International Neuroblastoma Pathology Classification.

PURPOSE:Historically, neuroblastoma risk stratification has been performed with clinical stage as the starting point and successively adding other prognostic factors thereafter. This study takes an alternative approach to define risk groups of patients with neuroblastoma by starting with the International Neuroblastoma Pathology Classification (INPC). EXPERIMENTAL DESIGN:The cohort of patients with neuroblastoma previously used for developing the Children's Oncology Group-Revised Neuroblastoma Risk Classification (RNRC) system was reanalyzed by survival tree regression analysis, starting with the INPC distinguishing favorable-histology and unfavorable-histology categories. The resultant two branches were further divided first by the International Neuroblastoma Risk Group Staging System and successively by other prognostic factors. RESULTS:This new stratification system, the INPC-Risk Grouping (INPC-RG), is simpler than the RNRC system, eliminating unnecessary decision trees, and distinguishes four risk groups (groups I-IV). Using only INPC (unfavorable histology) and International Neuroblastoma Risk Group Staging System (stage M), INPC-RG defines patients with highly aggressive group IV tumors, whose 5-year event-free survival was worse than that of the RNRC high-risk group. Additionally, it identifies group III patients whose 5-year event-free survival spanned 50% to 80%, which was not identified by the RNRC. CONCLUSIONS:The benefits of using this new INPC-RG system are fourfold: (1) it allows for the rapid identification of group IV patients, (2) it lays the foundation for further refinement of group III, (3) it can stratify patients when the amount of tumor tissue is limited, and (4) it allows patients in resource-limited areas to be appropriately stratified, potentially improving the worldwide treatment of patients with neuroblastoma.

Outcomes for pediatric patients with refractory or relapsed T-cell acute lymphoblastic leukemia (T-ALL) are poor, underscoring the need for improved therapeutic strategies. CD38, a type II transmembrane glycoprotein, is a promising target in T-ALL, with clinical trials evaluating CD38-targeting immunotherapies in frontline and relapsed settings. However, the biological role of CD38 in T-ALL has not been systematically defined. We interrogated CD38 biology through multimodal profiling of pediatric T-ALL samples. Bulk RNA sequencing of 1,335 primary tumors revealed that CD38 expression varies across genomic and immunophenotypic subtypes in T-ALL. Flow cytometry of 150 primary samples and CITE-sequencing of 40 cases demonstrated broad surface expression of CD38. A transcription factor CRISPR-screen identified RUNX1, RUNX3, and TP53 as candidate positive regulators of CD38. Metabolomic profiling of cell lines further revealed disruption of the polyamine pathway following CD38 perturbation. Supporting this finding, co-targeting CD38 with difluoromethylornithine (DFMO), a polyamine metabolism disruptor, improved survival in preclinical models. Across transcriptomic datasets, including primary tumors, cell lines, and patient-derived xenograft models, IL32 expression consistently decreased following CD38 loss or negativity, supporting an association between CD38 and inflammatory signaling pathways. Additionally, CD38 and LCK expression were positively correlated across majority of genomic subtypes, implicating SRC kinase signaling. Consistent with this, daratumumab in cell lines increased LCK phosphorylation, and combination therapy with dasatinib improved survival compared to monotherapy. Collectively, these findings define previously unrecognized interactions between CD38 and targetable pathways and genes in T-ALL and identify rational combinatorial strategies to enhance CD38-directed therapies and reduce relapse risk.

