BACKGROUND:Colorectal cancer (CRC) risk is increased in childhood cancer survivors (CCS). In France, fecal immunochemical testing (FIT) is recommended every 2 years for those aged 50-74 years, although no specific CRC-screening programs are dedicated to CCS. METHODS:We investigated the participation rate in CRC screening by using the national health data system to identify FIT in the French Childhood Cancer Survivor Study cohort, across three two-year periods-2016-17, 2018-19, and 2020-21-to compare it to the general population via indirect standardization and used multivariable logistic regression to investigate factors influencing CCS participation. RESULTS:In 2016-17, 2018-19, and 2020-21, respectively, 20.0%, 21.8%, and 23.2% participated in screening, which is lower than the rate for the general population [standardized incidence ratios (95% CI) = 0.62 (0.49-0.78), 0.72 (0.59-0.87), and 0.70 (0.59-0.83), respectively]. Demographic, clinical, therapeutic, and socio-economic determinants were not associated with CRC-screening participation. Although these patterns were not consistently observed across all subgroups, survivors with severe long-term complications tended to have higher participation [odds ratio (95% CI) = 1.64 (1.07-2.53)], whereas higher medical expenses were associated with lower participation (P < .01). CONCLUSION:Despite an increased risk of CRC after childhood cancer, participation in CRC-screening programs remains low in CCS. Survivors and their physicians require educational initiatives to promote CRC screening and provide risk-adapted surveillance guidelines.

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.

OBJECTIVES:The association between exposure to dinutuximab beta (DB) and event-free survival (EFS) or overall survival (OS) of neuroblastoma patients was assessed using data collected during three clinical trials (five cohorts). METHODS:A systematic review (March 2026) was conducted to identify relevant studies (prospective; registered DB indication and posology). Patient-level information on outcomes and their predictors was extracted from study reports. Because of immortal-time and reverse causation biases, survival was examined among patients who were event-free at their end-of-treatment (EOT) date (i.e., last dose + 25 days). To address selection bias, stabilised inverse-probability weights were estimated, and weighted post-EOT survival models were fitted. RESULTS:Of 665 patients, 98 had relapse or progression before EOT. The median duration of follow-up in the post-EOT cohort was 3.78 years. The total number of cycles was independently associated with both EFS (HR = 0.80, 95% CI: 0.70-0.90 per cycle, p < 0.001) and OS (HR = 0.78, 95% CI: 0.68-0.90 per cycle, p < 0.001). With each treatment cycle, post-EOT hazard of an EFS event decreased by 20% (95% CI: 10%-30%) and hazard of death decreased by 22% (95% CI: 10%-32%). The results were consistent across most sensitivity analyses (e.g., excluding IL-2 recipients, restricting to frontline maintenance immunotherapy, alternative specifications and exposure metrics), but not among patients with relapsed or refractory neuroblastoma. In a target-trial emulation (5 cycles vs. <5 cycles), associations were significant for EFS (HR = 0.46, 95% CI: 0.32-0.66, p < 0.001) and OS (HR = 0.44, 95% CI: 0.28-0.67, p < 0.001). CONCLUSIONS:Greater prior exposure to DB, particularly a higher number of treatment cycles, was associated with better post-EOT EFS and OS. The study did not estimate an on-treatment causal effect of DB, and the residual confounding cannot be fully excluded. Prior treatment exposure may help inform post-treatment risk stratification.

Objective:Dinutuximab beta (dB) immunotherapy is used as maintenance treatment for relapsed/refractory neuroblastoma (NBL); however, comparative studies directly comparing dB with no dB therapy in this setting are lacking. This study aimed to indirectly compare dB (with or without interleukin-2) with no immunotherapy in patients with relapsed NBL. Methods:Three studies of dB (APN311-202, APN311-304, and APN311-303) with individual patient data, along with two historical control cohorts (INBR and R1) were included. Both unadjusted (naïve) and population-adjusted comparisons of overall survival (OS) were performed, with adjustment conducted using inverse probability or odds weighting. Harmonized inclusion criteria were applied across all study populations. The adjusted comparison used the propensity score reweighting to balance the cohorts based on key baseline prognostic factors. Results:The base-case unadjusted indirect comparison revealed that dB (with or without IL-2) significantly prolonged OS compared to historical controls not treated with dB (hazard ratio [HR], 0.43; 95% confidence interval [CI], 0.31- 0.79; p<0.001). Similarly, in the adjusted comparison, dB significantly prolonged OS compared to historical controls (HR, 0.53; 95% CI, 0.35; 0.79, p=0.002). All sensitivity unadjusted and adjusted comparisons supported the results of the base-case analysis. Conclusion:Dinutuximab beta significantly prolonged OS compared to historical control cohorts not treated with dB in both unadjusted and adjusted indirect comparisons.

