Search

Purpose: In neuroblastoma (NB), the ALK receptor tyrosine kinase can be constitutively activated through activating point mutations or genomic amplification. We studied ALK genetic alterations in high-risk (HR) patients on the HR-NBL1/SIOPEN trial to determine their frequency, correlation with clinical parameters, and prognostic impact., Materials and Methods: Diagnostic tumor samples were available from 1,092 HR-NBL1/SIOPEN patients to determine ALK amplification status (n = 330), ALK mutational profile (n = 191), or both (n = 571)., Results: Genomic ALK amplification ( ALK a) was detected in 4.5% of cases (41 out of 901), all except one with MYCN amplification (MNA). ALK a was associated with a significantly poorer overall survival (OS) (5-year OS: ALK a [n = 41] 28% [95% CI, 15 to 42]; no- ALK a [n = 860] 51% [95% CI, 47 to 54], [ P < .001]), particularly in cases with metastatic disease. ALK mutations ( ALK m) were detected at a clonal level (> 20% mutated allele fraction) in 10% of cases (76 out of 762) and at a subclonal level (mutated allele fraction 0.1%-20%) in 3.9% of patients (30 out of 762), with a strong correlation between the presence of ALK m and MNA ( P < .001). Among 571 cases with known ALK a and ALK m status, a statistically significant difference in OS was observed between cases with ALK a or clonal ALK m versus subclonal ALK m or no ALK alterations (5-year OS: ALK a [n = 19], 26% [95% CI, 10 to 47], clonal ALK m [n = 65] 33% [95% CI, 21 to 44], subclonal ALK m (n = 22) 48% [95% CI, 26 to 67], and no alteration [n = 465], 51% [95% CI, 46 to 55], respectively; P = .001). Importantly, in a multivariate model, involvement of more than one metastatic compartment (hazard ratio [HR], 2.87; P < .001), ALK a (HR, 2.38; P = .004), and clonal ALKm (HR, 1.77; P = .001) were independent predictors of poor outcome., Conclusion: Genetic alterations of ALK (clonal mutations and amplifications) in HR-NB are independent predictors of poorer survival. These data provide a rationale for integration of ALK inhibitors in upfront treatment of HR-NB with ALK alterations., Competing Interests: Walentyna BalwierzHonoraria: Shire, Gilead Sciences, Novartis, AmgenConsulting or Advisory Role: Amgen, Novartis, Roche, TakedaTravel, Accommodations, Expenses: Jazz Pharmaceuticals, Shire, Roche, Servier Martin ElliottConsulting or Advisory Role: Bayer Dominique Valteau-CouanetConsulting or Advisory Role: EUSA PharmaResearch Funding: Orphelia PharmaPatents, Royalties, Other Intellectual Property: Royalties from Apeiron to SIOPENTravel, Accommodations, Expenses: EUSA Pharma, Jazz Pharmaceuticals Deborah A. TweddleHonoraria: Eusa PharmaTravel, Accommodations, Expenses: EUSA Pharma Ruth LadensteinHonoraria: Apeiron Biologics, Boehringer Ingelheim, EUSA PharmaConsulting or Advisory Role: Apeiron Biologics, Boehringer Ingelheim, EUSA PharmaResearch Funding: Apeiron Biologics, EUSA PharmaPatents, Royalties, Other Intellectual Property: Apeiron Biologics, EUSA PharmaExpert Testimony: Apeiron Biologics, EUSA PharmaTravel, Accommodations, Expenses: Apeiron Biologics, EUSA Pharma Gudrun SchleiermacherHonoraria: BMSResearch Funding: Bristol Myers Squibb, Pfizer, MSDavenir, RocheTravel, Accommodations, Expenses: RocheNo other potential conflicts of interest were reported.

Purpose: Induction therapy is a critical component of the therapy of high-risk neuroblastoma. We aimed to assess if the Memorial Sloan Kettering Cancer Center (MSKCC) N5 induction regimen (MSKCC-N5) would improve metastatic complete response (mCR) rate and 3-year event-free survival (EFS) compared with rapid COJEC (rCOJEC; cisplatin [C], vincristine [O], carboplatin [J], etoposide [E], and cyclophosphamide [C])., Patients and Methods: Patients (age 1-20 years) with stage 4 neuroblastoma or stage 4/4s aged < 1 year with MYCN amplification were eligible for random assignment to rCOJEC or MSKCC-N5. Random assignment was stratified according to national group and metastatic sites. Following induction, therapy comprised primary tumor resection, high-dose busulfan and melphalan, radiotherapy to the primary tumor site, and isotretinoin with ch14.18/CHO (dinutuximab beta) antibody with or without interleukin-2 immunotherapy. The primary end points were mCR rate and 3-year EFS., Results: A total of six hundred thirty patients were randomly assigned to receive rCOJEC (n = 313) or MSKCC-N5 (n = 317). Median age at diagnosis was 3.2 years (range, 1 month to 20 years), and 16 were younger than 1 year of age with MYCN amplification. mCR rate following rCOJEC induction (32%, 86/272 evaluable patients) was not significantly different from 35% (99/281) with MSKCC-N5 ( P = .368), and 3-year EFS was 44% ± 3% for rCOJEC compared with 47% ± 3% for MSKCC-N5 ( P = .527). Three-year overall survival was 60% ± 3% for rCOJEC compared with 65% ± 3% for MSKCC-N5 ( P = .379). Toxic death rates with both regimens were 1%. However, nonhematologic CTC grade 3 and 4 toxicities were higher with MSKCC-N5: 68% (193/283) versus 48% (129/268) ( P < .001); infection 35% versus 25% ( P = .011); stomatitis 25% versus 3% ( P < .001); nausea and vomiting 17% versus 7% ( P < .001); and diarrhea 7% versus 3% ( P = .011)., Conclusion: No difference in outcome was observed between rCOJEC and MSKCC-N5; however, acute toxicity was less with rCOJEC, and therefore rCOJEC is the preferred induction regimen for International Society of Pediatric Oncology European Neuroblastoma Group., Competing Interests: Alberto GaraventaTravel, Accommodations, Expenses: Takeda Dominique Valteau-CouanetConsulting or Advisory Role: EUSA PharmaResearch Funding: Orphelia PharmaPatents, Royalties, Other Intellectual Property: Royalties from Apeiron to SIOPENTravel, Accommodations, Expenses: EUSA Pharma, Jazz Pharmaceuticals Martin ElliottConsulting or Advisory Role: Bayer Godfrey C. F. ChanLeadership: Xelllera, PengeniaConsulting or Advisory Role: Xellera, PengeniaSpeakers' Bureau: Xellera, PengeniaPatents, Royalties, Other Intellectual Property: Xellera, Pengenia Walentyna BalwierzHonoraria: Shire, Gilead Sciences, Novartis, AmgenConsulting or Advisory Role: Amgen, Novartis, Roche, TakedaTravel, Accommodations, Expenses: Jazz Pharmaceuticals, Shire, Roche, Servier Cormac OwensEmployment: Ymabs Therapeutics Inc Vassilios PapadakisHonoraria: EUSA Pharma, NovartisConsulting or Advisory Role: SOBITravel, Accommodations, Expenses: Sanofi, Gilead Sciences, Novartis, Astellas Pharma Toby TrahairStock and Other Ownership Interests: CSL Limited, Osteopore Ltd, Medical Developments International, Cochlear Limited, Sonic Healthcare Limited, Medibank Private LimitedConsulting or Advisory Role: IPSOSExpert Testimony: EUSA Pharma, KMC HealthcareUncompensated Relationships: EUSA Pharma, KMC Healthcare Gudrun SchleiermacherHonoraria: BMSResearch Funding: Bristol Myers Squibb, Pfizer, MSDavenir, RocheTravel, Accommodations, Expenses: Roche Andrew D. J. PearsonConsulting or Advisory Role: Lilly, Takeda, Merck, CelgeneTravel, Accommodations, Expenses: Lilly, Takeda, Merck, Celgene Ruth Lydia LadensteinHonoraria: Apeiron Biologics, Boehringer Ingelheim, EUSA PharmaConsulting or Advisory Role: Apeiron Biologics, Boehringer Ingelheim, EUSA PharmaResearch Funding: Apeiron Biologics, EUSA PharmaPatents, Royalties, Other Intellectual Property: Apeiron Biologics, EUSA PharmaExpert Testimony: Apeiron Biologics, EUSA PharmaTravel, Accommodations, Expenses: Apeiron Biologics, EUSA PharmaNo other potential conflicts of interest were reported.

Intensive treatments including high-dose chemotherapy (HDC) with autologous stem cell rescue have improved high-risk neuroblastoma (HRNB) survival. We report the long-term health status of 145 HRNB survivors, alive and disease-free 5 years post HDC. Median follow-up was 15 years (range = 5-34). Six patients experienced late relapses, 11 developed second malignant neoplasms (SMNs), and 9 died. Event-free and overall survivals 20 years post HDC were 82% (95% CI = 70%-90%) and 89% (78%-95%), respectively. Compared with the French general population, the standardized mortality ratio was 19 (95% CI = 8.7-36.1; p < 0.0001) and the absolute excess risk was 37.6 (19.2-73.5). Late effects were observed in 135/145 patients (median = 3 events/patient); 103 had at least one severe event. SMNs arose at a median of 20 years post HDC and included carcinoma (n = 5), sarcoma (2), acute myeloid leukemia (2), melanoma (1), and malignant glioma (1). Non-oncologic health events included dental maldevelopment (60%), severe hearing loss (20% cumulative probability at 15 years), hepatic focal nodular hyperplasia (14%), thyroid (11%), cardiac (8%), and renal (7%) diseases and growth retardation (height-for-age z-score ≤ -2 for 21%). Gonadal insufficiency was near-universal after busulfan (40/43 females, 33/35 males). Severe late effects are frequent and progressive in HRNB survivors needing systematic very long-term follow-up., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

The survival of patients with high-risk neuroblastoma has improved significantly with the use of intensive multimodality treatment regimens, including chemotherapy, surgery, radiation therapy, myeloablative chemotherapy followed by stem cell rescue, and immunotherapy. This report summarizes the current treatment strategies used in the COG and SIOP for children with neuroblastoma. The improved global collaboration and the adoption of a uniform International Neuroblastoma Risk Group Staging System will help facilitate comparison of homogeneous pretreatment cohorts across clinical trials. Future research strategies regarding the indications for and dosages of radiation therapy to the primary and metastatic sites, and the integration of meta-iodobenzyl guanidine therapy into the multimodal treatment program, are discussed., (© 2021 Wiley Periodicals LLC.)

