcoma, congenital mesoblastic nephroma, secretory breast, or salivary gland carcinoma. NTRK gene fusions or TRK fusion proteins are considered strong oncogenic drivers. If NTRK gene fusions are detected, TRK inhibitors such as entrectinib and larotrectinib can be used regardless of the tumor entity. So far only larotrectinib is approved in the European Union. Both drugs have been shown to be effective and well tolerated in phase I and phase II studies. The low prevalence of TRK fusion-positive cancers poses challenges for diagnostic and clinical work-flows. On one hand, patients with NTRK gene fusions should be identified; on the other hand, epidemiological, histological, and resource-related aspects have to be taken into account. Based on these premises, we suggest a diagnostic algorithm for TRK fusion cancers and present current data on TRK inhibitors.
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http://dx.doi.org/10.1007/s00292-020-00864-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7858552PMC
February 2021

Association of candidate pharmacogenetic markers with platinum-induced ototoxicity: PanCareLIFE dataset.

Data Brief 2020 Oct 24;32:106227. Epub 2020 Aug 24.

Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland.

Genetic association studies suggest a genetic predisposition for cisplatin-induced ototoxicity. Among other candidate genes, thiopurine methyltransferase () is considered a critical gene for susceptibility to cisplatin-induced hearing loss in a pharmacogenetic guideline. The PanCareLIFE cross-sectional cohort study evaluated the genetic associations in a large pan-European population and assessed the diagnostic accuracy of the genetic markers. 1,112 pediatric cancer survivors who had provided biomaterial for genotyping were screened for participation in the pharmacogenetic association study. 900 participants qualified for inclusion. Based on the assessment of original audiograms, patients were assigned to three phenotype categories: no, minor, and clinically relevant hearing loss. Fourteen variants in eleven candidate genes ( and ) were genotyped. The genotype and phenotype data represent a resource for conducting meta-analyses to derive a more precise pooled estimate of the effects of genes on the risk of hearing loss due to platinum treatment.
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http://dx.doi.org/10.1016/j.dib.2020.106227DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7477761PMC
October 2020

Usefulness of current candidate genetic markers to identify childhood cancer patients at risk for platinum-induced ototoxicity: Results of the European PanCareLIFE cohort study.

Eur J Cancer 2020 10 6;138:212-224. Epub 2020 Sep 6.

Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland; Paediatric Oncology, Dept. of Paediatrics, Inselspital, University of Bern, Switzerland.

Background: Irreversible sensorineural hearing loss is a common side effect of platinum treatment with the potential to significantly impair the neurocognitive, social and educational development of childhood cancer survivors. Genetic association studies suggest a genetic predisposition for cisplatin-induced ototoxicity. Among other candidate genes, thiopurine methyltransferase (TPMT) is considered a critical gene for susceptibility to cisplatin-induced hearing loss in a pharmacogenetic guideline. The aim of this cross-sectional cohort study was to confirm the genetic associations in a large pan-European population and to evaluate the diagnostic accuracy of the genetic markers.

Methods: Eligibility criteria required patients to be aged less than 19 years at the start of chemotherapy, which had to include cisplatin and/or carboplatin. Patients were assigned to three phenotype categories: no, minor and clinically relevant hearing loss. Fourteen variants in eleven candidate genes (ABCC3, OTOS, TPMT, SLC22A2, NFE2L2, SLC16A5, LRP2, GSTP1, SOD2, WFS1 and ACYP2) were investigated. Multinomial logistic regression was performed to model the relationship between genetic predictors and platinum ototoxicity, adjusting for clinical risk factors. Additionally, measures of the diagnostic accuracy of the genetic markers were determined.

Results: 900 patients were included in this study. In the multinomial logistic regression, significant unique contributions were found from SLC22A2 rs316019, the age at the start of platinum treatment, cranial radiation and the interaction term [platinum compound]∗[cumulative dose of cisplatin]. The predictive performance of the genetic markers was poor compared with the clinical risk factors.

Conclusions: PanCareLIFE is the largest study of cisplatin-induced ototoxicity to date and confirmed a role for the polyspecific organic cation transporter SLC22A2. However, the predictive value of the current genetic candidate markers for clinical use is negligible, which puts the value of clinical factors for risk assessment of cisplatin-induced ototoxicity back into the foreground.
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http://dx.doi.org/10.1016/j.ejca.2020.07.019DOI Listing
October 2020

Malignant peripheral nerve sheath tumors in children, adolescents, and young adults: Treatment results of five Cooperative Weichteilsarkom Studiengruppe (CWS) trials and one registry.

J Surg Oncol 2020 Dec 18;122(7):1337-1347. Epub 2020 Aug 18.

Department of Pediatric Oncology and Hematology, University Hospital Frankfurt, Frankfurt/Main, Germany.

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.
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http://dx.doi.org/10.1002/jso.26153DOI Listing
December 2020

Spotlight on the treatment of infantile fibrosarcoma in the era of neurotrophic tropomyosin receptor kinase inhibitors: International consensus and remaining controversies.

