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The clinical development of immune checkpoint-targeted immunotherapies has been disappointing so far in paediatric solid tumours. However, as opposed to adults, very little is known about the immune contexture of paediatric malignancies.We investigated by gene expression and immunohistochemistry (IHC) the immune microenvironment of five major paediatric cancers: Ewing sarcoma (ES), osteosarcoma (OS), rhabdomyosarcoma (RMS), medulloblastoma (MB) and neuroblastoma (NB; 20 cases each; n = 100 samples total), and correlated them with overall survival.NB and RMS tumours had high immune cell gene expression values and high T-cell counts but were low for antigen processing cell (APC) genes. OS and ES tumours showed low levels of T-cells but the highest levels of APC genes. OS had the highest levels of macrophages (CSF1R, CD163 and CD68), whereas ES had the lowest. MB appeared as immune deserts. Tregs (FOXP3 staining) were higher in both RMS and OS. Most tumours scored negative for PD-L1 in tumour and immune cells, with only 11 of 100 samples positive for PD-L1 staining. PD-L1 and OX40 levels were generally low across all five indications. Interestingly, NB had comparable levels of CD8 by IHC and by gene expression to adult tumours. However, by gene expression, these tumours were low for T-cell cytotoxic molecules GZMB, GZMA and PRF1. Surprisingly, the lower the level of tumour infiltrative CD8 T-cells, the better the prognosis was in NB, RMS and ES. Gene expression analyses showed that MYCN-amplified NB have higher amounts of immune suppressive cells such as macrophages, myeloid-derived suppressor cells and Tregs, whereas the non-MYCN-amplified tumours were more infiltrated and had higher expression levels of Teff.Our results describe the quality and quantity of immune cells across five major paediatric cancers and provide some key features differentiating these tumours from adult tumour types. These findings explain why anti-PD(L)1 might not have had single agent success in paediatric cancers. These results provides the rationale for the development of biologically stratified and personalised immunotherapy strategies in children with relapsing/refractory cancers.

Supplementary Table 1 describes the clinical characteristics of patients.

Supplementary Table 4 provides the precise description of all STAG2 mutations in Ewing sarcoma.

Supplementary Figure 1. Representative CIRCOS plots. Supplementary Figure 2. Scheme of copy number alterations. Indicates the copy number alterations in Ewing sarcoma. Supplementary Figure 3. Mutation spectrum in Ewing sarcoma. Indicates the proportion of each somatic base changes in Ewing sarcoma. Supplementary Figure 4. CDKN2A analysis across cell lines. RT-QPCR and western blot results in cell lines. Supplementary Figure 5. CDKN2A analysis across the extended cohort. QPCR analysis of the CDKN2A locus across the whole series of patients.

Supplementary Table 3. Analysis of the statistical significance of mutations.

Supplementary Table 2 provides a summary (a), list of structural variants (b), list of copy number alterations (c), list of Tier 1 single nucleotide variants (d), indels (e), and purity analyses (f).

Ewing sarcoma is a primary bone tumor initiated by EWSR1–ETS gene fusions. To identify secondary genetic lesions that contribute to tumor progression, we performed whole-genome sequencing of 112 Ewing sarcoma samples and matched germline DNA. Overall, Ewing sarcoma tumors had relatively few single-nucleotide variants, indels, structural variants, and copy-number alterations. Apart from whole chromosome arm copy-number changes, the most common somatic mutations were detected in STAG2 (17%), CDKN2A (12%), TP53 (7%), EZH2, BCOR, and ZMYM3 (2.7% each). Strikingly, STAG2 mutations and CDKN2A deletions were mutually exclusive, as confirmed in Ewing sarcoma cell lines. In an expanded cohort of 299 patients with clinical data, we discovered that STAG2 and TP53 mutations are often concurrent and are associated with poor outcome. Finally, we detected subclonal STAG2 mutations in diagnostic tumors and expansion of STAG2-immunonegative cells in relapsed tumors as compared with matched diagnostic samples.Significance: Whole-genome sequencing reveals that the somatic mutation rate in Ewing sarcoma is low. Tumors that harbor STAG2 and TP53 mutations have a particularly dismal prognosis with current treatments and require alternative therapies. Novel drugs that target epigenetic regulators may constitute viable therapeutic strategies in a subset of patients with mutations in chromatin modifiers. Cancer Discov; 4(11); 1342–53. ©2014 AACR.This article is highlighted in the In This Issue feature, p. 1243

List of supplementary tables and figures.

STAG2 mutation in three cases that show a reduction of STAG2-immunopositive cells at disease recurrence.

