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Background: Neuroblastoma (NB) is one of the most frequent parenchymal tumors among children, with a high degree of heterogeneity and wide variation in clinical presentation. Despite significant therapeutic advances in recent years, long-term survival in high-risk patients remains low, emphasizing the urgent need to find new biomarkers and construct reliable prognostic models. Methods: In this study, data from neuroblastoma samples in the ArrayExpress database were utilized to identify key gene modules and pivotal genes associated with NB prognosis by weighted gene co-expression network analysis (WGCNA). The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional enrichment analysis was performed using the DAVID database. Based on these hub genes, survival prognosis models were constructed and validated on an independent validation set in the Gene Expression Omnibus (GEO) database. Differences in biological functions and immune microenvironments and the sensitivity to pharmacological and immunotherapeutic treatments of patients in the high- and low-risk groups were examined by gene set enrichment analysis (GSEA) and immune infiltration analysis. Results: WGCNA identified 14 gene modules and screened the module with the highest relevance to the International Neuroblastoma Staging System (INSS), containing 60 pivotal genes. GO and KEGG analyses demonstrated that these pivotal genes were mainly implicated in biological processes and signaling pathways including DNA replication, cell division, mitotic cell cycle, and cell cycle. Based on Lasso regression and COX regression analysis, a prognostic model containing DHFR, GMPS and E2F3 was constructed, and the RiskScore was significantly correlated with the 1-, 3- and 5-year survival of the patients. GSEA and immune infiltration analyses revealed significant differences in the levels of cell cycle-related pathways and immune cell infiltration between the high and low RiskScore groups. In particular, patients in the high-risk group are less likely to benefit from immunotherapy and may be better suited for treatment with drugs such as Oxaliplatin and Alpelisib. Conclusion: This research systematically identified biomarkers related to NB prognosis and developed a reliable prognostic model applying WGCNA and multiple bioinformatics methods. The model has important application value in predicting patients' prognosis, evaluating drug sensitivity and immunotherapy effect, and provides new ideas and directions for precise treatment of neuroblastoma. [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]

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Background: Neuroblastoma is the most common extracranial solid tumor in children and accounts for 15% of pediatric cancer related deaths. Targeting neuroblastoma with immunotherapies has proven challenging due to a paucity of immune cells in the tumor microenvironment and the release of immunosuppressive cytokines by neuroblastoma tumor cells. We hypothesized that combining an oncolytic Herpes Simplex Virus (oHSV) with natural killer (NK) cells might overcome these barriers and incite tumor cell death. Methods: We utilized MYCN amplified and non-amplified neuroblastoma cell lines, the IL-12 expressing oHSV, M002, and the human NK cell line, NK-92 MI. We assessed the cytotoxicity of NK cells against neuroblastoma with and without M002 infection, the effects of M002 on NK cell priming, and the impact of M002 and priming on the migratory capacity and CD107a expression of NK cells. To test clinical applicability, we then investigated the effects of M002 and NK cells on neuroblastoma in vivo. Results: NK cells were more attracted to neuroblastoma cells that were infected with M002. There was an increase in neuroblastoma cell death with the combination treatment of M002 and NK cells both in vitro and in vivo. Priming the NK cells enhanced their cytotoxicity, migratory capacity and CD107a expression. Conclusions: To the best of our knowledge, these investigations are the first to demonstrate the effects of an oncolytic virus combined with self-maintaining NK cells in neuroblastoma and the priming effect of neuroblastoma on NK cells. The current studies provide a deeper understanding of the relation between NK cells and neuroblastoma and these data suggest that oHSV increases NK cell cytotoxicity towards neuroblastoma. [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]

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]

Neuroblastoma (NB) is the most common and deadliest extracranial solid tumor in children. Targeting tumor-associated macrophages (TAMs) is a strategy for attenuating tumor-promoting states. The crosstalk between cancer cells and TAMs plays a pivotal role in mediating tumor progression in NB. The overexpression of Hexokinase-3 (HK3), a pivotal enzyme in glucose metabolism, has been associated with poor prognosis in NB patients. Furthermore, it correlates with the infiltration of M2-like macrophages within NB tumors, indicating its significant involvement in tumor progression. Therefore, HK3 not only directly regulates the malignant biological behaviors of tumor cells, such as proliferation, migration, and invasion, but also recruits and polarizes M2-like macrophages through the PI3K/AKT-CXCL14 axis in neuroblastoma. The secretion of lactate and histone lactylation alterations within tumor cells accompanies this interaction. Additionally, elevated expression of HK3 in M2-TAMs was found at the same time. Modulating HK3 within M2-TAMs alters the biological behavior of tumor cells, as demonstrated by our in vitro studies. This study highlights the pivotal role of HK3 in the progression of NB malignancy and its intricate regulatory network with M2-TAMs. It establishes HK3 as a promising dual-functional biomarker and therapeutic target in combating neuroblastoma. [ABSTRACT FROM AUTHOR]