Eur J Cancer 2020 09 9;137:183-192. Epub 2020 Aug 9.

Pediatric Oncology Unit, Fondazione IRCCS Istituto Nazionale Dei Tumori di Milano, Milano, Italy.

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.
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http://dx.doi.org/10.1016/j.ejca.2020.06.028DOI Listing
September 2020

Dermatofibrosarcoma protuberans in children and adolescents: Primary and Relapsed disease-Experience of the Cooperative Weichteilsarkomstudiengruppe (CWS).

J Surg Oncol 2020 Aug 19;122(2):263-272. Epub 2020 May 19.

Klinikum Stuttgart-Olgahospital, Stuttgart Cancer Center, Zentrum für Kinder-, Jugend- und Frauenmedizin, Pediatrics 5 (Oncology, Hematology, Immunology), Stuttgart, Germany.

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.
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http://dx.doi.org/10.1002/jso.25943DOI Listing
August 2020

Germline variants underlie a subset of paediatric osteosarcoma.

J Med Genet 2021 01 16;58(1):20-24. Epub 2020 Mar 16.

Institute for Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland.

Background: Although considerable effort has been put into decoding of the osteosarcoma genome, very little is known about germline mutations that underlie this primary malignant tumour of bone.

Methods And Results: We followed here a coincidental finding in a multiple endocrine neoplasia family in which a 32-year-old patient carrying a germline pathogenic mutation developed an osteosarcoma 2 years after the resection of a medullary thyroid carcinoma. Sequencing analysis of additional 336 patients with osteosarcoma led to the identification of germline activating mutations in the proto-oncogene in three cases and somatic amplifications of the gene locus in five matched tumours (4%, n=5/124 tumours). Functional analysis of the pathogenic variants together with an integrative analysis of osteosarcoma genomes confirmed that the mutant RET proteins couple functional kinase activity to dysfunctional ligand binding. mutations further co-operated with alterations in and , suggesting that osteosarcoma pathogenesis bears reminiscence to the stepwise model of medullary thyroid carcinoma.

Conclusions: After Li-Fraumeni-predisposing mutations in , becomes the second most mutated cancer-predisposing gene in the germline of patients with osteosarcoma. Hence, early identification of mutation carriers can help to identify at-risk family members and carry out preventive measures.
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http://dx.doi.org/10.1136/jmedgenet-2019-106734DOI Listing
January 2021

Larotrectinib in patients with TRK fusion-positive solid tumours: a pooled analysis of three phase 1/2 clinical trials.

Lancet Oncol 2020 04 24;21(4):531-540. Epub 2020 Feb 24.

Memorial Sloan Kettering Cancer Center, New York, NY, USA; Weill Cornell Medical College, New York, NY, USA. Electronic address:

Background: The selective TRK inhibitor larotrectinib was approved for paediatric and adult patients with advanced TRK fusion-positive solid tumours based on a primary analysis set of 55 patients. The aim of our analysis was to explore the efficacy and long-term safety of larotrectinib in a larger population of patients with TRK fusion-positive solid tumours.

Methods: Patients were enrolled and treated in a phase 1 adult, a phase 1/2 paediatric, or a phase 2 adolescent and adult trial. Some eligibility criteria differed between these studies. For this pooled analysis, eligible patients were aged 1 month or older, with a locally advanced or metastatic non-CNS primary, TRK fusion-positive solid tumour, who had received standard therapy previously if available. This analysis set includes the 55 patients on which approval of larotrectinib was based. Larotrectinib was administered orally (capsule or liquid formulation), on a continuous 28-day schedule, to adults mostly at a dose of 100 mg twice daily, and to paediatric patients mostly at a dose of 100 mg/m (maximum of 100 mg) twice daily. The primary endpoint was objective response as assessed by local investigators in an intention-to-treat analysis. Contributing trials are registered with ClinicalTrials.gov, NCT02122913 (active not recruiting), NCT02637687 (recruiting), and NCT02576431 (recruiting).

Findings: Between May 1, 2014, and Feb 19, 2019, 159 patients with TRK fusion-positive cancer were enrolled and treated with larotrectinib. Ages ranged from less than 1 month to 84 years. The proportion of patients with an objective response according to investigator assessment was 121 (79%, 95% CI 72-85) of 153 evaluable patients, with 24 (16%) having complete responses. In a safety population of 260 patients treated regardless of TRK fusion status, the most common grade 3 or 4 larotrectinib-related adverse events were increased alanine aminotransferase (eight [3%] of 260 patients), anaemia (six, 2%), and decreased neutrophil count (five [2%]). The most common larotrectinib-related serious adverse events were increased alanine aminotransferase (two [<1%] of 260 patients), increased aspartate aminotransferase (two [<1%]), and nausea (two [<1%]). No treatment-related deaths occurred.