Background: Long-term outcome remains poor for children with high-risk neuroblastoma (five-year overall survival [OS] ∼50%). Our objectives were to (a) identify prognostic biomarkers and apply them in a nomogram to identify the subgroup of ultra-high-risk patients at highest risk of disease progression/death, for whom novel frontline therapy is urgently needed; and (b) validate the nomogram in an independent cohort., Methods: A total of 1820 high-risk patients (≥18 months old with metastatic neuroblastoma), diagnosed 1998-2015, from the International Neuroblastoma Risk Groups (INRG) Data Commons were analyzed in a retrospective cohort study. Using multivariable Cox regression of OS from diagnosis, a nomogram was created from prognostic biomarkers to predict three-year OS. External validation was performed using the SIOPEN HR-NBL1 trial cohort (n = 521), evidenced by receiver operating characteristic curves., Results: The nomogram, including MYCN status (P < 0.0001), lactate dehydrogenase (LDH) (P = 0.0007), and presence of bone marrow metastases (P = 0.004), had robust performance and was validated. Applying the nomogram at diagnosis (a) gives prognosis of an individual patient and (b) identifies patients predicted to have poor outcome (three-year OS was 30% ± 5% for patients with a nomogram score of > 82 points; 58% ± 1% for those ≤82 points). Median follow-up time was 5.5 years (range, 0-14.1)., Conclusions: In high-risk neuroblastoma, a novel, publicly available nomogram using prognostic biomarkers (MYCN status, LDH, presence of bone marrow metastases; https://neuroblastoma.shinyapps.io/High-Risk-Neuroblastoma-Nomogram/) has the flexibility to apply a clinically suitable and context-specific cutoff to identify patients at highest risk of death. This will facilitate testing urgently needed new frontline treatment options to improve outcome for these children., (© 2020 Wiley Periodicals LLC.)

Background: There is rising concern on the impact of new strategies, such as high-dose chemotherapy (HDC) and immunotherapy, on the pattern of relapse in high-risk neuroblastoma (HR-NBL). Our aim is to evaluate the incidence and identify risk factors for first recurrence in the central nervous system (CNS) in HR-NBL., Patients and Methods: Data from patients with stage 4V HR-NBL included from February 2002 to June 2015 in the prospective HR-NBL trial of the European International Society of Pediatric Oncology Neuroblastoma Group were analysed. Characteristics at diagnosis, treatment and the pattern of first relapse were studied. CNS imaging at relapse was centrally reviewed., Results: The 1977 included patients had a median age of 3 years (1 day-20 years); 1163 were boys. Among the 1161 first relapses, 53 were in the CNS, with an overall incidence of 2.7%, representing 6.2% of all metastatic relapses. One- and three-year post-relapse overall survival was 25 ± 6% and 8 ± 4%, respectively. Higher risk of CNS recurrence was associated with female sex (hazard ratio [HR] = 2.0 [95% confidence interval {CI}: 1.1-3.5]; P = 0.016), MYCN-amplification (HR = 2.4 [95% CI: 1.2-4.4]; P = 0.008), liver (HR = 2.5 [95% CI: 1.2-5.1]; P = 0.01) or >1 metastatic compartment involvement (HR = 7.1 [95% CI: 1.0-48.4]; P = 0.047) at diagnosis. Neither HDC nor immunotherapy was associated with higher risk of CNS recurrence. Stable incidence of CNS relapse was reported over time., Conclusions: The risk of CNS recurrence is linked to both patient and disease characteristics, with neither impact of HDC nor immunotherapy. These findings support the current treatment strategy and do not justify a CNS prophylactic treatment., Competing Interests: Conflict of interest statement The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Given the very poor prognosis for children with recurrent medulloblastoma, we aimed to identify prognostic factors for survival post-relapse in children with childhood medulloblastoma. We retrospectively collected clinico-biological data at diagnosis and main clinical characteristics at relapse of children newly diagnosed with a medulloblastoma between 2007 and 2017 at Gustave Roussy and Necker Hospital. At a median follow-up of 6.6 years (range, 0.4-12.3 years), relapse occurred in 48 out 155 patients (31%). The median time from diagnosis to relapse was 14.3 months (range, 1.2-87.2 months). Relapse was local in 9, metastatic in 22 and combined (local and metastatic) in 17 patients. Second-line treatment consisted of chemotherapy in 31 cases, radiotherapy in 9, SHH-inhibitor in four and no treatment in the remaining four. The 1-year overall survival rate post-relapse was 44.8% (CI 95%, 31.5% to 59.0%). While molecular subgrouping at diagnosis was significantly associated with survival post-relapse, the use of radiotherapy at relapse and time to first relapse (>12 months) might also have a potential impact on post-relapse survival.

Background: Previous pilot studies have shown the feasibility of preoperative chemotherapy in patients with medulloblastoma, but benefits and risks compared with initial surgery have not been assessed., Methods: Two therapeutic strategies were retrospectively compared in 92 patients with metastatic medulloblastoma treated at Gustave Roussy between 2002 and 2015: surgery at diagnosis (n = 54, group A) and surgery delayed after carboplatin and etoposide-based neoadjuvant therapy (n = 38, group B). Treatment strategies were similar in both groups., Results: The rate of complete tumor excision was significantly higher in group B than in group A (93.3% vs 57.4%, P = 0.0013). Postoperative complications, chemotherapy-associated side effects, and local progressions were not increased in group B. Neoadjuvant chemotherapy led to a decrease in the primary tumor size in all patients; meanwhile 4/38 patients experienced a distant progression. The histological review of 19 matched tumor pairs (before and after chemotherapy) showed that proliferation was reduced and histological diagnosis feasible and accurate even after neoadjuvant chemotherapy. The 5-year progression-free and overall survival rates were comparable between groups. Comparison of the longitudinal neuropsychological data showed that intellectual outcome tended to be better in group B (the mean predicted intellectual quotient value was 6 points higher throughout the follow-up)., Conclusion: Preoperative chemotherapy is a safe and efficient strategy for metastatic medulloblastoma. It increases the rate of complete tumor excision and may improve the neuropsychological outcome without jeopardizing survival., Key Points: 1. Preoperative chemotherapy increases the rate of complete tumor removal.2. No additional risk (toxic or disease progression) is linked to the delayed surgery.3. Preoperative chemotherapy could have a positive impact on the neuropsychological outcome of patients., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)

Purpose: For localized, resectable neuroblastoma without MYCN amplification, surgery only is recommended even if incomplete. However, it is not known whether the genomic background of these tumors may influence outcome., Patients and Methods: Diagnostic samples were obtained from 317 tumors, International Neuroblastoma Staging System stages 1/2A/2B, from 3 cohorts: Localized Neuroblastoma European Study Group I/II and Children's Oncology Group. Genomic data were analyzed using multi- and pangenomic techniques and fluorescence in-situ hybridization in 2 age groups (cutoff age, 18 months) and were quality controlled by the International Society of Pediatric Oncology European Neuroblastoma (SIOPEN) Biology Group., Results: Patients with stage 1 tumors had an excellent outcome (5-year event-free survival [EFS] ± standard deviation [SD], 95% ± 2%; 5-year overall survival [OS], 99% ± 1%). In contrast, patients with stage 2 tumors had a reduced EFS in both age groups (5-year EFS ± SD, 84% ± 3% in patients < 18 months of age and 75% ± 7% in patients ≥ 18 months of age). However, OS was significantly decreased only in the latter group (5-year OS ± SD in < 18months and ≥ 18months, 96% ± 2% and 81% ± 7%, respectively; P = .001). In < 18months, relapses occurred independent of segmental chromosome aberrations (SCAs); only 1p loss decreased EFS (5-year EFS ± SD in patients 1p loss and no 1p loss, 62% ± 13% and 87% ± 3%, respectively; P = .019) but not OS (5-year OS ± SD, 92% ± 8% and 97% ± 2%, respectively). In patients ≥ 18 months, only SCAs led to relapse and death, with 11q loss as the strongest marker (11q loss and no 11q loss: 5-year EFS ± SD, 48% ± 16% and 85% ± 7%, P = .033; 5-year OS ± SD, 46% ± 22% and 92% ± 6%, P = .038)., Conclusion: Genomic aberrations of resectable non- MYCN- amplified stage 2 neuroblastomas have a distinct age-dependent prognostic impact. Chromosome 1p loss is a risk factor for relapse but not for diminished OS in patients < 18 months, SCAs (especially 11q loss) are risk factors for reduced EFS and OS in those > 18months. In older patients with SCA, a randomized trial of postoperative chemotherapy compared with observation alone may be indicated.

