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PURPOSE To analyze the efficacy of a risk-stratified treatment of children with relapsed anaplastic large cell lymphoma (ALCL). The ALCL-Relapse trial (ClinicalTrials.gov identifier: NCT00317408 ) stratified patients according to the time of relapse and CD3 expression to prospectively test reinduction approaches combined with consolidation by allogeneic or autologous hematopoietic stem cell transplantation (SCT) and vinblastine monotherapy. PATIENTS AND METHODS Patients with progression during frontline therapy (very high risk) or a CD3-positive relapse (high risk) were scheduled for allogeneic SCT after reinduction chemotherapy. Patients with a CD3-negative relapse within 1 year after initial diagnosis or prior exposure to vinblastine (intermediate risk) received autologous SCT after carmustine-etoposide-cytarabine-melphalan. This arm was terminated prematurely, and subsequent patients received vinblastine monotherapy instead. Patients with a CD3-negative relapse > 1 year after initial diagnosis (low risk) received vinblastine monotherapy. RESULTS One hundred sixteen patients met the inclusion criteria; 105 evaluable patients with CNS-negative disease had a 5-year event-free survival (EFS) of 53% ± 5% and a 5-year overall survival (OS) of 78% ± 4%. Before termination of autologous SCT, EFS rates of patients in the very-high- (n = 17), high- (n = 26), intermediate- (n = 32), and low- (n = 21) risk groups were 41% ± 12%, 62% ± 10%, 44% ± 9%, and 81% ± 9%; the respective OS rates were 59% ± 12%, 73% ± 9%, 78% ± 7%, and 90% ± 6%. Analyzing only the patients in the intermediate-risk group consolidated per protocol by autologous SCT, EFS and OS of 23 patients were 30% ± 10% and 78% ± 9%, respectively. All 5 patients with intermediate risk receiving vinblastine monotherapy after the amendment experienced relapse again. CONCLUSION Shorter time to relapse was the strongest predictor of subsequent relapse. Allogeneic SCT offers a chance for cure in patients with high-risk ALCL relapse. For early relapsed ALCL autologous SCT was not effective. Vinblastine monotherapy achieved cure in patients with late relapse; however, it was not effective for early relapses.

PURPOSE The identification of a heritable tumor predisposition often leads to changes in management and increased surveillance of individuals who are at risk; however, for many rare entities, our knowledge of heritable predisposition is incomplete. METHODS Families with childhood medulloblastoma, one of the most prevalent childhood malignant brain tumors, were investigated to identify predisposing germline mutations. Initial findings were extended to genomes and epigenomes of 1,044 medulloblastoma cases from international multicenter cohorts, including retrospective and prospective clinical studies and patient series. RESULTS We identified heterozygous germline mutations in the G protein-coupled receptor 161 ( GPR161) gene in six patients with infant-onset medulloblastoma (median age, 1.5 years). GPR161 mutations were exclusively associated with the sonic hedgehog medulloblastoma (MBSHH) subgroup and accounted for 5% of infant MBSHH cases in our cohorts. Molecular tumor profiling revealed a loss of heterozygosity at GPR161 in all affected MBSHH tumors, atypical somatic copy number landscapes, and no additional somatic driver events. Analysis of 226 MBSHH tumors revealed somatic copy-neutral loss of heterozygosity of chromosome 1q as the hallmark characteristic of GPR161 deficiency and the primary mechanism for biallelic inactivation of GPR161 in affected MBSHH tumors. CONCLUSION Here, we describe a novel brain tumor predisposition syndrome that is caused by germline GPR161 mutations and characterized by MBSHH in infants. Additional studies are needed to identify a potential broader tumor spectrum associated with germline GPR161 mutations.