Interpretation: These data confirm that TRK fusions define a unique molecular subgroup of advanced solid tumours for which larotrectinib is highly active. Safety data indicate that long-term administration of larotrectinib is feasible.

Funding: Bayer and Loxo Oncology.
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http://dx.doi.org/10.1016/S1470-2045(19)30856-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7497841PMC
April 2020

NTRK fusions in osteosarcoma are rare and non-functional events.

J Pathol Clin Res 2020 04 5;6(2):107-112. Epub 2020 Feb 5.

Bone Tumour Reference Center at the Institute of Pathology, University and University Hospital Basel, Basel, Switzerland.

Neurotrophic tyrosine receptor kinase (NTRK) fusions are promising molecular targets that have been described in a broad range of malignant tumours. Fusions commonly lead to the expression of chimeric proteins with constitutive tyrosine kinase activation that drives tumorigenesis. Despite a low prevalence among most solid tumours (<1%), the first encouraging results with pan-NTRK tyrosine kinase inhibitors (TKIs) such as larotrectinib or entrectinib stimulated the search for eligible patients. Here, we report the first three cases of osteosarcoma harbouring NTRK fusions, among 113 patients sequenced. It is also the first report on NTRK fusions within a tumour type characterised by highly rearranged genomes and abundant passenger mutations. Whereas the presence of NTRK gene fusions in many tumours is considered to be one of the main driver events for tumour progression, the three chimeric transcripts described here appear non-functional and likely represent randomly occurring passenger alterations. Particularly in tumours with complex karyotypes, it may therefore be advisable to specifically investigate the fusion transcripts for functional impact before considering targeted treatment approaches using pan-NTRK TKIs.
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http://dx.doi.org/10.1002/cjp2.158DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7164374PMC
April 2020

Synovial sarcoma disease characteristics and primary tumor sites differ between patient age groups: a report of the Cooperative Weichteilsarkom Studiengruppe (CWS).

J Cancer Res Clin Oncol 2020 Apr 13;146(4):953-960. Epub 2020 Jan 13.

Hospital for Children and Adolescents, Goethe-University, Frankfurt (Main), Germany.

Background: Older age is associated with worse outcome in synovial sarcoma (SS) patients. Differences in disease presentation among distinct age groups, however, are currently unknown.

Methods: SS patients < 21 years registered in consecutive CWS trials over the period of 1981-2018 were evaluated. Characteristics were analyzed according to age groups using the Fisher's exact test.

Results: The study population included 432 SS patients. Disease characteristics differed according to age groups of children (0-12 years, n = 176), adolescents (13-16 years, n = 178), and young adults (17-21 years, n = 78). The proportion of invasive tumors (T2) was significantly higher in older patients: children 33%, adolescents 39% and young adults 54%, p = 0.009805. Similarly, the proportion of tumors > 10 cm was higher (13%, 21%, 31%; p = 0.005657) whereas conversely, the proportion of small tumors < 3 cm was lower in older patients (29%, 24%, 6%; p = 0.000104). The presence of metastases at first diagnosis was also highest in older patients (6%, 10%, 21%, p = 0.000963). Notably, the proportion of thigh tumors was higher in older patients (p = 0.04173), whereas the proportion of head-neck tumors was lower in older patients (p = 0.08896).

Conclusions: The rates of large, invasive tumors and the presence of metastases are significantly associated with older patient age. Localization to the thigh is more frequent in older patients.

Discussion: The causes for these variations require further exploration.
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http://dx.doi.org/10.1007/s00432-019-03121-9DOI Listing
April 2020

Pathological Fracture and Prognosis of High-Grade Osteosarcoma of the Extremities: An Analysis of 2,847 Consecutive Cooperative Osteosarcoma Study Group (COSS) Patients.

J Clin Oncol 2020 03 13;38(8):823-833. Epub 2020 Jan 13.

Department of Pediatrics, Kinderklinik München Schwabing, Technical University of Munich School of Medicine, CCCM Munich Comprehensive Cancer Center and German Translational Cancer Research Consortium DKTK, Munich, Germany.

Purpose: The objective of this study was to investigate potential correlations between pathologic fractures (PFs) and prognosis of patients with primary central high-grade osteosarcoma of the extremities.

Methods: We retrospectively analyzed 2,847 patients registered in the Consecutive Cooperative Osteosarcoma Study Group database with primary central high-grade osteosarcoma of the extremities, treated between 1980 and 2010. Intended treatment included pre- and postoperative chemotherapy and surgery. Univariable and multivariable survival analyses were performed for all patients and then differentiated for adult and pediatric (≤ 18 years at time of diagnosis) patients.