Patients with cancer are presumed to be at increased risk of severe COVID-19 outcomes due to underlying malignancy and treatment-induced immunosuppression. Of the first 178 patients managed for COVID-19 at the Gustave Roussy Cancer Centre, 125 (70.2%) were hospitalized, 47 (26.4%) developed clinical worsening and 31 (17.4%) died. An age of over 70 years, smoking status, metastatic disease, cytotoxic chemotherapy and an Eastern Cooperative Oncology Group score of ≥2 at the last visit were the strongest determinants of increased risk of death. In multivariable analysis, the Eastern Cooperative Oncology Group score remained the only predictor of death. In contrast, immunotherapy, hormone therapy and targeted therapy did not increase clinical worsening or death risk. Biomarker studies found that C-reactive protein and lactate dehydrogenase levels were significantly associated with an increased risk of clinical worsening, while C-reactive protein and D-dimer levels were associated with an increased risk of death. COVID-19 management impacted the oncological treatment strategy, inducing a median 20 d delay in 41% of patients and adaptation of the therapeutic strategy in 30% of patients., (© 2020. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Purpose: To evaluate the impact of surgeon-assessed extent of primary tumor resection on local progression and survival in patients in the International Society of Pediatric Oncology Europe Neuroblastoma Group High-Risk Neuroblastoma 1 trial., Patients and Methods: Patients recruited between 2002 and 2015 with stage 4 disease > 1 year or stage 4/4S with MYCN amplification < 1 year who had completed induction without progression, achieved response criteria for high-dose therapy (HDT), and had no resection before induction were included. Data were collected on the extent of primary tumor excision, severe operative complications, and outcome., Results: A total of 1,531 patients were included (median observation time, 6.1 years). Surgeon-assessed extent of resection included complete macroscopic excision (CME) in 1,172 patients (77%) and incomplete macroscopic resection (IME) in 359 (23%). Surgical mortality was 7 (0.46%) of 1,531. Severe operative complications occurred in 142 patients (9.7%), and nephrectomy was performed in 124 (8.8%). Five-year event-free survival (EFS) ± SE (0.40 ± 0.01) and overall survival (OS; 0.45 ± 0.02) were significantly higher with CME compared with IME (5-year EFS, 0.33 ± 0.03; 5-year OS, 0.37 ± 0.03; P < .001 and P = .004). The cumulative incidence of local progression (CILP) was significantly lower after CME (0.17 ± 0.01) compared with IME (0.30 ± 0.02; P < .001). With immunotherapy, outcomes were still superior with CME versus IME (5-year EFS, 0.47 ± 0.02 v 0.39 ± 0.04; P = .038); CILP was 0.14 ± 0.01 after CME and 0.27 ± 0.03 after IME ( P < .002). A hazard ratio of 1.3 for EFS associated with IME compared with CME was observed before and after the introduction of immunotherapy ( P = .030 and P = .038)., Conclusion: In patients with stage 4 high-risk neuroblastoma who have responded to induction therapy, CME of the primary tumor is associated with improved survival and local control after HDT, local radiotherapy (21 Gy), and immunotherapy.

Purpose: The Children's Oncology Group (COG) stratifies the treatment of patients with neuroblastoma on the basis of a combination of biomarkers that include age and tumor histology classified by age-linked International Neuroblastoma Pathology Classification (INPC) criteria. By definition, this leads to a duplication of the prognostic contribution of age. The individual histologic features underlying the INPC have prognostic strength and are incorporated in the International Neuroblastoma Risk Group classification schema. Here, we analyzed data in the International Neuroblastoma Risk Group Data Commons to validate the prognostic strength of the underlying INPC criteria and to determine whether a risk classification devoid of the confounding of age and INPC criteria will identify new prognostic subgroups., Patients and Methods: Event-free survival of patients diagnosed between 1990 and 2002 (cohort 1; n = 10,104) and between 2003 and 2016 (cohort 2; n = 8,761) was analyzed. Recursive partitioning with univariate Cox models of event-free survival ("survival tree regression") was performed using (1) individual INPC criteria (age at diagnosis, histologic category, mitosis-karyorrhexis index (MKI), grade of differentiation) and (2) factors in (1) plus other COG-risk biomarkers (International Neuroblastoma Staging System [INSS] stage, MYCN status, ploidy)., Results: The independent prognostic ability of age, histologic category, MKI, and grade were validated. Four histologic prognostic groups were identified (< 18 months with low v high MKI, and ≥ 18 months with differentiating v undifferentiated/poorly differentiating tumors). Compared with survival trees generated with established COG risk criteria, an additional prognostic subgroup was identified and validated when individual histologic features were analyzed in lieu of INPC., Conclusion: Replacing INPC with individual histologic features in the COG risk classification will eliminate confounding, facilitate international harmonization of risk classification, and provide a schema for more precise prognostication and refined therapeutic approaches.

Purpose: Wilms tumor (WT), or nephroblastoma, is an embryonic tumor that constitutes the most common renal tumor in children. Little is known about the etiology of WT. The aim of this study was to investigate whether maternal or perinatal characteristics were associated with the risk of WT., Methods: The ESTELLE study is a national-based case-control study that included 117 cases of WT and 1,100 controls younger than 11 years old. The cases were children diagnosed in France in 2010-2011 and the controls were frequency matched with cases by age and gender. The mothers of case and control children responded to a telephone questionnaire addressing sociodemographic and perinatal characteristics, childhood environment, and lifestyle. Unconditional logistic regression models adjusted on potential cofounders were used to estimate the odds ratios (OR) and their confidence intervals (95% CI)., Results: High birth weight and the presence of congenital malformation were associated with WT (OR 1.9 [95% CI 1.0-3.7] and OR 2.5 [95% CI 1.1-5.8], respectively). No association with breastfeeding or folic acid supplementation was observed., Conclusions: Although potential recall bias cannot be excluded, our findings reinforce the hypothesis that high birth weight and the presence of congenital malformation may be associated with an increased risk of WT. Further investigations are needed to further elucidate the possible role of maternal characteristics in the etiology of WT.

To explore the effects of immunotherapy in the International Society of Paediatric Oncology Europe Neuroblastoma Group SIOPEN high-risk neuroblastoma 1 trial (HR-NBL1 trial), two cohorts were studied: one prior to and one after the introduction of dinutuximab beta. All patients received standard induction and high-dose therapy (HDT) with autologous stem cell rescue (ASCR); the local control comprised surgery and radiotherapy to the primary tumour site, followed by isotretinoin. A landmark timepoint of 109 days, resulting from the median time between ASCR and initiation of immunotherapy, was used to define patients' eligibility in the pre-immunotherapy analysis cohort. Median follow-up was 5.8 years (inter-quartile range (IQR): 4.2-8.2 years) for 844 eligible patients balanced for risk factors, such as age, sex, stage 4, MYCN amplification and response prior to HDT. The five-year event-free and overall survival (95% confidence interval (CI) of 466 patients not receiving immunotherapy was 42% (38-47%) and 50% (46-55%) but was 57% (51-62%) and 64% (59-69%) for 378 patients receiving immunotherapy ( p < 0.001). A multivariate analysis identified absence of immunotherapy (p = 0.0002, hazard ratio (HR) 1.573); type of HDT ( p = 0.0029, HR 1.431); less than complete response prior to maintenance therapy ( p = 0.0043, HR 1.494) and >1 metastatic compartment at diagnosis ( p < 0.001, HR 2.665) as risk factors for relapse or progression. Results suggest an important role for dinutuximab beta-based immunotherapy within the treatment concepts applied in HR-NBL1/SIOPEN., Competing Interests: The academic data supported APEIRON to obtain the dinutuximab beta product licensure in May 2017 in the European Union (EMA). SIOPEN and CCRI established a contract with APEIRON regarding the provision of academic data. Ruth Ladenstein and Holger Lode acted as consultants for APEIRON on behalf of SIOPEN for the ch14.18/CHO development. The other authors declare no conflict of interest.

Neuroblastoma is the most frequent extra-cranial pediatric solid tumor, occurring in young children, 90% being less than 5 years at diagnosis. It remains a therapeutic challenge since survival of high-risk neuroblastoma patients that represent around 50% of the patients is around 50% in spite of extensive combined treatments. Immunotherapy based on the use of antibodies directed to GD2, a ganglioside strongly expressed by almost all neuroblastoma cells, has been developed during the last decade. In SIOPEN studies have shown that dinatuximab beta (Qarziba ® ) is effective on refractory/relapsed patients and improves survival when administered in the first line maintenance treatment. Other strategies are currently explored using combination with chemotherapy at relapse and evaluating the benefits of an earlier administration during the induction treatment. In addition, more selective antibodies are also developed to decrease toxicity, especially neuropathic pain that is one of the major toxic effect., (© 2019 médecine/sciences – Inserm.)

The Ethics committee of Gustave Roussy cancer center is devoted to both reflection and action. The group has 40 members, professionals, patients and outside experts. These meet in plenary meetings or in specific working sessions and intervene at the request of any professional faced with ethical questions in the care. This Ethics Committee has voluntarily a double vocation: on one hand, a reflective group on major issues of ethics in health and its involvement in hospital life; on the other hand, a working group embedded in the daily lives of the care. The themes addressed at the meetings (plenary sessions, annual meetings) include shared-decision making, advance directives, refusal of care, religious aspects, or biomedical research… Daily activity centered on the care revolves around several times a week meetings, in various services, "Supportive Collegial Meetings" such as proposed in the 3rd French Cancer Plan; these include nursing staff members, oncologists, intensive and palliative care specialists, psychologist, around difficult medical and/or ethical situations. In case of situation requiring an urgent discussion, a referral to the Ethics Committee brings together within 24hours four to five members of the Committee and the care team. Moreover, the Ethics Committee helped develop Aid to Decision making Form upon care gradation for hospitalized cancer patients. Through these interventions on a daily basis, assistance of professionals, reflexive vocation or even delivery of training, the Ethics Committee contributes to an acculturation around anticipation and collegiality in the care. Its double polarity aims to reconcile "philosophical time' for the ethics process, and the connection with the routine issues raised by patients, their families and caregivers., (Copyright © 2019 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.)