10061 Background: Platinum chemotherapy (CT) and cranial radiotherapy (RT) are risk factors of ototoxicity. Effects of RT dose at inner ear and of other CT were investigated. Methods: Of 7670 5-year childhood cancer survivors from the FCCSS treated before 20 years of age in 1942-2000 for solid cancer or lymphoma, 5243 with ototoxicity long-term follow-up data were included. Severe ototoxicity, defined as the need of hearing aids or Brock grade 3-4 hearing loss, was identified from self-administrated questionnaires, clinical visits and cohort linkage with the French Hospital Database and health insurance information system (SNIIRAM). The mean RT dose at inner ear was estimated using home-made software. Multivariable Cox models adjusted for gender, age at diagnosis, time period and social deprivation index was used to identify risk factors for severe ototoxicity. Results: After a mean follow-up of 30 years, 199 cases of severe ototoxicity were identified. Cumulative incidences at 30 and 50 years of age (30,50y-CumInc) were, 2.8% (95%CI = 2.4-3.3) and 5.5% (4.6-6.5), respectively. Mean RT dose at inner ear (Hazard Ratio HR = 1.6 (95%CI = 1.0-2.5), 4.5 (2.7-7.2), 5.7 (3.0-10.8) and 14.0 (9.2-21.2) for 0- < 5, 5- < 30, 30- < 40 and ≥40 Gy), as well as cisplatin (HR = 2.8, 95%CI = 1.9-4.0), melphalan (HR = 3.3, 95%CI = 1.9-5.7) and busulfan exposure (HR = 2.6, 95%CI = 1.6-4.4) were significantly associated with severe ototoxicity. Concerning melphalan (n = 199/5243 exposed), almost all cases were identified in neuroblostma patients (NBL), who also received cisplatin 200mg/m²/cycle (26/92 NBL, 30y-CumInc = 36.4% (95%CI = 25.9-48.4), vs. 3/107 non-NBL, 30y-CumInc = 1.6% (0.4-5.6)). Concerning busulfan (n = 131/5243 exposed), all cases were identified in NBL (n = 16/63, all treated with melphalan and cisplatin) and brain tumors (n = 13/28, all with RT at inner ear ≥5Gy). The 30y-CumInc in patients with RT at inner ear ≥5Gy was 7.4% (95%CI = 5.7-9.6) and 39.8% (22.5-60.0) respectively with and without busulfan. Conclusions: RT at inner ear has significant deleterious impact on audition, with cumulative incidence still worsening > 30years after RT, and with likely potentiation by busulfan. The deleterious effect of melphalan was related to previous treatment with cisplatin, either by interaction between these drugs, or by the high cisplatin dose by cycle used in NBL.

11014 Background: The survival of pediatric OS is stable worldwide since two decades. The management of OS is lacking new approaches to classify closely the patients and adapt thereafter the treatments. The objectives of our molecular study, using allelotyping, quantitative PCR (qPCR) and droplet digital PCR (ddPCR), were to determine the survival impact of tumor molecular profiling in the initial tumor biopsy, in the tumor resection after neoadjuvant chemotherapy and on circulating DNA at different treatment steps. The gene panel based on biomarkers of bone dedifferentiation was already identified in the large tumor cohort of the French national protocol OS94 and demonstrated a significant prognostic impact of 3 genes MET, TWIST and APC. To go further and understand its significance throughout protocols, the same study was performed in OS2006 tumors. Methods: We applied retrospectively in the cohort of OS2006 protocol (135 patients) the same molecular assessment comprising the targeting of those 3 genes with 3 techniques evaluating their rearrangement by allelotyping, their copy number variations by qPCR and ddPCR. A preliminary cohort of 20 patients with liquid biopsies at diagnosis, before tumor surgery and at the end of chemotherapy was screened by ddPCR. Results: We were able to determine frequent rearrangements in the regions containing these 3 genes and a statistically significant correlation was made between the presence of a gene rearrangement and a worst outcome. The 3-gene signature was significantly predicting the outcome of more than 85% of patients diagnosed for an OS. Furthermore, the persistence of those genes’ rearrangements in the primitive tumor after neoadjuvant chemotherapy comparatively to the initial biopsy was correlated to a higher risk of relapse. This 3-gene signature was also used for assessment of residual disease (RD) in liquid biopsies and was able to determine before tumor surgery the level of RD. Conclusions: This molecular signature seems to be clearly associated with patient outcome and was able to provide evidence that this approach is a powerful tool to be used in pediatric OS follow up to determine early relapse or progression.