Results: A total of 2,193 patients were ≤ 18 years of age; 11.3% of all patients had PFs. In the overall cohort, presence of PF correlated significantly with tumor site, histologic subtype, relative tumor size, and primary metastases, but not with body mass index or local surgical remission. In univariable analysis, 5-year overall survival (OAS) of patients with and without PF was 63% versus 71%, respectively ( = .007), and 5-year event-free survival (EFS) was 51% versus 58% ( = .026). In pediatric patients, OAS and EFS did not differ significantly between patients with and without PF. In adults, 5-year OAS in patients with and without PF was 46% versus 69% ( < .001), and 5-year EFS was 36% versus 56% ( < .001). In multivariable analysis, PF was not a statistically significant factor for OAS or EFS in the total cohort or in pediatric patients. In adult patients, PF remained an independent prognostic factor for OAS ( = .013; hazard ratio [HR], 1.893). It was not a significant prognostic factor for EFS ( = .263; HR, 1.312).

Conclusion: In this largest study to date with extremity osteosarcomas, we observed the occurrence of PF to correlate with inferior OAS expectancies in adult but not in pediatric patients.
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http://dx.doi.org/10.1200/JCO.19.00827DOI Listing
March 2020

Endothelial cell malignancies in infants, children and adolescents: Treatment results of three Cooperative Weichteilsarkom Studiengruppe (CWS) trials and one registry.

Pediatr Blood Cancer 2020 03 8;67(3):e28095. Epub 2019 Dec 8.

Department for Children and Adolescents, University of Frankfurt, Frankfurt am Main, Germany.

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.
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http://dx.doi.org/10.1002/pbc.28095DOI Listing
March 2020

The impact of local control in the treatment of children with advanced infantile and adult-type fibrosarcoma: Experience of the cooperative weichteilsarkom studiengruppe (CWS).

J Pediatr Surg 2020 Sep 9;55(9):1740-1747. Epub 2019 Nov 9.

Klinikum Stuttgart - Olgahospital, Stuttgart Cancer Center, Zentrum für Kinder-, Jugend- und Frauenmedizin, Pediatrics 5 (Oncology, Hematology, Immunology), Stuttgart, Germany; Children's Hospital, Department of Pediatric Hematology and Oncology, Tuebingen, Germany.

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.
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http://dx.doi.org/10.1016/j.jpedsurg.2019.10.051DOI Listing
September 2020

Low-grade fibromyxoid sarcoma: A report of the Cooperative Weichteilsarkom Studiengruppe (CWS).

Pediatr Blood Cancer 2020 02 17;67(2):e28009. Epub 2019 Nov 17.

Department of Pediatric Oncology, University of Tuebingen, Tuebingen, Germany.

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 <21 years registered in Cooperative Weichteilsarkom Studiengruppe trials until 2017 were analyzed. Firstline treatment consisted of complete surgical resection whenever possible.

Results: Median age of 31 patients was 10.9 years (first month to 17.1 years). Twenty-six tumors were confirmed to the tissue of origin (T1), four invaded contiguous structures (T2), one was TX. Eight were >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.
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http://dx.doi.org/10.1002/pbc.28009DOI Listing
February 2020

Quality of Life of Patients With Osteosarcoma in the European American Osteosarcoma Study-1 (EURAMOS-1): Development and Implementation of a Questionnaire Substudy.

JMIR Res Protoc 2019 Sep 26;8(8):e14406. Epub 2019 Sep 26.

Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, United States.

Background: The quality of life (QoL) of patients with osteosarcoma (OS) may be adversely affected by the disease or its treatment. Therefore, it is important to understand the QoL of patients undergoing treatment for OS to improve the QoL. We report on the first prospective international QoL study that was embedded within a large randomized clinical trial from 4 national study groups.

Objective: This paper aimed to describe the QoL study development, methodology, accrual details, and characteristics of the QoL cohort.

Methods: A total of 2260 patients registered in the EURopean AMerican Osteosarcoma Study-1 (EURAMOS-1), of whom 97.92% (2213/2260) were eligible for the optional QoL assessment and could participate in terms of questionnaire availability. Overall, 61.86% (1369/2213) of patients and/or proxies completed the QoL evaluation at the first assessment time point (E1) after the start of preoperative treatment. The QoL measures used (self- and/or proxy reports) depending on the patient's age and national study group. Participants and nonparticipants in the ancillary QoL study were compared regarding relevant demographic and disease-related characteristics at registration in the trial.

Results: The participation rate at time point E1 did not differ with regard to age, gender, the occurrence of pathological fracture, or the presence of any metastases at diagnosis. No differences were found regarding the primary tumor site. Only the national study group affiliation had an influence on participation. Participation decreased linearly with trial progress up to 20% at the final time point of QoL assessment.

Conclusions: This study demonstrates the feasibility of international cooperation for the purpose of assessing and understanding the QoL of pediatric and adolescent/young adult patients with cancer. Future outcomes of this QoL substudy will help to adapt interventions to improve QoL.
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http://dx.doi.org/10.2196/14406DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6819132PMC
September 2019

Genotyping circulating tumor DNA of pediatric Hodgkin lymphoma.

Leukemia 2020 01 20;34(1):151-166. Epub 2019 Aug 20.

General Pediatrics, Oncology and Hematology, Vestische Kinder und Jugendklinik Datteln, Witten/Herdecke University, Witten, Germany.