Neuroblastoma (NB) is the most common extra-cranial tumour in children. Little is known about the aetiology of NB. The early age at onset and the embryonic nature suggest a role for perinatal exposures. We conducted a pooled analysis of two French national population-based case-control studies to explore whether there was an association between parental smoking and alcohol consumption and the risk of NB. The mothers of 357 NB cases and 1,783 controls from general population, frequency matched by age and sex, were interviewed on demographic, socioeconomic and perinatal characteristics, maternal reproductive story, and life-style and childhood environment. Unconditional logistic regression was used to estimate pooled odds ratios and 95% confidence intervals. A meta-analysis of our findings with those of previous studies was also conducted. Maternal smoking during pregnancy was slightly more often reported for the cases (24.1%) than for the controls (19.7%) (OR 1.3 [95% CI 0.9-1.7]; summary OR from meta-analysis 1.1 [95% CI 1.0-1.3]. Paternal smoking in the year before child's birth were not associated with NB as independent exposure (OR 1.1 [95% CI 0.9-1.4] but the association was stronger when both parents reported having smoked during pregnancy (OR 1.5 [95% CI 1.1-2.1]. No association was observed with maternal alcohol intake during pregnancy (OR 1.0 [95% CI 0.8-1.4], summary OR from meta-analysis 1.0 [95% CI 0.9-1.2]. Our findings provide some evidence of an association between maternal smoking during pregnancy and NB and add another reason to recommend that women refrain from smoking during pregnancy., (© 2019 UICC.)

In neuroblastoma (NB), genetic alterations in chromatin remodeling (CRGs) and epigenetic modifier genes (EMGs) have been described. We sought to determine their frequency and clinical impact. Whole exome (WES)/whole genome sequencing (WGS) data and targeted sequencing (TSCA®) of exonic regions of 33 CRGs/EMGs were analyzed in tumor samples from 283 NB patients, with constitutional material available for 55 patients. The frequency of CRG/EMG variations in NB cases was then compared to the Genome Aggregation Database (gnomAD). The sequencing revealed SNVs/small InDels or focal CNAs of CRGs/EMGs in 20% (56/283) of all cases, occurring at a somatic level in 4 (7.2%), at a germline level in 12 (22%) cases, whereas for the remaining cases, only tumor material could be analyzed. The most frequently altered genes were ATRX (5%), SMARCA4 (2.5%), MLL3 (2.5%) and ARID1B (2.5%). Double events (SNVs/small InDels/CNAs associated with LOH) were observed in SMARCA4 (n = 3), ATRX (n = 1) and PBRM1 (n = 1). Among the 60 variations, 24 (8.4%) targeted domains of functional importance for chromatin remodeling or highly conserved domains but of unknown function. Variations in SMARCA4 and ATRX occurred more frequently in the NB as compared to the gnomAD control cohort (OR = 4.49, 95%CI: 1.63-9.97, p = 0.038; OR 3.44, 95%CI: 1.46-6.91, p = 0.043, respectively). Cases with CRG/EMG variations showed a poorer overall survival compared to cases without variations. Genetic variations of CRGs/EMGs with likely functional impact were observed in 8.4% (24/283) of NB. Our case-control approach suggests a role of SMARCA4 as a player of NB oncogenesis., (© 2019 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Introduction: Prognosis of dumbbell neuroblastoma (NBL) is mainly determined by the sequelae induced by the tumor itself and the neurosurgical approach. However, after primary chemotherapy, surgical management of the residual tumor, especially the spinal canal component, remains controversial., Methods: We conducted a single-center retrospective cohort study over the last 15 years (2002-2017) including patients treated for NBL with spinal canal extension focusing on timing and type of surgery, complications, and functional and oncological follow-up., Results: Thirty-two children (14 M, 18 F) were managed for NBL, with the majority (26) presenting with NBL stroma poor while four had ganglioneuroblastoma intermixed, one nodular, and one ganglioneuroma. All but two patients received neoadjuvant chemotherapy. Upfront laminotomy for spinal cord decompression was performed in two patients; nine patients had extraspinal surgery with a follow-up neurosurgical procedure in seven cases; eight patients had initial neurosurgery followed by an extraspinal procedure, while six patients underwent a combined multidisciplinary approach. With a median follow up of 3.6 years (0.1-14.9), 29 patients (90.6) are alive and two out of three (19, 65.5%) have functional sequelae., Conclusion: Patients with NBL with persistent spinal canal extension of the tumor after neoadjuvant chemotherapy treated at our center had outcomes that compare favorably with the literature. This is likely due to the multidisciplinary approach to optimal surgical strategy and continuous evaluation of the respective risks of tumor progression. Neurological disability results from initial spinal cord compression or the radicular sacrifice required for tumor resection., (© 2019 Wiley Periodicals, Inc.)

Introduction: The preservation of fertility is an integral part of care of children requiring gonadotoxic treatments for cancer or non-malignant diseases. In France, the cryopreservation of ovarian tissue has been considered and has been offered as a clinical treatment since its inception. The aim of this study is to review 20 years of activity in fertility preservation by ovarian tissue cryopreservation (OTC) for children and the feasibility of oocyte isolation and cryopreservation from the ovarian tissue at a single center., Material and Methods: Retrospective study including patients aged 15 years or younger who underwent OTC, combined for some with oocyte cryopreservation of isolated oocytes, before a highly gonadotoxic treatment for malignant or non-malignant disease was initiated. We describe the evolution of activities in our program for fertility preservation and patient characteristics at the time of OTC and follow up., Results: From April 1998 to December 2018, 418 girls and adolescents younger than 15 years of age underwent OTC, representing 40.5% of all females who have had ovarian tissue cryopreserved at our center. In all, 313 patients had malignant diseases and 105 had benign conditions. Between November 2009 and July 2013, oocytes were isolated and also cryopreserved in 50 cases. The mean age of patients was 6.9 years (range 0.3-15). The most frequent diagnoses in this cohort included neuroblastoma, acute leukemia and hemoglobinopathies; neuroblastoma being the most common diagnosis in very young patients. During follow up, three patients requested the use of their cryopreserved ovarian tissue. All had undergone ovarian tissue transplantation, one for puberty induction and the two others for restoring fertility. So far, no pregnancies have been achieved. Eighty-four patients who had OTC died., Conclusions: Ovarian tissue cryopreservation is the only available technique for preserving fertility of girls. To our knowledge this is the largest series of girls and adolescents younger than 15 years so far reported on procedures of OTC before highly gonadotoxic treatment in a single center., (© 2019 Nordic Federation of Societies of Obstetrics and Gynecology.)

Given the biological and clinical heterogeneity of neuroblastoma, risk stratification is vital to determining appropriate treatment. Historically, most patients with high-risk neuroblastoma (HR-NBL) have been treated uniformly without further stratification. Attempts have been made to identify factors that can be used to risk stratify these patients and to characterize an "ultra-high-risk" (UHR) subpopulation with particularly poor outcome. However, among published data, there is a lack of consensus in the definition of the UHR population and heterogeneity in the endpoints and statistical methods used. This review summarizes our current understanding of stratification of HR-NBL and discusses the complex issues in defining UHR neuroblastoma., (© 2018 Wiley Periodicals, Inc.)

Background and Purpose: Conventional treatments of systemic chemotherapy and surgical resection for recurrent or metastatic hepatoblastoma (HB) may be inhibitive for the pediatric patient and family who have already been through extensive therapies. This single-institution case series evaluates the safety and efficacy of percutaneous radiofrequency ablation (RFA) in the management of metastatic HB., Materials and Methods: Between March 2008 and February 2015, RFA was used as part of multidisciplinary management for HB recurrence or metastasis in 5 children (median 5.0 years old) in an attempt to provide locoregional control and preclude additional surgery. Combined local treatments of 38 metachronous metastases included surgical metastasectomy (14 lesions: 7 lung, 7 liver), percutaneous RFA (23 lesions: 21 lung, 1 liver, 1 bone), and stereotactic radiotherapy (1 liver lesion)., Results: For lesions treated with RFA (median diameter 6 mm, range 3-15 mm), local control was achieved in 22/23 metastases (95.6%) with median follow-up of 30.1 months after RFA (range 18.9-65.7). Median hospitalization was 3 days (2-7), with major complications limited to 1 pneumothorax requiring temporary small-caliber chest tube. Four children remain in complete remission with median follow-up of 67 months (range 41.2-88.8) after primary tumor resection, with mean disease-free survival of 31.7 months after last local treatment. One child succumbed to rapidly progressive disease 12 months after RFA (23.9 months after primary tumor resection)., Conclusion: RFA provides a safe and effective reiterative treatment option in the multidisciplinary management of children with metastatic HB.

Purpose: To investigate intellectual and situation-based social outcome and educational achievement in adult survivors of childhood medulloblastoma and analyse factors influencing outcome Methods: We collected demographic, medical and cognitive data, and social and educational outcome at a mean time since the end of treatments of 14.9 years in 58 adults, aged 19-35 years, consecutively treated in a single cancer center between 1989 and 2005., Results: Ten survivors had severe intellectual disability, 12 were still studying, 23 had a regular employment and 13 were unemployed. Full Scale Intellectual Quotient, assessed 6.6 years after the end of treatments, ranged from 46 to 131. It was strongly associated with educational achievement and significantly lower in patients who experienced postoperative cerebellar mutism, and when parental education level was low., Conclusion: These factors should be systematically considered at diagnosis in order to offer adequate and timely assessments and interventions.