Purpose Germline mutations of the SUFU gene have been shown to be associated with genetic predisposition to medulloblastoma, mainly in families with multiple cases of medulloblastoma and/or in patients with symptoms similar to those of Gorlin syndrome. To evaluate the contribution of these mutations to the genesis of sporadic medulloblastomas, we screened a series of unselected patients with medulloblastoma for germline SUFU mutations. Patients and Methods A complete mutational analysis of the SUFU gene was performed on genomic DNA in all 131 consecutive patients treated for medulloblastoma in the pediatrics department of the Institut Gustave Roussy between 1972 and 2009 and for whom a blood sample was available. Results We identified eight germline mutations of the SUFU gene: one large genomic duplication and seven point mutations. Mutations were identified in three of three individuals with medulloblastoma with extensive nodularity, four of 20 with desmoplastic/nodular medulloblastomas, and one of 108 with other subtypes. All eight patients were younger than 3 years of age at diagnosis. The mutations were inherited from the healthy father in four of six patient cases in which the parents accepted genetic testing; de novo mutations accounted for the other two patient cases. Associated events were macrocrania in six patients, hypertelorism in three patients, and multiple basal cell carcinomas in the radiation field after age 18 years in one patient. Conclusion These data indicate that germline SUFU mutations were responsible for a high proportion of desmoplastic medulloblastoma in children younger than 3 years of age. Genetic testing should be offered to all children diagnosed with sonic hedgehog–driven medulloblastoma at a young age.

Purpose The prognostic value of pathologic characteristics of childhood ALK-positive anaplastic large-cell lymphomas (ALCL), such as histologic subtypes, immunophenotype, and presence of the t(2;5) translocation or its variants, was assessed. Patients and Methods All 375 patients with systemic ALK-positive ALCL included in an international trial launched by the European Intergroup for Childhood Non-Hodgkin's Lymphoma were reviewed by an international panel of pathologists based on conventional hematoxylin and eosin–stained and immunostained sections and classified according to the 2001 WHO classification. Results A small-cell (SC) or lymphohistiocytic (LH) component was observed in 114 (32%) of 361 patients, whereas ALCL of common type was diagnosed in 235 (65%) of 361 patients. Regarding the histologic subtyping of patients within the two categories of ALCL (with v without SC/LH component), the concordance between the national and international reviews was quite good, with a κ index equal to 0.67 (95% CI, 0.57 to 0.75). The presence of an SC/LH component was significantly associated with a high risk of failure (hazard ratio [HR], 2.0; 95% CI, 1.3 to 3.0; P = .002) in the multivariate analysis controlling for clinical characteristics, as well as the perivascular pattern (HR, 1.7; 95% CI, 1.1 to 2.7; P = .01), whereas CD3 positivity was significantly associated with a high risk of failure only in univariate analysis. Conclusion Our study, which to our knowledge includes the largest series of childhood systemic ALK-positive ALCL so far, demonstrates the adverse prognostic value of SC and/or LH morphologic features. Combining these histologic characteristics with other biologic or clinical factors might have a high potential for future risk stratification and treatment.

2504Background: Crizotinib (czb) is registered for the treatment of patients (pts) with ALK+ or ROS1+ lung cancer. Czb targets (ALK, MET, ROS1) are also altered (translocation [tlc], amplification ...

1527Background: Li Fraumeni syndrome (LFS) is a rare cancer predisposition caused by TP53 germline mutation associated with a broad tumor spectrum making surveillance very complex. Whole body MRI (...

1535Background: Li Fraumeni syndrome (LFS) is a rare cancer predisposition caused by TP53germline mutation. Its broad cancer spectrum includes breast, sarcoma, brain tumor and leukemia, typically occurring in childhood or young adulthood. The challenge of the LFS clinical management is made even more complex by the suspicion of a much broader spectrum. Methods: The LIFSCREEN French study is an open, randomized, multicentric prospective trial, designed to assess whole body MRI performance. It will evaluate the efficacy and tolerability of 2 screening schemes, performed yearly at least 3 times. At each round, quality of life (QOL) and psychological impact (PI) is assessed. To better define the tumor spectrum, we report here data of the LIFSCREEN participants (pts) and their families, collected at inclusion. Moreover, we describe the cancers identified to date. Results: Any TP53 germline mutation carrier, with or without personal cancer history, aged > 5 and < 71, were included from Oct-2011 to Jan-2015 in 1...

4575 Background: To describe the specific features of malignant renal tumors occurring in young adults. Methods: Medical charts of all 15-35 yo pts diagnosed with a primary renal malignant tumor fr...

10047 Background: Oncologic doses of zoledronic acid (ZOL) are currently evaluated in phase III clinical trials in Europe for the treatment of malignant primary bone tumors in children and adolesce...

10050 Background: This feasibility study intends to characterize genomic alterations in recurrent tumors of an individual pediatric patient in order to select a targeted therapy approach. Methods: ...