We used hybrid capture-targeted next-generation sequencing of circulating cell-free DNA (ccfDNA) of pediatric Hodgkin lymphoma (PHL) patients to determine pathogenic mechanisms and assess the clinical utility of this method. Hodgkin-Reed/Sternberg (HRS) cell-derived single nucleotide variants, insertions/deletions, translocations and VH-DH-JH rearrangements were detected in pretherapy ccfDNA of 72 of 96 patients. Number of variants per patient ranged from 1 to 21 with allele frequencies from 0.6 to 42%. Nine translocation breakpoints were detected. Genes involved in JAK/STAT, NFkB and PI3K signaling and antigen presentation were most frequently affected. SOCS1 variants, mainly deletions, were found in most circulating tumor (ct) DNAs, and seven of the nine translocation breakpoints involved SOCS1. Analysis of VH-DH-JH rearrangements revealed an origin of PHL HRS cells from partially selected germinal center B cells. Amounts of pretherapy ctDNA were correlated with metabolic tumor volumes. Furthermore, in all ccfDNA samples of 43 patients with early response assessment quantitative qPET < 3, indicative of a favorable clinical course, ctDNA was not detectable. In contrast, in five of six patients with qPET > 3, indicative of an unfavorable clinical course, ctDNA remained detectable. ccfDNA analysis of PHL is thus a suitable approach to determine pathogenic mechanisms and monitor therapy response.
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http://dx.doi.org/10.1038/s41375-019-0541-6DOI Listing
January 2020

The German National Registry of Primary Immunodeficiencies (2012-2017).

Front Immunol 2019 19;10:1272. Epub 2019 Jul 19.

Department of Pediatrics, Dr. von Hauner Children's Hospital, University Hospital, Ludwig-Maximilians-University Munich, Munich, Germany.

The German PID-NET registry was founded in 2009, serving as the first national registry of patients with primary immunodeficiencies (PID) in Germany. It is part of the European Society for Immunodeficiencies (ESID) registry. The primary purpose of the registry is to gather data on the epidemiology, diagnostic delay, diagnosis, and treatment of PIDs. Clinical and laboratory data was collected from 2,453 patients from 36 German PID centres in an online registry. Data was analysed with the software Stata® and Excel. The minimum prevalence of PID in Germany is 2.72 per 100,000 inhabitants. Among patients aged 1-25, there was a clear predominance of males. The median age of living patients ranged between 7 and 40 years, depending on the respective PID. Predominantly antibody disorders were the most prevalent group with 57% of all 2,453 PID patients (including 728 CVID patients). A gene defect was identified in 36% of patients. Familial cases were observed in 21% of patients. The age of onset for presenting symptoms ranged from birth to late adulthood (range 0-88 years). Presenting symptoms comprised infections (74%) and immune dysregulation (22%). Ninety-three patients were diagnosed without prior clinical symptoms. Regarding the general and clinical diagnostic delay, no PID had undergone a slight decrease within the last decade. However, both, SCID and hyper IgE- syndrome showed a substantial improvement in shortening the time between onset of symptoms and genetic diagnosis. Regarding treatment, 49% of all patients received immunoglobulin G (IgG) substitution (70%-subcutaneous; 29%-intravenous; 1%-unknown). Three-hundred patients underwent at least one hematopoietic stem cell transplantation (HSCT). Five patients had gene therapy. The German PID-NET registry is a precious tool for physicians, researchers, the pharmaceutical industry, politicians, and ultimately the patients, for whom the outcomes will eventually lead to a more timely diagnosis and better treatment.
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http://dx.doi.org/10.3389/fimmu.2019.01272DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6659583PMC
October 2020

Care of adolescents and young adults with cancer in Asia: results of an ESMO/SIOPE/SIOP Asia survey.

ESMO Open 2019 6;4(3):e000467. Epub 2019 Jun 6.

2nd Department of Oncology, Henry Dunant Hospital Center, Athens, Greece.

Background: Adolescents and young adults (AYAs) with cancer require dedicated management encompassing both adult and paediatric cancer services. Following a European survey, the European Society for Medical Oncology, the European Society for Paediatric Oncology and the Asian continental branch of International Society of Paediatric Oncology undertook a similar survey to assess AYA cancer care across Asia.

Methods: A link to the online survey was sent to healthcare professionals (HCPs) in Asia interested in AYA cancer care. Questions covered the demographics and training of HCPs, their understanding of AYA definition, availability and access to specialised AYA services, the support and advice offered during and after treatment, and factors of treatment non-compliance.

