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Olfactory neuroblastomas rarely secrete adrenocorticotropic hormone, leading to ectopic adrenocorticotropic hormone syndrome. However, the prevalence, timing, and triggers of ectopic adrenocorticotropic hormone syndrome in patients with olfactory neuroblastomas remain unclear. This study aimed to investigate these factors and conduct a literature review. Fifteen patients with olfactory neuroblastomas who underwent surgery at our institution were included. The prevalence of ectopic adrenocorticotropic hormone syndrome development was assessed by evaluating adrenocorticotropic hormone expression using immunohistochemistry. Furthermore, 26 patients with olfactory neuroblastomas who developed ectopic adrenocorticotropic hormone syndrome from previous reports were reviewed. Among the 15 patients, three (20%) showed adrenocorticotropic hormone-positive tumor cells at the time of initial surgery, and two (13%) developed ectopic adrenocorticotropic hormone syndrome. The timing of developing ectopic adrenocorticotropic hormone syndrome was 2.5 and 10 years following the initial treatment of olfactory neuroblastoma. Based on the literature review, nine patients with recurrent and metastatic olfactory neuroblastoma developed ectopic adrenocorticotropic hormone syndrome after the initial surgery, of whom, three had confirmed disease after developing ectopic adrenocorticotropic hormone syndrome, three developed during disease progression, two developed after receiving chemotherapy, and one developed after undergoing a biopsy. The timing of ectopic adrenocorticotropic hormone syndrome was 2.5–15 years after initial treatment. Our study revealed that acknowledging olfactory neuroblastomas can manifest as ectopic adrenocorticotropic hormone syndrome with a certain low prevalence is crucial. Moreover, our study speculated that tumor stimulation, such as biopsy or chemotherapy, as well as disease progression, could trigger ectopic adrenocorticotropic hormone syndrome onset. Thus, olfactory neuroblastomas can develop into ectopic adrenocorticotropic hormone syndrome, even long after the initial treatment. [ABSTRACT FROM AUTHOR]

Background: Neuroblastoma (NB) is the most prevalent and deadliest pediatric solid tumor. With of over 50% of high-risk neuroblastoma cases relapse, the imperative for novel drug targets and therapeutic strategies is accentuated. In neuroblastoma, the existence of tumor-associated macrophages (TAMs) correlates with an unfavorable patient prognosis. However, the clinical relevance and prognostic implications of regulatory genes linked to TAMs infiltration in neuroblastoma remain unclear, and further study is required. Methods: We conducted a comprehensive analysis utilizing transcriptome expression profiles from three primary datasets associated with neuroblastoma (GSE45547, GSE49710, TARGET) to identify hub genes implicated in immune evasion within neuroblastoma. Subsequently, we utilized single-cell RNA sequencing analysis on 17 clinical neuroblastoma samples to investigate the expression and distribution of these hub genes, leading to the identification of TNFAIP3. The above three public databases were merged to allowed for the validation of TNFAIP3's molecular functions through GO and KEGG analysis. Furthermore, we assessed TNFAIP3's correlation with immune infiltration and its potential immunotherapeutic impact by multiple algorithms. Our single-cell transcriptome data revealed the role of TNFAIP3 in macrophage polarization. Finally, preliminary experimental verifications to confirm the biological functions of TNFAIP3-mediated TAMs in NB. Results: A total of 6 genes related to immune evasion were screened and we found that TNFAIP3 exhibited notably higher expression in macrophages than other immune cell types, based on the scRNA-sequencing data. GO and KEGG analysis showed that low expression of TNFAIP3 significantly correlated with the activation of multiple oncogenic pathways as well as immune-related pathways. Then validation affirmed that individuals within the TNFAIP3 high-expression cohort could potentially derive greater advantages from immunotherapeutic interventions, alongside exhibiting heightened immune responsiveness. Deciphering the pseudotime trajectory of macrophages, we revealed the potential of TNFAIP3 in inducing the polarization of macrophages towards the M1 phenotype. Finally, we confirmed that patients in the TNFAIP3 high expression group might benefit more from immunotherapy or chemotherapy as substantiated by RT-qPCR and immunofluorescence examinations. Moreover, the role of TNFAIP3 in macrophage polarization was validated. Preliminary experiment showed that TNFAIP3-mediated TAMs inhibit the proliferation, migration and invasion capabilities of NB cells. Conclusions: Our results suggest that TNFAIP3 was first identified as a promising biomarker for immunotherapy and potential molecular target in NB. Besides, the presence of TNFAIP3 within TAMs may offer a novel therapeutic strategy for NB. [ABSTRACT FROM AUTHOR]

Background: With modern treatment paradigms, olfactory neuroblastoma (ONB) has favorable overall survival (OS); however, the incidence of recurrence remains high. The primary aims of this study were to delineate the prognosis of recurrence of ONB and explore how recurrence subsites are associated with OS, disease‐specific survival (DSS), and further recurrence. Methods: A retrospective chart review of ONB cases from nine academic centers between 2005 and 2021 was completed. Tumor characteristics, recurrence subsites, timelines to recurrence, additional recurrences, and survival estimates were determined using descriptive and time‐to‐event analyses. Results: A final cohort of 233 patients was identified, with 70 (30.0%) patients recurring within 50.4 (standard deviation ±40.9) months of diagnosis on average, consisting of local (50%), neck (36%), intracranial (9%), and distant (6%) recurrence. Compared with subjects without recurrence, patients with recurrence had significantly different primary American Joint Committee on Cancer T stage (p < 0.001), overall stage (p < 0.001), and modified Kadish scores (p < 0.001). Histopathology identified that dural involvement and positive margins were significantly greater in recurrent cases. First recurrence was significantly associated with worse 5‐year DSS (hazard ratio = 5.62; p = 0.003), and subjects with neck or local recurrence had a significantly better DSS compared to intracranial or distant recurrence. Conclusions: Recurrent cases of ONB have significantly different stages and preoperative imaging factors. Patients with local or neck recurrence, however, have better DSS than those with intracranial or distant recurrence, independent of initial tumor stage or Hyams grade. Identifying specific factors that confer an increased risk of recurrence and DSS is important for patient counseling in addition to surveillance planning. [ABSTRACT FROM AUTHOR]

Merkel cell carcinoma (MCC) is an aggressive skin cancer frequently caused by genomic integration of the Merkel cell polyomavirus (MCPyV). MCPyV‐negative cases often present as combined MCCs, which represent a distinctive subset of tumors characterized by association of an MCC with a second tumor component, mostly squamous cell carcinoma. Up to now, only exceptional cases of combined MCC with neuroblastic differentiation have been reported. Herein we describe two additional combined MCCs with neuroblastic differentiation and provide comprehensive morphologic, immunohistochemical, transcriptomic, genetic and epigenetic characterization of these tumors, which both arose in elderly men and appeared as an isolated inguinal adenopathy. Microscopic examination revealed biphasic tumors combining a poorly differentiated high‐grade carcinoma with a poorly differentiated neuroblastic component lacking signs of proliferation. Immunohistochemical investigation revealed keratin 20 and MCPyV T antigen (TA) in the MCC parts, while neuroblastic differentiation was confirmed in the other component in both cases. A clonal relation of the two components can be deduced from 20 and 14 shared acquired point mutations detected by whole exome analysis in both combined tumors, respectively. Spatial transcriptomics demonstrated a lower expression of stem cell marker genes such as SOX2 and MCM2 in the neuroblastic component. Interestingly, although the neuroblastic part lacked TA expression, the same genomic MCPyV integration and the same large T‐truncating mutations were observed in both tumor parts. Given that neuronal transdifferentiation upon TA repression has been reported for MCC cell lines, the most likely scenario for the two combined MCC/neuroblastic tumors is that neuroblastic transdifferentiation resulted from loss of TA expression in a subset of MCC cells. Indeed, DNA methylation profiling suggests an MCC‐typical cellular origin for the combined MCC/neuroblastomas. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland. [ABSTRACT FROM AUTHOR]

The biological heterogeneity of neuroblastoma underscores the need for an in vitro model of each molecularly defined subgroup to investigate tumorigenesis and develop targeted therapies. We have established a permanently growing cell line from a 12-year-old girl who developed a late recurrent stage MS, MDM2-amplified neuroblastoma arising in the liver and performed histological, molecular, cytogenetic, exome, and telomere analyses of the recurrent tumor and the cell line. On histology, the recurrent tumor was immunoreactive for TP53, CDKN1A, and MDM2. A molecular cytogenetic study of the recurrent tumor revealed the amplification of MDM2 but no amplification of MYCN. The established cell line, NBM-SHIM, showed amplification of both MDM2 and MYCN on double-minute chromosomes. A copy number evaluation based on exome data confirmed the finding for MYCN and MDM2 and further identified high ploidy on CDK4 and GLI2 loci in the recurrent tumor and the cell line. The telomere maintenance mechanism on the cell line is unusual in terms of the low expression of TERT despite MYCN amplification and alternative lengthening of telomeres suggested by positive value for C-circle assay and telomere contents quantitative assay. The cell line is unique because it was established from a MYCN-nonamplified, MDM2-amplified, late-relapsed stage MS neuroblastoma, and MYCN amplification was acquired during cell culture. Therefore, the cell line is a valuable tool for investigating neuroblastoma tumorigenesis and new molecular targeted therapies for disrupted ARF–TP53–MDM2 pathway and amplification of MDM2 and CDK4. [ABSTRACT FROM AUTHOR]