Background: Immunotherapy with the chimeric anti-GD2 monoclonal antibody dinutuximab, combined with alternating granulocyte-macrophage colony-stimulating factor and intravenous interleukin-2 (IL-2), improves survival in patients with high-risk neuroblastoma. We aimed to assess event-free survival after treatment with ch14.18/CHO (dinutuximab beta) and subcutaneous IL-2, compared with dinutuximab beta alone in children and young people with high-risk neuroblastoma., Methods: We did an international, open-label, phase 3, randomised, controlled trial in patients with high-risk neuroblastoma at 104 institutions in 12 countries. Eligible patients were aged 1-20 years and had MYCN-amplified neuroblastoma with stages 2, 3, or 4S, or stage 4 neuroblastoma of any MYCN status, according to the International Neuroblastoma Staging System. Patients were eligible if they had been enrolled at diagnosis in the HR-NBL1/SIOPEN trial, had completed the multidrug induction regimen (cisplatin, carboplatin, cyclophosphamide, vincristine, and etoposide, with or without topotecan, vincristine, and doxorubicin), had achieved a disease response that fulfilled prespecified criteria, had received high-dose therapy (busulfan and melphalan or carboplatin, etoposide, and melphalan) and had received radiotherapy to the primary tumour site. In this component of the trial, patients were randomly assigned (1:1) to receive dinutuximab beta (20 mg/m 2 per day as an 8 h infusion for 5 consecutive days) or dinutuximab beta plus subcutaneous IL-2 (6 × 10 6 IU/m 2 per day on days 1-5 and days 8-12 of each cycle) with the minimisation method to balance randomisation for national groups and type of high-dose therapy. All participants received oral isotretinoin (160 mg/m 2 per day for 2 weeks) before the first immunotherapy cycle and after each immunotherapy cycle, for six cycles. The primary endpoint was 3-year event-free survival, analysed by intention to treat. This trial was registered with ClinicalTrials.gov, number NCT01704716, and EudraCT, number 2006-001489-17, and recruitment to this randomisation is closed., Findings: Between Oct 22, 2009, and Aug 12, 2013, 422 patients were eligible to participate in the immunotherapy randomisation, of whom 406 (96%) were randomly assigned to a treatment group (n=200 to dinutuximab beta and n=206 to dinutuximab beta with subcutaneous IL-2). Median follow-up was 4·7 years (IQR 3·9-5·3). Because of toxicity, 117 (62%) of 188 patients assigned to dinutuximab beta and subcutaneous IL-2 received their allocated treatment, by contrast with 160 (87%) of 183 patients who received dinutuximab beta alone (p<0·0001). 3-year event-free survival was 56% (95% CI 49-63) with dinutuximab beta (83 patients had an event) and 60% (53-66) with dinutuximab beta and subcutaneous IL-2 (80 patients had an event; p=0·76). Four patients died of toxicity (n=2 in each group); one patient in each group while receiving immunotherapy (n=1 congestive heart failure and pulmonary hypertension due to capillary leak syndrome; n=1 infection-related acute respiratory distress syndrome), and one patient in each group after five cycles of immunotherapy (n=1 fungal infection and multi-organ failure; n=1 pulmonary fibrosis). The most common grade 3-4 adverse events were hypersensitivity reactions (19 [10%] of 185 patients in the dinutuximab beta group vs 39 [20%] of 191 patients in the dinutuximab plus subcutaneous IL-2 group), capillary leak (five [4%] of 119 vs 19 [15%] of 125), fever (25 [14%] of 185 vs 76 [40%] of 190), infection (47 [25%] of 185 vs 64 [33%] of 191), immunotherapy-related pain (19 [16%] of 122 vs 32 [26%] of 124), and impaired general condition (30 [16%] of 185 vs 78 [41%] of 192)., Interpretation: There is no evidence that addition of subcutaneous IL-2 to immunotherapy with dinutuximab beta, given as an 8 h infusion, improved outcomes in patients with high-risk neuroblastoma who had responded to standard induction and consolidation treatment. Subcutaneous IL-2 with dinutuximab beta was associated with greater toxicity than dinutuximab beta alone. Dinutuximab beta and isotretinoin without subcutaneous IL-2 should thus be considered the standard of care until results of ongoing randomised trials using a modified schedule of dinutuximab beta and subcutaneous IL-2 are available., Funding: European Commission 5th Frame Work Grant, St. Anna Kinderkrebsforschung, Fondation ARC pour la recherche sur le Cancer., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

New Perspectives in Immunotherapies for Pediatric Malignancies: New therapeutic paradigms are needed to improve the survival of children and adolescents with high-risk malignancies, and to reduce the sequelae associated with treatment. Immunotherapies, targeting tumor cells and/or the immune system to enhance existing anti-tumor immunity or induce novel anti-tumor immune responses, are becoming increasingly successful in adult oncology. Based on the results obtained with anti-ganglioside2 antibodies in neuroblastoma, rituximab in mature B malignancies, immune checkpoint inhibitors in lymphoma and especially in Hodgkin lymphoma, blinatumomab and CAR-T CD19 cells for B-cell acute lymphoblastic leukemia, immunotherapy has demonstrated irrefutable benefits in pediatric patients. However, these results are currently limited to a minority of patients and histologies. Current and ongoing trials tend to focus on a single type of immunotherapy, but it is likely that combinations of immunotherapies with different mechanisms of action or combination with other classes of anti-cancer treatments will be additives or even synergistic. The development of this new class of drugs in the treatment of pediatric cancers has multiple challenges: to better evaluate the response to treatment, to define the optimal doses and schedules, to manage immuno-mediated toxicities, to identify its specific sequelae, and, finally, to better understand the strategies of immune evasion of pediatric cancers in order to develop efficient immunotherapies., (© 2018 Société Française du Cancer. Publié par Elsevier Masson SAS. Tous droits réservés.)

Background: Risk stratification is crucial to treatment decision-making in neuroblastoma. This study aimed to explore factors present at diagnosis affecting outcome in patients aged ≥18 months with metastatic neuroblastoma and to develop a simple risk score for prognostication., Procedure: Data were derived from the European high-risk neuroblastoma 1 (HR-NBL1)/International Society for Paediatric Oncology European Neuroblastoma (SIOPEN) trial with analysis restricted to patients aged ≥18 months with metastatic disease and treated prior to the introduction of immunotherapy. Primary endpoint was 5-year event-free survival (EFS). Prognostic factors assessed were sex, age, tumour MYCN amplification (MNA) status, serum lactate dehydrogenase (LDH)/ferritin, primary tumour and metastatic sites. Factors significant in univariate analysis were incorporated into a multi-variable model and an additive scoring system developed based on estimated log-cumulative hazard ratios., Results: The cohort included 1053 patients with median follow-up 5.5 years and EFS 27 ± 1%. In univariate analyses, age; serum LDH and ferritin; involvement of bone marrow, bone, liver or lung; and >1 metastatic system/compartment were associated with worse EFS. Tumour MNA was not associated with worse EFS. A multi-variable model and risk score incorporating age (>5 years, 2 points), serum LDH (>1250 U/L, 1 point) and number of metastatic systems (>1, 2 points) were developed. EFS was significantly correlated with risk score: EFS 52 ± 9% for score = 0 versus 6 ± 3% for score = 5 (P < 0.0001)., Conclusions: A simple score can identify an "ultra-high risk" (UHR) cohort (score = 5) comprising 8% of patients with 5-year EFS <10%. These patients appear not to benefit from induction therapy and could potentially be directed earlier to alternative experimental therapies in future trials., (© 2018 Wiley Periodicals, Inc.)

GD₂-directed immunotherapies improve survival of high-risk neuroblastoma (NB) patients (pts). Treatment with chimeric anti-GD₂ antibodies (Ab), such as ch14.18, can induce development of human anti-chimeric Ab (HACA). Here, we report HACA effects on ch14.18/CHO pharmacokinetics, pharmacodynamics and pain intensity in pts treated by long-term infusion (LTI) of ch14.18/CHO combined with IL-2. 124 pts received up to 5 cycles of ch14.18/CHO 10 days (d) infusion (10 mg/m²/d; d8⁻18) combined with s.c. IL-2 (6 × 10⁶ IU/m²/d; d1⁻5, d8⁻12). HACA, treatment toxicity, ch14.18/CHO levels, Ab-dependent cellular- (ADCC) and complement-dependent cytotoxicity (CDC) were assessed using respective validated assays. HACA-negative pts showed a steadily decreased pain in cycle 1 (74% pts without morphine by d5 of LTI) with further decrease in subsequent cycles. Ch14.18/CHO peak concentrations of 11.26 ± 0.50 µg/mL found in cycle 1 were further elevated in subsequent cycles and resulted in robust GD₂-specific CDC and ADCC. Development of HACA (21% of pts) resulted in strong reduction of ch14.18/CHO levels, abrogated CDC and ADCC. Surprisingly, no difference in pain toxicity between HACA-positive and -negative pts was found. In conclusion, ch14.18/CHO LTI combined with IL-2 results in strong activation of Ab effector functions. Importantly, HACA response abrogated CDC but did not affect pain intensity indicating CDC-independent pain induction.

Background: Neuroblastoma is characterized by substantial clinical heterogeneity. Despite intensive treatment, the survival rates of high-risk neuroblastoma patients are still disappointingly low. Somatic chromosomal copy number aberrations have been shown to be associated with patient outcome, particularly in low- and intermediate-risk neuroblastoma patients. To improve outcome prediction in high-risk neuroblastoma, we aimed to design a prognostic classification method based on copy number aberrations., Methods: In an international collaboration, normalized high-resolution DNA copy number data (arrayCGH and SNP arrays) from 556 high-risk neuroblastomas obtained at diagnosis were collected from nine collaborative groups and segmented using the same method. We applied logistic and Cox proportional hazard regression to identify genomic aberrations associated with poor outcome., Results: In this study, we identified two types of copy number aberrations that are associated with extremely poor outcome. Distal 6q losses were detected in 5.9% of patients and were associated with a 10-year survival probability of only 3.4% (95% confidence interval [CI] = 0.5% to 23.3%, two-sided P = .002). Amplifications of regions not encompassing the MYCN locus were detected in 18.1% of patients and were associated with a 10-year survival probability of only 5.8% (95% CI = 1.5% to 22.2%, two-sided P < .001)., Conclusions: Using a unique large copy number data set of high-risk neuroblastoma cases, we identified a small subset of high-risk neuroblastoma patients with extremely low survival probability that might be eligible for inclusion in clinical trials of new therapeutics. The amplicons may also nominate alternative treatments that target the amplified genes.