Results: We received 268 responses from 22 Asian countries. There was a striking variation in the definition of AYA (median lower age 15 years, median higher age 29 years). The majority of the respondents (78%) did not have access to specialised cancer services and 73% were not aware of any research initiatives for AYA. Over two-thirds (69%) had the option to refer their patients for psychological and/or nutritional support and most advised their patients on a healthy lifestyle. Even so, 46% did not ask about smokeless tobacco habits and only half referred smokers to a smoking cessation service. Furthermore, 29% did not promote human papillomavirus vaccination for girls and 17% did not promote hepatitis B virus vaccination for high-risk individuals. In terms of funding, 69% reported governmental insurance coverage, although 65% reported that patients self-paid, at least partially. Almost half (47%) reported treatment non-compliance or abandonment as an issue, attributed to financial and family problems (72%), loss of follow-up (74%) and seeking of alternative treatments (77%).

Conclusions: Lack of access to and suboptimal delivery of AYA-specialised cancer care services across Asia pose major challenges and require specific interventions.
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http://dx.doi.org/10.1136/esmoopen-2018-000467DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6555609PMC
June 2019

Epithelioid sarcoma in children, adolescents, and young adults: Localized, primary metastatic and relapsed disease. Treatment results of five Cooperative Weichteilsarkom Studiengruppe (CWS) trials and one registry.

Pediatr Blood Cancer 2019 09 19;66(9):e27879. Epub 2019 Jun 19.

University of Frankfurt, Hospital for Children and Adolescents, Frankfurt, Germany.

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.
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http://dx.doi.org/10.1002/pbc.27879DOI Listing
September 2019

Rhabdomyosarcoma diagnosed in the first year of life: Localized, metastatic, and relapsed disease. Outcome data from five trials and one registry of the Cooperative Weichteilsarkom Studiengruppe (CWS).

Pediatr Blood Cancer 2019 06 14;66(6):e27652. Epub 2019 Feb 14.

Department for Children and Adolescents, University Hospital of Frankfurt, Frankfurt/M., Germany.

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.
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http://dx.doi.org/10.1002/pbc.27652DOI Listing
June 2019

Survival and prognosis with osteosarcoma: outcomes in more than 2000 patients in the EURAMOS-1 (European and American Osteosarcoma Study) cohort.

Eur J Cancer 2019 03 25;109:36-50. Epub 2019 Jan 25.

CDC MRC Clinical Trials Unit at UCL, London, UK.

Background: High-grade osteosarcoma is a primary malignant bone tumour mainly affecting children and young adults. The European and American Osteosarcoma Study (EURAMOS)-1 is a collaboration of four study groups aiming to improve outcomes of this rare disease by facilitating randomised controlled trials.

Methods: Patients eligible for EURAMOS-1 were aged ≤40 years with M0 or M1 skeletal high-grade osteosarcoma in which case complete surgical resection at all sites was deemed to be possible. A three-drug combination with methotrexate, doxorubicin and cisplatin was defined as standard chemotherapy, and between April 2005 and June 2011, 2260 patients were registered. We report survival outcomes and prognostic factors in the full cohort of registered patients.

Results: For all registered patients at a median follow-up of 54 months (interquartile range: 38-73) from biopsy, 3-year and 5-year event-free survival were 59% (95% confidence interval [CI]: 57-61%) and 54% (95% CI: 52-56%), respectively. Multivariate analyses showed that the most adverse factors at diagnosis were pulmonary metastases (hazard ratio [HR] = 2.34, 95% CI: 1.95-2.81), non-pulmonary metastases (HR = 1.94, 95% CI: 1.38-2.73) or an axial skeleton tumour site (HR = 1.53, 95% CI: 1.10-2.13). The histological subtypes telangiectatic (HR = 0.52, 95% CI: 0.33-0.80) and unspecified conventional (HR = 0.67, 95% CI: 0.52-0.88) were associated with a favourable prognosis compared with chondroblastic subtype. The 3-year and 5-year overall survival from biopsy were 79% (95% CI: 77-81%) and 71% (95% CI: 68-73%), respectively. For patients with localised disease at presentation and in complete remission after surgery, having a poor histological response was associated with worse outcome after surgery (HR = 2.13, 95% CI: 1.76-2.58). In radically operated patients, there was no good evidence that axial tumour site was associated with worse outcome.

Conclusions: In conclusion, data from >2000 patients registered to EURAMOS-1 demonstrated survival rates in concordance with institution- or group-level osteosarcoma trials. Further efforts are required to drive improvements for patients who can be identified to be at higher risk of adverse outcome. This trial reaffirms known prognostic factors, and owing to the large numbers of patients registered, it sheds light on some additional factors to consider.
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http://dx.doi.org/10.1016/j.ejca.2018.11.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6506906PMC
March 2019

Desmoplastic small round cell tumors: Multimodality treatment and new risk factors.

Cancer Med 2019 02 16;8(2):527-542. Epub 2019 Jan 16.

Pediatrics 5, Olgahospital, Klinikum Stuttgart, Stuttgart, Germany.

Background: To evaluate optimal therapy and potential risk factors.

Methods: Data of DSRCT patients <40 years treated in prospective CWS trials 1997-2015 were analyzed.