Background: Neuroblastoma (NB) is a heterogeneous embryonal malignancy and the deadliest tumor of infancy. It is a complex disease that can result in diverse clinical outcomes. In some children, tumors regress spontaneously. Others respond well to existing treatments. But for the high-risk group, which constitutes approximately 40% of all patients, the prognosis remains dire despite collaborative efforts in basic and clinical research. While its exact cellular origin is still under debate, NB is assumed to arise from the neural crest cell lineage including multipotent Schwann cell precursors (SCPs), which differentiate into sympatho-adrenal cell states eventually producing chromaffin cells and sympathoblasts. Methods: To investigate clonal development of neuroblastoma cell states, we performed haplotype-specific analysis of human tumor samples using single-cell multi-omics, including joint DNA/RNA sequencing of sorted single cells (DNTR-seq). Samples were also assessed using immunofluorescence stainings and fluorescence in-situ hybridization (FISH). Results: Beyond adrenergic tumor cells, we identify subpopulations of aneuploid SCP-like cells, characterized by clonal expansion, whole-chromosome 17 gains, as well as expression programs of proliferation, apoptosis, and a non-immunomodulatory phenotype. Conclusion: Aneuploid pre-malignant SCP-like cells represent a novel feature of NB. Genetic evidence and tumor phylogeny suggest that these clones and malignant adrenergic populations originate from aneuploidy-prone cells of migrating neural crest or SCP origin, before lineage commitment to sympatho-adrenal cell states. Our findings expand the phenotypic spectrum of NB cell states. Considering the multipotency of SCPs in development, we suggest that the transformation of fetal SCPs may represent one possible mechanism of tumor initiation in NB with chromosome 17 aberrations as a characteristic element. [ABSTRACT FROM AUTHOR]

Background: Neuroblastoma (NB) is a complex disease, and the current understanding of NB biology is limited. Deregulation in genomic imprinting is a common event in malignancy. Since imprinted genes play crucial roles in early fetal growth and development, their role in NB pathogenesis could be suggested. Methods: We examined alterations in DNA methylation patterns of 369 NB tumours at 49 imprinted differentially methylated regions (DMRs) and assessed its association with overall survival probabilities and selected clinical and genomic features of the tumours. In addition, an integrated analysis of DNA methylation and allele-specific copy number alterations (CNAs) was performed, to understand the correlation between the two molecular events. Results: Several imprinted regions with aberrant methylation patterns in NB were identified. Regions that underwent loss of methylation in > 30% of NB samples were DMRs annotated to the genes NDN, SNRPN, IGF2, MAGEL2 and HTR5A and regions with gain of methylation were NNAT, RB1 and GPR1. Methylation alterations at six of the 49 imprinted DMRs were statistically significantly associated with reduced overall survival: MIR886, RB1, NNAT/BLCAP, MAGEL2, MKRN3 and INPP5F. RB1, NNAT/BLCAP and MKRN3 were further able to stratify low-risk NB tumours i.e. tumours that lacked MYCN amplification and 11q deletion into risk groups. Methylation alterations at NNAT/BLCAP, MAGEL2 and MIR886 predicted risk independently of MYCN amplification or 11q deletion and age at diagnosis. Investigation of the allele-specific CNAs demonstrated that the imprinted regions that displayed most alterations in NB tumours harbor true epigenetic changes and are not result of the underlying CNAs. Conclusions: Aberrant methylation in imprinted regions is frequently occurring in NB tumours and several of these regions have independent prognostic value. Thus, these could serve as potentially important clinical epigenetic markers to identify individuals with adverse prognosis. Incorporation of methylation status of these regions together with the established risk predictors may further refine the prognostication of NB patients. [ABSTRACT FROM AUTHOR]

Epigenetic alterations critically affect tumor development. Polycomb‐group complexes constitute an evolutionarily conserved epigenetic machinery that regulates stem cell fate and development. They are implicated in tumorigenesis, primarily via histone modification. Polycomb repressive complex 1 (PRC1) complexes 1–6 (PRC1.1–6) mediate the ubiquitination of histone H2A on lysine 119 (H2AK119ub). Here, we studied the functional roles of a PRC1.6 molecule, L3MBTL2, in neuroblastoma (NB) cells. L3MBTL2‐knockout and knockdown revealed that L3MBTL2 depletion suppressed NB cell proliferation via cell‐cycle arrest and gamma‐H2A.X upregulation. L3MBTL2‐knockout profoundly suppressed xenograft tumor formation. Transcriptome analysis revealed suppressed cell‐cycle‐related and activated differentiation‐related pathways. Break repair meiotic recombinase recruitment factor 1 (BRME1) and nuclear receptor interacting protein 3 (NRIP3) were notably de‐repressed by L3MBTL2‐knockout. The deletion of L3MBTL2 reduced enrichment of H2AK119ub and PCGF6 at transcriptional start site proximal regions of the targets. Add‐back studies unveiled the importance of L3MBTL2‐BRME1 and ‐NRIP3 axes for NB cell proliferation. We further manifested the association of MYCN with de‐repression of NRIP3 in an L3MBTL2‐deficient context. Therefore, this study first revealed the significance of L3MBTL2‐mediated gene silencing in MYCN‐amplified NB cells. [ABSTRACT FROM AUTHOR]

Neuroblastomas are the most common solid tumors outside of the brain that originate from immature neural crest cells, accounting for about 10% of all pediatric malignancies. The treatment for neuroblastomas involves a multimodal schedule, including surgery, radiation, chemotherapy, and immunotherapy. All these modalities are limited by side effects that might be severe, poor prognosis, and a high risk of recurrence. In the quest for additional therapeutic approaches, phytochemicals have attracted attention owing to their reported antitumor properties, safety, and multimechanistic mode of action. Several studies have used plant‐derived bioactive compounds such as phenolics and flavonoids, suggesting modulation of biomolecules and signal transduction pathways involved in neuroblastoma. We reviewed the findings of recent preclinical and clinical studies demonstrating the effects of phytochemicals on neuroblastoma, shedding light on their molecular mechanism of action and potential therapeutic applications. [ABSTRACT FROM AUTHOR]

Objectives Materials and methods Results Conclusion To evaluate the treatment outcomes in patients with advanced‐stage olfactory neuroblastoma (ONB) who received induction chemotherapy (IC).The clinical data of 38 patients with advanced‐stage ONB who received initial IC were retrospectively analyzed. The response was defined using the Response Evaluation Criteria in Solid Tumors version 1.1. Patients with complete remission or partial remission were defined as responders.Seventeen (44.7%) patients responded to IC. The response rate was higher in patients with high Hyams grade tumor (III/IV) compared to those with low‐grade tumors (I/II) (60% vs. 22.2%, p = 0.038). Overall, the 5‐year cancer‐specific survival (CSS) rate was 76.0%. Among nonresponders to IC, a significant difference in 5‐year CSS rates was observed between surgery with adjuvant radiotherapy (RT) (100%) versus definitive RT or chemoradiotherapy (CRT) (68.6%) (log‐rank p = 0.006). However, for responders, there was no significant difference in 5‐year CSS rates between surgery with adjuvant therapy (75%) and definitive RT or CRT (51.1%) (log‐rank p = 0.536). When only high‐grade tumors were considered among responders, the 5‐year CSS rate was significantly higher in patients who received RT or CRT (51.4%) compared to those who underwent surgery with adjuvant therapy (0%) (log‐rank p = 0.008).In advanced‐stage ONB, RT or CRT may be preferable for high‐grade tumor responding to IC. Higher response rate and a potential role for induction IC in determining the optimal definitive treatment modality suggest a positive role for advanced‐stage high‐grade ONB. [ABSTRACT FROM AUTHOR]

Objectives: Neuroblastoma (NB), a pediatric malignancy of the peripheral nervous system, is characterized by epigenetic and transcriptional (EP-TF) anomalies. This study aimed to develop an EP-TF clinical prognostic model for NB using CRISPR-Cas9 knockout screening. Results: An integrative analysis was conducted using CRISPR-Cas9 screening in vitro and in vivo with public NB datasets to identify 35 EP-TF genes that exhibited the highest expression in NB and were highly dependent on cancer viability. After univariate analysis, 27 of these 35 genes were included in the least absolute shrinkage and selection operator screen. We established and biologically validated a prognostic EP-TF model encompassing RUVBL1, LARP7, GTF3C4, THAP10, SUPT16H, TIGD1, SUV39H2, TAF1A, SMAD9, and FEM1B across diverse NB cohorts. MYCNserves a potential upstreamregulator of EP-TF genes. The highrisk subtype exhibited traits associated with the malignant cell cycle, MYCN-linked signaling and chromatin remodeling, all of which are correlated with poor prognosis and immunosuppression. MEK inhibitors have emerged as promising therapeutic agents for targeting most EP-TF risk genes in NB. Conclusion: Our novel prognostic model shows significant potential for predicting and evaluating the overall survival of NB patients, offering insights into therapeutic targets. [ABSTRACT FROM AUTHOR]

