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.

PURPOSETo 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 METHODSPatients 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.RESULTSA 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).CONCLUSIONIn 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.

10521 Background: The effect of complete macroscopic excision (CME) of the primary tumour on event free survival (EFS) in high-risk neuroblastoma remains controversial. We therefore investigated the influence of CME in patients enrolled on the HR-NBL1/SIOPEN Trial and compared the effect in the pre immunotherapy era. Methods: Eligibility criteria were: inclusion in HR-NBL1/SIOPEN Trial between 2002-2015, stage 4 disease; completion of Rapid COJEC induction ± 2 courses of TVD; no progression/relapse/death; no prior attempt at resection and complete operation data. Intended therapy following operation comprised: HDT/SCT (BuMel or CEM, after 2011 BuMel), 21Gy radiotherapy to the primary site, 13-cis RA and after 2009 ch14.18/CHO antibody ± IL2 in addition. 1504 patients fulfilled these criteria; 737 were treated prior to ch14.18/CHO availability (2002-2009) and 767 in the immunotherapy era. Median observation time was 4.9 years (0.1-14 years). Results: CME was achieved in 77%, incomplete macroscopic excision (IME) in 21% and 2% were inoperable (0E). Surgical mortality was 0.46% (7/1504). Five year event-free survival (5y-EFS ± standard error) was 39%±2% with CME and 30%±3% with IME or 0E (p = 0.002). The cumulative incidence of local relapse (CILR) was 0.17±0.01 (CME); 0.31±0.03 (IME) and 0.42 ±0.10 (0E) (p < 0.001). 88% of patients received radiotherapy (78% CME; 21% IME and 1% 0E). 5y-EFS for patients with CME who received radiotherapy was 44±2%, but 31±6% without (reasons included very young age and very large primary tumours) (p = 0.013) and 35±3% with less than CME compared to 20±1% without radiotherapy (NS). CILR was 0.14±0.01 in patients with CME who received radiotherapy compared to 0.28±0.06 in patients who did not (p = 0.005). 5y-EFS was significantly higher (42±2%) for patients enrolled after 2009 compared to before (32±2%) (p = 0.000). 5-y EFS for patients after 2009 who achieved CME was 45±2% vs. 36±2% after IME and 26±13% after 0E respectively (p = 0.034); compared to 33±2% vs. 26±4% (IME) and 17±11% (0E) (p = 0.059) prior to 2009. Conclusions: In the immunotherapy era, CME in Stage 4 patients who received local radiotherapy resulted in improved 5-EFS. Clinical trial information: NCT01704716.

BackgroundThe European multicenter study LNESG1 was designed to evaluate the safety and efficacy of surgical treatment alone in patients with localised neuroblastoma. In a retrospective, observational study we examined the impact of image‐defined risk factors (IDRF) on operative complications and survival (EFS and OS).Procedure534 patients with localised, non‐MYCN amplified neuroblastoma were recruited between 1995 and 1999. Group 1 consisted of 291 patients without IDRF (Stage L1 in the International Neuroblastoma Risk Group (INRG) staging system), all treated with primary surgery. Group 2: 118 patients with IDRF (INRG Stage L2), also treated with primary surgery. Group 3: 125 patients in whom primary surgery was not attempted, 106 receiving neo‐adjuvant chemotherapy.ResultsIn L1 patients (Group 1) 5‐year EFS was 92% and OS 98%. In L2 patients (Group 2 and 3) EFS was 79% and OS 89%. The differences in both EFS and OS were significant. EFS and OS in Group 2 (86% and 95%) were significantly better than 73% and 83% in Group 3. In INSS stage 1, 2 and 3, EFS were respectively 94%, 81% and 76%. Except between stage 2 and 3 the differences were significant. OS were respectively 99%, 93% and 83%, all significantly different. The 17% operative complication rate in L2 patients was significantly higher than 5% in L1 patients.ConclusionsIn localised neuroblastoma, IDRF at diagnosis are associated with worse survival rates and higher rates of operative complications. The impact of IDRF should become an integrated part of therapy planning. Pediatr Blood Cancer 2015;62:1536–1542. © 2015 Wiley Periodicals, Inc.

