10007 Background: Patients with metastatic neuroblastoma confined to distant lymph nodes (4N) were identified as a subgroup with superior outcomes to those with metastases to other sites. Over the past two decades, outcomes for high-risk neuroblastoma have improved from increasingly effective and intense therapy, while intermediate-risk patients have maintained excellent outcomes with biology and response-based therapy. We aimed to determine if 4N patients remained a favorable subgroup with contemporary therapy. Methods: Patients with International Neuroblastoma Staging System (INSS) stage 4 disease in the International Neuroblastoma Risk Group Data Commons diagnosed between 1990-2020 were evaluated. Those with metastases only to the distant lymph nodes were defined as 4N. All other patients were defined as non-4N. Treatment eras included: 1999 and prior, 2000-2009, 2010 and later which correspond to standardization of multimodal therapy, stem cell transplant, and anti-GD2 immunotherapy for high-risk patients. Differences between 4N and non-4N patients were assessed with chi-square, Wilcoxon rank sum, and t-tests. Five-year Kaplan-Meier estimates of survival with 95% confidence intervals and multivariable Cox proportional hazards modeling were used to evaluate event-free (EFS) and overall (OS) survival. Results: The analytic cohort included 107 4N and 5976 non-4N patients. There were no clinical differences between 4N and non-4N patients apart from unfavorable histology (74.2% [4N] versus 60.1% [non-4N]; p=0.02). 5-year EFS and OS were higher for 4N compared to non-4N patients (p=0.001 and 0.001, respectively). Though survival estimates for 4N were higher in each era, the difference was not statistically significant for patients diagnosed from 2000-2009 nor 2010 and beyond; (1999 and prior: EFS 58.7% (40.9-72.7%) versus 31.8% (29.7-33.9%) p=0.001; OS, 66.2% (48.1-79.3%) versus 37.9% (35.7-40.1%) p=0.002, 2000-2009: EFS, 47.9% (34.0-60.5%) versus 36% (34.1-37.9%) p=0.179; OS, 55.4% (40.7-67.8%) versus 45.1% (43.1-47.1%) p=0.122, and 2010 and later: EFS, 63.6% (29.7-84.5%) versus 42.8% (39.9-45.6%) p=0.178; OS, 71.6% (35.0-89.9%) versus 52.3% (49.2-55.3%) p=0.207. Log-rank calculations may have been underpowered in part due to small sample sizes (n=39, 56, and 12) of each 4N subgroup, respectively. 4N patients had superior EFS (HR=0.48; p=0.0004) and OS (HR=0.49; p=0.0009) in a model which included age, MYCN -amplification status, treatment era, ferritin, and LDH. A sensitivity analysis using only high-risk patients age >18 months yielded similar results. Conclusions: Patients with stage 4N neuroblastoma are a rare subgroup which appears to continue to have favorable outcomes with contemporary therapy. Additional studies to identify opportunities to reduce therapy intensity for this subgroup are warranted.

PURPOSE Intermediate-risk neuroblastoma patients older than 18 months, with non-MYCN amplified, International Neuroblastoma Risk Group Staging System localized, unresectable or International Neuroblastoma Staging System stage 3 tumors, and unfavorable histology have inferior outcomes compared with other intermediate-risk patients. This study aimed to identify genetic prognostic biomarkers within this rare subgroup. METHODS We conducted a large, international study including chromosomal copy number in all cases, next-generation DNA sequencing in most, and telomere maintenance mechanisms and gene expression in a subset, and correlated results with patient survival. RESULTS Among 98 tumors, 9/98 (9.2%) had oncogene amplifications (CDK4/MDM2/TERT coamplification (n = 1), CDK4/MDM2 coamplification (n = 4), CDK4 (n = 2), TERT (n = 1), and MYC (n = 1)), while 63/98 (64.3%) had typical segmental chromosomal aberrations (tSCAs). Patients with tumors with oncogene amplification had the worst 5-year event-free survival (EFS; 0%; P < .0001 log-rank test) and 5-year overall survival (OS; 44.4% [95% CI, 21.4 to 92.3]; P < .01 log-rank test). Patients with tumors harboring tSCAs had inferior EFS compared with those with numerical chromosomal aberrations only (51.7% [95% CI, 40.6 to 65.8] v 93.3% [95% CI, 81.5 to 100]; P < .01). Patients with p53 pathway tumor alterations (n = 10) had worse EFS than those without (0% v 61.1% [95% CI, 50.3 to 74.3]; P < .0001, log-rank test) and worse OS (26.7% [95% CI, 8.9 to 80.3] v 80.9% [95% CI, 71.8 to 91.3]; P < .001 log-rank test). Multivariable analysis identified tSCAs as an independent prognostic variable for EFS and oncogene amplification or p53 pathway abnormalities as independent prognostic variables for EFS and OS. CONCLUSION Oncogene amplification and/or p53 pathway abnormalities and/or typical SCAs identify patients with intermediate-risk neuroblastoma with inferior outcome for whom intensified or alternative treatments should be considered.