International audience; In Euro-EWING99-R1 randomized trial, cyclophosphamide was shown to be noninferior to ifosfamide in the consolidation of standard-risk Ewing sarcoma (SR-EWS) after a common induction with VIDE (vincristine-ifosfamide-doxorubicin-etoposide). We present the results of the late effects analysis of VAC (vincristine-dactinomycin-cyclophoshamide) vs VAI (vincristine-dactinomycin-ifosfamide) conducted in Euro-EWING99-R1 French cohort. Of 267 French randomized patients, 204 were alive and free-of-relapse at 5-years including 172 with available long-term follow-up data concerning cardiac, renal and/or gonadal functions (sex-ratio M/F = 1.3, median age at diagnosis = 14 years): 84 randomized in VAC (median cumulative doses: cyclophosphamide = 9.7 g/m2, ifosfamide = 59.4 g/m2) and 88 in VAI (ifosfamide = 97.1 g/m2). With a median follow-up of 10 years (range = 5-17), five late relapses and five second malignancies were recorded. The 10-year event-free survival among 5-year free-of-relapse survivors was similar between VAC and VAI (93% vs 95%, P =.63). We estimated the 10-year cumulative probabilities of cardiac and kidney toxicities at 4.4% (95% confidence interval [95% CI] = 1.1%-7.6%) and 34.8% (95% CI = 26.8%-42.0%), respectively. Cardiac toxicity cumulative probability was similar in both arms, whereas kidney toxicity was higher in VAI (at 10 years, 43.0% vs 25.7%, P =.02), resulting from significant difference in glomerular toxicity (31.1% vs 13.1%, P

CIC-rearranged sarcomas (CIC-RS) represent the most frequent subset of "Ewing-like" undifferentiated small round cell sarcomas. These tumors tend to be more aggressive than Ewing sarcomas. Moreover, treatment strategy can differ according to teams. The primary aim of this retrospective study was to describe the characteristics, treatments, and outcome for patients with CIC-RS included in the French NETSARC+ database.Pediatric and adult patients from 13 French centers with a diagnosis of CIC-RS were registered from October 2008 to March 2021. Patients and tumors characteristics were collected from the national network NETSARC+ database (http://netsarc.sarcomabcb.org). CIC-RS diagnosis was pathologically and molecularly confirmed with a central review by expert pathologists. Two groups of patients were studied: those treated as classical Ewing sarcomas (cohort EwS) and those treated as high-grade soft tissue sarcomas (cohort STS) according to ESMO and/or EpSSG guidelines. Survival was calculated using the Kaplan-Meier method and the log-rank test was used to compare survival.Among 79 patients, the male/female sex ratio was 0.7 and the median age at diagnosis was 27 years (range 2-87). With a median follow-up of 37 months, 39 patients died of the disease. Median overall survival from diagnosis was 18 months, with no significant difference between both cohorts (p = 0.9). Nevertheless, when focusing on patients with metastatic disease at diagnosis (N = 21), all patients from cohort STS died of disease while some patients from cohort EwS were still alive and in complete remission.FSG experience confirms the aggressive clinical course of CDS patients regardless of chemotherapy regimen.

Internationally, a single standard chemotherapy treatment for Ewing sarcoma is not defined. Because different chemotherapy regimens were standard in Europe and the USA for newly diagnosed Ewing sarcoma, and in the absence of novel agents to investigate, we aimed to compare these two strategies.EURO EWING 2012 was a European investigator-initiated, open-label, randomised, controlled phase 3 trial done in 10 countries. We included patients aged 2-49 years, with any histologically and genetically confirmed Ewing sarcoma of bone or soft tissue, or Ewing-like sarcomas. The eligibility criteria originally excluded patients with extrapulmonary metastatic disease, but this was amended in the protocol (version 3.0) in September, 2016. Patients were randomly assigned (1:1) to either the European regimen of vincristine, ifosfamide, doxorubicin, and etoposide induction, and consolidation using vincristine, actinomycin D, with ifosfamide or cyclophosphamide, or busulfan and melphalan (group 1); or the US regimen of vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide induction, plus ifosfamide and etoposide, and consolidation using vincristine and cyclophosphamide, or vincristine, actinomycin D, and ifosfamide, with busulfan and melphalan (group 2). All drugs were administered intravenously. The primary outcome measure was event-free survival. We used a Bayesian approach for the design, analysis, and interpretation of the results. Patients who received at least one dose of study treatment were considered in the safety analysis. The trial was registered with EudraCT, 2012-002107-17, and ISRCTN, 54540667.Between March 21, 2014, and May 1, 2019, 640 patients were entered into EE2012, 320 (50%) randomly allocated to each group. Median follow-up of surviving patients was 47 months (range 0-84). Event-free survival at 3 years was 61% with group 1 and 67% with group 2 (adjusted hazard ratio [HR] 0·71 [95% credible interval 0·55-0·92 in favour of group 1). The probability that the true HR was less than 1·0 was greater than 0·99. Febrile neutropenia as a grade 3-5 treatment toxicity occurred in 234 (74%) patients in group 1 and in 183 (58%) patients in group 2. More patients in group 1 (n=205 [64%]) required at least one platelet transfusion compared with those in group 2 (n=138 [43%]). Conversely, more patients required blood transfusions in group 2 (n=286 [89%]) than in group 1 (n=277 [87%]).Dose-intensive chemotherapy with vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide is more effective, less toxic, and shorter in duration for all stages of newly diagnosed Ewing sarcoma than vincristine, ifosfamide, doxorubicin, and etoposide induction and should now be the standard of care for Ewing sarcoma.The European Union's Seventh Framework Programme for Research, Technological Development, and Demonstration; The National Coordinating Centre in France, Centre Léon Bérard; SFCE; Ligue contre le cancer; Cancer Research UK.

