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.

Objective: Immunotherapy with dinutuximab beta (DB) improves the prognosis of patients with high-risk neuroblastoma (HR-NB) but can be associated with severe immune-mediated side effects. A comprehensive side effect management is necessary to improve tolerability and avoid treatment discontinuation. To date, standardized guidelines on co-medication and on the management of acute and chronic side effects are not available in Germany. In a survey, German pediatric oncology departments were therefore asked about their experiences and procedures from which the recommendations described here were developed. Method: A survey was conducted among German pediatric oncology centers to assess their approaches to managing DB-related adverse effects. Centers were asked about their experiences and procedures, and consensus recommendations were subsequently developed by an expert panel based on these findings. Results: Existing international recommendations were expanded by incorporating current clinical practices from German centers, resulting in comprehensive guidelines for adverse event management during DB immunotherapy. Conclusion: These recommendations can contribute to improving tolerability and thereby help prevent treatment discontinuation.

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.

Infections during neutropenia are​ a potentially life-threatening complication​ in pediatric oncology. International guidelines recommend antipseudomonal β-lactam monotherapy for stable patients, however, modification​ to carbapenems often occurs without confirmed infection.​ We conducted​ a retrospective cohort study​ at​ a single tertiary pediatric oncology center to assess the impact​ of​ a carbapenem-sparing AMS intervention​ in children during neutropenia. All pediatric cancer patients with​ at least one episode​ of​ suspected infection between January 2021 and October 2024 were included.​ The intervention combined training, updated standard operating procedures, multidrug-resistant (MDR) surveillance swabs, and​ a structured protocol reassessing meropenem treatment​. Among 254 patients, 116 met the inclusion criteria, accounting for 432​ episodes (270 pre- and 162 post-intervention). Re-modification​ of antimicrobial therapy from meropenem​ to piperacillin/tazobactam was achieved​ in​ 16​ of​ 50 post-intervention episodes. The median duration​ of meropenem treatment decreased from​ 9​ to​ 6 days​ (p​ = 0.006). Interrupted time series analysis showed​ a non-significant reduction​ in meropenem use, corresponding​ to​ an estimated decline​ of 40.7 days of therapy (DOT) per 1000 patient-days per quarter. Mortality was unchanged (3.8

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

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.

Die Immuntherapie mit Dinutuximab beta (DB) verbessert die Prognose bei Patienten mit einem Hochrisiko-Neuroblastom, kann aber mit schweren immunvermittelten Nebenwirkungen verbunden sein. Ein umfassendes Nebenwirkungsmanagement ist notwendig, um die Verträglichkeit zu verbessern und Therapieabbrüche zu vermeiden. Bislang fehlen in Deutschland einheitliche Vorgaben zur Co-Medikation und zum Umgang mit akuten und chronischen Nebenwirkungen. In einer Umfrage wurden daher deutsche kinderonkologische Zentren zu ihren Erfahrungen und Verfahren angefragt und hieraus die beschriebenen Empfehlungen erarbeitet. In einer Umfrage wurde das Vorgehen bei DB-Nebenwirkungen an deutschen kinderonkologischen Zentren erhoben; hieraus wurden konsensual Empfehlungen in einem Expertengremium erarbeitet. Existierende internationale Empfehlungen wurden um das Vorgehen aus gängiger Praxis an deutschen Zentren zu einem umfassenden Leitfaden des Nebenwirkungsmanagements bei DB-Immuntherapie erweitert. Diese Empfehlung kann einen Beitrag leisten, die Verträglichkeit zu verbessern, um so Therapieabbrüche zu vermeiden.

Background:Diffuse intrinsic pontine glioma (DIPG) remains uniformly lethal. Stereotactic biopsy confirms the diagnosis and enables molecular profiling. Metastasis along the biopsy track (BTM) has been reported only anecdotally; its prevalence, clinical relevance, and implications for treatment remain unclear. Methods:A multicenter retrospective study in patients with confirmed DIPG and BTM was conducted based on central neuroradiologic review. Radiotherapy schedules were re-assessed to evaluate the feasibility of upfront biopsy track irradiation. Results:Ten children met inclusion criteria (median age 6.8 years). Biopsy route was supratentorial in six and infratentorial in four children, and side-cutting needles were used predominantly. H3F3A mutations were most frequent (n = 8); TP53 alterations were common in tumors with extended molecular profiling available. Median PFS was 8.1 months. Five patients each developed BTM prior to (median 2.7 months) or concurrently with progression of primary tumor. There was no difference in overall survival (median OS 12.0 months) compared with the reference cohort. Estimated BTM prevalence among biopsied DIPG from additional registry data was between 6.9% and 13.0%. Primary biopsy track irradiation proved to be feasible, and comparing the surgical access routes, the infratentorial biopsy track hardly increased radiation exposure of the whole brain. Conclusions:Needle track metastasis is a rare progression pattern in stereotactic biopsied DIPG. Upfront irradiation of the biopsy track may represent a strategy to mitigate the potential risk of BTM. From a dosimetric perspective, an infratentorial approach may therefore be considered, as it was associated with only marginally increased radiation exposure.