Novel chimeric antigen receptor (CAR) T-cell approaches are needed to improve therapeutic efficacy in solid tumors. High-risk neuroblastoma is an aggressive pediatric solid tumor that expresses cell-surface GPC2 and GD2 with a tumor microenvironment infiltrated by CD16a-expressing innate immune cells. Here we engineer T-cells to express a GPC2-directed CAR and simultaneously secrete a bispecific innate immune cell engager (BiCE) targeting both GD2 and CD16a. In vitro, GPC2.CAR-GD2.BiCE T-cells induce GPC2-dependent cytotoxicity and secrete GD2.BiCE that promotes GD2-dependent activation of antitumor innate immunity. In vivo, GPC2.CAR-GD2.BiCE T-cells locally deliver GD2.BiCE and increase intratumor retention of NK-cells. In mice bearing neuroblastoma patient-derived xenografts and reconstituted with human CD16a-expressing immune cells, GD2.BiCEs enhance GPC2.CAR antitumor efficacy. A CAR.BiCE strategy should be considered for tumor histologies where antigen escape limits CAR efficacy, especially for solid tumors like neuroblastoma that are infiltrated by innate immune cells. GPC2 and GD2 have been described as immunotherapeutic targets in neuroblastoma. Here the authors engineer T cells to simultaneously express a GPC2-directed CAR and a bispecific innate immune cell engager targeting GD2 and CD16a, showing antitumor activity in neuroblastoma preclinical models. [ABSTRACT FROM AUTHOR]

Immunotherapy has emerged as an attractive option for patients with relapsed or refractory high-risk neuroblastoma (HRNB). Neuroblastoma (NB), a sympathetic nervous system cancer arising from an embryonic neural crest cell, is heterogeneous clinically, with outcomes ranging from an isolated abdominal mass that spontaneously regresses to a widely metastatic disease with cure rates of about 50% despite intensive multimodal treatment. Risk group stratification and stage-adapted therapy to achieve cure with minimal toxicities have accomplished major milestones. Targeted immunotherapeutic approaches including monoclonal antibodies, vaccines, adoptive cellular therapies, their combinations, and their integration into standard of care are attractive therapeutic options, although curative challenges and toxicity concerns remain. In this review, we provide an overview of immune approaches to NB and the tumor microenvironment (TME) within the clinical translational framework. We propose a novel T cell-based therapeutic approach that leverages the unique properties of tumor surface antigens such as ganglioside GD2, incorporating specific monoclonal antibodies and recent advancements in adoptive cell therapy. [ABSTRACT FROM AUTHOR]

Simple Summary: This review explores the emerging area of the therapeutic use of chimeric antigen receptor (CAR)-T cells in nervous tissue tumors. Through a detailed analysis of the existing literature, this paper highlights the most recent applications of CAR-T cells to the therapy of pediatric and adult nervous system neoplasia. Furthermore, it discusses the potential mechanisms underlying sensitivity or resistance to CAR-T cell-based therapies. Overall, this review underscores the importance of CAR-T cell therapies to the treatment of some nervous system tumors. Chimeric antigen receptor T cells (CAR-Ts) have shown a remarkable efficacy in hematological malignancies but limited responses in solid tumors. Among solid tumors, CAR-T cell therapy has been particularly explored in brain tumors. CAR-T cells have shown a limited clinical efficacy in various types of brain tumors due to several factors that have hampered their activity, including tumor antigen heterogeneity, the limited access of CAR-T cells to brain tumor cells, limited CAR-T cell trafficking and in vivo persistence and the presence of a highly immunosuppressive tumor microenvironment. Despite these considerations, some recent studies have shown promising antitumor activity of GD2-CAR-T cells on diffuse midline gliomas and neuroblastomas and of CARv3-TEAM-E cells in glioblastomas. However, strategies are required to improve the effect of CAR-T cells in brain tumors, including advanced CAR-T cell design with multiple antigenic targeting and incorporation of combination therapies. [ABSTRACT FROM AUTHOR]

Simple Summary: Neuroblastoma (NBL) is the most common extracranial cancer in children. High-risk NBL is characterized by bone marrow metastasis and MYCN oncogene amplification and is associated with a dismal five-year overall survival of approximately 50%, despite an intensive multimodal treatment regimen including chemotherapy, surgery, high-dose chemotherapy with autologous stem cell rescue, and radiation. Herein, we systemically reviewed contemporary therapy schemes and their challenges as well as recent advancement in effective treatments for NBL. Due to its relative rarity, we hope this review can serve as a useful guidebook and potentially provide new insights to researchers and clinicians interested in this field. Neuroblastoma (NBL) cells highly express disialoganglioside GD2, which is restricted and weakly expressed in selected healthy cells, making it a desirable target of immunotherapy. Over the past two decades, application of dinutuximab, an anti-GD2 monoclonal antibody (mAb), has been one of the few new therapies to substantially improve outcomes to current levels. Given the persistent challenge of relapse and therapeutic resistance, there is an urgent need for new effective and tolerable treatment options for high-risk NBL. Recent breakthroughs in immune checkpoint inhibitor (ICI) therapeutics have not translated into high-risk NBL, like many other major pediatric solid tumors. Given the suppressed tumor microenvironment (TME), single ICIs like anti-CTLA4 and anti-PD1 have not demonstrated significant antitumor response rates. Meanwhile, emerging studies are reporting novel advancements in GD2-based therapies, targeted therapies, nanomedicines, and other immunotherapies such as adoptive transfer of natural killer (NK) cells and chimeric antigen receptors (CARs), and these hold interesting promise for the future of high-risk NBL patient care. Herein, we summarize the current state of the art in NBL therapeutic options and highlight the unique challenges posed by NBL that have limited the successful adoption of immune-modifying therapies. Through this review, we aim to direct the field's attention to opportunities that may benefit from a combination immunotherapy strategy. [ABSTRACT FROM AUTHOR]

AbstractBackgroundMethodsResultsConclusionNeuroblastoma, a pediatric malignancy, is significantly influenced by genetic factors. Prior research indicates that the OGG1 rs1052133 G > C polymorphism correlates with a decreased risk of neuroblastoma.We analyzed 57 neuroblastoma and 21 adrenal samples, using immunohistochemistry to measure OGG1 and STUB1 expression levels. We conducted a survival analysis to explore relationship between the expressions and neuroblastoma prognosis.Notably higher OGG1 expression and significantly lower STUB1 expression in neuroblastoma. OGG1 levels were significantly correlated with patient age, tumor location, histological grade, Shimada classification, INSS stage, and risk category. A negative association was observed between OGG1 and STUB1 expressions. Higher OGG1 expression was linked to reduced PFS and OS. Lower STUB1 expression was associated with unfavorable PFS. Additionally, OGG1 expression and risk category emerged as independent predictors of prognosis.OGG1 potentially functions as an oncogene in NB, with its activity possibly modulated by STUB1 through the ubiquitination pathway. [ABSTRACT FROM AUTHOR]

Neuroblastoma, the deadliest solid tumor in children, exhibits alarming mortality rates, particularly among high-risk cases. To enhance survival rates, a more precise risk stratification for patients is imperative. Utilizing proteomic data from 34 cases with or without N-Myc amplification, we identified 28 differentially expressed ubiquitination-related proteins (URGs). From these, a prognostic signature comprising 6 URGs was constructed. A nomogram incorporating clinical-pathological parameters yielded impressive AUC values of 0.88, 0.93, and 0.95 at 1, 3, and 5 years, respectively. Functional experiments targeting the E3 ubiquitin ligase FBXO42, a component of the prognostic signature, revealed its TP53-dependent promotion of neuroblastoma cell proliferation. In conclusion, our ubiquitination-related prognostic model robustly predicts patient outcomes, guiding clinical decisions. Additionally, the newfound pro-proliferative role of FBXO42 offers a novel foundation for understanding the molecular mechanisms of neuroblastoma. [ABSTRACT FROM AUTHOR]