ABSTRACT:Langerhans cell histiocytosis (LCH) and non-Langerhans cell (non-LC) histiocytosis are rare neoplastic diseases with variable behavior. Although chemotherapy is often effective, some patients respond poorly to treatment, experience disease recurrence and/or develop long-term complications. Clofarabine (Clolar), a deoxyadenosine analog, has shown encouraging activity in histiocytic disorders. Here, we report a prospective, multicenter, phase 2 study evaluating the efficacy and toxicity of clofarabine in recurrent/refractory (R/R) LCH (stratum 1) and non-LC histiocytosis (stratum 2). All participants received clofarabine on days 1 through 5 of each 28-day cycle. Response was assessed after 2 cycles; participants without evidence of disease progression received 4 additional cycles. A total of 25 participants enrolled: 20 in stratum 1 and 5 in stratum 2. In stratum 1, 17 of 20 participants (85%; 95% confidence interval [CI], 62%-97%) were responders, and 3 had stable disease after cycle 2. Overall, 19 stratum-1 participants completed 6 cycles; 1 withdrew after cycle 3. No stratum-1 participants progressed during treatment and 3 had disease recurrence after cycle 6, resulting in 2-year progression-free survival ± standard error and overall survival of 89% ± 7% and 100%, respectively (n = 20; median follow-up, 40.9 months [range, 2.7-49.4]). In stratum 2, 3 of 4 evaluable participants (75%; 95% CI, 19%-99%) had partial response. Overall, 20 of 25 (80%) of participants had ≥1 grade ≥3 toxicity attributed to protocol therapy. In conclusion, clofarabine is active and tolerable in children with R/R LCH and warrants further study in patients with non-LC histiocytosis. Further study of clofarabine in these populations is warranted. This trial was registered at www.clinicaltrials.gov (#NCT02425904).

Statistical Framework of INPC-Risk Grouping System

PURPOSE:Prior studies of features impacting post-relapse survival in high-risk neuroblastoma (HRNB) evaluated patient cohorts that did not receive contemporary high-risk or relapse therapies. We describe overall survival (OS) after first progression or first relapse of HRNB in a modern cohort. METHODS:Patients with HRNB enrolled on COG ANBL00B1(NCT00904241) between 2000 and 2019, who had relapsed or progressive disease were eligible. Clinical and molecular risk factors at diagnosis, therapy era, clinical trial enrollment, and clinical features at relapse, including site of and time to relapse, were evaluated. OS post-relapse was compared between groups using log-rank tests and Cox models. RESULTS:Among 4253 eligible HRNB patients, 1616 had relapse or progression as a first event. Five-year OS post-relapse was 19.1 ± 1.1%. The risk group with the lowest post-relapse survival was observed in patients with INSS Stage 4 or 4S disease < 18 months of age at diagnosis with MYCN amplified (MYCN-A) tumors. The other significant most unfavorable factors at diagnosis included diagnosis 2000-2004, tumor MYCN-A, 1p loss of heterozygosity (LOH), and elevated LDH or ferritin. Unfavorable factors at relapse included the time to relapse < 36 months from diagnosis, and combined local and metastatic disease at relapse. Multivariable analysis indicated that those with tumors harboring 1p LOH, age ≤ 5 years at diagnosis, or earlier treatment therapy era (2000-2004) had a higher risk of post-relapse death. CONCLUSIONS:While the 5-year OS rate was low in this cohort, there are subsets of patients with relapsed HRNB who demonstrate long-term survival. TRIALS REGISTRATION:ClinicalTrials.gov identifier: NCT00904241.

10044 Background: Accurate and reproducible response assessment is critical for evaluating efficacy in clinical trials. Central response review is frequently used to reduce inter-site variability but is resource intensive and may delay data availability. Whether centralized review meaningfully alters response endpoints compared with remote source verification of site assessment remains unclear. Methods: We evaluated response assessments from eight NANT phase 1–2 trials conducted between February 2013 and December 2022 in relapsed/refractory high-risk neuroblastoma. Initial investigator-assessed response, remote source-verified response (remote review of radiology/bone marrow [BM] reports), and centrally-reviewed responses (review of radiographic images and BM biopsy slides) were assessed. Each patient’s best overall response (BOR) and individual component responses (BM, MIBG/bone, and soft tissue [ST]) at time of BOR as determined by these three review methods were assessed. Only patients with MIBG-avid disease were included in bone response. Results: Among 244 evaluable patients, concordance between remote source-verified response and central review response exceeded the concordance between initial investigator-assessed response and central review response (BOR: 89% vs 79%, BM: 91% vs 74%, MIBG/bone: 92% vs 83%, ST: 82% vs 74%). Concordance between initial investigator-assessed response and remote source-verified response was 86% for BOR and similar for component response (BM: 83%, MIBG/bone: 91%, ST: 86%). Remote source-verified assessment compared to central review demonstrated higher level of concordance than initial investigator assessment for complete response (CR) (90.0% vs 81.0%), partial response (PR) (85.7% vs 72.7%), minor response (MR) (80.6% vs 71.0%), and stable disease (SD) (92.1% vs 86.7%), indicating improved response classification consistency across all major BOR categories. Overall, the initial investigator-assessed response for CR, PR, and MR agreed with central review 74.0% of the time, while remote source-verified agreed 84.7%. Most discordance reflects relabeling within adjacent categories (e.g., CR vs PR or PR vs MR). A change in response from CR/PR/MR to SD/PD when compared to central review was uncommon: 9.4% for initial investigator-assessed response, and decreased with remote source verification down to 7.1%. A change from CR/PR to MR/SD/PD was more frequent but also improved with remote source verification (from 20% to 11.3%). Conclusions: Remote source verification substantially improves agreement with central review and reduces responder misclassification. These findings demonstrate that structured remote source verification improves response assessment reliability and harmonization with central review, reinforcing its role as an important quality-control mechanism in multicenter trials.