Purpose: The purpose of this study was to evaluate the long-term cognitive sequelae and to describe the neuropsychological profile of patients with intracranial germ cell tumors according to tumor location (pineal or suprasellar site)., Patients and Methods: Forty-five children treated at Gustave Roussy between 1991 and 2010 were assessed with neuropsychological tests to measure IQ, memory, visuospatial, motor, and executive skills at a mean delay of 4.2 years after diagnosis. All patients have received chemotherapy associated with surgery in 17 cases. Thirty-nine patients received, radiotherapy (focal 27, focal plus ventricles 8, craniospinal 4). Twenty-three patients had 2 IQ assessments with a mean delay of 4.1 years between the first and second., Results: Full scale IQ was preserved, with higher verbal IQ than other IQ indexes. Visuospatial, fine-motor, and executive difficulties were present in a significant proportion of patients. Visuospatial and fine-motor deficits were significantly associated with oculomotor difficulties, more present in the pineal than in the suprasellar group. No cognitive decline was observed between the first and the second IQ assessment., Conclusions: Overall cognitive abilities were preserved in children treated for central nervous system germ cell tumor.

High-risk neuroblastoma comprises nearly half of cases of neuroblastoma and the long-term survival is less than 50% despite complex and intensive treatments. Studies conducted in Europe and in North America in the last two decades have identified a strategy based on four therapeutic phases: an intensive induction therapy, a local control by surgery and radiation, a consolidation phase with single or tandem high dose chemotherapy and autologous transplant, and immunotherapy to eliminate residual disease. Future treatment improvements are based on progress at each of these therapeutic steps and ultimately a better stratification of the strategy adapted to the type of risk. A more extensive tumor molecular profiling at diagnosis and relapse will help to develop new therapeutics and to guide risk-based strategies. Earlier use of immunotherapy and identification of more effective combinations in induction or in maintenance treatment, identification of indications of more intense consolidations using high-dose chemotherapy combined or not with metabolic irradiation by 131I-MIBG and the introduction of other targeted treatments are tracks being explored., (Copyright © 2018. Published by Elsevier Masson SAS.)

High-risk neuroblastoma is characterized by poor long-term survival, especially for very high-risk (VHR) patients (poor response of metastases after induction therapy). The benefits of a tandem high-dose therapy and hematologic stem cell reinfusion (HSCR) have been shown in these patients. Further dose escalation will be limited by toxicity. It is thus important to evaluate the efficacy and tolerability of the addition of new agents such as I-MIBG (131Iode metaiodobenzylguanidine) to be combined with high-dose therapy in the consolidation phase. We report the feasibility of busulfan/melphalan (BuMel) after I-MIBG therapy with HSCR in patients with refractory or relapsed metastatic neuroblastoma. From November 2008 to March 2015, 9 patients received BuMel after I-MIBG therapy and topotecan. The main toxicity was digestive with only 1 patient developing grade 4 sinusoidal obstructive syndrome. Seven patients are alive at a median follow-up of 25 months. Among them, 2 are in ongoing complete remission and 1 in ongoing stable disease. These results suggest that BuMel with HSCR can be administered safely 2 months after I-MIBG therapy associated with topotecan for VHR patients. This strategy will be compared with tandem high-dose chemotherapy (thiotepa and busulfan-melphalan), followed by HSCR in the upcoming SIOPEN VHR Neuroblastoma Protocol.

Background: Germline mutations of suppressor of fused homolog (SUFU) predispose to sonic hedgehog (SHH) medulloblastoma. Germline SUFU mutations have been reported in nevoid basal cell carcinoma syndrome (NBCCS), but little is known about the cancer risk and clinical spectrum., Methods: We performed a retrospective review of all patients with medulloblastoma and a germline SUFU mutation in France., Results: Twenty-two patients from 17 families were identified with medulloblastoma and a germline SUFU mutation (median age at diagnosis: 16.5 mo). Macrocrania was present in 20 patients, but only 5 met the diagnostic criteria for NBCCS. Despite treatment with surgery and chemotherapy, to avoid radiotherapy in all patients except one, the outcome was worse than expected for SHH medulloblastoma, due to the high incidence of local relapses (8/22 patients) and second malignancies (n = 6 in 4/22 patients). The 5-year progression-free survival and overall survival rates were 42% and 66%. Mutations were inherited in 79% of patients, and 34 additional SUFU mutation carriers were identified within 14 families. Medulloblastoma penetrance was incomplete, but higher than in Patched 1 (PTCH1) mutation carriers. Besides medulloblastoma, 19 other tumors were recorded among the 56 SUFU mutation carriers, including basal cell carcinoma (BCC) in 2 patients and meningioma in 3 patients., Conclusion: Germline SUFU mutations strongly predispose to medulloblastoma in the first years of life, with worse prognosis than usually observed for SHH medulloblastoma. The clinical spectrum differs between SUFU and PTCH1 mutation carriers, and BCC incidence is much lower in SUFU mutation carriers. The optimal treatment of SUFU mutation-associated medulloblastoma has not been defined.

Background: The purpose of this study was to evaluate whether levels of neuroblastoma mRNAs in bone marrow and peripheral blood from stage M infants (≤12 months of age at diagnosis, MYCN amplified) and toddlers (between 12 and 18 months, any MYCN status) predict event-free survival (EFS)., Methods: Bone marrow aspirates and peripheral blood samples from 97 infants/toddlers enrolled in the European High-Risk Neuroblastoma trial were collected at diagnosis in PAXgene ™ blood RNA tubes. Samples were analyzed by reverse transcription quantitative polymerase chain reaction according to standardized procedures., Results: Bone marrow tyrosine hydroxylase (TH) or paired-like homeobox 2b (PHOX2B) levels in the highest tertile were associated with worse EFS; hazard ratios, adjusted for age and MYCN status, were 1.5 and 1.8 respectively. Expression of both TH and PHOX2B in the highest tertile predicted worse outcome (p = 0.015), and identified 20 (23%) infants/toddlers with 5-year EFS of 20% (95%CI: 4%-44%). Prognostic significance was maintained after adjusting for over-fitting bias (p = 0.038), age and MYCN status. In peripheral blood, PHOX2B levels in the highest tertile predicted a two-fold increased risk of an event (p = 0.032), and identified 23 (34%) infants/toddlers with 5-year EFS of 29% (95%CI: 12%-48%). Time-dependent receiver operating characteristic analysis confirmed the prognostic value of combined TH and PHOX2B in bone marrow and of PHOX2B in peripheral blood during the first year of follow-up., Conclusions: High levels of bone marrow TH and PHOX2B and of peripheral blood PHOX2B at diagnosis allow early identification of a group of high-risk infant and toddlers with neuroblastoma who may be candidates for alternative treatments. Integration with additional biomarkers, as well as validation in additional international trials is warranted., (© 2018 Wiley Periodicals, Inc.)

A semiquantitative 123 I-metaiodobenzylguanidine ( 123 I-MIBG) scoring method (the Curie score, or CS) was previously examined in the Children's Oncology Group (COG) high-risk neuroblastoma trial, COG A3973, with a postinduction CS of more than 2 being associated with poor event-free survival (EFS). The validation of the CS in an independent dataset, International Society of Paediatric Oncology European Neuroblastoma/High-Risk Neuroblastoma 1 (SIOPEN/HR-NBL1), is now reported. Methods: A retrospective analysis of 123 I-MIBG scans obtained from patients who had been prospectively enrolled in SIOPEN/HR-NBL1 was performed. All patients exhibited 123 I-MIBG-avid, International Neuroblastoma Staging System stage 4 neuroblastoma. 123 I-MIBG scans were evaluated at 2 time points, diagnosis ( n = 345) and postinduction ( n = 330), before consolidation myeloablative therapy. Scans of 10 anatomic regions were evaluated, with each region being scored 0-3 on the basis of disease extent and a cumulative CS generated. Cut points for outcome analysis were identified by Youden methodology. CSs from patients enrolled in COG A3973 were used for comparison. Results: The optimal cut point for CS at diagnosis was 12 in SIOPEN/HR-NBL1, with a significant outcome difference by CS noted (5-y EFS, 43.0% ± 5.7% [CS ≤ 12] vs. 21.4% ± 3.6% [CS > 12], P < 0.0001). The optimal CS cut point after induction was 2 in SIOPEN/HR-NBL1, with a postinduction CS of more than 2 being associated with an inferior outcome (5-y EFS, 39.2% ± 4.7% [CS ≤ 2] vs. 16.4% ± 4.2% [CS > 2], P < 0.0001). The postinduction CS maintained independent statistical significance in Cox models when adjusted for the covariates of age and MYCN gene copy number. Conclusion: The prognostic significance of postinduction CSs has now been validated in an independent cohort of patients (SIOPEN/HR-NBL1), with a postinduction CS of more than 2 being associated with an inferior outcome in 2 independent large, cooperative group trials., (© 2018 by the Society of Nuclear Medicine and Molecular Imaging.)