Background: Neuroblastoma (NB), characterized by its marked heterogeneity, is the most common extracranial solid tumor in children. The status and functionality of mitochondria are crucial in regulating NB cell behavior. While the significance of mitochondria-related genes (MRGs) in NB is still missing in key knowledge. Materials and methods: This study leverages consensus clustering and machine learning algorithms to construct and validate an MRGs-related signature in NB. Single-cell data analysis and experimental validation were employed to characterize the pivotal role of FEN1 within NB cells. Results: MRGs facilitated the classification of NB patients into 2 distinct clusters with considerable differences. The constructed MRGs-related signature and its quantitative indicators, mtScore and mtRisk, effectively characterize the MRGsrelated patient clusters. Notably, the MRGs-related signature outperformed MYCN in predicting NB patient prognosis and was adept at representing the tumor microenvironment (TME), tumor cell stemness, and sensitivity to the chemotherapeutic agents Cisplatin, Topotecan, and Irinotecan. FEN1, identified as the most contributory gene within the MRGs-related signature, was found to play a crucial role in the communication between NB cells and the TME, and in the developmental trajectory of NB cells. Experimental validations confirmed FEN1's significant influence on NB cell proliferation, apoptosis, cell cycle, and invasiveness. Conclusion: The MRGs-related signature developed in this study offers a novel predictive tool for assessing NB patient prognosis, immune infiltration, stemness, and chemotherapeutic sensitivity. Our findings unveil the critical function of FEN1 in NB, suggesting its potential as a therapeutic target. [ABSTRACT FROM AUTHOR]

The evolutionarily conserved Wnt signaling has a significant and diverse role in maintaining cell homeostasis and tissue maintenance. It is necessary in the regulation of crucial biological functions such as embryonal development, proliferation, differentiation, cell fate, and stem cell pluripotency. The deregulation of Wnt/β-catenin signaling often leads to various diseases, including cancer and non-cancer diseases. The role of Wnt/β-catenin signaling in adult tumors has been extensively studied in literature. Although the Wnt signaling pathway has been well explored and recognized to play a role in the initiation and progression of cancer, there is still a lack of understanding on how it affects pediatric tumors. This review discusses the recent developments of this signaling pathway in pediatric tumors. We also focus on understanding how different types of variations in Wnt signaling pathway contribute to cancer development and provide an insight of tissue specific mutations that lead to clinical progression of these tumors. [ABSTRACT FROM AUTHOR]

Simple Summary: Survival for many pediatric cancers has improved over recent decades. However, for pediatric patients with solid tumors that fail to respond to standard therapies, or relapse after initial response, outcomes generally remain poor, indicating a need for novel and improved treatments. Many cancers have an impaired ability to repair DNA damage, which in excess can become toxic to cells. As such, one potential approach for these challenging cancers is to target the DNA damage repair pathways of cancer cells, with the goal of inducing a lethal amount of DNA damage. This article reviews the current research efforts into targeting DNA damage repair pathways in pediatric extracranial solid tumors. It reviews the biology of DNA damage repair pathways, the biology of several extracranial pediatric cancers, the preclinical research investigating targeting the DNA damage repair in pediatric cancers, and the clinical trials using these agents in patients. This article also reviews the ability to harness a patient's immune system to kill cancer cells, and the research that has been done investigating ways in which DNA damage can activate the anti-tumor immune response. DNA damage is fundamental to tumorigenesis, and the inability to repair DNA damage is a hallmark of many human cancers. DNA is repaired via the DNA damage repair (DDR) apparatus, which includes five major pathways. DDR deficiencies in cancers give rise to potential therapeutic targets, as cancers harboring DDR deficiencies become increasingly dependent on alternative DDR pathways for survival. In this review, we summarize the DDR apparatus, and examine the current state of research efforts focused on identifying vulnerabilities in DDR pathways that can be therapeutically exploited in pediatric extracranial solid tumors. We assess the potential for synergistic combinations of different DDR inhibitors as well as combinations of DDR inhibitors with chemotherapy. Lastly, we discuss the immunomodulatory implications of targeting DDR pathways and the potential for using DDR inhibitors to enhance tumor immunogenicity, with the goal of improving the response to immune checkpoint blockade in pediatric solid tumors. We review the ongoing and future research into DDR in pediatric tumors and the subsequent pediatric clinical trials that will be critical to further elucidate the efficacy of the approaches targeting DDR. [ABSTRACT FROM AUTHOR]