Pediatric very rare tumors (VRTs) are a highly heterogeneous group of neoplasms defined by an annual incidence of <2 cases per million children under 18 years. Their rarity precludes prospective clinical trials, resulting in limited evidence-based guidelines and largely individualized treatment approaches. Olfactory neuroblastoma (ON) is an exceptionally rare pediatric VRT arising from the olfactory neuroepithelium, typically affecting adults. In children, ON is locally aggressive and may present with regional or distant metastases. Prognosis depends on stage, histology, and multimodal treatment. Owing to the absence of pediatric-specific guidelines, this project aims to develop internationally harmonized consensus recommendations for diagnosis and management.

Very high-risk neuroblastoma is induction-refractory and often harbors mutations in RAS and/or p53 signaling combined with telomere maintenance mechanisms. Event-free survival is <20% in these children. Patients unable to mobilize sufficient hematopoietic stem cells to harvest for busulfan/melphalan-based high-dose chemotherapy before autologous transplantation are also at high risk for relapse. Haploidentical stem cell transplantation (haplo-SCT), offering graft-versus-tumor effects and enhanced antibody-dependent cellular cytotoxicity, has emerged as a feasible treatment. We report administration of a conditioning regimen combining myeloablative busulfan/melphalan anti-tumor therapy with the immunological advantages of haplo-SCT and GD2-directed antibody-based immunotherapy with dinutuximab beta (DB). A 5-patient pilot cohort was treated with systemic induction (salvage) therapy and local therapy per national guidelines. Prior to busulfan, melphalan, fludarabine and antithymocyte globulin conditioning followed by T/B-cell-depleted haplo-SCT and 6 DB cycles, 2 patients received [131I]MIBG therapy. All patients were successfully engrafted. Three of five patients are alive and have remained in first complete remission for 7.3, 6.3 and 1.5 years after haplo-SCT, while two patients experienced events (one relapse, one non-relapse death). Primary busulfan-based haplo-SCT combined with DB immunotherapy was feasible and effective. Early results suggest a survival benefit for these pediatric patient subgroups at very high risk. Confirmation in a larger controlled trial is warranted.

Fractal analysis of vascularity using routine MRI in primary high-risk neuroblastomas predicted local tumor tissue response to chemotherapy at diagnosis and stratified prognosis of patient subgroups after chemotherapy.

Fibroblast growth factor receptor 1 (FGFR1) is recurrently mutated at p.N546 in neuroblastoma. We examined whether mutant FGFR1 is an oncogenic driver, a predictive biomarker, and an actionable vulnerability in this malignancy. FGFR1 mutations at p.N546 were associated with high-risk disease and rapid tumor progression, resulting in dismal outcome for these patients. Ectopic expression of FGFR1N546K induced constitutive downstream signaling and IL-3-independent growth in Ba/F3 cells, indicating oncogene-addicted proliferation. In FGFR1N546K;MYCNtransgenic mice, neuroblastoma developed within the first days of life, with fatal outcome within 3 weeks, reflecting the devastating clinical phenotypes of patients with FGFR1-mutant, high-risk neuroblastoma. Treatment with FGFR inhibitors impaired proliferation and pathway activation in FGFR1N546K-expressing Ba/F3 and patient-derived FGFR1N546K-mutant neuroblastoma cells and inhibited tumor growth in FGFR1N546K;MYCNtransgenic mice and in a chemotherapy-resistant, patient-derived xenograft mouse model. In addition, partial regression of FGFR1N546K-mutant tumor lesions occurred upon treatment with the FGFR inhibitor futibatinib and low-intensity chemotherapy in a patient with refractory neuroblastoma. Together, our data demonstrate that FGFR1N546K is a strong oncogenic driver in neuroblastoma associated with failure of current standard chemotherapy and suggest potential clinical benefit of FGFR-directed therapies in patients with high-risk mutant FGFR1.