Object: This study aims to identify differentially expressed genes (DEGs) between high-risk and non-high-risk groups in neuroblastoma (NB), construct a prognostic model, and establish a risk score formula. Materials and methods: The NB dataset GSE49710 (n = 498) from the GEO database served as the training cohort to select DEGs between high-risk and non-high-risk NB groups. Cellular senescence-related genes were obtained from the Aging Atlas database. Intersection genes from both datasets were identified as key genes of cellular senescence-related genes (SRGs). A prognostic model was constructed using Univariate Cox regression analysis and the Lasso algorithm with SRGs. Validation was performed using the E-MTAB-8248 cohort (n = 223). The expression levels of AURKA and CENPA were evaluated via RT-qPCR in two clinical NB sample groups. Results: Eight SRGs were identified, and a prognostic model comprising five genes related to cellular senescence was constructed. AURKA and CENPA showed significant expression in clinical samples and were closely associated with cellular senescence. Conclusion: The prognostic model consisted with five cellular senescence related genes effectively predicts the prognosis of NB patients. AURKA and CENPA represent promising targets in NB for predicting cellular senescence, offering potential insights for NB therapy. [ABSTRACT FROM AUTHOR]

Super‐enhancer‐associated transcription factor networks define cell identity in neuroblastoma (NB). Dysregulation of these transcription factors contributes to the initiation and maintenance of NB by enforcing early developmental identity states. We report that the class I basic helix–loop–helix (bHLH) transcription factor 4 (TCF4; also known as E2‐2) is a critical NB dependency gene that significantly contributes to these identity states through heterodimerization with cell‐identity‐specific bHLH transcription factors. Knockdown of TCF4 significantly induces apoptosis in vitro and inhibits tumorigenicity in vivo. We used genome‐wide expression profiling, TCF4 chromatin immunoprecipitation sequencing (ChIP‐seq) and TCF4 immunoprecipitation–mass spectrometry to determine the role of TCF4 in NB cells. Our results, along with recent findings in NB for the transcription factors T‐box transcription factor TBX2, heart‐ and neural crest derivatives‐expressed protein 2 (HAND2) and twist‐related protein 1 (TWIST1), propose a role for TCF4 in regulating forkhead box protein M1 (FOXM1)/transcription factor E2F‐driven gene regulatory networks that control cell cycle progression in cooperation with N‐myc proto‐oncogene protein (MYCN), TBX2, and the TCF4 dimerization partners HAND2 and TWIST1. Collectively, we showed that TCF4 promotes cell proliferation through direct transcriptional regulation of the c‐MYC/MYCN oncogenic program that drives high‐risk NB. Mechanistically, our data suggest the novel finding that TCF4 acts to support MYC activity by recruiting multiple factors known to regulate MYC function to sites of colocalization between critical NB transcription factors, TCF4 and MYC oncoproteins. Many of the TCF4‐recruited factors are druggable, giving insight into potential therapies for high‐risk NB. This study identifies a new function for class I bHLH transcription factors (e.g., TCF3, TCF4, and TCF12) that are important in cancer and development. [ABSTRACT FROM AUTHOR]

Background: Neuroblastoma (NB) is a heterogeneous pediatric solid tumour strongly influenced by epigenetic modifications. Methods: This review explores the role of N6‐methyladenosine (m6A) modifications and their readers in NB progression. Results: Dysregulation of m6A readers, including YTHDF1/2, YTHDC1, IGF2BP1/2/3, HNRNPA2B1 and HNRNPC, has been associated with susceptibility and progression. Conclusion: Understanding the crosstalk between m6A readers and NB could offer new insights into diagnosis, prognosis, and treatment strategies. [ABSTRACT FROM AUTHOR]

There is some evidence that the serotonin receptor subtype 7 (5-HT7) could be new therapeutic target for neuroprotection. The aim of this study was to compare the neuroprotective and neurite outgrowth potential of new 5-HT7 receptor agonists (AH-494, AGH-238, AGH-194) with 5-CT (5-carboxyamidotryptamine) in human neuroblastoma SH-SY5Y cells. The results revealed that 5-HT7 mRNA expression was significantly higher in retinoic acid (RA)-differentiated cells when compared to undifferentiated ones and it was higher in cell cultured in neuroblastoma experimental medium (DMEM) compared to those placed in neuronal (NB) medium. Furthermore, the safety profile of compounds was favorable for all tested compounds at concentration used for neuroprotection evaluation (up to 1 μM), whereas at higher concentrations (above 10 μM) the one of the tested compounds, AGH-194 appeared to be cytotoxic. While we observed relatively modest protective effects of 5-CT and AH-494 in UN-SH-SY5Y cells cultured in DMEM, in UN-SH-SY5Y cells cultured in NB medium we found a significant reduction of H2O2-evoked cell damage by all tested 5-HT7 agonists. However, 5-HT7-mediated neuroprotection was not associated with inhibition of caspase-3 activity and was not observed in RA-SH-SY5Y cells exposed to H2O2. Furthermore, none of the tested 5-HT7 agonists altered the damage induced by 6-hydroxydopamine (6-OHDA), 1-methyl-4-phenylpyridinium ion (MPP +) and doxorubicin (Dox) in UN- and RA-SH-SY5Y cells cultured in NB. Finally we showed a stimulating effect of AH-494 and AGH-194 on neurite outgrowth. The obtained results provide insight into neuroprotective and neurite outgrowth potential of new 5-HT7 agonists. [ABSTRACT FROM AUTHOR]

Non‐immune hydrops fetalis represents the end‐stage status of a variety of diseases, including metastatic tumors. We report a case of non‐immune hydrops fetalis associated with multiple disseminated echogenic nodular lesions detected by ultrasound and confirmed by magnetic resonance. Cordocentesis demonstrated anemia and thrombopenia. Differential diagnosis included histiocytosis X, acute leukemia or metastatic disease. A stillbirth was diagnosed at week 25 + 6. The autopsy revealed hydrops fetalis, a right adrenal gland mass, multiple disseminated nodules histologically composed of small round blue cells positive for synaptophysin, and placental involvement, concordant findings with congenital undifferentiated neuroblastoma Stage M. No chromosomal abnormalities were associated, nor amplification abnormalities in MYCN and ALK genes. Metastatic neuroblastoma should be considered in the differential diagnosis of non‐immune hydrops fetalis associated with multiple nodular lesions. [ABSTRACT FROM AUTHOR]

The pterocarpan fraction from aerial parts of Bituminaria bituminosa was investigated for both chemical characterization and biological evaluation. Chemical studies were in accordance with the literature data on Bituminaria genus resulting in the identification of typical 4,8-prenyl pterocarpans. Three new members, bituminarins A–C (1–3), were isolated along with main bitucarpin A (4), erybraedin C (5) and erybraedin D (6) already reported from this plant. Further, biological studies evidenced antiproliferative properties of the most abundant pterocarpans 4 and 5 on neuroblastoma SH-SY5Y cell line, in agreement with previously described antiproliferative activity of these compounds against cancer cell lines other than neuroblastoma. The structure and the stereochemistry of the new molecules was determined by extensive spectroscopic analysis and chemical derivatization methods. The biological investigation was carried out by using an assay platform based on a live-cell imaging system revealing an apoptotic cell death induction. [ABSTRACT FROM AUTHOR]

AbstractPurposeMaterials and methodsResultsConclusionsNeuroblastoma, a prevalent childhood tumor, poses significant challenges in therapeutic interventions, especially for high-risk cases. This study aims to fill a crucial gap in our understanding of neuroblastoma treatment by investigating the potential molecular impacts of short- and long-term pulsed magnetic field exposure on the neuronal apoptosis mechanism in an in vitro model of neuroblastoma treated with oleic acid (OA).Cells were cultured and divided into six following experimental groups: (I) Nontreated group (NT); (II) OA-treated group (OA); (III) Group treated with OA after being exposed to the pulsed magnetic field for 15-min (15 min PEMF + OA); (IV) Group treated with OA after being exposed to the pulsed magnetic field for 12 h (12 h PEMF + OA); (V) Group exposed to the pulsed magnetic field for 15 min (15 min PEMF); and (VI) Group exposed to the pulsed magnetic field for 12 h (12 h PEMF). Cell viability, rates of apoptosis, and mRNA levels of key apoptotic genes (TP53, Bcl2, Bax, and Caspase-3) were assessed.Significant reductions in cell viability were observed, particularly in the group treated with OA following long-term pulsed magnetic field exposure. Flow cytometry revealed elevated apoptosis rates, notably in the early stages of apoptosis. qRT-PCR analysis demonstrated increased expression of cleaved Caspase-3, Bax/Bcl2 ratio, and TP53 in cells treated with OA following long-term pulsed magnetic field exposure, signifying enhanced apoptotic pathways.The findings indicate that long-term pulsed magnetic field exposure and OA treatment exhibit potential synergistic effects leading to the induction of apoptosis in SH-SY5Y cells. We have concluded that stimulations of pulsed magnetic field have the potential to serve as an adjuvant therapy for oleic acid-based treatment of neuroblastoma. [ABSTRACT FROM AUTHOR]

This article discusses the distribution of normal and malignant cells in the bone marrow of children suspected of having a hematological malignancy. The study found that malignant cells are generally homogeneously distributed throughout the bone marrow, and the location of the bone marrow puncture does not significantly impact flow cytometric diagnostics. The study analyzed paired bone marrow samples from 42 pediatric patients and found that the percentages of leukocyte subpopulations and maturation patterns were highly comparable between the paired samples. The authors conclude that a single bone marrow sample is sufficient for flow cytometric analysis in pediatric patients suspected of having a hematological malignancy. [Extracted from the article]