Neuroblastoma (NB) is the most commonly diagnosed extracranial solid tumor in children, accounting for 15% of all childhood cancer deaths. Although the 5-year survival rate of patients with a high-risk disease has increased in recent decades, NB remains a challenge in pediatric oncology, and the identification of novel potential therapeutic targets and agents is an urgent clinical need. The RNA-binding protein LIN28B has been identified as an oncogene in NB and is associated with a poor prognosis. Given that LIN28B acts by negatively regulating the biogenesis of the tumor suppressor let-7 miRNAs, we reasoned that selective interference with the LIN28B/let-7 miRNA interaction would increase let-7 miRNA levels, ultimately leading to reduced NB aggressiveness. Here, we selected (−)-epigallocatechin 3-gallate (EGCG) out of 4959 molecules screened as the molecule with the best inhibitory activity on LIN28B/let-7 miRNA interaction and showed that treatment with PLC/PLGA-PEG nanoparticles containing EGCG (EGCG-NPs) led to an increase in mature let-7 miRNAs and a consequent inhibition of NB cell growth. In addition, EGCG-NP pretreatment reduced the tumorigenic potential of NB cells in vivo. These experiments suggest that the LIN28B/let-7 miRNA axis is a good therapeutic target in NB and that EGCG, which can interfere with this interaction, deserves further preclinical evaluation. [ABSTRACT FROM AUTHOR]

Neuroblastoma is the most common extracranial solid tumor in children. It is a highly heterogeneous tumor consisting of different subcellular types and genetic abnormalities. Literature data confirm the biological and clinical complexity of this cancer, which requires a wider availability of gene targets for the implementation of personalized therapy. This paper presents a study of neuroblastoma samples from primary tumors of untreated patients. The focus of this analysis is to evaluate the impact that the inflammatory process may have on the pathogenesis of neuroblastoma. Eighty-eight gene profiles were selected and analyzed using a non-negative matrix factorization framework to extract a subset of genes relevant to the identification of an inflammatory phenotype, whose targets (PIK3CG, NFATC2, PIK3R2, VAV1, RAC2, COL6A2, COL6A3, COL12A1, COL14A1, ITGAL, ITGB7, FOS, PTGS2, PTPRC, ITPR3) allow further investigation. Based on the genetic signals automatically derived from the data used, neuroblastoma could be classified according to stage rather than as a "cold" or "poorly immunogenic" tumor. [ABSTRACT FROM AUTHOR]

Solid abdominal malignancies are not frequent in children, however, they present with serious challenges for all of the experts dealing with the problem, and paediatric surgeons in particular. This review deals with the surgical approaches to most frequent abdominal tumors in children -- neuroblastoma, hepatoblastoma and pancreatic tumors. Different aspects in the surgical treatment of tumors of the retroperitoneum, liver and pancreas are discussed with an emphasis on the differences in surgical approaches between children and adults. [ABSTRACT FROM AUTHOR]

Background: Neuroblastoma is one of the most common extracranial malignant solid tumors in children. AlkB homolog 5 (ALKBH5) is an RNA N6‐methyladenosine (m6A) demethylase that plays a critical role in tumorigenesis and development. We assessed the association between single nucleotide polymorphisms (SNPs) in ALKBH5 and the risk of neuroblastoma in a case‐control study including 402 patients and 473 non‐cancer controls. Methods: Genotyping was determined by the TaqMan method. The association between ALKBH5 polymorphisms (rs1378602 and rs8400) and the risk of neuroblastoma was evaluated using the odds ratio (OR) and 95% confidence interval (CI). Results: We found no strong association of ALKBH5 rs1378602 and rs8400 with neuroblastoma risk. Further stratification analysis by age, sex, primary site, and clinical stage showed that the rs1378602 AG/AA genotype was associated with a lower risk of neuroblastoma in males (adjusted OR = 0.58, 95% CI = 0.35–0.97, p = 0.036) and children with retroperitoneal neuroblastoma (adjusted OR = 0.58, 95% CI = 0.34–0.98, p = 0.040). Conclusions: ALKBH5 SNPs do not seem to be associated with neuroblastoma risk. More studies are required to confirm this negative result and reveal the relationship between gene polymorphisms of the m6A modifier ALKBH5 and neuroblastoma. [ABSTRACT FROM AUTHOR]