Das Neuroblastom ist der häufigste extrakranielle solide Tumor im Kindesalter. Es entsteht aus Vorläuferzellen des peripheren Nervensystems im Nebennierenmark oder in den sympathischen Grenzsträngen. In Deutschland werden jährlich 120 Neuerkrankungen registriert, entsprechend 5–6

More than 50 % of patients with high-risk neuroblastoma (HRNB) will relapse despite intensive multimodal therapy. Most relapses occur within 2 years of diagnosis. Overall survival at relapse is 20 % at 4 years, but long-term survival can be achieved in a patient subset. A biopsy at relapse with in-depth molecular characterization should now become accepted as standard of care to confirm active neuroblastoma and identify potential targets for biomarker-based targeted therapy or immunotherapy. No clear consensus currently exists about optimal therapy because the field lacks umbrella trials covering all phases of relapse treatment (re-induction, consolidation, maintenance) in a homogenous strategy. Recruitment into clinical trials (e.g. BEACON2) should be prioritized. Current evidence supports starting re-induction therapy with a camptothecin-based chemotherapy regimen combined with monoclonal antibody therapy targeting GD2 or VEGF (or ALK inhibitors if ALK-aberrant) as the first choice. The RIST regimen is a promising first choice for MYCN-amplified disease. After an objective response to re-induction therapy, GD2-directed immunotherapy or cellular therapies harnessing the immune system (haploidentical stem cell transplantation, CAR T cells) are of high interest as a consolidation strategy. Long-term maintenance therapy must be feasible as outpatient treatment, have a low toxicity profile and be well-tolerable to suit patients with relapsed HRNB. For optimal care, new options must be tested as maintenance therapy in randomized trials. The most promising salvage options for patients responding insufficiently to treatment are the chemotherapy combinations, topotecan/vincristine/doxorubicin (TVD), topotecan/cyclophosphamide/etoposide (TCE), ifosfamide/carboplatin/etoposide (ICE) or topotecan/cyclophosphamide (TopoCy), or [131I]-mIBG therapy. Early-phase clinical trials are also a possible option in this setting.

It is critical to share knowledge and harmonize approaches to optimize progress in rare cancers. The International Neuroblastoma Risk Group (INRG) Task Force was formed by the 4 major neuroblastoma cooperative groups in 2004 to achieve this goal. Strategies developed for neuroblastoma are an exemplar for other rare malignancies. Data from an initial cohort of 8800 patients were transferred to the INRG Data Commons, and a data-sharing model was developed. Currently, information on more than 25 000 patients is available to the research community. The INRG staging and risk classification systems have led to harmonized approaches for therapeutic groupings. INRG consensus manuscripts have led to uniform criteria for classifying biological data, evaluating the extent of disease, and defining treatment response. More than 40 INRG research studies have been performed by investigators from around the world, including analyses of rare patients, which would not otherwise be possible. The success of this approach for neuroblastoma has been leveraged to create the Pediatric Cancer Data Commons and the Data for the Common Good. Efforts to enrich the INRG Commons with additional genomic and biomarker data, extracted electronic health records, and digital medical images are ongoing. The international networking model developed by the INRG Task Force has led to new research discoveries and progress in neuroblastoma. The approach has now been applied to 16 other cancers and conditions, including rhabdomyosarcoma, germ cell tumor, Lynch syndrome, and cancer predisposition. This framework of international collaboration and data sharing serves as a model for advancing rare adult malignancies.