Results: Median age of 60 patients was 14.5 years. Male:female ratio was 4:1. Tumors were abdominal/retroperitoneal in 56/60 (93%). 6/60 (10%) presented with a localized mass, 16/60 (27%) regionally disseminated nodes, and 38/60 (63%) with extraperitoneal metastases. At diagnosis, 23/60 (38%) patients had effusions, 4/60 (7%) a thrombosis, and 37/54 (69%) elevated CRP. 40/60 (67%) patients underwent tumor resection, 21/60 (35%) macroscopically complete. 37/60 (62%) received chemotherapy according to CEVAIE (ifosfamide, vincristine, actinomycin D, carboplatin, epirubicin, etoposide), 15/60 (25%) VAIA (ifosfamide, vincristine, adriamycin, actinomycin D) and, 5/60 (8%) P6 (cyclophosphamide, doxorubicin, vincristine, ifosfamide, etoposide). Nine received high-dose chemotherapy, 6 received regional hyperthermia, and 20 received radiotherapy. Among 25 patients achieving complete remission, 18 (72%) received metronomic therapies. Three-year event-free (EFS) and overall survival (OS) were 11% (±8 confidence interval [CI] 95%) and 30% (±12 CI 95%), respectively, for all patients and 26.7% (±18.0 CI 95%) and 56.9% (±20.4 CI 95%) for 25 patients achieving remission. Extra-abdominal site, localized disease, no effusion or ascites only, absence of thrombosis, normal CRP, complete tumor resection, and chemotherapy with VAIA correlated with EFS in univariate analysis. In multivariate analysis, significant factors were no thrombosis and chemotherapy with VAIA. In patients achieving complete remission, metronomic therapy with cyclophosphamide/vinblastine correlated with prolonged time to relapse.

Conclusion: Pleural effusions, venous thrombosis, and CRP elevation were identified as potential risk factors. The VAIA scheme showed best outcome. Maintenance therapy should be investigated further.
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http://dx.doi.org/10.1002/cam4.1940DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6382921PMC
February 2019

Localized synovial sarcoma of the foot or ankle: A series of 32 Cooperative Weichteilsarkom Study Group patients.

J Surg Oncol 2019 Jan 13;119(1):109-119. Epub 2018 Nov 13.

Pediatrics 5 (Oncology, Hematology, Immunology), Olgahospital, Klinikum Stuttgart, Stuttgart, Germany.

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.
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http://dx.doi.org/10.1002/jso.25284DOI Listing
January 2019

PanCareLIFE: The scientific basis for a European project to improve long-term care regarding fertility, ototoxicity and health-related quality of life after cancer occurring among children and adolescents.

Eur J Cancer 2018 11 29;103:227-237. Epub 2018 Sep 29.

Department of Paediatrics &- Oncology, Hematology and Immunology, Centre for Paediatric, Adolescent and Women's Medicine, Klinikum Stuttgart - Olgahospital, Stuttgart, Germany.

Aims: Survival after cancer diagnosed during childhood or adolescence continues to improve with new treatments and supportive therapies. Optimal long-term care requires that risks to vulnerable organs are clearly defined and translated into guidelines that are implemented into practice. PanCareLIFE is a pan-European consortium that addresses survivorship issues comprising fertility, hearing impairment and quality of life. This article describes the scientific basis of PanCareLIFE's studies.

Methods: PanCareLIFE involves 17 partner institutions from eight European countries, with additional 11 data providers from five other countries. Study designs and methods include molecular genetic, cohort and case-control studies, a longitudinal study and an intervention study. Ethics and data protection issues have been taken into account from the beginning.

Results: PanCareLIFE will investigate the way that treatment impairs female fertility, by evaluating anti-Müllerian hormone levels and the underlying genetic susceptibility to loss of fertility. For our fertility studies, more than 6000 survivors have completed questionnaires, more than 1500 provided serum samples and more than 400 case-control triads have been identified. Fertility preservation guidelines for boys and girls will be developed. More than 2000 survivors have contributed audiograms for the ototoxicity study. Almost 1000 samples were sent for genetic analysis related to ototoxicity and gonadal reserve. The SF-36 questionnaire will measure quality of life in more than 10,000 survivors.

Conclusions: The large number of subjects enrolled in PanCareLIFE and the detailed information accumulated will allow in-depth evaluation of important outcomes. Fertility preservation guidelines will help patients and their families make informed decisions and contribute to their long-term well-being.
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http://dx.doi.org/10.1016/j.ejca.2018.08.007DOI Listing
November 2018

High-Dose Chemotherapy and Blood Autologous Stem-Cell Rescue Compared With Standard Chemotherapy in Localized High-Risk Ewing Sarcoma: Results of Euro-E.W.I.N.G.99 and Ewing-2008.

J Clin Oncol 2018 Sep 6:JCO2018782516. Epub 2018 Sep 6.