Children with diffuse intrinsic pontine glioma (DIPG) need new and more efficient treatments. They can be developed at relapse or at diagnosis, but therefore they must be combined with radiotherapy. Survival of children after recurrence and its predictors were studied to inform the possibility to design early phase clinical trials for DIPG at this stage. Among 142 DIPG patients treated between 1998 and 2014, 114 had biopsy-proven DIPG with histone H3 status available for 83. We defined as long survivors' patients who survived more than 3 months after relapse which corresponds to the minimal life expectancy requested for phase I/II trials. Factors influencing post-relapse survival were accordingly compared between short and long-term survivors after relapse. Fifty-seven percent of patients were considered long survivors and 70% of them had a Lansky Play Scale (LPS) above 50% at relapse. Patients who became steroids-independent after initial treatment for at least 2 months had better survival after relapse (3.7 versus 2.6 months, p = 0.001). LPS above 50% at relapse was correlated with better survival after relapse (3.8 versus 1.8 months, p < 0.001). Patients with H3.1 mutation survived longer after relapse (4.9 versus 2.7 months, p = 0.007). Patients who received a second radiotherapy at the time of relapse had an improved survival (7.5 versus 4 months, p = 0.001). In the two-way ANOVA analysis, steroid-independence and LPS predicted survival best and the type of histone H3 (H3.1 or H3.3) mutated did not improve prediction. Survival of many DIPG patients after relapse over 3 months would make possible to propose specific trials for this condition. Steroid-independence, H3 mutation status and LPS should be considered to predict eligibility.

Opsoclonus myoclonus syndrome (OMS), often called "dancing eyed syndrome," is a rare neurological condition associated with neuroblastoma in the majority of all childhood cases. Genomic copy number profiles have shown to be of prognostic significance for neuroblastoma patients. The aim of this retrospective multicenter study was to analyze the genomic copy number profiles of tumors from children with neuroblastoma presenting with OMS at diagnosis. In 44 cases of neuroblastoma associated with OMS, overall genomic profiling by either array-comparative genomic hybridization or single nucleotide polymorphism array proved successful in 91% of the cases, distinguishing tumors harboring segmental chromosome alterations from those with numerical chromosome alterations only. A total of 23/44 (52%) tumors showed an segmental chromosome alterations genomic profile, 16/44 (36%) an numerical chromosome alterations genomic profile, and 1 case displayed an atypical profile (12q amplicon). No recurrently small interstitial copy number alterations were identified. With no tumor relapse nor disease-related deaths, the overall genomic profile was not of prognostic impact with regard to the oncological outcome in this series of patients. Thus, the observation of an excellent oncological outcome, even for those with an unfavorable genomic profile of neuroblastoma, supports the hypothesis that an immune response might be involved in tumor control in these patients with OMS.

Purpose: Neuroblastoma displays important clinical and genetic heterogeneity, with emergence of new mutations at tumor progression. Experimental Design: To study clonal evolution during treatment and follow-up, an innovative method based on circulating cell-free DNA (cfDNA) analysis by whole-exome sequencing (WES) paired with target sequencing was realized in sequential liquid biopsy samples of 19 neuroblastoma patients. Results: WES of the primary tumor and cfDNA at diagnosis showed overlap of single-nucleotide variants (SNV) and copy number alterations, with 41% and 93% of all detected alterations common to the primary neuroblastoma and cfDNA. CfDNA WES at a second time point indicated a mean of 22 new SNVs for patients with progressive disease. Relapse-specific alterations included genes of the MAPK pathway and targeted the protein kinase A signaling pathway. Deep coverage target sequencing of intermediate time points during treatment and follow-up identified distinct subclones. For 17 seemingly relapse-specific SNVs detected by cfDNA WES at relapse but not tumor or cfDNA WES at diagnosis, deep coverage target sequencing detected these alterations in minor subclones, with relapse-emerging SNVs targeting genes of neuritogenesis and cell cycle. Furthermore a persisting, resistant clone with concomitant disappearance of other clones was identified by a mutation in the ubiquitin protein ligase HERC2 Conclusions: Modelization of mutated allele fractions in cfDNA indicated distinct patterns of clonal evolution, with either a minor, treatment-resistant clone expanding to a major clone at relapse, or minor clones collaborating toward tumor progression. Identification of treatment-resistant clones will enable development of more efficient treatment strategies. Clin Cancer Res; 24(4); 939-49. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Background: Serious neurological adverse events (NAE) have occurred during treatment with high-dose thiotepa regimens of children with high-risk solid tumours. The objective was to assess the incidence of NAE related to high-dose thiotepa and to identify potential contributing factors that could exacerbate the occurrence of this neurotoxicity., Methods: From May 1987 to March 2011, children with solid tumours treated with high-dose thiotepa were retrospectively identified. Each NAE detected led to an independent case analysis. Potential contributing factors were pre-specified and univariate/multivariable analyses were performed., Results: Three hundred seven courses of thiotepa (251 patients) were identified. The total dose per treatment ranged from 600 to 900 mg/m 2 . 81 NAE (26%) were identified. 46 NAE were related to high-dose thiotepa during the first course (18.3%) and 11 during the second course (19.6%). The symptoms appeared in a median time of 2 days after the introduction of thiotepa. Central and peripheral symptoms were headaches, tremors, confusion, seizures, cerebellar syndrome, and coma. High-dose thiotepa was reintroduced in 18 cases and symptoms reappeared in 5 children. For 3 patients who had seizures during the first course, premedication with clonazepam for the second course has prevented recurrence of NAE. As contributing factors, brain tumour and tramadol treatment increased the risk of thiotepa-related neurotoxicity by 2 to 6 times respectively., Conclusions: The incidence of neurotoxicity was 18.3%. Brain tumours and tramadol treatment are risk factors to consider when using high-dose thiotepa. The outcome of patients was favourable without sequelae in all cases and rechallenge with thiotepa was possible.

Background: Validation of the prognostic value of the SIOPEN mIBG skeletal scoring system in two independent stage 4, mIBG avid, high-risk neuroblastoma populations., Results: The semi-quantitative SIOPEN score evaluates skeletal meta-iodobenzylguanidine (mIBG) uptake on a 0-6 scale in 12 anatomical regions. Evaluable mIBG scans from 216 COG-A3973 and 341 SIOPEN/HR-NBL1 trial patients were reviewed pre- and post-induction chemotherapy. The prognostic value of skeletal scores for 5-year event free survival (5 yr.-EFS) was tested in the source and validation cohorts. At diagnosis, both cohorts showed a gradual non-linear increase in risk with cumulative scores. Several approaches were explored to test the relationship between score and EFS. Ultimately, a cutoff score of ≤3 was the most useful predictor across trials. A SIOPEN score ≤ 3 pre-induction was found in 15% SIOPEN patients and in 22% of COG patients and increased post-induction to 60% in SIOPEN patients and to 73% in COG patients. Baseline 5 yr.-EFS rates in the SIOPEN/HR-NBL1 cohort for scores ≤3 were 47% ± 7% versus 26% ± 3% for higher scores at diagnosis (p < 0.007) and 36% ± 4% versus 14% ± 4% (p < 0.001) for scores obtained post-induction. The COG-A3973 showed 5 yr.-EFS rates for scores ≤3 of 51% ± 7% versus 34% ± 4% for higher scores (p < 0.001) at diagnosis and 43% ± 5% versus 16% ± 6% (p = 0.004) for post-induction scores. Hazard ratios (HR) significantly favoured patients with scores ≤3 after adjustment for age and MYCN-amplification. Optimal outcomes were recorded in patients who achieved complete skeletal response., Conclusions: Validation in two independent cohorts confirms the prognostic value of the SIOPEN skeletal score. In particular, patients with an absolute SIOPEN score > 3 after induction have very poor outcomes and should be considered for alternative therapeutic strategies.

Purpose: Metastatic response to induction therapy for high-risk neuroblastoma is a prognostic factor. In the International Society of Paediatric Oncology Europe Neuroblastoma (SIOPEN) HR-NBL-1 protocol, only patients with metastatic complete response (CR) or partial response (PR) with ≤ three abnormal skeletal areas on iodine 123-metaiodobenzylguanidine ([ 123 I]mIBG) scintigraphy and no bone marrow disease proceed to high dose therapy (HDT). In this study, topotecan-vincristine-doxorubicin (TVD) was evaluated in patients failing to achieve these criteria, with the aim of improving the metastatic response rate., Materials and Methods: Patients with metastatic high-risk neuroblastoma who had not achieved the SIOPEN criteria for HDT after induction received two courses of topotecan 1.5 mg/m 2 /day for 5 days, followed by a 48-hour infusion of vincristine, 2 mg/m 2 , and doxorubicin, 45 mg/m 2 ., Results: Sixty-three patients were eligible and evaluable. Following two courses of TVD, four (6.4%) patients had an overall CR, while 28 (44.4%) had a PR with a combined response rate of 50.8% (95% confidence interval [CI], 37.9 to 63.6). Of these, 23 patients achieved a metastatic CR or a PR with ≤ 3 mIBG skeletal areas and no bone marrow disease (36.5%; 95% CI, 24.7 to 49.6) and were eligible to receive HDT. Toxicity was mostly haematological, affecting 106 of the 126 courses (84.1%; 95% CI, 76.5 to 90.0), and dose reduction was necessary in six patients. Stomatitis was the second most common nonhematological toxicity, occurring in 20 patients (31.7%)., Conclusion: TVD was effective in improving the response rate of high-risk neuroblastoma patients after induction with COJEC enabling them to proceed to HDT. However, the long-term benefits of TVD needs to be determined in randomized clinical trials.