BackgroundIn oncological pediatrics, exercise therapy is still not part of regular medical care in Germany and exercise therapy projects are currently financed by charity organizations. Nevertheless, the scientific evidence for the benefit of exercise therapy in pediatric oncology has led to the implementation of exercise therapy programs at most of the German hospitals. At the Pediatric Oncology Department of the University Hospital of Cologne the exercise therapy program was established in 2021. Between 2023 and 2025 a comprehensive survey was carried out to assess the perception of various groups such as patients, family and staff with offered program.MethodsA monocentric survey was conducted to assess the perception of patients, parents, siblings, and staff members regarding the exercise project using non-validated questionnaires. The questionnaires addressed the exercise project during intensive medical therapy in both the outpatient and inpatient phases. The questionnaires contained both open and closed questions and were evaluated using the following categories: “Communication/Education”, “Participation”, “Satisfaction”, “Need for Support”, “Online Exercise Sessions”, and “Barriers and Motives”.ResultsThe survey was completed by 33 patients, 63 parents, 14 siblings and 48 staff members. The evaluation of the survey showed that more than 50% of the patients and parents surveyed were satisfied with the existing program. Parents and staff have particularly noted the lack of exercise therapy programs for patients during their outpatient phases.DiscussionDespite the generally positive evaluation, patients, parents, siblings and staff still see potential for further development of the exercise therapy program, especially for the outpatient phases.ConclusionAlthough the physical activity program is highly regarded, its potential is limited by gaps in outpatient care and inadequate sibling integration. To improve exercise therapy further, a holistic, family-centered approach must expand beyond the inpatient setting. Overcoming skepticism toward telehealth is crucial to ensuring accessible, sustainable exercise therapy outside the hospital.Clinical Trial Registration:https://drks.de/search/de/trial/DRKS00034629/details, identifier (DRKS00034629).

IntroductionNeuroblastoma, the most prevalent solid cancer in children, presents significant biological and clinical heterogeneity. This inherent heterogeneity underscores the need for more precise prognostic markers at the time of diagnosis to enhance patient stratification, allowing for more personalized treatment strategies. In response, this investigation developed a machine learning model using clinical, molecular, and magnetic resonance (MR) radiomics features at diagnosis to predict patient’s overall survival (OS) and improve their risk stratification.MethodsPRIMAGE database, including 513 patients (discovery cohort), was used for model training, validation, and testing. Additional 22 patients from different hospitals served as an external independent cohort. Primary tumor segmentation on T2-weighted MR images was semi-automatically edited by an experienced radiologist. From this area, 107 radiomics features were extracted. For the development of the prediction model, radiomics features were harmonized following the nested ComBat methodology and nested cross-validation approach was employed to determine the optimal preprocessing and model configuration.ResultsThe discovery cohort yielded a 78.8 ± 4.9 and 77.7 ± 6.1 of C index and time-dependent area under de curve (AUC), respectively, over the test set, with a random survival forest exhibiting the best performance. In the independent cohort, a C-index of 93.4 and a time-dependent AUC of 95.4 were achieved. Interpretability analysis identified lesion heterogeneity, size, and molecular variables as crucial factors in OS prediction. The model stratified neuroblastoma patients into low-, intermediate-, and high-risk categories, demonstrating a superior stratification compared to standard-of-care classification system in both cohorts.DiscussionOur results suggested that radiomics features improve current risk stratification systems in patients with neuroblastoma.