Histologic response to chemotherapy for osteosarcoma is one of the most important prognostic factors for survival, but assessment occurs after surgery. Although tumor imaging is used for surgical planning and follow-up, it lacks predictive value. Therefore, a radiomics model was developed to predict the response to neoadjuvant chemotherapy based on pretreatment T1-weighted contrast-enhanced MRI. A total of 176 patients (median age, 20 years [range, 5–71 years]; 107 male patients) with osteosarcoma treated with neoadjuvant chemotherapy and surgery between January 2007 and December 2018 in three different centers in France (Centre Léon Bérard in Lyon, Centre Hospitalier Universitaire de Nantes in Nantes, and Hôpital Cochin in Paris) were retrospectively analyzed. Various models were trained from different configurations of the data sets. Two different methods of feature selection were tested with and without ComBat harmonization (ReliefF and t test) to select the most relevant features, and two different classifiers were used to build the models (an artificial neural network and a support vector machine). Sixteen radiomics models were built using the different combinations of feature selection and classifier applied on the various data sets. The most predictive model had an area under the receiver operating characteristic curve of 0.95, a sensitivity of 91%, and a specificity 92% in the training set; respective values in the validation set were 0.97, 91%, and 92%. In conclusion, MRI-based radiomics may be useful to stratify patients receiving neoadjuvant chemotherapy for osteosarcomas. Keywords: MRI, Skeletal-Axial, Oncology, Radiomics, Osteosarcoma, Pediatrics Supplemental material is available for this article. © RSNA, 2022

Ewing sarcoma (ES) is an aggressive bone or extraosseous tumour with an unfavourable prognosis when bone marrow metastases are present at diagnosis. The gold standard diagnosis for bone marrow (BM) involvement is cytological and pathological analysis through bone marrow aspiration and biopsy (BMAB). Several recent studies suggest that these invasive and painful procedures could be replaced by 18F-fluorodeoxyglucose-positron emission tomography/computed tomography ((18)FDG-PET/CT), as this nuclear imaging technique is highly sensitive at detecting bone and extraosseous metastases of ES.In order to study the precision of (18)FDG-PET/CT in the evaluation of bone marrow metastases at diagnosis, we compared the imaging results with cytological/histological analyses performed on BM samples. We retrospectively studied 180 patients with ES recorded at the Léon Bérard Centre over the past 10 years, who were evaluated by (18)FDG-PET/CT and BMAB at diagnosis.Of the 180 patients, 13 displayed marrow metastases by cytological/histological examination, and only one of these did not have (18)FDG-PET/CT signs of bone marrow involvement, whereas the 167 remaining patients without marrow metastasis all had a negative (18)FDG-PET/CT, except for one. Hence, the sensitivity and specificity of (18)FDG-PET/CT in these patients was 92.3% and 99.4%, respectively. The overall survival at five years of all patients was 67.4% but decrease to 38.5% in the group with bone marrow metastases.Given the results presented herein the bone sarcoma group of the French Sarcoma Group suggests that invasive BMAB no longer be systematically performed for the staging at the diagnosis of ES.

Background. The initial management of patients with sarcoma is critical. We used the French National Cancer Institute-funded nationwide sarcoma database NETSARC to report the management and oncologic outcomes in children, adolescents and young adults (AYAs) patients with sarcoma at the national level. Patients and methods. Data from patients with sarcoma are collected, regularly monitored and updated using NETSARC. NETSARC was searched for pediatric (Results. We collected data from 3,972 pediatric and AYA patients with sarcoma diagnosed between 2010 and 2017, including 714 children, 1,290 AYAs treated in RSC, and 937 AYAs in non-RSC. Significant differences in compliance to guidelines were observed regarding pre-treatment biopsy (Children: 83.5%; AYA in RSC: 85.9%; AYA in non-RSC 48.1%), pre-treatment imaging (Children: 81.2%; AYA in RSC: 86.8%; AYA in non-RSC: 56.5%) and R0 margins (Children: 52%; AYA in RSC 57.6%; AYA in non-RSC: 20.2%) (pConclusions. This study highlights the importance for AYA patients with sarcoma to be managed in national sarcoma reference centers involving multidisciplinary medical teams with paediatric and adult oncologists.