Children’s Oncology Group Revised Neuroblastoma Risk Classification.

10033 Background: Patients with relapsed/refractory (RR) high-risk neuroblastoma (HR-NB) have poor survival. Tumor response may be an early predictive endpoint, though response may not reflect long term survival. We evaluated the association between NANT Response Criteria (NANTRC) v1.2/2.0 with event-free survival (EFS) and overall survival (OS) in patients with RR-NB treated on contemporary NANT Phase 1/2 trials. Methods: Patients enrolled on 8 NANT trials from 2013 to 2022 were included. For patients enrolled on more than one trial, the first trial data was included. NANTRC were utilized to grade individual response components (soft tissue [ST], bone/MIBG, bone marrow [BM]) and overall response (complete [CR], partial [PR], minor [MR] response, stable disease [SD], or progressive disease [PD]). Patient/tumor characteristics, prior therapy and relapse, and disease at enrollment were analyzed for association with best overall response (BOR). Component and BOR were analyzed for association with EFS and OS from trial treatment initiation. EFS and OS were compared with the log-rank test and estimated by the Kaplan-Meier methods. Results: Among 244 patients, 3-year OS was 52% (95% confidence interval [CI] 46-58%), and EFS was 22% (95% CI 14-32%). OS differed significantly by best overall response (p<0.001), driven primarily by inferior outcomes of patients with PD. The 3-year OS was 16% (95% CI 9-29%) for patients with PD. Patients achieving objective response (CR/PR/MR) had an OS of 63% (95% CI 55-74%) and EFS 25% (95% CI 15-43%), while those achieving disease control (CR/PR/MR/SD) had very similar OS of 63% (95% CI 57-71%) and EFS 29% (95% CI 20-43%). Among patients with response of CR, PR, MR, or SD, OS and EFS were not significantly different. For individual components, a similar impact on OS was seen for PD vs no PD (all p<0.001), with BOR of PD in MIBG/bone and ST having OS <10%. Patients lacking either BM or bone/MIBG involvement (but not ST) at baseline and remained not involved in those components demonstrated superior OS (both p<0.001). Patients with BOR of PD had shorter time from diagnosis to first progression (median of 1.4 vs 1.8 years, p=0.035), and higher incidence of MYCN -amplified disease (46% vs. 14%, p<0.001) and prior history of progression (95% vs 73%, p<0.001). Conclusions: In RR-HRNB treated on contemporary NANT trials, BOR of PD is associated with inferior OS. Patients achieving disease control (CR/PR/MR/SD) experienced comparable outcomes regardless of response achieved. These findings support disease-control as a clinically meaningful efficacy endpoint for early-phase neuroblastoma trials. 3-year survival by component response. Component Response N OS % (95% CI) EFS* % (95% CI) BM Non-PD 100 47 (38, 58) 17 (7, 38) PD 18 29 (14, 61) - Bone/MIBG Non-PD 180 59 (52, 66) 22 (13, 35) PD 30 7 (2, 26) - ST Non-PD 142 61 (53, 70) 28 (18, 44) PD 35 9 (3, 25) - *EFS censored at time of new therapy.

Metabolites are central to cellular homeostasis. Although much emphasis has been placed on their relevance to meet energetic and biosynthetic demands, metabolic intermediates also function as signalling molecules. Here we show that polyamines, small polycations that are critical to cellular homeostasis1-3, regulate the process of alternative pre-mRNA splicing. We find that inhibition of polyamine synthesis increases phosphorylation of spliceosomal proteins, concomitant with perturbation of alternative splicing in cells and tissues. Mechanistically, molecular modelling combined with biochemical assays revealed that polyamines bind to acidic phosphorylatable motifs in splicing factors of the U2 small nuclear ribonucleoprotein SF3 subcomplex, thus preventing the action of upstream kinases. We refer to this molecular process by which polyamines regulate protein phosphorylation as metabolic shielding.