PURPOSE:About 60% of patients with high-risk neuroblastoma relapse. Specific mRNA detection in bone marrow (BM) by reverse transcriptase quantitative PCR (RT-qPCR) is associated with survival outcomes. Peripheral blood (PB) sampling is less invasive. Therefore, we prospectively validated an RT-qPCR panel of neuroblastoma mRNA in PB of patients with high-risk neuroblastoma, treated in NB2004-HR (GPOH) and NBL2009 (DCOG). METHODS:From 312 patients, 634 PB samples were prospectively collected (2009-2017) at diagnosis, after two cycles and end-of-induction therapy. RT-qPCR was performed using our panel of neuroblastoma mRNA markers: PHOX2B, TH, DDC, CHRNA3, and DBH. Results were compared with paired BM samples. The association between neuroblastoma detection and event-free survival (EFS) and overall survival (OS) was estimated using Kaplan-Meier's methodology and multivariable Cox regression model. RESULTS:Clear correlation between calculated infiltration by neuroblastoma mRNA expression in PB and BM was seen at diagnosis (rs 0.70 [95% CI, 0.62 to 0.76]), and heterogeneity was seen after two cycles (0.37 [95% CI, 0.12 to 0.58]) and end of induction (0.61 [95% CI, 0.10 to 0.87]). mRNA expression was significantly lower in PB compared with BM. At diagnosis, PB infiltration ≥1% was a prognostic factor for survival: adjusted hazard ratio (HR) was 2.37 [95% CI, 1.56 to 3.60] for EFS and 2.60 [1.65-4.08] for OS. At the end of induction, PHOX2B positivity in PB samples (n = 11) was associated with poor outcomes: HR 3.06 [1.51-6.20] for EFS and 2.88 [1.36-6.11] for OS. In patients with ≥10% BM infiltration at diagnosis, detection of the mRNA panel in PB samples could significantly distinguish between survival groups; the adjusted HR of PB infiltration ≥1% was 2.09 [1.01-4.30] for OS. CONCLUSION:PB infiltration is associated with EFS and OS at diagnosis; it is also significantly associated with survival outcomes of patients with ≥10% BM infiltration at diagnosis. During follow-up, neuroblastoma mRNA detection in PB can be of added value, when BM analysis is not possible.

BACKGROUND:Long-term childhood cancer survivors (CCS) may develop anthracycline-induced cardiomyopathy. Our cross-sectional study focused on the question of whether a central echocardiographic reference assessment is associated with a higher detection rate of cardiac dysfunction in a population-based cohort of affected children with neuroblastoma or nephroblastoma. We also examined the prevalence of anthracycline-induced cardiomyopathy and its risk factors. METHODS AND PATIENTS:The cohort of this subproject comprises 370 nephroblastoma or neuroblastoma survivors diagnosed with cancer between 1990 and 2012. At study entry, participants were younger than 18 years old, had been treated with anthracyclines, and had no documented previous cardiac disease. Data were collected via patient questionnaires, cardiologic examinations in the network of adults with congenital heart defects (Erwachsene mit angeborenem Herzfehler [EMAH]) and a reference assessment of the recorded echocardiography. RESULTS:The prevalence of cardiomyopathy in the study cohort (mean age: 12 years) was 6.3% at a median of 9.1 years after initial cancer diagnosis. Risk factors were an age under 5 years at tumor diagnosis and concomitant treatment with cyclophosphamide or radiation. As a central and novel finding, the detection rates by the EMAH cardiologists and the reference center are similarly high but discrepant. DISCUSSION:Limitations were mainly due to the low responder rate and incomplete data. This study established a nationwide competence network linking pediatric oncology and cardiology centers across six university hospitals in Germany, enabling data collection on pediatric CCS. Despite lower case numbers compared to adult CCS cohorts, meaningful data were gathered and analyzed. CONCLUSION:Cardiac late effects after anthracycline-based therapy in childhood affect a relevant proportion of long-term CCS at pediatric age. In order to enable timely diagnosis and treatment, preventive examinations are essential and might benefit from additional central reference assessments. Discrepancy in detection of cardiomyopathy by reference and EMAH cardiologists requires further investigation.

The clinical course of neuroblastoma is more heterogeneous than any other malignant disease. Many low-risk patients experience regression after limited or even no chemotherapy. However, more than half of high-risk patients die from disease despite intensive multimodal treatment. Precise disease characterization for each patient at diagnosis is key for risk-adapted treatment. The guidelines presented here incorporate results from national and international clinical trials to produce recommendations for diagnosing and treating neuroblastoma patients in German hospitals outside of clinical trials.