A 15-month-old boy was diagnosed with malignant hypertension caused by a catecholamine excreting retroperitoneal paraganglioma consisting of a composite phaeochromocytoma/differentiating neuroblastoma. After alpha-blockade the tumor was excised. No adjuvant treatment was given, and he is doing well eight years after the diagnosis. The patient is the first child known to have an extra-adrenal retroperitoneal composite tumor, and also the youngest child with a composite phaeochromocytoma/neuroblastoma reported in the English literature.

BackgroundNeuroblastoma in older children and adolescents has a distinctive, indolent phenotype, but little is known about the clinical and biological characteristics that distinguish this rare subgroup. Our goal was to determine if an optimal age cut-off exists that defines indolent disease and if accepted prognostic factors and treatment approaches are applicable to older children.ProcedureUsing data from the International Neuroblastoma Risk Group, among patients 18 months old (n=4,027), monthly age cut-offs were tested to determine the effect of age on survival. The prognostic effect of baseline characteristics and autologous hematopoietic cell transplant (AHCT) for advanced disease was assessed within two age cohorts; 5 to <10 years (n=730) and 10 years (n=200).ResultsOlder age was prognostic of poor survival, with outcome gradually worsening with increasing age at diagnosis, without statistical evidence for an optimal age cut-off beyond 18 months. Among patients 5 years, factors significantly prognostic of lower event-free survival (EFS) and overall survival (OS) in multivariable analyses were INSS stage 4, MYCN amplification and unfavorable INPC histology classification. Among stage 4 patients, AHCT provided a significant EFS and OS benefit. Following relapse, patients in both older cohorts had prolonged OS compared to those 18 months to <5 years (P<0.0001).ConclusionsDespite indolent disease and infrequent MYCN amplification, older children with advanced disease have poor survival, without evidence for a specific age cut-off. Our data suggest that AHCT may provide a survival benefit in older children with advanced disease. Novel therapeutic approaches are required to more effectively treat these patients. Pediatr Blood Cancer 2014;61:627-635. (c) 2013 Wiley Periodicals, Inc.

BackgroundInternational Neuroblastoma Staging System (INSS) Stage 3 neuroblastoma is a heterogeneous disease. Data from the International Neuroblastoma Risk Group (INRG) database were analyzed to define patient and tumor characteristics predictive of outcome.ProcedureOf 8,800 patients in the INRG database, 1,483 with INSS Stage 3 neuroblastoma and complete follow-up data were analyzed. Secondary analysis was performed in 1,013 patients (68%) with MYCN-non-amplified (NA) tumors. Significant prognostic factors were identified via log-rank test comparisons of survival curves. Multivariable Cox proportional hazards regression model was used to identify factors independently predictive of event-free survival (EFS).ResultsAge at diagnosis (P<0.0001), tumor MYCN status (P<0.0001), and poorly differentiating/undifferentiated histology (P=0.03) were independent predictors of EFS. Compared to other Stage 3 subgroups, outcome was inferior for patients 547 days with MYCN-NA neuroblastoma (P<0.0001), and within this cohort, serum ferritin 96ng/ml was associated with inferior EFS (P=0.02). For patients <547 days of age with MYCN-NA tumors, serum ferritin levels were prognostic of overall survival (OS) (P=0.04) and chromosome 11q aberration was prognostic of EFS (P=0.03).ConclusionsAmong patients with INSS Stage 3 neuroblastoma patients, age at diagnosis, MYCN status and histology predict outcome. Patients <547 days of age with MYCN-NA tumors that lack chromosome 11q aberrations or those with serum ferritin <96ng/ml have excellent prognosis and should be considered for therapy reduction. Prospective clinical trials are needed to identify optimal therapy for those patients 547 days of age with undifferentiated histology or elevated serum ferritin. Pediatr Blood Cancer 2014;61:1932-1939. (c) 2014 Wiley Periodicals, Inc.