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.

Accurate detection of macroscopic residual disease after neuroblastoma resection is essential for postoperative treatment decisions, including radiotherapy. Standard imaging follow-up is often performed at a time point when postoperative and therapy-related changes may hamper reliable differentiation between residual disease and reactive findings. To assess inter-reader agreement and the diagnostic accuracy of early postoperative magnetic resonance imaging (MRI) for detecting residual disease after neuroblastoma surgery. This retrospective single-center study included patients with histologically confirmed neuroblastic tumors who underwent surgical resection at a reference center and received standardized early postoperative MRI with adequate preoperative imaging. Two independent pediatric radiologists, blinded to all clinical data, assessed all examinations. A hierarchical multimodal reference standard was established based on surgical reports including expert consensus between a senior pediatric radiologist and a pediatric surgeon, and follow-up imaging (median follow-up 33 months). Thirty-nine patients (median age 46 months), predominantly with International Neuroblastoma Staging System (INSS) stage 4 neuroblastoma, were included; all patients had at least one image-defined risk factor. MRI was performed at a mean of 8±5 days after surgery. Residual disease was identified in 14 patients and confirmed by the reference standard. Five residual diseases were expected by the surgeons (median volume 8 ml), whereas nine were unexpected and small (median volume 1 ml). Diagnostic accuracy were 95

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).

BACKGROUND:Oligodendrogliomas, characterized by isocitrate dehydrogenase (IDH) mutations and 1p/19q codeletion, often exhibit telomerase reverse transcriptase promoter (TERTp) mutations, which have been linked to telomere maintenance (TM) and tumor proliferation. Although there are a few reports on a TERTp-wildtype subset of these tumors in adolescents and young adults, the frequency, molecular characteristics, and prognostic implications of TERTp-wildtype status in oligodendrogliomas remain elusive. METHODS:We retrospectively analyzed 166 IDH-mutant and 1p/19q-codeleted oligodendroglioma cases through comprehensive histopathological review and molecular analyses, including Sanger sequencing, DNA methylation profiling, and whole-exome sequencing (WES). RESULTS:A TERTp-wildtype status was observed in 20/166 cases (12.0%) and was significantly associated with noticeably young age (age range: 14-27, P < .001), CNS WHO grade 2 (P = .003), and the absence of additional DNA copy number variations (CNVs) beyond the pathognomonic 1p/19q codeletion (P < .001). Epigenetic profiling demonstrated TERTp-wildtype tumors shaped a distinct subgroup at the utmost periphery of TERTp-mutant oligodendrogliomas. Methylation analysis of the upstream and proximal TERTp regions revealed that, in line with the absence of genetic alterations, epigenetic regulation does not favor TERT overexpression in TERTp-wildtype oligodendrogliomas. WES showed no TM-related gene alterations in TERTp-wildtype cases. Cox regression analysis confirmed TERTp-wildtype status as an independent prognostic factor for more favorable progression-free survival (PFS) (P = .009). CONCLUSIONS:In conclusion, "oligodendroglioma, IDH-mutant, 1p/19q-codeleted, and TERTp-wildtype" represent a distinct molecular subgroup associated with younger age and a better clinical course compared to CNS WHO grade 2 oligodendrogliomas.

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:In Ewing sarcoma (EwS), metastases, including those to bone marrow (BM), are the main factors influencing prognosis. Although reverse transcription polymerase chain reaction (RT-PCR) offers greater sensitivity, the current EWING protocol defines BM metastases solely using light microscopic detection. However, the prognostic relevance of BM metastases remains unclear. We evaluated the diagnostic validity and prognostic relevance of RT-PCR for detecting BM involvement in EwS. PROCEDURE:We retrospectively analyzed 316 patients from the EWING 2008 trial (NCT00987636), stratified by BM status: Group 1 (RT-PCR-/microscopy-), Group 2 (RT-PCR+/microscopy-), and Group 3 (RT-PCR+/microscopy+). Event-free survival (EFS) and overall survival (OS) were assessed using Kaplan-Meier and Cox regression analyses, including subgroup analyses by metastatic status at diagnosis. RESULTS:Kaplan-Meier analysis of EFS showed relevant differences (overall [Group 2 vs Group 1: HR = 2.27; 95% CI: 1.33-3.87, p = 0.003; Group 3 vs Group 1: HR = 2.98; 95% CI: 0.94-9.45, p = 0.064], localized disease [Group 2 vs Group 1: HR = 1.30; 95% CI: 0.47-3.62, p = 0.61], metastatic disease [Group 2 vs Group 1: HR = 2.56; 95% CI: 1.32-4.96, p = 0.006; Group 3 vs Group 1: HR = 1.85; 95% CI: 0.57-6.01, p = 0.307]). OS analysis showed comparable results. CONCLUSIONS:The validity of RT-PCR is at least comparable to that of microscopy, and it additionally detects submicroscopic BM involvement, supporting its use as a standalone method for initial staging. The prognostic implications of BM assessment remain relevant.

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.