TPS1607 Background: The TP53 germline mutation carriers have a huge increase of cancer risk. The cancer spectrum is particularly broad (breast, sarcoma, brain tumour, leukaemia, …). The clinical management of these people is challenging, mainly concerning sarcoma screening. Moreover, some data let speculate that normal cells of these carriers are particular hypersensitive to X-rays. Among major breakthroughs in radiology, whole-body MRI (WBMRI) may contribute to TP53 carriers surveillance. In order to update the french guidelines on Li-Fraumeni families management, the LIFSCREEN study ( NCT01464086 ) was designed to assess its usefulness in France. Methods: This open, randomized, multicentric trial will evaluate the efficacy and tolerability of two screening schemes, avoiding irradiating exams. In the standard arm, people undergo clinical exam, abdominal sonography, brain MRI, Complete Blood Count, breast MRI, breast sonography, depending on the age) at inclusion, Month 12, Month 24, and a study visit at Month 36. In the experimental arm, people included undergo the same scheme, completed by a diffusion WBMRI at M0, M12, M24. At each round, quality of life and psychological impact will be assessed by self-questionnaires and semi-structured qualitative interviews. In an ancillary study, serums will be collected at each step. Subjects meeting these criteria are eligible: any TP53 germline mutation carrier, with or without personal cancer history, aged >5 and

6058 Background: In France pathways of care for adolescent cancer patients are different between pediatric and adult medical background. Health care professionals need to have a population-based vi...

e20665 Background: During the last 30 years, polychemotherapies, surgery and radiotherapy have been established as standard therapies for treating pediatric cancers thus leading to a significant improvement in terms of 5-year-overall-survival which is now around 70% among children and adolescents. On the other hand, these treatments cause severe sequelae such as ovarian failure (OF) in young girls leading to a premature menopause and infertility. Methods: 29 patients treated at the Institute Gustave Roussy (Villejuif, France) have been investigated in an attempt to find biological and/or clinical markers, and imaging predictive of a partial ovarian insufficiency leading to an early menopause. Eligibility criteria: age >12 years at time of analysis; peripheral stem cell graft between 2–20 years; high dose chemotherapy. Results: 23/29 were eligible for this analysis (6 withdrawn due to oral contraception). 13/23 patients (56.5%) show no clinical evidence of ovarian treatment-related toxicity with a 13 years median time to transplant. 10/23 (43.5%) have complete ovarian insufficiency, among whom the majority have already received substitution hormone therapy (SHT). Out of 75% of pre-pubescent patients at transplant, only 2 have OF. All patients grafted at puberty (15.3 years) have high-dose chemotherapy-related immediate or definitive OF. Thiotepa >900mg/mq is castrating (odds ratio-10.1; p-0.04). Dosages of anti-müllerian hormone (AMH) collapses in patients with IO (p=0.002). Mensed patients have lower AMH dosages compared to normal population (p=2.10-e9) as for antral follicule count (>2mm). Conclusions: 1) 13/23 patients show no evidence of OF. 2) Main risk factors of OF: age ≥ 12 years; post pubertal status; thiotepa >900 mg/m2 (OR=10.1 and p=0.04). 3) Despite normal menses, many women who underwent high dose chemotherapy exhibit low AMH and Inhibine B levels and low count of follicles at a young age. These are possible markers of ovarian depletion. Cryopreservation of the ovarian cortex should be proposed to patients grafted due to a cancer independently of the age at which they have undergone high-dose chemotherapy. No significant financial relationships to disclose.

10030 Background: High grade osteosarcomas are the most common malignant bone tumors at adolescence. In the French group, they were treated until 2005 with OS94 guidelines, using a first line therapy of combined high dose-methotrexate and VP16- ifosfamide courses. In the poor response to these drugs, a second line therapy was administered associating doxorubicin and cisplatine. Both therapeutic strategies were based on topisomerase IIα inhibitor. Therefore, a retrospective and prospective molecular study of topoisomerase genes (TOP2A, TOP2B and TOP1) was conducted on diagnostic tumors consecutively collected from this population to understand their therapeutic and prognostic role. Methods: 91 patients were included. Paired normal and tumor biopsy tissues were analyzed by allelotyping, using microsatellites flanking on both sides each locus containing TOP1, TOP2A and TOP2B, coding for topoisomerase genes. These loci are respectively 20q12, 17q21 and 3p24. In addition to these genomic data, quantitative rea...