Currarino syndrome (CS) is a clinically variable disorder characterized by anorectal, sacral and presacral anomalies. It is associated with loss-of-function mutations in the motor neuron and pancreas homeobox 1 (MNX1) gene. Inheritance is autosomal dominant, expression variable and penetrance incomplete. We describe a Norwegian family with typical CS in which a heterozygous deletion removes the entire MNX1 gene but no other known genes. We also report MNX1 mutations in three other Norwegian families and confirm that the GCC12 repeat (c.373_375[12]) is a normal allelic variant. This work underscores the importance of dosage analysis of MNX1 when Sanger sequencing is negative.

Clinical information, "-omic" datasets, and tissue samples are difficult to harmonize and manage for data mining. We have developed a platform for storing clinical research data while providing access to associated data from other information stores. Data on 34 metrics from 11,000 neuroblastoma patients were instantiated into a database. The Django web framework was used to create a model for rapid development of tools and views with a front-end interface for generating complex queries. Working with Nationwide Children's Hospital, we can now consume their tissue inventory data through an API. The end-user sees the number of patients who both match their search and have tissue available. Since initial implementation, the current tasks revolve around developing a governance structure and the necessary data use agreements. Efforts now are to (1) update the data with 5000 more patients, and (2) link to genomic data stores, facilitating disparate data acquisition for research studies.

BACKGROUND:Currarino syndrome is a rare hereditary condition with constipation as the main symptom. The typical patient has a combination of sacral, anorectal, intraspinal and presacral anomalies. Familial cases most often have a mutation in the MNX1 gene. The majority of Norwegian Currarino patients are treated at Rikshospitalet. This article gives an account of 50 years of experience with the condition.MATERIAL AND METHOD:The study is based on the medical records of patients with Currarino syndrome, as well as some first-degree relatives, from the period 1961-2012. We recorded the results of mutation analysis, X-ray of the sacrum, and ultrasound, MRI and/or CT scans, as well as the treatments administered.RESULTS:We treated 29 patients over the period in question, and in addition identified seven healthy relatives with a mutation in MNX1 and one relative with a pathognomonic sacral anomaly. There were 15 familial and 14 sporadic cases. Fourteen familial cases and one of the sporadic cases were shown to have a mutation in the MNX1 gene. Phenotypic variation was pronounced, and we saw no obvious correlation between genotype and phenotype. Twenty-six of the patients had constipation and 15 underwent a colostomy. Fourteen patients required neurosurgical and seven urogenital interventions. No patients had malignant disease.INTERPRETATION:Patients with Currarino syndrome have a highly variable clinical presentation with constipation as the main problem. In patients with a familial syndrome, a mutation in the MNX1 gene can be expected.

Background: In the INRG dataset, the hypothesis that any segmental chromosomal alteration might be of prognostic impact in neuroblastoma without MYCN amplification (MNA) was tested. Methods: The presence of any segmental chromosomal alteration (chromosome 1p deletion, 11q deletion and/or chromosome 17q gain) defined a segmental genomic profile. Only tumours with a confirmed unaltered status for all three chromosome arms were considered as having no segmental chromosomal alterations. Results: Among the 8800 patients in the INRG database, a genomic type could be attributed for 505 patients without MNA: 397 cases had a segmental genomic type, whereas 108 cases had an absence of any segmental alteration. A segmental genomic type was more frequent in patients >18 months and in stage 4 disease ( P <0.0001). In univariate analysis, 11q deletion, 17q gain and a segmental genomic type were associated with a poorer event-free survival (EFS) ( P <0.0001, P =0.0002 and P <0.0001, respectively). In multivariate analysis modelling EFS, the parameters age, stage and a segmental genomic type were retained in the model, whereas the individual genetic markers were not ( P <0.0001 and RR=2.56; P =0.0002 and RR=1.8; P =0.01 and RR=1.7, respectively). Conclusion: A segmental genomic profile, rather than the single genetic markers, adds prognostic information to the clinical markers age and stage in neuroblastoma patients without MNA, underlining the importance of pangenomic studies.