Caffeic acid phenethyl ester (CAPE) is a phenolic natural product with a wide range of biological activities, including anticancer activity; however, the ester group of CAPE is metabolically labile. The corresponding amide, CAPA, has improved metabolic stability but limited anticancer activity relative to CAPE. We report the synthesis using flow and on-water Wittig reaction approaches of five previously reported and five novel CAPA analogues. All of these analogues lack the reactive catechol functionality of CAPA and CAPE. Cytotoxicity studies of CAPE, CAPA, and these CAPA analogues in HeLa and BE(2)-C cells were carried out. Surprisingly, we found that CAPA is cytotoxic against the neuroblastoma BE(2)-C cell line (IC50 = 12 µM), in contrast to the weak activity of CAPA against HeLa cells (IC50 = 112 µM), and the literature reports of the absence of activity for CAPA against a variety of other cancer cell lines. One novel CAPA analogue, 3f, was identified as having cytotoxic activity similar to CAPE in HeLa cells (IC50 = 63 µM for 3f vs. 32 µM for CAPE), albeit with lower activity against BE(2)-C cells (IC50 = 91 µM) than CAPA. A different CAPA analogue, 3g, was found to have similar effects against BE(2)-C cells (IC50 = 92 µM). These results show that CAPA is uniquely active against neuroblastoma cells and that specific CAPA analogues that are predicted to be more metabolically stable than CAPE can reproduce CAPA's activity against neuroblastoma cells and CAPE's activity against HeLa cells. [ABSTRACT FROM AUTHOR]

Purpose: To compare the performance of radiomics from contrast-enhanced computed tomography (CECT) and non-contrast magnetic resonance imaging (MRI) in assessing cellular behavior in pediatric peripheral neuroblastic tumors (PNTs). Materials and methods: A retrospective analysis of 81 PNT patients who underwent venous phase CECT, T1-weighted imaging (T1WI), and T2-weighted imaging (T2WI) scans was conducted. The patients were classified into neuroblastoma and ganglioneuroblastoma/ganglioneuroma based on their pathological subtypes. Additionally, they were categorized into favorable histology and unfavorable histology according to the International Neuroblastoma Pathology Classification (INPC). Tumor regions of interest were segmented on CECT, axial T1WI, and axial T2WI images, and radiomics models were developed based on the selected radiomics features. Following five-fold cross-validation, the performance of the radiomics models derived from CECT and MRI was compared using the area under the receiver operating characteristic curve (AUC) and accuracy. Results: For discriminating pathological subtypes, the AUC for CECT radiomics models ranged from 0.765 to 0.870, with an accuracy range of 0.728 to 0.815. In contrast, the AUC for MRI radiomics models ranged from 0.549 to 0.748, with an accuracy range of 0.531 to 0.778. Regarding the discrimination of INPC subgroups, the AUC for CECT radiomics models ranged from 0.503 to 0.759, with an accuracy range of 0.432 to 0.741. Meanwhile, the AUC for MRI radiomics models ranged from 0.512 to 0.739, with an accuracy range of 0.605 to 0.815. Conclusions: CECT radiomics outperforms non-contrast MRI radiomics in evaluating pathological subtypes. When assessing INPC subgroups, CECT radiomics demonstrates comparability with non-contrast MRI radiomics. [ABSTRACT FROM AUTHOR]

Objectives: Neuroblastoma is the most common extracranial solid tumor in childhood. YAP (Yes‐associated protein) is a highly expressed protein in NB. Nestin is an important marker of neuronal differentiation in NB. Orthodenticle homeobox (OTX) is a transcription factor and is overexpressed in blastoma‐derived tumors. The aim of this study was to examine the potential roles of YAP‐1, Nestin, and OTX‐2 proteins in prognosis and risk stratification in neuroblastoma Methods: Tumor sections of 56 patients with different NB risk groups were analyzed. YAP‐1, Nestin, and OTX‐2 protein expression levels were evaluated by immunohistochemical staining in NB patient tissue samples. Results: YAP‐1, Nestin, and OTX‐2 protein expression levels were evaluated together with the clinical findings of NB patients. YAP‐1 was expressed in 18% of all tissues, while Nestin was expressed in 20.4%. OTX‐2 protein expression was found in 41.1% of the NB patients. YAP‐1 was expressed in 26.9% of high‐risk and 11.5% of low‐risk patients. Nestin was expressed in 24.4% high‐risk and 33.3% low‐risk patients. OTX‐2 was expressed in 68.2% high‐risk and 60% low‐risk patients.YAP‐1 was shown to provide survival advantages among risk groups. Interpretation: The findings of this study support that YAP‐1 may be a potential prognostic biomarker for staging and risk‐group assignment of NB patients. YAP‐1 expression in neuroblastoma is associated with significantly poorer survival probabilities and should be considered as a potential therapeutic target. OTX‐2 is a promising predictive biomarker candidate, but its mechanisms need further investigation in neuroblastoma, as nestin expression is not significantly linked to patient survival. [ABSTRACT FROM AUTHOR]

Objectives: Machine learning methods can be applied successfully to various medical imaging tasks. Our aim with this study was to build a robust classifier using radiomics and clinical data for preoperative diagnosis of Wilms tumor (WT) or neuroblastoma (NB) in pediatric abdominal CT. Material and methods: This is a single-center retrospective study approved by the Institutional Ethical Board. CT scans of consecutive patients diagnosed with WT or NB admitted to our hospital from January 2005 to December 2021 were evaluated. Three distinct datasets based on clinical centers and CT machines were curated. Robust, non-redundant, high variance, and relevant radiomics features were selected using data science methods. Clinically relevant variables were integrated into the final model. Dice score for similarity of tumor ROI, Cohen's kappa for interobserver agreement among observers, and AUC for model selection were used. Results: A total of 147 patients, including 90 WT (mean age 34.78 SD: 22.06 months; 43 male) and 57 NB (mean age 23.77 SD:22.56 months; 31 male), were analyzed. After binarization at 24 months cut-off, there was no statistically significant difference between the two groups for age (p =.07) and gender (p =.54). CT clinic radiomics combined model achieved an F1 score of 0.94, 0.93 accuracy, and an AUC 0.96. Conclusion: In conclusion, the CT-based clinic-radiologic-radiomics combined model could noninvasively predict WT or NB preoperatively. Notably, that model correctly predicted two patients, which none of the radiologists could correctly predict. This model may serve as a noninvasive preoperative predictor of NB/WT differentiation in CT, which should be further validated in large prospective models. Clinical relevance statement: CT-based clinic-radiologic-radiomics combined model could noninvasively predict Wilms tumor or neuroblastoma preoperatively. Key Points: • CT radiomics features can predict Wilms tumor or neuroblastoma from abdominal CT preoperatively. • Integrating clinic variables may further improve the performance of the model. • The performance of the combined model is equal to or greater than human readers, depending on the lesion size. [ABSTRACT FROM AUTHOR]

In the present study, histopathological and immunohistochemical findings of olfactory ganglioneuroblastoma in a dog were compared to those of canine olfactory neuroepithelia and neuroblastomas. Olfactory ganglioneuroblastoma consists of ganglion cell-like tumor cells with Schwannian stroma and neuroblast-like tumor cells. Immunohistochemically, ganglion cell-like tumor cells were immunopositive for synaptophysin, β3-tubulin, and tyrosine hydroxylase, Schwannian stroma was immunopositive for GFAP and SOX2, and neuroblast-like tumor cells were immunopositive for OLIG2, β3-tubulin, SOX2, cytokeratin AE1/AE3, and p63. The immunohistochemical results of olfactory neuroepithelia and olfactory neuroblastomas were similar to those of neuroblast-like tumor cells. These results suggest that the ganglion cell-like tumor cells in the present case have a sympathetic neuron immunophenotype, whereas neuroblast-like tumor cells have an olfactory neuroepithelial immunophenotype. [ABSTRACT FROM AUTHOR]

Patient-specific 3D models of neuroblastoma and relevant anatomy are useful tools for surgical planning. However, these models do not represent the heterogenous biology of neuroblastoma. This heterogeneity is visualized with the ADC and 123I-MIGB-SPECT-CT imaging. Combining these multi-modal data into preoperative 3D heatmaps, may allow differentiation of the areas of vital and non-vital tumor tissue. We developed a workflow to create multi-modal preoperative 3D models for neuroblastoma surgery. We included 7 patients who underwent neuroblastoma surgery between 2022 and 2023. We developed 3D models based on the contrast enhanced T1-weighted MRI scans. Subsequently, we aligned the corresponding ADC and 123I-MIBG-SPECT-CT images using rigid transformation. We estimated registration precision using the Dice score and the target registration error (TRE). 3D heatmaps were computed based on ADC and 123I-MIBG uptake. The registration algorithm had a median Dice score of 0.81 (0.75–0.90) for ADC and 0.77 (0.65–0.91) for 123I-MIBG-SPECT. For the ADC registration, the median TRE of renal vessels was 4.90 mm (0.86–10.18) and of the aorta 4.67 mm (1.59–12.20). For the 123I -MIBG-SPECT imaging the TRE of the renal vessels was 5.52 mm (1.71–10.97) and 5.28 mm (3.33–16.77) for the aorta. We successfully developed a registration workflow to create multi-modal 3D models which allows the surgeon to visualize the tumor and its biological behavior in relation to the surrounding tissue. Future research will include linking of pathological results to imaging data, to validate these multi-modal 3D models. Level IV. Clinical Research. [ABSTRACT FROM AUTHOR]

