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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 < .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. Keywords: Pediatrics, MR Imaging, Oncology, Radiomics, Reproducibility, Repeatability, Neuroblastic Tumors Supplemental material is available for this article. © RSNA, 2024 See also the commentary by Safdar and Galaria in this issue.

Neuroblastoma is the most common extracranial solid tumor in children. The chromatin remodeler ATRX is frequently mutated in high-risk patients with a poor prognosis. Although many studies have reported ATRX aberrations and the associated clinical characteristics in neuroblastoma, a comprehensive overview is currently lacking. In this study, we extensively characterize the mutational spectrum of ATRX aberrations in neuroblastoma tumors reported in previous studies and present an overview of patient and tumor characteristics. We collected the data of a total of 127 neuroblastoma patients and three cell lines with ATRX aberrations originating from 20 papers. We subdivide the ATRX aberrations into nonsense, missense, and multiexon deletions (MEDs) and show that 68% of them are MEDs. Of these MEDs, 75% are predicted to be in-frame. Furthermore, we identify a missense mutational hotspot region in the helicase domain. We also confirm that all three ATRX mutation types are more often identified in patients diagnosed at an older age, but still approximately 40% of the patients are aged 5 years or younger at diagnosis. Surprisingly, we found that 11q deletions are enriched in neuroblastomas with ATRX deletions compared to a reference cohort, but not in neuroblastomas with ATRX point mutations. Taken together, our data emphasizes a distinct ATRX mutation spectrum in neuroblastoma, which should be considered when studying molecular phenotypes and therapeutic strategies., (© 2022 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

This chapter emphasizes detailed protocols for the effective establishment of highly enriched human Schwann cell cultures and their characterization via immunostaining. The Schwann cells are isolated from immediately dissociated fascicle tissue and expanded prior to purification. Two purification methods are described that use either fluorescence-activated cell sorting for the Schwann cell marker TNR16 (p75 NTR ) or a less-manipulative two-step enrichment exploiting the differential adhesion properties of Schwann cells and fibroblasts, which is especially useful for low Schwann cell numbers. In addition, a method to determine Schwann cell purity via stained cytospin slides is introduced. Together with an immunofluorescence staining procedure for the combined analysis of extra- and intracellular markers, this chapter provides a solid basis to study human primary Schwann cells.

Poor prognosis and frequent relapses are major challenges for patients with high-risk neuroblastoma (NB), especially when tumors show MYCN amplification. High-dose chemotherapy triggers apoptosis, necrosis and senescence, a cellular stress response leading to permanent proliferative arrest and a typical senescence-associated secretome (SASP). SASP components reinforce growth-arrest and act immune-stimulatory, while others are tumor-promoting. We evaluated whether metronomic, i.e. long-term, repetitive low-dose, drug treatment induces senescence in vitro and in vivo. And importantly, by using the secretome as a discriminator for beneficial versus adverse effects of senescence, drugs with a tumor-inhibiting SASP were identified.We demonstrate that metronomic application of chemotherapeutic drugs induces therapy-induced senescence, characterized by cell cycle arrest, p21(WAF/CIP1) up-regulation and DNA double-strand breaks selectively in MYCN-amplified NB. Low-dose topotecan (TPT) was identified as an inducer of a favorable SASP while lacking NFKB1/p50 activation. In contrast, Bromo-deoxy-uridine induced senescent NB-cells secret a tumor-promoting SASP in a NFKB1/p50-dependent manner. Importantly, TPT-treated senescent tumor cells act growth-inhibitory in a dose-dependent manner on non-senescent tumor cells and MYCN expression is significantly reduced in vitro and in vivo. Furthermore, in a mouse xenotransplant-model for MYCN-amplified NB metronomic TPT leads to senescence selectively in tumor cells, complete or partial remission, prolonged survival and a favorable SASP.This new mode-of-action of metronomic TPT treatment, i.e. promoting a tumor-inhibiting type of senescence in MYCN-amplified tumors, is clinically relevant as metronomic regimens are increasingly implemented in therapy protocols of various cancer entities and are considered as a feasible maintenance treatment option with moderate adverse event profiles.