9583 Background: Clinical information, “-omic” datasets, and tissue samples are becoming more difficult to harmonize and manage for advanced data mining. We believe that clinical research data can be centralized and provide direct access to sample availability and associated data from a variety of information stores. Methods: We obtained a standardized set of anonymized patient data from the International Neuroblastoma Risk Group. The cohort consists of more than 11,000 children diagnosed worldwide between 1974 and 2002. The data consist of 34 metrics, such as age at diagnosis, stage of tumor, and other clinical and biological markers. We instantiated the dataset into a Postgres database, and using the Django web framework, created a data model for rapid development of tools and views and built a front-end interface for generating complex queries. To test the feasibility of accessing information on disparate and geographically distinct data samples, we have a formal agreement with the Children's Oncology Group Tumor Bank at The Research Institute at Nationwide Children's Hospital. Based on query results, we consume the Tumor Bank tissue inventory data through a web-facing application programming interface. The end-user is presented only with the number of patients who match their query search terms and for whom tissue samples are available. Results: We have completed our initial implementation and have agreements for collaboration with other international consortium groups. We have created a paradigm for statisticians to securely update and add data, and a verification system checks for internal validity and provides a report of the transaction. Our system can initiate queries and accept results in a variety of standards-compliant formats, and will be available in demonstration form by May 2012. Conclusions: Querying patient data while interrogating external sources allows researchers to observe which ancillary data and samples are available and to quickly download data or request any samples. While designed around a neuroblastoma dataset, our system can be applied to a variety of clinical scenarios and will be made available through an open-source license.

PURPOSESurvival after neuroblastoma relapse is poor. Understanding the relationship between clinical and biologic features and outcome after relapse may help in selection of optimal therapy. Our aim was to determine which factors were significantly predictive of postrelapse overall survival (OS) in patients with recurrent neuroblastoma--particularly whether time from diagnosis to first relapse (TTFR) was a significant predictor of OS.PATIENTS AND METHODSPatients with first relapse/progression were identified in the International Neuroblastoma Risk Group (INRG) database. Time from study enrollment until first event and OS time starting from first event were calculated. Cox regression models were used to calculate the hazard ratio of increased death risk and perform survival tree regression. TTFR was tested in a multivariable Cox model with other factors.RESULTSIn the INRG database (N = 8,800), 2,266 patients experienced first progression/relapse. Median time to relapse was 13.2 months (range, 1 day to 11.4 years). Five-year OS from time of first event was 20% (SE, ± 1%). TTFR was statistically significantly associated with OS time in a nonlinear relationship; patients with TTFR of 36 months or longer had the lowest risk of death, followed by patients who relapsed in the period of 0 to less than 6 months or 18 to 36 months. Patients who relapsed between 6 and 18 months after diagnosis had the highest risk of death. TTFR, age, International Neuroblastoma Staging System stage, and MYCN copy number status were independently predictive of postrelapse OS in multivariable analysis.CONCLUSIONAge, stage, MYCN status, and TTFR are significant prognostic factors for postrelapse survival and may help in the design of clinical trials evaluating novel agents.