Chyle leakage/ascites after surgical resection of neuroblastic tumors may delay the start of chemotherapy and worsen prognosis. Previous studies have reported a highly variable incidence and risk factors remain largely unknown. This study aims to analyze the true incidence of chyle leaks and ascites and seeks to identify risk factors and optimal treatment strategies. Medline/Embase databases were searched according to PRISMA guidelines. Literature reviews, case reports, and non-English papers were excluded. Data were extracted independently following paper selection by 2 authors. The final analysis yielded 15 studies with N = 1468 patients. Chylous ascites was recorded postoperatively in 171 patients (12%). Most patients experiencing chyle leaks were successfully treated conservatively with drainage, bowel rest, parenteral nutrition and octreotide with variable combinations of these treatment options. 7/171 (4%) patients required operative exploration to control troublesome persistent chyle leaks. In risk factor analysis, higher tumor stage was significantly associated with the risk of chyle leak (P < 0.0001) whereas no correlation was observed with adrenal vs non-adrenal tumor location, INRG risk groups and tumor laterality. Chyle leakage after surgery for neuroblastic tumors is a common morbid complication occurring in some 12% of patients. Higher INSS tumor stage portends greater risk(s). Conservative therapy strategies appear successful in the majority of cases. To avert this complication meticulous mesenteric lymphatic ligation is recommended especially for those patients with higher tumor stage(s) requiring extensive radical surgery including retroperitoneal lymph node resection. III. Systematic review. • Chyle leak after surgical resection of neuroblastic tumors may delay the start of chemotherapy and its risk factors remain largely unknown. • To avert this complication meticulous mesenteric lymphatic ligation is recommended especially for those patients with higher tumor stage(s) requiring extensive radical surgery. [ABSTRACT FROM AUTHOR]

Gross total resection of neuroblastoma is associated with lymphatic leaks that can delay postoperative resumption of treatment. To prevent postoperative lymphatic leak, we introduced systematic lymphatic repair (SLR), which involved oversewing the entire edge of the disrupted lymphatic plane after neuroblastoma resection. We sought to study the impact of SLR on postoperative lymphatic leak and time to return to treatment. We reviewed 60 neuroblastoma patients who underwent gross total resection at KK Women's and Children's Hospital. Patient, disease, and operative factors were correlated with surgical drainage, treatment delay and length of stay (LOS). Among patients with sufficient records, the interaction between variables associated with drainage, delay and LOS outcomes were compared in 14 patients who had SLR versus 35 historical controls who had targeted lymphatic repair (TLR). Postoperative drain duration and volume were significantly higher in tumors with ≥2 image-derived risk factors (IDRFs, P = 0.005 and P = 0.013, respectively) or vessel encasement (P = 0.031 and P = 0.024, respectively). Longer LOS was significantly associated with ≥2 IDRFs (P = 0.006). All forms of suture repair of lymphatics and use of Tachosil™ were associated with significantly longer postoperative drain duration (P < 0.05); the former was also associated with significantly higher total drain volume (P < 0.05) – indicating appropriate use of these adjuncts in patients at risk of chyle leak. In patients who had suture repair of lymphatics, SLR was significantly associated with reduced postoperative interval to chemotherapy resumption (P = 0.014, two-way ANOVA). A systematic approach to repair of lymphatic channels following neuroblastoma resection can significantly reduce time to postoperative resumption of treatment. Clinical Research. III. • What is currently known about this topic? Lymphatic leak is a common postoperative complication of neuroblastoma resection that current solutions like intraoperative thrombostatic agents don't fully address. • What new information is contained in this article? Systematic lymphatic repair of divided lymphatic channels (based on anatomical templates) is a novel method that reduces postoperative lymphatic leak and time to resumption of chemotherapy after neuroblastoma resection. [ABSTRACT FROM AUTHOR]

Neuroblastoma is a common pediatric malignancy with poor survival for high-risk disease. Mesenchymal stromal cells (MSCs) have innate tumor-homing properties, enabling them to serve as a cellular delivery vehicle, but MSCs have demonstrated variable effects on tumor growth. We compared how placental MSCs (PMSCs) and bone marrow-derived MSCs (BM-MSCs) affect proliferation of neuroblastoma (NB) cells in vitro. Indirect co-culture assessed proliferative effects of 18 MSCs (early-gestation PMSCs (n = 9), term PMSCs (n = 5), BM-MSCs (n = 4) on three high-risk NB cell lines (NB1643, SH-SY5Y, and CHLA90). Controls were NB cells cultured in media alone. Proliferation was assessed using MTS assay and measured by fold change (fc) over controls. PMSCs were sub-grouped by neuroprotective effect: strong (n = 7), intermediate (n = 3), and weak (n = 4). The relationship between MSC type, PMSC neuroprotection, and PMSC gestational age on NB cell proliferation was assessed. NB cell proliferation varied between MSC groups. BM-MSCs demonstrated lower proliferative effects than PMSCs (fc 1.18 vs 1.44, p < 0.001). Neither gestational age nor neuroprotection significantly predicted degree of proliferation. Proliferative effects of MSCs varied among NB cell lines. BM-MSCs had less effect on CHLA90 (fc 1.01) compared to NB1643 (fc 1.33) and SH-SY5Y (fc 1.20). Only NB1643 showed a difference between early and term PMSCs (p = 0.04). Effects of MSCs on NB cell proliferation vary by MSC source and NB cell line. BM-MSCs demonstrated lower proliferative effects than most PMSCs. MSC neuroprotection was not correlated with proliferation. Improved understanding of MSC proliferation-promoting mechanisms may provide valuable insight into selection of cells best suited as drug delivery vehicles. N/A. Original Research. [ABSTRACT FROM AUTHOR]

Neuroblastoma is a common nervous system tumor in childhood, and current treatments are not adequate. HSP90 is a molecular chaperone protein that plays a critical role in the regulation of cancer-related proteins. HSP90 inhibition may exert anticancer effects by targeting cancer-related processes such as tumor growth, cell proliferation, metastasis, and apoptosis. Therefore, HSP90 inhibition is a promising strategy in the treatment of various types of cancer, and the development of next-generation inhibitors could potentially lead to more effective and safer treatments. XL-888 and Debio0932 is a next-generation HSP90 inhibitor and can inhibit the correct folding and stabilization of client proteins that cancer-associated HSP90 helps to fold correctly. In this study, we aimed to investigate the comprehensive molecular pathways of the anticancer activity of XL-888 and Debio0932 in human neuroblastoma cells SH-SY5Y. The cytotoxic effects of XL-888 and Debio0932 on the neuroblastoma cell line SH-SY5Y cells were evaluated by MTT assay. Then, the effect of these HSP90 inhibitors on the expression of important genes in cancer was revealed by Quantitative Real Time Polymerase Chain Reaction (qRT-PCR) method. The qRT-PCR data were evaluated using Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) biological process tools. Finally, the effect of HSP90 inhibitors on HSP27, HSP70 and HSP90 protein expression was investigated by Western blotting analysis. The results revealed that XL-888 and Debio0932 had a role in regulating many cancer-related pathways such as migration, invasion, metastasis, angiogenesis, and apoptosis in SH-SY5Y cells. In conclusion, it shows that HSP90 inhibitors can be considered as a promising candidate in the treatment of neuroblastoma and resistance to chemotherapy. [ABSTRACT FROM AUTHOR]

Neuroblastoma is a pediatric tumor that originates during embryonic development and progresses into aggressive tumors, primarily affecting children under two years old. Many patients are diagnosed as high-risk and undergo chemotherapy, often leading to short- and long-term toxicities. Nanomedicine offers a promising solution to enhance drug efficacy and improve physical properties. In this study, lipid-based nanomedicines were developed with an average size of 140 nm, achieving a high encapsulation efficiency of over 90% for the anticancer drug etoposide. Then, cytotoxicity and apoptosis-inducing effects of these etoposide nanomedicines were assessed in vitro using human cell lines, both cancerous and non-cancerous. The results demonstrated that etoposide nanomedicines exhibited high toxicity and selectively induced apoptosis only in cancerous cells. Next, the biosafety of these nanomedicines in C. elegans, a model organism, was evaluated by measuring survival, body size, and the effect on dividing cells. The findings showed that the nanomedicines had a safer profile than the free etoposide in this model. Notably, nanomedicines exerted etoposide's antiproliferative effect only in highly proliferative germline cells. Therefore, the developed nanomedicines hold promise as safe drug delivery systems for etoposide, potentially leading to an improved therapeutic index for neuroblastoma treatment. [ABSTRACT FROM AUTHOR]