High-risk neuroblastoma, a leading cause of pediatric cancer mortality, exhibits substantial intratumoral heterogeneity, contributing to therapeutic resistance. To understand tumor microenvironment evolution during therapy, we longitudinally profiled 22 patients with high-risk neuroblastoma before and after induction chemotherapy using single-nucleus RNA and ATAC sequencing and whole-genome sequencing. This revealed profound shifts in tumor and immune cell subpopulations after therapy and identified enhancer-driven transcriptional regulators of neuroblastoma neoplastic states. Poor outcome correlated with proliferative and metabolically active neoplastic states, whereas more differentiated neuronal-like states predicted better prognosis. Proportions of mesenchymal neoplastic cells increased after therapy and a high proportion correlated with a poorer chemotherapy response. Macrophages significantly expanded towards pro-angiogenic, immunosuppressive and metabolic phenotypes. We identified paracrine signaling networks and validated the HB-EGF-ERBB4 axis between macrophage and neoplastic subsets, which promoted tumor growth through the induction of ERK signaling. These findings collectively reveal intrinsic and extrinsic regulators of therapy response in high-risk neuroblastoma.

Supplemental Figure S1 Outcome by Chromosome 5 Status. (A) EFS and (B) OS by Chromosome 5 status

Neuroblastoma is the most common extracranial solid tumor in children. Survival rates of children with high-risk disease are ∼50%, reducing to 10% for relapsed/refractory disease, highlighting the need for more effective treatments. Glycogen synthase kinase-3β (GSK-3β) is a serine/threonine kinase, highly expressed in cancers including neuroblastoma. In addition to its well-established role in driving cell growth and proliferation, there is increasing evidence suggesting a role in supporting tumor immune evasion. 9-ING-41 (Elraglusib), a GSK-3β inhibitor with clinical activity in adult cancers, is effective as a single agent in neuroblastoma animal models, and is currently in Phase 1/2 clinical trial in pediatric patients with refractory malignancies (NCT04239092). However, the efficacy of 9-ING-41 in combination with current clinically relevant chemotherapy and chemoimmunotherapy neuroblastoma protocols that include anti-GD2 antibody for high-risk patients, has not been established. To establish, in the Th-MYCN mouse model of neuroblastoma, clinically relevant chemoimmunotherapy treatment protocols that include anti-GD2 antibody (14G2a), and to evaluate whether and how 9-ING-41 enhances their efficacy. METHODS: Efficacy and pharmacokinetic studies were performed in Th-MYCN mice. Th-MYCN tumor cells were allografted into fully immunocompetent versus immunocompromised mouse strains. Th-MYCN mice relapsed within 60 days following treatment with 2 consecutive daily doses of temozolomide/irinotecan (TEMIRI) or cyclophosphamide/topotecan (CYCLO/TOPO), in addition to 15µg 14G2a on day 1 and day 5. Pharmacokinetics of radiolabelled 14G2a confirmed that this regimen resulted in equivalent 14G2a serum levels in tumor-bearing Th-MYCN mice as observed for Dinutuximab in neuroblastoma patients. Addition of 9-ING-41 to TEMIRI or 14G2a alone, or combined TEMIRI/14G2a, delayed tumor growth in a dose-dependent manner, resulting in significantly extended survival compared to mice receiving the same treatments without 9-ING-41. 6/10 mice treated with TEMIRI/14G2a/70 mg/kg 9-ING-41 were long-term tumor-free survivors at 1 year of age (P<0.0001). Similar results were obtained for CYCLO/TOPO. TEMIRI/9-ING-41 was significantly more effective against Th-MYCN allografts injected into wild-type littermates than when the same cells were injected into immunocompromised NSG mice, suggesting that a fully functional immune system is required to achieve the highest efficacy of this combination. Together with the observation that 9-ING-41 alone enhanced the efficacy of anti-GD2 antibody, this data also suggests that 9-ING-41 exerts part of its potentiating role through boosting anti-tumour immunity. 9-ING-41 in combination with chemoimmunotherapy is highly potent, resulting in long-term tumor-free survival in the Th-MYCN mouse model of neuroblastoma. Our data suggests that 9-ING-41 at least in part works through modulating anti-tumour immunity, and we are currently investigating this further. Jayne Murray, Klaartje Somers, Crystal Mak, Stephanie Alfred, Jennifer Brand, Evon Poon, Nicholas Fletcher, Pei Li, Kristofer Thurecht, Juliet Gray, Andrew DJ. Pearson, Louis Chesler, Michael D. Hogarty, Francis Giles, Jamie Fletcher, David S. Ziegler, Murray D. Norris, Michelle Haber. The glycogen synthase kinase-3β inhibitor 9-ING-41 in combination with chemoimmunotherapy provides long-term survival in the Th-MYCN mouse model [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr B079.