Objectives Neuroblastoma is the most common extracranial solid tumor in infants, with a possibility of spontaneous regression even in disseminated disease. Despite an overall good prognosis, relapse can worsen the outcome for some patients. A long-term analysis is crucial to identify subgroups of patients with poorer prognosis, assessing the risks of late relapse, progression or long-term toxicity associated with multimodal treatment in very young children.Methods Estimation of the 10-year event-free and overall survivals in 750 infants under 12 months with neuroblastoma, enrolled in the prospective INES protocols between 1999 and 2004. Follow-up data from INES patients were updated, and survival analyses were performed in order to determine prognostic factors such as age, stage, genomic profile, or MYCN amplification.Results Overall, 10-year overall survival was 91.1% +/- 1.0%, and 10-year event-free survival was 82.4% +/- 1.4%, with significantly better outcomes in infants under 6 months compared with those aged 6-12 months, even considering the MYCN-amplified tumors only. MYCN amplification was the strongest prognostic factor and was correlated with lower survival in patients with metastatic disease.Discussion Survival in patients less than 12 months remains excellent and stable even at long term, as a 10-year follow-up did not change the number of events. However, survival in MYCN-amplified tumors remained poor. Patients with metastatic tumors require accurate risk stratification. For each treatment group, there was no significant difference in long-term outcomes compared with previous publications from INES. No lethal toxicity affecting long-term survival occurred.

10000 Background: Dinutuximab beta (DB) delivered as long-term infusion is associated with a lower frequency and magnitude of side effects compared to short-term infusion (STI). Here, we evaluated the efficacy (event free survival- and cumulative incidence of relapse-rates at 5 years) of LTI compared to STI within the HR-NBL1/SIOPEN trial (EudraCT:2006-001489-17). Methods: High-risk patients as defined by metastatic disease (stage M) or local stage with MYC-N amplification received high intensity induction, surgery, high dose therapy with busulfan/melphalan followed by autologous stem cell transplantation (HDT/SCT) and local radiotherapy. Patients who achieved at least a partial response prior to HDT/SCT within equal or less than 9 months between diagnosis and HDT/SCT without progression were randomized to receive 5 cycles of 100 mg/m 2 DB per cycle either as STI (20 mg/m 2 per day as 8 h infusion; days 1-5) with or without subcutaneous interleukin-2 (scIL2) (6 × 10 6 IU/m 2 per day; days 1-5 and days 8-12) (R2 randomization) or as LTI (10 mg/m 2 per day as 24h infusion; days 1-10) (d8-17) ± 3x10 6 IU/m 2 scIL2 (d1-5; d8, d10, d12, d14, d16) (R4 randomization). All patients received 160 mg/m 2 oral isotretinoin (d19-32). Results: From 2009-2018, 705 patients (pts) from 18 countries were randomized and eligible for this analysis. The median follow-up time is7.7 years. Key patient characteristics were age 1.5-5yrs: 65% (460 pts), disease status before HDCT: CR 56% (396 pts) versus non-CR 38% (268 pts), MYC-N amplification (MNA): 43% (304 pts); > 1 metastatic compartment (MC): 78% (553 pts); time between diagnosis to DB treatment start: > 9 months 48% (302 pts). There were no significantly different patient characteristics between STI and LTI cohorts, except for time to DB start > 9 months: 59% in the LTI cohort vs. 37% in STI.The 5yr EFS was 0.65±0.03 for LTI vs. 0.56±0.03 for STI (p = 0.041). The cumulative incidence of relapse was 0.33±0.03 for LTI vs. 0.42±0.03 for STI (p = 0.034). Multivariable pseudovalue-regression analysis for 5-year EFS found a significantly worse outcome for stage 4 patients with > 1MC (p = 0.025; cHR = 1,97), < CR (p = 0.059; cHR = 1.32) and for STI (p = 0.044; cHR = 0.74). Conclusions: We previously reported that LTI of DB increased the safety profile (less pain and inflammation) (Lancet Oncol 2018;19(12):1617-1629; J Clin Oncol 37, 2019 (suppl; abstr 10013). Here we demonstrate that LTI is also associated with an improved outcome. Clinical trial information: 2006-001489-17 .