Epiphyseal preservation surgery and biological reconstruction after resection of metaphyseal bone sarcoma in children is a surgical challenge which can only be justified if future joint function is maintained.The main hypothesis of this work was that long-term function was maintained. The secondary hypotheses were that local control of the disease and growth restoration were achieved, at the cost of an acceptable number of complications.This was a retrospective study of 14 children with a median age of 8 years [2-14] at the time of surgery. The tumors (Ewing's sarcoma or osteosarcoma) were mostly situated at the knee (n=9) and hip (n=3). The reconstruction used an induced membrane (n=7) or an allograft (n=7). We studied joint function, mechanisms contributing to loss of growth, surgical complications and survival at the last follow-up.At the median follow-up of 76 months [24-130], 9 out of 14 patients required revision for non-union, and 4 of them required a second revision. At the last follow-up, 82% of the length had been restored, due to 3 bone lengthenings and 7 contralateral epiphysiodeses. Preserved joint function was excellent with an average modified MSTS score of 28.3/30 [24-30]. No local recurrence was reported.Our experience of epiphyseal preservation allows local control of the disease and very good function but at the cost of a cumbersome surgical program (12 out of 14 patients were reoperated on, with an average of 1.2 interventions per patient). The main difficulty is the growth management, most often by complex programs of alternating bone lengthening and shortening.IV, retrospective study.

Ewing sarcoma (ES) is a highly malignant round cell sarcoma, characterized by gene fusion involving FET (FUS, EWSR1, TAF15) and ETS family genes, respectively. The involvement of the EWSR1 gene has been reported in approximately 90% of cases of ES, with the EWSR1::FLI1 fusion being the most frequent. We report the case of a newborn with a localized soft tissue paravertebral neoplasm diagnosed prenatally. Histopathology and immunophenotype were consistent with a CD99 + , NKX2.2 + undifferentiated round cell sarcoma (URSC); whole-exome RNA-sequencing demonstrated an undescribed in-frame TAF15::ETV4 fusion transcript, while consensus clustering analysis showed high transcriptomic proximity to the ES group. Given clinical context, high tumor chemosensitivity to ES conventional drugs, morphological characteristics, nature of the fusion partners involved, and high transcriptomic proximity to bona fide ESs, this case may represent a new genetic variant of ES.

A biopsy is a prerequisite for the diagnosis and evaluation of musculoskeletal tumors. It is considered that surgical biopsy provides a more reliable diagnosis because it can obtain more tumor material for pathological analysis. However, it is often associated with a significant complication rate. Imaging-guided percutaneous core needle biopsy (PCNB) is now widely used as an alternative to surgical biopsy, it appears to be minimally invasive, possibly with lower complication rates. This study evaluates the diagnostic yield of the preferred use of PCNB in a referral center, its accuracy, and its complication rate. The data relating to the biopsy and the histological analysis were extracted from the database of a bone tumor reference center where PCNB of bone tumors was discussed as a first-line option. 196 bone tumors were biopsied percutaneously between 2016 and 2020. They were located in the axial skeleton in 21.4% (42) of cases, in the lower limb in 58.7% (115), and in the upper limb in 19.9% (39) cases. We obtained a diagnosis yield of 84.7% and a diagnosis accuracy of 91.7%. The overall complication rate of the percutaneous biopsies observed was 1.0% (n = 2), consisting of two hematomas. PCNB performed in a referral center is a safe, precise procedure, with a very low complication rate, and which avoids the need for first-line open surgical biopsy. The consultation between pathologist, radiologist, and clinician in an expert reference center makes this technique an effective choice as a first-line diagnosis tool.

PLOS ONE 15(9), e0237792 (2020). doi:10.1371/journal.pone.0237792, Published by PLOS, San Francisco, California, US

Ewing sarcoma (EWS) is a pediatric cancer characterized by the EWSR1-FLI1 fusion. We performed a genome-wide association study of 733 EWS cases and 1346 unaffected individuals of European ancestry. Our study replicates previously reported susceptibility loci at 1p36.22, 10q21.3 and 15q15.1, and identifies new loci at 6p25.1, 20p11.22 and 20p11.23. Effect estimates exhibit odds ratios in excess of 1.7, which is high for cancer GWAS, and striking in light of the rarity of EWS cases in familial cancer syndromes. Expression quantitative trait locus (eQTL) analyses identify candidate genes at 6p25.1 (RREB1) and 20p11.23 (KIZ). The 20p11.22 locus is near NKX2-2, a highly overexpressed gene in EWS. Interestingly, most loci reside near GGAA repeat sequences and may disrupt binding of the EWSR1-FLI1 fusion protein. The high locus to case discovery ratio from 733 EWS cases suggests a genetic architecture in which moderate risk SNPs constitute a significant fraction of risk., Ewing sarcoma (EWS) is a rare pediatric bone cancer typically involving the EWSR1-FLI1 fusion. Here the authors perform a genome-wide association study and report three new EWS risk loci that reside near GGAA repeat sequences, and identify candidate genes (RREB1 and KIZ) from eQTL analysis.