10001 Background: Dinutuximab, irinotecan, temozolomide and GM-CSF (DIT) is widely used in first relapsed/ refractory high-risk neuroblastoma (r/r HRNB), however <50% of patients (pts) respond. ODC1 is a key enzyme important for NB cell survival. Difluoromethylornithine (DFMO) irreversibly inhibits ODC1, suppressing polyamine biosynthesis and driving anti-NB activity. DFMO also inhibits arginase and may enhance immunotherapy in r/r NB. COG ANBL1821 was a randomized phase 2 study for pts with r/r NB that evaluated response to DIT with or without DFMO (NCT03794349). Methods: Patients with first episode of r/r NB were randomized 1:1 to DIT (Arm A) or DIT with DFMO (6750 mg/m 2 divided TID; Arm B). They were stratified by measurable/evaluable disease, MYCN status, prior anti-GD2 therapy, and prior DFMO therapy. Cycles were 21 days. On Arm B, DFMO was initially given continuously; discontinuous DFMO dosing (days 1-7 and 15-21) was instituted due to ototoxicity in the initial cohort. Objective Response Rate [(ORR); sum of complete (CR), partial (PR), and minor (MR) responses per the 2017 International Neuroblastoma Response Criteria (INRC)] was determined based on central review of imaging. Toxicities were graded per CTCAE v5.0. Results: 91 eligible and evaluable pts (44 Arm A, 47 Arm B) were randomized May 2019-Jan 2024. 28/44 (63.6%) of Arm A pts and 32/47 (68.1%) of Arm B pts had relapsed or progressive disease (RPD); the remaining pts had refractory disease. The ORR was 61.4% (27/44) for Arm A and 57.4% (27/47) for Arm B (p=0.566). On Arm A, 22/44 (50%) achieved CR or PR compared to 23/27 (48.9%) on Arm B. Response rates for pts with RPD were similar to those with refractory disease in both arms. The 1-year progression-free survival (PFS) for Arm A was 70.0±8.0% and 56.8±8.2% for Arm B. Overall survival was 87.0±5.7% and 81.4±6.3% for Arms A and B, respectively. The most common toxicities reported on both arms were hematologic and gastrointestinal. Fewer pts on Arm B (n=7) had Grade 3+ pain than on Arm A (n=15) (p=0.0326). Hearing loss was a toxicity of interest; with continuous dosing, 55.6% (5/9) of Arm B pts developed hearing loss requiring DFMO dose hold. With discontinuous dosing, hearing loss was 15.8% (6/38) on Arm B compared to 6.3% (2/32) on Arm A (p=0.275). 14/16 (87.5%) NB+ marrows were GD2+ at enrollment; loss of GD2 was not detected on persisting NB cells in on therapy marrows analyzed. Conclusions: The addition of DFMO to DIT did not improve response rates in pts with first r/r HRNB, though the response rates in both arms confirmed DIT activity in this population. The ORR to DIT is higher than previously reported, likely due to use of the 2017 INRC that includes MR in calculation of ORR. Rates of CR+PR in this trial were similar to those previously reported. DFMO was associated with an increased incidence of hearing loss which was partially mitigated by discontinuous dosing. Clinical trial information: NCT03794349 .

Supplemental Figure S3 Non-negative Matrix Factorization (NMF) Clustering of Tumor Specimens. (A) Clustering similarity matrix and (B) Silhouette plot of samples by cluster id. (C) Enrichment score for adrenergic (ADRN), mesenchymal (MES), and Schwann cell profile (SCP) gene signatures.