Supplementary Table S3. Toxicity according to HACA response.

Supplementary Table S5. Multivariate analysis.

Supplementary Table S2. Representativeness of study participants.

Alterations of PHOX2B function is associated with a wide range of diseases, including congenital central hypoventilation syndrome (CCHS) and neural crest-derived tumors, from low-grade (ganglioneuromas) to malignant forms (neuroblastomas). We report a case bearing a novel nonpolyalanine repeat PHOX2B pathogenic variant presenting both as high-risk neuroblastoma and late-onset CCHS. CCHS was revealed upon severe respiratory decompensation while the patient was administered the anti-GD2 antibody dinutuximab-beta, as part of neuroblastoma treatment. From this experience, we make propositions for the management of patients with high-risk neuroblastoma and a constitutional pathogenic variant of PHOX2B .

Supplementary Figure S1. Consort flow diagram of (A) patient disposition; (B) schematic of recruitment periods; and (C) treatment schedule. IL-2, interleukin-2; LTI, long-term infusion.

Supplementary Figure S5. Event-free survival and overall survival in HACA-positive and HACA-negative patients (A and B) and by dinutuximab beta exposure of above and below median AUC (C and D). AUC, area under the curve; EFS, event-free survival; HACA, human anti-chimeric antibodies; OS, overall survival; SE, standard error.

PURPOSE:Outcomes for children with relapsed and refractory high-risk neuroblastoma (RR-HR-NBL) remain dismal. Here, we investigate addition of the anti-GD2 monoclonal antibody, dinutuximab beta (dB), to temozolomide (T)-based chemotherapy. MATERIALS AND METHODS:Patients with RR-HR-NBL were randomly assigned in a 1:2 ratio to receive chemotherapy alone or chemotherapy with dB, given concurrently as a 7-day infusion (10 mg/m2/24 h). The trial had a factorial design, with some patients also randomly assigned between chemotherapy regimens (T v T-topotecan [TTo]). Crossover to dB with To/cyclophosphamide was allowed for patients randomly assigned to chemotherapy alone with disease progression (PD). The primary outcome was best objective response (complete or partial) rate (overall response rate [ORR]) during six cycles of treatment. Progression-free (PFS), overall survival (OS), and safety were secondary outcomes. RESULTS:Sixty-five patients were randomly assigned to chemotherapy alone (3 T, 19 TTo) or with dB (6 dBT, 37 dBTTo). The median age was 4 years; 28 and 37 patients had refractory and relapsed diseases, respectively. Baseline characteristics were balanced between arms. The ORR was 30.2% (13 of 43) and 18.2% (4 of 22) in dB and non-dB arms, the median PFS was 11.1 months (95% CI, 4.3 to 15.5) for dB patients and 3.8 months (95% CI, 1.9 to 7.9) for non-dB patients, respectively. The median OS was 25.7 months (95% CI, 11.4 to not reached [NR]) for dB patients and 17.1 months (95% CI, 7.6 to 54.6) for non-dB patients (upper 95% CI, NR in dB arm). Thirteen of 22 patients in the non-dB arm crossed over to dB with cyclophosphamide/To because of PD. Neurotoxicity was more common in the dB arm (grade 1 and 2: 26% v 9%, grade 3: 2.3% v 4.5%), but other toxicities were similar. CONCLUSION:Within a randomized phase II setting, results observed with addition of dB to T-based chemotherapy in RR-HR-NB warrant further evaluation.