Background: The incorporation of anti-GD2 antibodies such as ch14.18/SP2/0 into the multimodal treatment of high-risk neuroblastoma (HR-NB) patients has improved their outcomes. As studies assessing the long-term outcomes, long-term sequelae, and health-related quality of life (HRQoL) of this treatment are limited, this retrospective analysis aimed to explore these. Patients and Methods: Between 1991 and 2002, 65 children received a multimodal treatment, including ch14.18/SP2/0, for primary HR-NB. All received chemotherapy according to the NB90/NB97 trial, 51 received high-dose chemotherapy, and all received ch14.18/SP2/0 treatment. We analyzed the long-term sequelae and HRQoL (EORTC QLQ-C30), and evaluated overall and event-free survival (OS/EFS). Results: Twenty-five survivors were evaluated for HRQoL and long-term effects. All reported long-term sequelae, including ototoxicity in 16/25 (64%), cardiac toxicity in 6/25 (24%), and endocrine toxicity in 19/25 (76%) patients. Chronic diarrhea was reported in 20% of female patients. Seven patients developed autoimmune diseases. HRQoL scores were better across multiple scales than those of the matched German general population. Twenty-five-year OS and EFS were 50.8% (95% confidence interval: 31–55) and 43% (30.1–55.3), with 33 (50.8%) long-term survivors. Thirty-two patients died: 28 (43.1%) because of progression/relapse and 4 (6.2%) because of secondary neoplasms. Conclusions: Multimodal treatment, including ch14.18/SP2/0, can achieve long-term survival in HR-NB patients, with a substantial proportion of survivors reporting better HRQoL compared to the general population. All patients reported long-term side effects mostly attributable to chemotherapy and radiotherapy. The relatively high prevalence of autoimmune diseases and persistent diarrhea warrants additional longitudinal research on individuals treated with anti-GD2 antibodies.

Purpose: To evaluate the reproducibility of radiomics features extracted from T2-weighted MR images in patients with neuroblastoma. Materials and Methods: A retrospective study included 419 patients (mean age, 29 months +/- 34 [SD]; 220 male, 199 female) with neuroblastic tumors diagnosed between 2002 and 2023, within the scope of the PRedictive In-silico Multiscale Analytics to support cancer personalized diaGnosis and prognosis, Empowered by imaging biomarkers (ie, PRIMAGE) project, involving 746 T2/T2*-weighted MRI sequences at diagnosis and/or after initial chemotherapy. Images underwent processing steps (denoising, inhomogeneity bias field correction, normalization, and resampling). Tumors were automatically segmented, and 107 shape, first-order, and second-order radiomics features were extracted, considered as the reference standard. Subsequently, the previous image processing settings were modified, and volumetric masks were applied. New radiomics features were extracted and compared with the reference standard. Reproducibility was assessed using the concordance correlation coefficient (CCC); intrasubject repeatability was measured using the coefficient of variation (CoV). Results: When normalization was omitted, only 5% of the radiomics features demonstrated high reproducibility. Statistical analysis revealed significant changes in the normalization and resampling processes (P P < .001). Inhomogeneities removal had the least impact on radiomics (83% of parameters remained stable). Shape features remained stable after mask modifications, with a CCC greater than 0.90. Mask modifications were the most favorable changes for achieving high CCC values, with a radiomics features stability of 70%. Only 7% of second-order radiomics features showed an excellent CoV of less than 0.10. Conclusion: Modifications in the T2-weighted MRI preparation process in patients with neuroblastoma resulted in changes in radiomics features, with normalization identified as the most influential factor for reproducibility. Inhomogeneities removal had the least impact on radiomics features.

The analysis of multiple time-to-event outcomes in a randomised controlled clinical trial can be accomplished with exisiting methods. However, depending on the characteristics of the disease under investigation and the circumstances in which the study is planned, it may be of interest to conduct interim analyses and adapt the study design if necessary. Due to the expected dependency of the endpoints, the full available information on the involved endpoints may not be used for this purpose. We suggest a solution to this problem by embedding the endpoints in a multi-state model. If this model is Markovian, it is possible to take the disease history of the patients into account and allow for data-dependent design adaptiations. To this end, we introduce a flexible test procedure for a variety of applications, but are particularly concerned with the simultaneous consideration of progression-free survival (PFS) and overall survival (OS). This setting is of key interest in oncological trials. We conduct simulation studies to determine the properties for small sample sizes and demonstrate an application based on data from the NB2004-HR study.