Introduction: Pediatric pulmonary Langerhans cell histiocytosis (pPLCH) is a rare multisystem disease. We describe a 17-month-old male presenting with respiratory failure who was found to have extensive cystic pulmonary lesions with recurrent pneumothoraces and persistent air-leaks. He ultimately required venovenous (VV) – Extracorporeal Membrane Oxygenation (ECMO) for lung preservation, given his chance for survival and concern for barotrauma from conventional ventilation. Description: On the day of admission, he was evaluated for parotid gland swelling and seborrheic dermatitis. He later developed subcostal retractions and tachypnea, prompting presentation to the Emergency Department. He had no cough, wheeze, dyspnea or exercise limitation prior to presentation. Travel history included a trip to Dubai. There was no history of smoke exposure or foreign body inhalation. Vaccinations were up to date. A venous blood gas revealed a pH 7.36 and pCO2 46 mm Hg. Due to respiratory distress, bilevel positive airway pressure support was started. A chest radiograph demonstrated cystic pulmonary lesions with a left-sided pneumothorax, necessitating emergency decompression. He underwent airway intubation, mechanical ventilation and chest tube placement. A chest tomography (CT) scan showed diffuse extensive bilateral cystic lesions, concerning for pPLCH (Figure 1A). Skin biopsy results confirmed the diagnosis of pPLCH, which prompted LCH-directed chemotherapy. He continued to have recurrent pneumothoraces with impaired ventilation and oxygenation while receiving high frequency oscillatory ventilation. He therefore underwent cannulation for VV-ECMO to allow for lung rest and to avoid further trauma. A CT scan performed 2-months later demonstrated extensive cystic changes and large right sided bullae (Figure 2B). Improvement in his respiratory status allowed for ECMO decannulation, after which he underwent tracheostomy tube placement to facilitate rehabilitation. He weaned to heat/moisture exchanger during the day and T-piece at night. However, he continued to have pneumothoraces secondary to bullae formation (Figure 2C). Discussion: pPLCH is a disease characterized by abnormal proliferation of immature histiocytes in multiple organs. Common presentations include multifocal osteolysis, skin rash, lymphadenopathy, pancytopenia and diabetes insipidus. pPLCH skin rashes mimic psoriasis, seborrheic dermatitis and viral exanthema, and our patient was initially diagnosed with seborrheic dermatitis. Extensive lung involvement, while rare, presents as diffuse cystic interstitial lung disease. Prognosis is excellent for single-organ disease; however, it is variable with multi-system disease although cases of remission have been reported. ECMO should be considered in extreme cases of pPLCH with extensive lung involvement, given the efficacy of LCH-directed chemotherapies and the potential for recovery.

Background: The International Neuroblastoma Risk Group (INRG) classifier utilizes a staging system based on pretreatment imaging criteria in which image-defined risk factors (IDRFs) are used to evaluate the extent of locoregional disease. Children's Oncology Group (COG) study ANBL0531 prospectively examined institutional determination of IDRF status and compared that to a standardized central review. Methods: Between 9/2009-6/2011, patients with intermediate-risk neuroblastoma were enrolled on ANBL0531 and had IDRF assessment at treating institutions. Paired COG pediatric surgeons and radiologists performed blinded central review of diagnostic imaging for the presence or absence of IDRFs. Second blinded review was performed in cases of discordance. Comparison of local and central review was performed using the Kappa coefficient to determine concordance in IDRF assessment. Results: 211 patients enrolled in ANBL0531 underwent IDRF assessment; 3 patients were excluded due to poor image quality. Central reviewer pairs agreed on the presence or absence of any IDRF in 170/208 (81.7%; K = 0.48) cases. Thirteen (6.3%) cases could not be adjudicated after second blinded review. Radiologists were more likely to identify IRDFs as present than surgeons (p < 0.001). Local and central reviewers agreed on the presence or absence of any IDRF in only108/208 (51.9%; K = 0.06) cases. Conclusions: Among experienced pediatric surgeons and radiologists participating in central review, concordance was moderate, with agreement in 81.7% of cases. On comparison of local and central assessment of IDRFs, concordance was poor. These data indicate that greater standardization, education, technology, and training are needed to improve the assessment of IDRFs in children with neuroblastoma. Level of Evidence: Treatment Study, Level III. (c) 2024 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).