Growing evidence suggests that polymorphisms of genes coding for transporters or enzymes may partially explain the large between subject variability reported for methotrexate (MTX) pharmacokinetics (PK). This prospective study aimed to develop a population PK-pharmacogenetic model to evaluate the part of between-subject variability due to single-nucleotide polymorphisms (SNPs) in transporters and enzyme genes implicated in MTX distribution and elimination. MTX concentrations and 54 SNPs (located in ABCB1, ABCC1, ABCC2, ABCC3, ABCC4, ABCG2, SLC19A1, SLCO1B1, and UGT1A1 genes) were analyzed in patients treated with MTX included in the OS2006/sarcoma-09 trial (a multicenter, open-label, phase III trial, ClinicalTrials.gov. Identifier: NCT00470223). PK data were analyzed using the nonlinear mixed-effect modeling software program Monolix. The influence of each SNP was evaluated using a stepwise procedure under additive, recessive, or dominant genetic model. The likelihood ratio test was used to test the effect of each SNP on PK parameters. Overall, 187 patients with 7898 MTX blood concentrations were included in the PK-pharmacogenetic analysis. A 2-compartment model adequately described the data. Although high-dose MTX dosing recommendations in pediatric patients are currently based on body surface area, body weight was more predictive of clearance between-subject variability than body surface area. The most significant polymorphism associated with MTX clearance was rs13120400 (on the ABCG2 gene) under the recessive genetic model (P < .0001). GG genotype carriers for rs13120400 appeared to have a moderate decrease in MTX exposure compared to AA or GA carriers.

CONTEXT: Neuroblastoma is the most common extracranial solid tumor in children. Patients with low- and intermediate-risk neuroblastoma (LIRNB) have favorable prognosis and an excellent five-year survival rate of more than 90%. However, in the case of high-risk neuroblastoma (HRNB; ~50% of cases), the prognosis of treatment remains unfavorable and the five-year survival rate remains under 40% despite aggressive multi modal therapy. QUESTION: We wanted to know if there was a defect in immune surveillance that could explain part of the aggressive phenotype of HRNB. METHODS: We performed a prospective multi-center study on thirty two new cases of neuroblastoma at all stages. We performed a wide phenotyping of immune cells by flow cytometry in fresh whole blood, and fresh whole bone marrow at diagnosis of children diagnosed for neuroblastoma. Cell counts were performed in order to be able to reason in absolute values (G/L) rather than only percentages. RESULTS: Blood and bone marrow from 20 LIRNB and 12 HRNB were prospectively analyzed. We found that specific subsets of circulating immune cells such as myeloid dendritic cells BDCA-1+, plasmacytoid dendritic cells, Teff/Treg CD4+ T-cells, were decreased in HRNB blood compared to LIRNB groups as opposed to other subsets (e.g iNKT, g9d2 T-cells,⋯). More surprisingly, these differences were not due to defects in cell production as there was no difference found for the same cell populations in the bone marrow between LIRNB and HRNB children. CONCLUSION: Specific immune cell defects are found in the blood from High risk neuroblastoma children that are not present in the blood of low & intermediate risk neuroblastoma children. These defects are not due to bone marrow production impairment. These results suggest that high risk neuroblastoma disease generates an impairment in the immune homeostasis of children. Gene expression analysis of cytokine/chemokine from these neuroblastoma tumors is underway (NCT01295762). Citation Format: Sandrine Susini, Isabelle Rochet, Estelle Verronèse, Christine Bardin, Chantal Rigal, Cécile Conter, Perrine Marec-Bérard, Christophe Bergeron, Audrey Lardy-Cleaud, Séverine Neymarc, Séverine Metzger, Jean-Louis Stephan, Dominique Plantaz, Christophe Caux, Christine Ménétrier-Caux, Aurelien Marabelle. Prospective immune phenotyping of neuroblastoma children at diagnosis reveals specific immune defects related to the aggressiveness of the disease [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3112.

To determine whether a risk factor adapted chemotherapy would improve the outcome of non-metastatic bone Ewing's sarcoma.Standard risk tumours (SR, good histological response to chemotherapy or small unresected tumours) received the previous EW88 chemotherapy. Ifosfamide/etoposide (IE) were introduced after 3 courses of cyclophosphamide/doxorubicine when tumour regression was50% or during consolidation therapy for the intermediate risk tumours (IR, intermediate histological response 5-30% residual cells or large unresected tumours100ml). High risk tumours (HR, histological poor response30% residual cells or clinical poor response50% for unresectable tumours), received IE prior high dose busulfan/melphalan with stem cell rescue.From 1993 to 1999, 214 patients were enrolled. 5 y-EFS and OS were 60% (95% confidence interval (CI), 53-66) and 69% (95% CI, 63-75), respectively. 116 (54%), 46 (21%), 48 (22%) patients were considered as SR, IR and HR of relapse, respectively. No advantage to IE was observed in the IR group. As compared to previous study, tumour with poor histological response to induction chemotherapy seemed to benefit from the consolidation strategy including busulfan/melphalan: EFS were 45% (95% CI, 30-60) and 20% (95% CI, 7-43) for EW93 and EW88, respectively. Despite a risk-adapted strategy, histological response to chemotherapy remains the main prognostic factor in resected tumours, while initial tumour volume is the main prognostic factor for unresected tumours.These results showing a potential benefit of a consolidation strategy including busulfan/melphalan as compared to conventional chemotherapy needed confirmation by a randomised trial and were one of the bases of the ongoing EuroEwing99.