Purpose Patients with neuroblastoma younger than 12 months of age with a 4S pattern of disease (metastases limited to liver, skin, bone marrow) have better outcomes than infants with stage 4 disease. The new International Neuroblastoma Risk Group (INRG) staging system extends age to 18 months for the 4S pattern. Our aim was to determine which prognostic features could be used for optimal risk classification among patients younger than 18 months with metastatic disease. Methods Event-free survival (EFS) and overall survival were analyzed by log-rank tests, Cox models, and survival tree regression for 656 infants with stage 4S neuroblastoma younger than 12 months of age and 1,019 patients with stage 4 disease younger than 18 months of age in the INRG database. Results Unfavorable biologic features were more frequent in infants with stage 4 disease than in infants with 4S tumors and higher overall in those age 12 to 18 months (although not different for stage 4 v 4S pattern). EFS was significantly better for infants younger than 12 months with 4S pattern than with stage 4 disease (P < .01) but similar for toddlers age 12 to 18 months with stage 4 versus 4S pattern. Among 717 patients with stage 4S pattern, patients age 12 to 18 months had worse EFS than those age younger than 12 months (P < .01). MYCN, 11q, mitosis-karyorrhexis index (MKI), ploidy, and lactate dehydrogenase were independently statistically significant predictors of EFS and more highly predictive than age or metastatic pattern. MYCN, 11q, MKI, histology, and 1p were combined in a survival tree for improved risk stratification. Conclusion Tumor biology is more critical than age or metastatic pattern for prognosis of patients age younger than 18 months with metastatic neuroblastoma and should be considered for risk stratification.

Aim: Describe characteristics and outcome of INRG patients with ganglioneuroblastoma, nodular subtype (GNBn).Patients and methods: Amongst 4071 patients in the INRG database with known INPC histological category, 232 patients with GNBn were identified. Patients were categorised by clinical, pathological and genetic characteristic. For event-free survival (EFS) and overall survival (OS), Kaplan-Meier curves and lifetables were generated, and the outcome of subgroups was compared using log rank test.Results: Patients with GNBn were older (83% > 18 months), a higher proportion had unfavourable INPC pathology (83%), and rarely had MYCN gene amplified tumours (2%). Otherwise, the distribution of clinical and biological risk factors including stage, ferritin, initial treatment, grade of NB differentiation, MKI, 11q, 1p, and 17q were similar between patients with GNBn and the overall INRG cohort. EFS and OS were 54% +/- 5% and 68% +/- 5%, respectively. A cohort with superior outcome was identified: OS for GNBn patients younger than 18 months was 95% +/- 5% (n = 39) and for GNBn patients with stage 1, 2, 3, 4s was 95% +/- 3% (n = 125). Conversely, a poor outcome sub-group could also be identified: OS for stage 4 was 35% +/- 7% (n = 107).Conclusions: Patients with GNBn tumours are rare and have a very heterogeneous outcome. Except for LDH and MKI, the factors prognostic in the overall NB cohort are also prognostic in patients with GNBn. Similar to the overall NB cohort, patients with GNBn older than 18 months of age, with stage 4 disease represent a high-risk sub-group and should be considered for aggressive treatment upfront. (C) 2011 Elsevier Ltd. All rights reserved.

Neuroblastoma is an enigmatic disease entity; some tumors disappear spontaneously without any therapy, while others progress with a fatal outcome despite the implementation of maximal modern therapy. However, strong prognostic factors can accurately predict whether children have "good" or "bad" disease at diagnosis, and the clinical stage is currently the most significant and clinically relevant prognostic factor. Therefore, for an individual patient, proper staging is of paramount importance for risk assessment and selection of optimal treatment. In 2009, the International Neuroblastoma Risk Group (INRG) Project proposed a new staging system designed for tumor staging before any treatment, including surgery. Compared with the focus of the International Neuroblastoma Staging System, which is currently the most used, the focus has now shifted from surgicopathologic findings to imaging findings. The new INRG Staging System includes two stages of localized disease, which are dependent on whether image-defined risk factors (IDRFs) are or are not present. IDRFs are features detected with imaging at the time of diagnosis. The present consensus report was written by the INRG Imaging Committee to optimize imaging and staging and reduce interobserver variability. The rationales for using imaging methods (ultrasonography, magnetic resonance imaging, computed tomography, and scintigraphy), as well as technical guidelines, are described. Definitions of the terms recommended for assessing IDRFs are provided with examples. It is anticipated that the use of standardized nomenclature will contribute substantially to more uniform staging and thereby facilitate comparisons of clinical trials conducted in different parts of the world.