Objective: Dinutuximab beta (DB) and naxitamab (NAXI) with GM-CSF are used for maintenance treatment of relapsed/refractory neuroblastoma. The objective of this study was to systematically assess comparative efficacy of the two therapies within their designated indications in accordance with established clinical guidelines. Methods: Relevant evidence was identified in systematic literature review. Individual patient data (IPD) from prospective clinical trials of DB were assessed and data on patients with disease in bone or bone marrow, as assessed in MRI, CT, mIBG or biopsy, with incomplete response to previous therapy were included. Patients with complete response, progressive disease and/or soft tissue disease were excluded. DB population was adjusted for sex, MYCN amplification, disease type (relapsed, refractory), and disease site (bone marrow and/or bone) to balance aggregated characteristics of NAXI population. More characteristics were included in sensitivity analyses, including DB treatment without interleukin-2, as currently recommended. Overall response rate (ORR) was assessed as best response. Results: Aggregated data for NAXI from Study 201 (n = 52) and Study 230 (n = 38) and IPD from DB studies (APN311-202, APN311-304, c = 77) met the inclusion criteria. Compared to NAXI, DB significantly extended progression-free survival (PFS): hazard ratio, DB vs. NAXI of 0.47 (95% CI: 0.26 to 0.87, p = 0.015). ORR was 60.1% (95% CI: 48.5% to 71.6%) for DB vs. 43.3% (33.1% to 53.6%) for NAXI (ORR odds ratio, DB vs. NAXI was 1.97, 95% CI: 1.02 to 3.80, p = 0.044). Sensitivity analyses and unadjusted comparisons supported the results. Conclusion: In the indirect comparison, dinutuximab beta significantly extended PFS and increased ORR compared to naxitamab.

Supplementary Table S4. Response rates (mid-treatment, end-of-treatment and best response) in the overall population and various subgroups.

BACKGROUND:Methotrexate-associated leukoencephalopathy is poorly documented in osteosarcoma. Since 2007, our institution has monitored osteosarcoma patients with sequential magnetic resonance imaging (MRI) and neuropsychological evaluations during treatment and follow-up. METHODS:We analyzed data from consecutive osteosarcoma patients younger than 25 years enrolled at Gustave Roussy in the OS2006 study (2007-2015) and treated with high-dose methotrexate (MTX) and etoposide-ifosfamide. Eligible patients received four or more MTX courses and at least one brain MRI. MTX-related neurotoxicity was defined as neurological symptoms attributed to MTX after excluding other causes. RESULTS:MTX-related neurotoxicity occurred in seven (13%) of 53 eligible patients. Additionally, 12 had severe depression, nine reported attention/memory deficits, and 25 had headaches during MTX infusion. Acute symptoms resolved in all but one. Forty-nine patients had an MRI during treatment, and 47 after. Leukoencephalopathy was found in 44 (83%): Grade 1 in six, Grade 2 in 15, and Grade 3 in 23. Grade 2-3 leukoencephalopathy was more frequent in patients with severe depression (p = 0.02) and those receiving more than 12 MTX courses (p = 0.03); no association was found with age, sex, MTX-related neurotoxicity, or cognitive complaints. Among 24 patients with MRI ≥3 years post-treatment, 20 still showed leukoencephalopathy (12 Grade 1, eight Grade 2). Neurocognitive evaluations showed IQ scores consistent with norms, except for lower processing speed, which improved post-treatment. At last follow-up (median 8.5 years), most patients had integrated into school or work. CONCLUSION:MTX-associated leukoencephalopathy is frequent in osteosarcoma, even in asymptomatic patients, and often persists after treatment. Serious neurocognitive sequelae appear uncommon, but long-term cognitive monitoring is essential to detect subtle deficits.

Supplementary Figure S3. Event-free survival and overall survival by age ≤5 years and >5 years (A and B) and by NK cells on day 15/cycle 1 above or below the median level (C and D). EFS, event-free survival; OS, overall survival; NK, natural killer; SE, standard error.