Jeremy Whelan, University College Hospital; Ian Judson, Institute of Cancer Research, London; Bernadette Brennan, Royal Manchester Children's Hospital, Manchester; Bruce Morland, Birmingham Children's Hospital; Keith Wheatley, University of Birmingham, Birmingham; Ian Lewis, Leeds Community Healthcare National Health Service Trust, Leeds; Alan Craft, Newcastle University, Newcastle upon Tyne, United Kingdom; Marie-Cecile Le Deley and Cyril Lervat, Centre Oscar Lambret, Lille; Gwénaël Le Teuff, Nathalie Gaspar, and Odile Oberlin, Institut Gustave Roussy, Villejuif; Jean-Yves Blay, Centre Léon Bérard; Perrine Marec-Berard, Institute of Pediatric Onco-Haematology, Lyon; Marie-Pierre Castex, Centre Hospitalier Universitaire de Toulouse, Toulouse; Jean-Claude Gentet, Centre Hospitalier Universitaire La Timone, Marseille; Marta Jimenez, Unicancer; Valerie Laurence and Jean Michon, Institut Curie, Paris; France; Uta Dirksen, Sebastian Bauer, Andreas Ranft, University Hospital Essen, Essen; Susanne Amler, Institut für Biometrie und Klinische Forschung; Wolfgang Hartmann and Heribert Juergens, Universitätsklinikum, Münster, Münster; Stefan Bielack, Klinikum Stuttgart, Stuttgart; Stefan Burdach, Comprehensive Cancer Center, München; Dagmar Dilloo, University-Clinic Bonn, Bonn; Angelika Eggert, Charité University; Peter Reichardt, HELIOS Klinikum Berlin-Buch, Berlin; Wolf-Achim Hassenpflug, University Medical Center Hamburg-Eppendorf, Hamburg; Thomas Klingebiel, Childrens University Hospital, Frankfurt; Udo Kontny, University Medical Center Aachen, Aachen; Michael Paulussen, Children's and Adolescents' Hospital, Datteln; Germany; Douglas S. Hawkins, Seattle Children's Hospital, Seattle, WA; Hans Gelderblom, Leiden University Medical Center, Leiden; Hendrik van den Berg, University of Amsterdam, Amsterdam, the Netherlands; Lars Hjorth, Skane University Hospital, Lund, Sweden; Jarmila Kruseova, Faculty Hospital Motol Prague, Prague, Czech Republic; Ruth Ladenstein, St Anna Children's Hospital and Children's Cancer Research Institute, Vienna, Austria; Sandrine Marreaud, European Organisation for Research and Treatment of Cancer, Brussels, Belgium.

Purpose For over 30 years, the place of consolidation high-dose chemotherapy in Ewing sarcoma (ES) has been controversial. A randomized study was conducted to determine whether consolidation high-dose chemotherapy improved survival in patients with localized ES at high risk for relapse. Methods Randomization between busulfan and melphalan (BuMel) or standard chemotherapy (vincristine, dactinomycin, and ifosfamide [VAI], seven courses) was offered to patients if they were younger than 50 years of age with poor histologic response (≥ 10% viable cells) after receiving vincristine, ifosfamide, doxorubicin, and etoposide (six courses); or had a tumor volume at diagnosis ≥ 200 mL if unresected, or initially resected, or resected after radiotherapy. A 15% improvement in 3-year event-free survival (EFS) was sought (hazard ratio [HR], 0.60). Results Between 2000 and 2015, 240 patients classified as high risk (median age, 17.1 years) were randomly assigned to VAI (n = 118) or BuMel (n = 122). Seventy-eight percent entered the trial because of poor histologic response after chemotherapy alone. Median follow-up was 7.8 years. In an intent-to-treat analysis, the risk of event was significantly decreased by BuMel compared with VAI: HR, 0.64 (95% CI, 0.43 to 0.95; P = .026); 3- and 8-year EFS were, respectively, 69.0% (95% CI, 60.2% to 76.6%) versus 56.7% (95% CI, 47.6% to 65.4%) and 60.7% (95% CI, 51.1% to 69.6%) versus 47.1% (95% CI, 37.7% to 56.8%). Overall survival (OS) also favored BuMel: HR, 0.63 (95% CI, 0.41 to 0.95; P = .028); 3- and 8-year OS were, respectively, 78.0% (95% CI, 69.6% to 84.5%) versus 72.2% (95% CI, 63.3% to 79.6%) and 64.5% (95% CI, 54.4% to 73.5%) versus 55.6% (95% CI, 45.8% to 65.1%). Results were consistent in the sensitivity analysis. Two patients died as a result of BuMel-related toxicity, one after standard chemotherapy. Significantly more BuMel patients experienced severe acute toxicities from this course of chemotherapy compared with multiple VAI courses. Conclusion BuMel improved EFS and OS when given after vincristine, ifosfamide, doxorubicin, and etoposide induction in localized ES with predefined high-risk factors. For this group of patients, BuMel may be an important addition to the standard of care.
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http://dx.doi.org/10.1200/JCO.2018.78.2516DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6209090PMC
September 2018
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