Cancer is a serious public health concern worldwide, and nervous system (NS) cancers are among the most life-threatening malignancies. Efforts have been devoted to introduce natural anticancer agents with minimal side effects. Apigenin is an edible flavonoid that is abundantly found in many vegetables and fruits. Various pharmaceutical activities, including anti-inflammatory, antioxidative, antimicrobial, and anticancer effects have been reported for apigenin. This review provides insights into the therapeutic effects of apigenin and flavonoids with similar structure on glioblastoma and neuroblastoma. Current evidence indicates that apigenin has the unique ability to cross the blood-brain barrier, and its antioxidative, anti-inflammatory, neurogenic, and neuroprotective effects have made this flavonoid a great option for the treatment of neurodegenerative disorders. Meanwhile, apigenin has low toxicity on normal neuronal cells, while induces cytotoxicity on NS cancer cells via triggering several signal pathways and molecular targets. Anticancer effects of apigenin have been contributed to various mechanisms such as induction of cell cycle arrest and apoptosis, and inhibition of migration, invasion, and angiogenesis. Although apigenin is a promising pharmaceutical agent, its low bioavailability is an important issue that must be solved before introducing to clinic. Recently, nano-delivery of apigenin by liposomes and poly lactic-co-glycolide nanoparticles has greatly improved functionality of this agent. Hence, investigating pharmaceutical effects of apigenin-loaded nanocarriers on NS cancer cell lines and animal models is recommended for future studies. [ABSTRACT FROM AUTHOR]

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Purpose (i) To analyze age-adjusted incidence rates of synchronous bone metastases diagnosed alongside primary malignancy from 2010 to 2018 in the US population, (ii) determine the incidence proportions (IPs) and characteristics of synchronous bone metastases among newly diagnosed cancer patients in the USA especially pediatric cases, and (iii) assess the implications of synchronous bone metastases on cancer patient's survival, and identify the survival risk factors for these cancer patients. Methods Utilizing data from the Surveillance, Epidemiology, and End Results (SEER) program (2010–2018), we calculated age-adjusted IPs and annual percentage change (APC), and employed logistic regression and Cox regression models for our analysis. Results 3 300 736 cancer patients were identified. The age-adjusted incidence rates of synchronous bone metastases increased from 2010 (18.04/100 000) to 2018 (20.89/100 000; APC: 2.3, 95% confidence interval [CI], 1.4–3.1), but decreased in lung cancer (average APC: –1.0, 95% CI, −1.8 to −0.3). The highest IPs were observed in pediatric neuroblastoma (43.2%; 95% CI, 39.8%–46.7%) and adult small cell carcinoma (23.1%; 95% CI, 22.7%–23.4%). Multivariate logistic analyses revealed that primary tumor characteristics were correlated with higher bone metastases risk. Survival analyses also showed varied prognostic outcomes based on metastasis sites and demographics among cancer patients. Landmark analyses further indicated among long-term cancer survivors (≥3 and ≥5 years), patients with de novo bone metastases had the poorest survival rates compared with those with other synchronous metastases (P  < 0.001). Conclusion This study provides a population-based estimation of the incidence and prognosis for synchronous bone metastases. Our findings highlight the need for early identification of high-risk groups and multidisciplinary approaches to improve prognosis of cancer patients with de novo bone metastases. What is already known on this topic: The incidence of de novo bone metastases between 2010 and 2015 that SEER database documented was average 18.8 per 100 000 per year. In adult patients, the most frequent sites for de novo metastases are the lungs, prostate, and breast. The cancer patients with synchronous bone metastases are likely to have a modest reduction in survival. What this study adds: The age-adjusted incidence rates of synchronous bone metastasis steadily rose from 18.04 per 100 000 in 2010 to 20.89 per 100 000 in 2018. Pediatric patients had higher incidence proportions of synchronous bone metastases compared to adult patients, among pediatric patients specifically, those diagnosed with neuroblastoma had the highest risk of synchronous bone metastases. In the short term, cancer patients with synchronous brain metastases had the poorest survival rates. However, among long-term cancer survivors, those with synchronous bone metastases had the worst prognosis. How this study might affect research, practice, or policy: Pediatric clinicians need to be acutely aware of the significant possibility of simultaneous development of bone metastases and neuroblastoma in pediatric patients. For long-term survivors, Clinicians should prioritize the care of them with synchronous bone metastases over those with metastases from other sites. For cancer patients with synchronous bone metastases, we advocate for surgery of the primary cancer sites to improve prognosis. Remained research questions: How does the differential utilization of bone scans across different tumors affect the accuracy of detecting synchronous bone metastases in cancer patients? What is the impact of bone metastases on patients' physical status, comorbidities, performance status, and quality of life? How do radiotherapy, chemotherapy, and surgical treatments for sites of bone metastases affect the prognosis of cancer patients with synchronous bone metastases? [ABSTRACT FROM AUTHOR]

Neuroblastoma (NB) is one of the most common childhood malignancies. Sixty percent of patients present with widely disseminated clinical signs at diagnosis and exhibit poor outcomes. However, the molecular mechanisms triggering NB metastasis remain largely uncharacterized. In this study, we generated a transcriptomic atlas of 15 447 NB cells from eight NB samples, including paired samples of primary tumors and bone marrow metastases. We used time-resolved analysis to chart the evolutionary trajectory of NB cells from the primary tumor to the metastases in the same patient and identified a common 'starter' subpopulation that initiates tumor development and metastasis. The 'starter' population exhibited high expression levels of multiple cell cycle-related genes, indicating the important role of cell cycle upregulation in NB tumor progression. In addition, our evolutionary trajectory analysis demonstrated the involvement of partial epithelial-to-mesenchymal transition (p-EMT) along the metastatic route from the primary site to the bone marrow. Our study provides insights into the program driving NB metastasis and presents a signature of metastasis-initiating cells as an independent prognostic indicator and potential therapeutic target to inhibit the initiation of NB metastasis. [ABSTRACT FROM AUTHOR]

Purpose: Neuroblastoma, the most common extracranial solid tumor in children under 5 years, often surrounds visceral arteries. This study aimed to analyze the working space provided by standardized surgical techniques at key arterial landmarks in adult cadavers. Methods: We assessed in eight adult cadavers the mobilization of the left colon, spleen and pancreas, right colon, duodenum and mesenteric root, access to the bursa omentalis. The average working space score (AWSS) was evaluated at the left and right renal artery, left and right side of the coeliac trunk, superior mesenteric and common hepatic artery. The score was defined as: (0) vessel not visible, (1) working space at the vessel ≤ 1x diameter of the aorta, (2) < 3x the diameter of the aorta, (3) ≥ 3x diameter of the aorta. Results: The maximum AWSS of 3 was achieved at key vascular landmarks through specific mobilization techniques. Conclusion: Additional mobilization of spleen, pancreas and mesenteric root and access to the bursa omentalis increase surgical working space at major visceral arteries. The results of our investigation provide surgeons with a useful guide to prepare for abdominal neuroblastoma resection. [ABSTRACT FROM AUTHOR]

Liquid biopsy, an advanced technology for analyzing body fluid samples, is gaining traction in cancer diagnostics and monitoring. Blood-based liquid biopsy, particularly focusing on cell-free DNAs (cf-DNAs), circulating tumor cells (CTCs), and extracellular vesicles (EVs), has garnered significant attention. EVs stand out for their potential in tumor diagnosis, prognosis prediction, and treatment response assessment, owing to their stable molecular cargo and clear extraction process. At the recent American Association for Cancer Research (AACR) Annual Meeting 2024, groundbreaking EVs-based liquid biopsy studies showcased promising strides in early detection and diagnosis of various cancers, including breast cancer (BC), high-grade serous ovarian cancer (HGSOC), pancreatic ductal adenocarcinoma (PDAC), colorectal cancer (CRC), colon adenocarcinoma (COAD), head and neck cancer (HNC), neuroblastoma, and retinoblastoma (RB). Despite these advancements, challenges persist in translating EVs biomarkers into clinical practice. Overcoming these challenges promises to propel EVs-based liquid biopsy into a new era of personalized precision medicine, revolutionizing cancer detection, monitoring, and treatment. [ABSTRACT FROM AUTHOR]