Immunotherapy with short term infusion (STI) of monoclonal anti-GD 2 antibody (mAb) ch14.18 (4 × 25 mg/m 2 /d; 8-20 h) in combination with cytokines and 13-cis retinoic acid (RA) prolonged survival in high-risk neuroblastoma (NB) patients. Here, we investigated long-term infusion (LTI) of ch14.18 produced in Chinese hamster ovary cells (ch14.18/CHO; 10 × 10 mg/m 2 ; 24 h) in combination with subcutaneous (s.c.) interleukin-2 (IL-2) in a single center program and report clinical response, toxicity and survival. Fifty-three high-risk NB patients received up to 6 cycles of 100 mg/m 2 ch14.18/CHO (d8-17) as LTI combined with 6 × 10 6 IU/m 2 s.c. IL-2 (d1-5; 8-12) and 160 mg/m 2 oral RA (d19-32). Pain toxicity was documented with validated pain scores and intravenous (i.v.) morphine usage. Response was assessed in 37/53 evaluable patients following International Neuroblastoma Risk Group criteria. Progression-free (PFS) and overall survival (OS) was analyzed by the Kaplan-Meier method and compared to a matched historical control group from the database of AIEOP, the "Italian Pediatric Ematology and Oncology Association". LTI of ch14.18/CHO showed acceptable toxicity profile indicated by low pain scores, reduced i.v. morphine usage and low frequency of Grade ≥3 adverse events that allowed outpatient treatment. We observed a best response rate of 40.5% (15/37; 5 CR, 10 PR), 4-year (4 y) PFS of 33.1% (observation 0.1- 4.9 y, mean: 2.2 y) and a 4 y OS of 47.7% (observation 0.27 - 5.20 y, mean: 3.6 y). Survival of the entire cohort (53/53) and the relapsed patients (29/53) was significantly improved compared to historical controls. LTI of ch14.18/CHO thus shows an acceptable toxicity profile, objective clinical responses and a strong signal of clinical efficacy in NB patients.

Purpose: To evaluate the impact of image-defined risk factor (IDRF) modification after chemotherapy on surgical outcomes, event-free survival (EFS), and overall survival (OS) among patients enrolled in the European Unresectable Neuroblastoma (EUNB) study., Methods: IDRFs were assigned according to the corresponding surgical risk factors list reported in the database. Surgical outcomes, EFS, and OS were related to IDRF modification with chemotherapy. The predictive value of preoperative IDRF for surgical outcomes was analyzed. Cox proportional hazards models for EFS and OS, including preoperative IDRF, surgical outcomes, and other known clinical risk factors, were created., Results: Of the 160 patients enrolled in the EUNB study, 143 patients met the inclusion criteria. A total of 228 IDRF were thus collected. Following chemotherapy, 76 (33%) IDRF disappeared in 32.2% of patients, 33 (14%) new IDRF appeared in 18.8% of patients, and 49% of patients did not show any IDRF change. Complete resection/minimal residual disease (71.2%) was more frequent among children who had disappearance/numerical reduction of IDRF (P = 0.005). Infiltration of the branches of the mesenteric artery was predictive of an unfavorable surgical outcome. Prolonged preoperative chemotherapy over five courses and encasement of the celiac axis and/or mesenteric artery origin impacted EFS and OS., Conclusions: The unchanged IDRF pattern in 50% of patients and the appearance of new IDRF during chemotherapy in approximately 20% of patients strengthens the idea that prolonged chemotherapy is useless for improving surgical resection in this population of patients. In addition, midline perivascular abdominal preoperative IDRF appeared to be predictive not only of surgical outcomes but also of EFS and OS., (© 2017 Wiley Periodicals, Inc.)

Purpose: This single-institutional feasibility study prospectively characterized genomic alterations in recurrent or refractory solid tumors of pediatric patients to select a targeted therapy. Experimental Design: Following treatment failure, patients with signed consent and ages above 6 months, underwent tumor biopsy or surgical resection of primary or metastatic tumor site. These newly acquired samples were analyzed by comparative genomic hybridization array, next-generation sequencing for 75 target genes, whole-exome and RNA sequencing. Biological significance of the alterations and suggestion of most relevant targeted therapies available were discussed in a multidisciplinary tumor board. Results: From December 2012 to January 2016, 75 patients were included, 73 patients underwent 79 interventions, 56 of which were research biopsies with a low complication rate. All patients were pretreated, 37.0% had a brain tumor, and 63.0% had an extra-cranial solid tumor. Median tumor cell content was 70% (range, 0%-100%). Successful molecular analysis in 69 patients detected in 60.9% of patients an actionable alteration in various oncogenic pathways (42.4% with copy-number change, 33.3% with mutation, 2.1% with fusion), and change in diagnosis in three patients. Fourteen patients received 17 targeted therapies; two had received a matched treatment before inclusion. Conclusions: Research biopsies are feasible in advanced pediatric malignancies that exhibit a considerable amount of potentially actionable alterations. Genetic events affecting different cancer hallmarks and limited access to targeted agents within pediatric clinical trials remain the main obstacles that are addressed in our two subsequent precision medicine studies MAPPYACTS and AcSé-ESMART. Clin Cancer Res; 23(20); 6101-12. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Purpose: Neuroblastoma (NB) is an embryonic tumor that occurs almost exclusively in infancy and early childhood. While considerable evidence suggests that it may be initiated during embryonic development, the etiology of NB is still unknown. The aim of this study was to explore whether there is an association between maternal use of household pesticides during pregnancy and the risk of NB in the offspring., Methods: We conducted a pooled analysis of two French national-based case-control studies. The mothers of 357 NB cases and 1,783 controls younger than 6 years, frequency-matched by age and gender, responded to a telephone interview that focused on sociodemographic and perinatal characteristics, childhood environment, and life-style. Unconditional logistic regression was used to estimate pooled odds ratios and 95% confidence intervals., Results: After controlling for matching variables, study of origin, and potential confounders, the maternal use of any type of pesticide during pregnancy was associated with NB (OR 1.5 [95% CI 1.2-1.9]). The most commonly used type of pesticides were insecticides and there was a positive association with their use alone (OR 1.4 [95% CI 1.1-1.9]) or with other pesticides (OR 2.0 [95% CI 1.1-3.4])., Conclusions: Although there is the potential for recall bias due to the study design, our findings add to the evidence of an association between the household use of pesticides and NB. Until a better study design can be found, our findings add yet another reason why to advise pregnant women to limit pesticide exposure during the periconceptional period.

Pediatric posterior fossa tumor (PFT) survivors who have been treated with cranial radiation therapy often suffer from cognitive impairments that might relate to IQ decline. Radiotherapy (RT) distinctly affects brain regions involved in different cognitive functions. However, the relative contribution of regional irradiation to the different cognitive impairments still remains unclear. We investigated the relationships between the changes in different cognitive scores and radiation dose distribution in 30 children treated for a PFT. Our exploratory analysis was based on a principal component analysis (PCA) and an ordinary least square regression approach. The use of a PCA was an innovative way to cluster correlated irradiated regions due to similar radiation therapy protocols across patients. Our results suggest an association between working memory decline and a high dose (equivalent uniform dose, EUD) delivered to the orbitofrontal regions, whereas the decline of processing speed seemed more related to EUD in the temporal lobes and posterior fossa. To identify regional effects of RT on cognitive functions may help to propose a rehabilitation program adapted to the risk of cognitive impairment.

Introduction: Neuroblastoma, the commonest paediatric extra-cranial tumour, remains a leading cause of death from cancer in children. There is an urgent need to develop new drugs to improve cure rates and reduce long-term toxicity and to incorporate molecularly targeted therapies into treatment. Many potential drugs are becoming available, but have to be prioritised for clinical trials due to the relatively small numbers of patients. Areas covered: The current drug development model has been slow, associated with significant attrition, and few new drugs have been developed for neuroblastoma. The Neuroblastoma New Drug Development Strategy (NDDS) has: 1) established a group with expertise in drug development; 2) prioritised targets and drugs according to tumour biology (target expression, dependency, pre-clinical data; potential combinations; biomarkers), identifying as priority targets ALK, MEK, CDK4/6, MDM2, MYCN (druggable by BET bromodomain, aurora kinase, mTORC1/2) BIRC5 and checkpoint kinase 1; 3) promoted clinical trials with target-prioritised drugs. Drugs showing activity can be rapidly transitioned via parallel randomised trials into front-line studies. Expert opinion: The Neuroblastoma NDDS is based on the premise that optimal drug development is reliant on knowledge of tumour biology and prioritisation. This approach will accelerate neuroblastoma drug development and other poor prognosis childhood malignancies.

Purpose: Access to insurance for a loan or a mortgage is an important issue for childhood cancer survivors. The aim of this study was to describe difficulties experienced by adult survivors., Methods: A total of 1920 survivors treated before the age of 18 in five French cancer centers responded to a questionnaire in 2010. Survivors who had tried to obtain a loan were asked if they had experienced difficulties, which were defined as experiencing rejection, higher premiums, or exclusions. The questionnaire investigated health problems related to the circulatory, respiratory, digestive, urinary, endocrine, hormonal, and nervous systems. Second tumors, diabetes mellitus, cardiac disease, and stroke were ascertained from a physician's report or medical records. Multivariable analyses were conducted to identify the characteristics of survivors reporting difficulties., Results: Difficulties were experienced by 10.4% of those who had tried to obtain a small loan (n = 787) and by 30.1% of those who had tried to obtain a home loan (n = 909). Disclosure of childhood cancer to the insurer and amputation surgery were negatively associated with insurance accessibility, even when controlling for age, gender, education, health-related unemployment, familial situation, and severe or life-threatening conditions such as cardiovascular diseases, second cancers, or diabetes., Conclusion: This study showed that the financial burden of cancer can extend decades after diagnosis., Implications for Cancer Survivors: Thanks to a 2016 law, French cancer survivors no longer have to disclose their cancer to insurers after a fixed number of years. This law will probably lessen the socioeconomic burden of cancer.