Background Bevacizumab, a monoclonal antibody targeting the vascular endothelial growth factor, has proven efficacy in some adult tumors; it is now proposed as a new therapeutic strategy for refractory or recurrent brain tumors in some children, either alone or combinated. Procedure We retrospectively analyzed 28 children who received bevacizumab on a compassionate basis for refractory or recurrent brain tumors between June 2007 and August 2010 in 7 French centers. Among them, 12 had high-grade gliomas, 7 low-grade gliomas, 4 ependymomas, 2 primitive neurectodermal tumors, 3 neuroglial tumors. The median age at start of bevacizumab was 11.0 years. Bevacizumab was administered at 5–10 mg/kg every 2 weeks, with concomitant chemotherapy for 27 patients. Results Bevacizumab was used in combination with irinotecan in 27 patients. Bevacizumab-related toxicity was mild. Toxicities reported were grade I–II hypertension (n = 4), proteinuria (n = 1), lymphopenia (n = 2), wound healing delay (n = 2). Whereas tumor reduction could be observed in 6:7 patients with low-grade gliomas, no efficacy could be documented in patients with high-grade glioma, nor PNET nor ependymoma. Conclusion Bevacizumab-related acute toxicity appears to be low in children, even in combination with irinotecan. Further prospective trials are required to confirm the hypothetical efficacy of bevacizumab and to assess the risk of long-term toxicity especially in the youngest children. Pediatr Blood Cancer 2012; 59: 34–38. © 2012 Wiley Periodicals, Inc.

The use of oral complementary and alternative medicine (CAM) is widespread among cancer patients, but considerably less known in pediatric cancer patients. Our survey was conducted in a pediatric onco-hematology unit to study the frequency and the circumstances of CAM use.This study included 50 children treated for malignant diseases. A questionnaire was used to collect support general data on the child as well as information on the CAM use. One of the child's parents was interviewed.Most of parents (48%) used one or more CAM for their child in the context of cancer. The most used type of CAM was homeopathy, dietary supplements and aromatherapy. The most frequent goal for CAM use was to limit the side effects of conventional treatment (75% of parents). For 87.5% of users, the CAM was effective. Physicians were not aware of this use for 33.3% of users, in spite of the fact that the family physician was the main source of information for this use. Most of parents (48%) needed more information about the CAM and they bought CAM in a pharmacy.The use of oral CAM in this survey was common. For most parents, this use was effective and appreciated because they generated fewer side effects than conventional treatments. However, doctors were not systematically informed of this use. This is problematic because some CAM such as herbal supplements could potentially cause interactions with cancer treatments. More information about CAM is necessary in pediatric onco-hematology.

Objectif de l’etude Le sarcome d’Ewing de la cote represente la tumeur thoracique primitive la plus frequente de l’enfant et du jeune adulte, cependant les etudes et donnees specifiques sont rares. Les objectifs principaux de cette etude etaient d’evaluer la survie en fonction du traitement local et de definir des facteurs pronostiques. Materiel et methode Les patients inclus dans l’etude Euro-EWING99 (EE99) etait atteints d’un sarcome d’Ewing localise de la cote, avec ou sans epanchement pleural au diagnostic etaient eligibles. Les donnees ont ete recueillies de maniere prospective grâce a l’etude EE99 et completees retrospectivement. Resultats Les dossiers de 82 patients pris en charge de decembre 1999 a avril 2013 ont ete analyses. Le suivi median etait de 8,4 mois. Cinquante et un pour cent etaient atteints d’un epanchement pleural au moment du diagnostic. Le traitement local comportait une chirurgie d’exerese chez 81/82 patients, le plus frequemment apres une chimiotherapie d’induction. Soixante patients (73 %) ont ete irradies, 28 % dans le lit operatoire, 13 % dans l’hemithorax et 32 % sur les deux. Les probabilites de survie sans recidive et globale a 5 ans etaient respectivement de 69 % et 71 %. Vingt-six tumeurs (31 %) ont recidive en mediane 19 mois apres le diagnostic. La presence d’un epanchement pleural et des marges chirurgicales non saines (R1 ou R2) etaient des facteurs pronostiques independants defavorables de survies globale et sans recidive. L’irradiation de l’hemithorax ameliorait significativement la probabilite de survie globale en cas d’epanchement pleural : 27 % contre 68 % (p = 0,01). L’irradiation du lit operatoire ameliorait significativement la probabilite de survie en cas de mauvaise reponse histologique. Conclusion La presence d’un epanchement pleural au diagnostic et la qualite de l’exerese chirurgicale sont des facteurs pronostiques defavorables independants des sarcomes d’Ewing localises de la cote. L’irradiation hemithoracique ameliore significativement la probabilite de survie en cas d’epanchement pleural initial.