Background: The majority of experimental approaches for cancer immunotherapy are tested against relatively small tumors in tumor-bearing mice, because in most cases advanced cancers are resistant to the treatments. In this study, we asked if even late-stage mouse tumors can be eradicated by a rationally designed combined radio-immunotherapy (CRI) regimen. Methods: CRI consisted of local radiotherapy, intratumoral IL-12, slow-release systemic IL-2 and anti-CTLA-4 antibody. Therapeutic effects of CRI against several weakly immunogenic and immunogenic mouse tumors including B78 melanoma, MC38 and CT26 colon carcinomas and 9464D neuroblastoma were evaluated. Immune cell depletion and flow cytometric analysis were performed to determine the mechanisms of the antitumor effects. Results: Tumors with volumes of 2,000 mm³ or larger were eradicated by CRI. Flow analyses of the tumors revealed reduction of T regulatory (Treg) cells and increase of CD8/Treg ratios following CRI. Rapid shrinkage of the treated tumors did not require T cells, whereas T cells were involved in the systemic effect against the distant tumors. Cured mice developed immunological memory. Conclusions: These findings underscore that rationally designed combination immunotherapy regimens can be effective even against large, late-stage tumors. [ABSTRACT FROM AUTHOR]

Estramustine (EM), a clinically successful hormone‐refractory anti‐prostate cancer drug, exhibited potent anti‐proliferative activity, depolymerized microtubules, blocked cells at mitosis, and induced cell death in different cancer cells. Altered iron metabolism is a feature of cancer cells. Using EM, we examined the plausible relationship between microtubule depolymerization and induction of ferroptosis in human neuroblastoma (SH‐SY5Y and IMR‐32) cells. EM reduced glutathione (GSH) levels and induced reactive oxygen species (ROS) generation. The pre‐treatment of neuroblastoma cells with ROS scavengers (N‐acetyl cysteine and dithiothreitol) reduced the anti‐proliferative effects of EM. EM treatment increased labile iron pool (LIP), depleted glutathione peroxidase 4 (GPX4) levels, and lipid peroxidation, hallmark features of ferroptosis, highlighting ferroptosis induction. Ferroptosis inhibitors (deferoxamine mesylate and liproxstatin‐1) abrogated the cytotoxic effects of EM, further confirming ferroptosis induction. Vinblastine and nocodazole also increased LIP and induced lipid peroxidation in neuroblastoma cells. This study provides evidence for the coupling of microtubule integrity to ferroptosis. The results also suggest that microtubule‐depolymerizing agents may be considered for developing pro‐ferroptosis chemotherapeutics. [ABSTRACT FROM AUTHOR]

In therapies, curcumin is now commonly formulated in liposomal form, administered through injections or creams. This enhances its concentration at the cellular level compared to its natural form ingestion. Due to its hydrophobic nature, curcumin is situated in the lipid part of the membrane, thereby modifying its properties and influencing processes The aim of the research was to investigate whether the toxicity of specific concentrations of curcumin, assessed through biochemical tests for the SK-N-SH and H-60 cell lines, is related to structural changes in the membranes of these cells, caused by the localization of curcumin in their hydrophobic regions. Biochemical tests were performed using spectrophotometric methods. Langmuir technique were used to evaluate the interaction of the curcumin with the studied lipids. Direct introduction of curcumin into the membranes alters their physicochemical parameters. The extent of these changes depends on the initial properties of the membrane. In the conducted research, it has been demonstrated that curcumin may exhibit toxicity to human cells. The mechanism of this toxicity is related to its localization in cell membranes, leading to their dysfunction. The sensitivity of cells to curcumin presence depends on the saturation level of their membranes; the more rigid the membrane, the lower the concentration of curcumin causes its disruption. [ABSTRACT FROM AUTHOR]

This study explores migrasomes' role in neuroblastoma, a common malignant tumor in children, and their potential impact on tumor formation. We analyzed neuroblastoma RNA-seq datasets from public databases, including GSE62564, GSE181559, target, and fwr144. Through data normalization and unsupervised classification using migrasome-specific molecular markers, Differentially Expressed Genes were identified, followed by functional enrichment analysis. Our novel migrasome-associated machine learning model, MigScore, was developed using ten algorithms and 101 combinations, validated on two single-cell datasets. This enabled immune infiltration assessment and drug compatibility prediction, highlighting the utility of MS275, a histone deacetylase inhibitor. Results showed a significant inverse relationship between MigScore and favorable clinical outcomes, elucidating the link between migrasome pathways and tumor immunogenicity. These findings suggest that migrasomes are crucial in neuroblastoma prognosis, leading to the possibility of personalized treatment strategies and improved outcomes. [ABSTRACT FROM AUTHOR]

Background: We previously showed that total tumor resection enhances metastatic growth in a syngeneic metastatic mouse model of neuroblastoma. In this study, we further investigated which surgical factors contributed most to metastatic growth. Methods: Tumor cells derived from MYCN transgenic mice were subcutaneously injected into wild-type mice. Mice were randomly assigned to receive partial resection (PR group), subcutaneous implantation of a sponge (Sp group), or observation (Obs group). The lymph node metastasis volume and the frequency of lung metastasis were compared 14 days after assignment by measuring C-reactive protein (CRP) and interleukin-6 (IL-6) levels. Results: The lymph node metastasis volume in the Sp group was larger than in the Obs group (148.4 [standard deviation {SD}: 209.5] vs. 10.2 [SD 12.8] mm3). The frequency of lung metastasis was greater in the Sp group than in the PR group (11.9 [SD 12.2] vs. 6.6 [SD 4.0] counts/slide). The CRP level in the Sp group was higher than in the PR group (2.3 [SD 0.5] vs. 1.5 [SD 0.4] μg/mL), and the IL-6 level in the Sp group was higher than in the PR or Obs groups (28.4 [SD 34.5] vs. 12.4 [SD 19.0] vs. 5.4 [SD 8.1] pg/mL). Conclusion: Metastatic growth may be enhanced by systemic inflammation. [ABSTRACT FROM AUTHOR]

Protein arginine methyltransferase 5 (PRMT5) is over‐expressed in a wide variety of cancers and is implicated as having a key oncogenic role, achieved in part through its control of the master transcription regulator E2F1. We investigated the relevance of PRMT5 and E2F1 in neuroblastoma (NB) and found that elevated expression of PRMT5 and E2F1 occurs in poor prognosis high‐risk disease and correlates with an amplified Myelocytomatosis viral‐related oncogene, neuroblastoma‐derived (MYCN) gene. Our results show that MYCN drives the expression of splicing factor genes that, together with PRMT5 and E2F1, lead to a deregulated alternative RNA splicing programme that impedes apoptosis. Pharmacological inhibition of PRMT5 or inactivation of E2F1 restores normal splicing and renders NB cells sensitive to apoptosis. Our findings suggest that a sustained cancer‐relevant alternative RNA splicing programme desensitises NB cells to apoptosis, and identify PRMT5 as a potential therapeutic target for high‐risk disease. [ABSTRACT FROM AUTHOR]

Neuroblastoma is the most common extracranial solid tumor found in childhood and is responsible for 15% of deaths among children with cancer. Although multimodal therapies focused on surgery, chemotherapy, radiotherapy, and stem cell transplants have favorable results in many cases, the use of conventional therapies has probably reached the limit their possibility. Almost half of the patients with neuroblastoma belong to the high-risk group. Patients in this group require a combination of several therapeutic approaches. It has been shown that various immunotherapies combined with conventional methods can work synergistically. Due to the development of such therapeutic methods, we present combinations and forms of combining immunotherapy, focusing on their mechanisms and benefits but also their limitations and potential side effects. [ABSTRACT FROM AUTHOR]

International comparisons of cancer surveillance measures may provide insight into inequalities in registration practices, etiological factors, and treatment strategies. This study aimed to compare incidence, survival, and mortality of cancer in children and young adolescents between Belgium and the Netherlands. All children (0–14 years) and young adolescents (15–17 years) diagnosed with cancer between 2004 and 2015 were selected from the population‐based cancer registries of Belgium (N = 4739) and the Netherlands (N = 7322). Differences in incidence and mortality were expressed as standardized rate ratios (SRR; BE/NL). Five‐year observed survival was calculated using the Kaplan–Meier method. During 2004–2015, the overall cancer incidence among children and young adolescents was similar in both countries. Incidence of neuroblastoma was significantly higher in Belgian children (2010–2015: SRR = 1.3, 95% CI 1.0–1.6). Five‐year survival of all malignant cancers was comparable in 2010–2015, exceeding 80% in both age groups. Remarkable differences in survival existed in children for malignant central nervous system (CNS) tumors in 2004–2009 (BE = 62%, NL = 45%), for acute myeloid leukemia (BE = 68%, NL = 78%) and rhabdomyosarcomas (BE = 60%, NL = 79%) in 2010–2015, and for neuroblastoma in both periods (2004–2009: BE = 76%, NL = 64%; 2010–2015: BE = 82%, NL = 64%). Overall cancer mortality in children decreased by approximately 3 percent‐points annually in both countries, but was slightly lower in Belgium in 2004–2009 (SRR = 0.9, 95% CI 0.7–1.0). Despite differences for specific cancer types, overall cancer incidence, survival, and mortality were comparable between Dutch and Belgian children and young adolescents in 2010–2015. Variability in screening, diagnosis, and registration practices probably explains the observed differences in incidence and survival of neuroblastoma and malignant CNS tumors. [ABSTRACT FROM AUTHOR]