Primary cutaneous/subcutaneous Ewing sarcoma (scEWS) is extremely rare. We describe clinical features, treatment, and outcome of this Ewing localization.Retrospective study (1996-2012) on 56 patients.Most primary scEWS occurred in late adolescent/young adult females (F/M = 1.9; median age 21.5 years), with primary tumor in the extremity/trunk (48.5%/39%). Only 35/56 samples had Real-Time-Polymerase-Chain-Reaction/Fluorescent-In-Situ-Hybridization analysis, 32/35 had EWS-translocation. Most of them exhibited known favorable prognostic factors: localized disease (54/56), initial tumor volume 200 ml (51/53). Thirty and 25 patients received chemotherapy according to Euro-Ewing99 or a shorter/less intense chemotherapy regimen associated with milder toxicity. One patient had not received chemotherapy. Surgery was performed at diagnosis in 37 patients (18/37 marginal/intra-lesional resections) followed by secondary surgery in 8/37 (three remained marginal). Nineteen other patients had an initial biopsy followed by chemotherapy, 15/19 underwent late surgery (4/15 marginal/intra-lesional resections). Overall, 27/56 patients received radiotherapy. Median follow-up was six years (1-15). Two patients with metastatic disease progressed at metastatic sites. Four patients with localized disease experienced progression/relapse (local n = 3, metastatic n = 1). Survival was excellent: 5y-OS and 5y-EFS were 93.8% (95%CI = 83-98%) and 88.5% (95%CI-= 77-95), respectively.Unplanned primary surgery should be avoided to try to minimize potential long term sequels due to secondary surgery or radiotherapy. Biopsy with molecular analysis and staging should be performed at diagnosis to inform treatment recommendations. Patients with metastases should be treated aggressively as for other metastatic EWS. Further studies are necessary to clarify whether a less intensive chemotherapy regimen could be safely used in localized disease to minimize acute/late toxicities.

Purpose Relative efficacy and toxicity of cyclophosphamide compared with ifosfamide are debatable. The Euro-EWING99-R1 trial asked whether cyclophosphamide may replace ifosfamide in combination with vincristine and dactinomycin (vincristine, dactinomycin, and cyclophosphamide [VAC] v vincristine, dactinomycin, and ifosfamide [VAI]) after an intensive induction chemotherapy containing vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) in standard-risk localized disease (NCT00020566). Methods Standard-risk Ewing sarcomas were localized tumors with either a good histologic response to chemotherapy (< 10% cells) or small tumors (< 200 mL) resected at diagnosis or receiving radiotherapy alone as local treatment. Patients entered the trial after six VIDE+1 VAI courses. Allocated treatment was either 7 VAC courses with 1.5 g/m2 of cyclophosphamide or seven VAI-courses with 6 g/m2 ifosfamide. The limit of noninferiority was set at −8.5% for the 3-year event-free survival rate (EFS), equivalent to 1.43 in terms of the hazard ratio of event (HRevent). Results This large international trial recruited 856 patients between February 2000 and March 2010 (n = 431 receiving VAC and n = 425 receiving VAI). With a median follow-up of 5.9 years, the 3-year EFSs were 75.4% and 78.2%, respectively, the 3-year EFS difference was −2.8% (91.4% CI, −7.8 to 2.2%), the HRevent was 1.12 (91.4% CI, 0.89 to 1.41), and the HRdeath was 1.09 (91.4% CI, 0.84 to 1.42; intention-to-treat). The HRevent was 1.22 (91.4% CI, 0.96 to 1.54) on the per-protocol population. Major treatment modifications were significantly less frequent in the VAC arm (< 1%) than in the VAI arm (7%), mainly resulting from toxicity. Patients experienced more frequent thrombocytopenia in the VAC arm (45% v 35%) but fewer grade 2 to 4 acute tubular toxicities (16% v 31%). Conclusion Cyclophosphamide may be able to replace ifosfamide in consolidation treatment of standard-risk Ewing sarcoma. However, some uncertainty surrounding the noninferiority of VAC compared with VAI remains at this stage. The ongoing comparative evaluation of long-term renal and gonadal toxicity is crucial to decisions regarding future patients.

Rare cancer issues have not been much explored yet because of their low incidence. That is why epidemiological studies have difficulties in identifying indisputable etiological risk factors. An expert opinion, mainly concentrated in some establishments, is required for these cancers' management. However, on account of the potential remoteness of these therapeutic resources, the patients' way of care remains also unstudied. By means of a geographical analysis of a regional exhaustive cohort of sarcoma, diagnosed in 2006 and 2007 and followed during five years at least, we can make progress on these different issues. Gastro-Intestinal and Stromal Tumors (GIST) occur more frequently in privileged territories while liposarcomas arise in more deprived areas. The association between liposarcomas and areas deprivation is significant (P=0.05). Moreover, pre-operative biopsy and some clinical patient characteristics, age, grade or tumor localization, are associated with an increase in the distance covered by patients for the first-line treatment (p ≤ 0,001). In the scope of an interdisciplinary collaboration, the geographical approach develops some hypothesis for rare cancers research, which must be tested by other larger scale studies.

Le reseau RESOS a ete finance par l’Inca en 2013 dans le cadre d’un appel d’offre sur la mise en place de centres experts de reference pour la prise en charge des cancers rares en France. Une des missions de RESOS est la mise en place d’une base d’enregistrement nationale des activites en RCP et des diagnostics de tumeurs osseuses malignes (hors metastases) et TCG. L’objectif de ce travail est de rapporter le premier bilan exhaustif d’activite d’enregistrement, adulte et pediatrique en 2015. Materiel et methodes Les donnees ont ete saisies sur les bases nationales Netsarc RESOS (activites cliniques, tissus mous et os) et RESOS donnees pathologiques (patho). L’ensemble des donnees (> 20 000 sarcomes tissus mous et 2211 sarcomes osseux) ont ete basculees sur un entrepot de donnees (I2B2) fonctionnel en mars 2016. Resultats Le choix s’est tourne vers un systeme integre d’enregistrement integrant les sarcomes tissus mous, visceraux osseux, sur le plan clinique (activites cliniques et de RCP) et ana path. Les donnees sont colliges et saisies par les anatomo-pathologistes du groupe d’expert RESOS, les cliniciens (oncologues medicaux, chirurgiens) et les ARC finances dans le cadre du reseau ou mutualises avec le reseau tissus mous (Netsarc). Les liens ont ete etablis avec la Societe francaise des cancers de l’enfant (SFCE) et les Rcp labellisees pediatriques pour le recueil de donnees pediatriques. Nous avons en 2015 enregistre 602 cas incidents, dont 122 (20 %) de cas pediatriques. Cette incidence est proche de l’incidence attendue de tumeurs primitives en France sur la base des donnees epidemiologiques publiees. Les voies de saisies dans le reseau etaient majoritairement par les ana-path (respectivement 76,2 % pour la pediatrie et 72 % pour les adultes). Les sarcomes pediatriques sont significativement plus frequents chez le garcon (2 3 des cas) alors que la sex-ratio est de 1 chez les adultes. Le sarcome d’Ewing est le plus frequent chez l’enfant (42 %) et le chondrosarcome le plus frequent chez l’adulte (34 %). Discussion conclusion . Ces premieres donnees permettent d’identifier les difficultes pour le recueil qualitatif et quantitatif des pathologies malignes primitives en France. Bien qu’il ne s’agisse pas d’un registre epidemiologique, la couverture de ce reseau permet pour la premiere fois en France d’avoir des donnees sur l’incidence, le type de sarcome osseux, leur localisation. Une confrontation avec le registre du cancer des enfants et des controles de qualite s’imposent pour ameliorer ces donnees sur le plan qualitatif. Ce travail permet d’evaluer les besoins en moyens humains pour assurer l’exhaustivite des donnees et le suivi des patients.

Background Vinblastine (VBL) is the standard treatment for systemic Langerhans cell histiocytosis (LCH), but little is known about its efficacy in central nervous system (CNS) mass lesions. Methods A retrospective chart review was conducted. Twenty patients from the French LCH Study Group register met the inclusion criteria. In brief, they had CNS mass lesions, had been treated with VBL, and were evaluable for radiologic response. Results The median age at diagnosis of LCH was 11.5 years (range: 1-50). Intravenous VBL 6 mg/m2 was given in a 6-week induction treatment, followed by a maintenance treatment. The median total duration was 12 months (range: 3-30). Eleven patients received steroids concomitantly. Fifteen patients achieved an objective response; five had a complete response (CR: 25%), ten had a partial response (PR: 50%), four had stable disease (SD: 20%) and one patient progressed (PD: 5%). Of interest, four out of the six patients who received VBL without concomitant steroids achieved an objective response. With a median follow-up of 6.8 years, the 5-year event-free and overall survival was 61% and 84%, respectively. VBL was well-tolerated and there were no patient withdrawals due to adverse events. Conclusion VBL, with or without steroids, could potentially be a useful therapeutic option in LCH with CNS mass lesions, especially for those with inoperable lesions or multiple lesions. Prospective clinical trials are warranted for the evaluation of VBL in this indication.