Simple Summary: The aim of this study was to analyze the safety and effectiveness of ICIs used in 42 pediatric patients with various types of highly advanced malignancies. Good outcomes were achieved in patients with malignant cutaneous melanoma or Hodgkin lymphoma. Age > 14 years and good performance status were favorable prognostic factors. Background/aim: The role of immune checkpoint inhibitors (ICIs; anti-PD1) in the treatment of childhood cancers is still evolving. The aim of this nationwide retrospective study was to assess the safety and effectiveness of ICIs used in a group of 42 patients, with a median age of 13.6 years, with various types of advanced malignancies treated in pediatric oncology centers in Poland between 2015 and 2023. Results: The indications for treatment with anti-PD1 were as follows: Hodgkin lymphoma (11); malignant skin melanoma (9); neuroblastoma (8); and other malignancies (14). At the end of follow-up, complete remission (CR) was observed in 37.7% (15/42) of children and disease stabilization in 9.5% (4/42), with a mean survival 3.6 (95% CI = 2.6–4.6) years. The best survival (OS = 1.0) was observed in the group of patients with Hodgkin lymphoma. For malignant melanoma of the skin, neuroblastoma, and other rare malignancies, the estimated 3-year OS values were, respectively, 0.78, 0.33, and 0.25 (p = 0.002). The best progression-free survival value (0.78) was observed in the group with malignant melanoma. Significantly better effects of immunotherapy were confirmed in patients ≥ 14 years of age and good overall performance ECOG status. Severe adverse events were observed in 30.9% (13/42) patients. [ABSTRACT FROM AUTHOR]

Aims: Neuroblastoma (NB) is the most common extracranial solid tumor in children, with a 5‐year survival rate of <50% in high‐risk patients. MYCN amplification is an important factor that influences the survival rate of high‐risk patients. Our results indicated MYCN regulates the expression of SESN1. Therefore, this study aimed to investigate the role and mechanisms of SESN1 in NB. Methods: siRNAs or overexpression plasmids were used to change MYCN, SESN1, or MyD88's expression. The role of SESN1 in NB cell proliferation, migration, and invasion was elucidated. Xenograft mice models were built to evaluate SESN1's effect in vivo. The correlation between SESN1 expression and clinicopathological data of patients with NB was analyzed. RNA‐Seq was done to explore SESN1's downstream targets. Results: SESN1 was regulated by MYCN in NB cells. Knockdown SESN1 promoted NB cell proliferation, cell migration, and cell invasion, and overexpressing SESN1 had opposite functions. Knockdown SESN1 promoted tumor growth and shortened tumor‐bearing mice survival time. Low expression of SESN1 had a positive correlation with poor prognosis in patients with NB. RNA‐Seq showed that Toll‐like receptor (TLR) signaling pathway, and PD‐L1 expression and PD‐1 checkpoint pathway in cancer were potential downstream targets of SESN1. Knockdown MyD88 or TLRs inhibitor HCQ reversed the effect of knockdown SESN1 in NB cells. High expression of SESN1 was significantly associated with a higher immune score and indicated an active immune microenvironment for patients with NB. Conclusions: SESN1 functions as a new tumor suppressor gene via TLR signaling pathway in NB. [ABSTRACT FROM AUTHOR]

Aim Opsoclonus–myoclonus–ataxia syndrome (OMAS) is a rare autoimmune disorder. Approximately half of the cases are associated with neuroblastoma in children. This study's aim is to review management of our cases with OMAS-associated neuroblastoma for treatment approach as well as long-term follow-up. Methods Age at onset of symptoms and tumor diagnosis, tumor location, histopathology, stage, chemotherapy, OMAS protocol, surgery, and follow-up period were evaluated retrospectively in six patients between 2007 and 2022. Results Mean age of onset of OMAS findings was 13.5 months and mean age at tumor diagnosis was 15.1 months. Tumor was located at thorax in three patients and surrenal in others. Four patients underwent primary surgery. Histopathological diagnosis was ganglioneuroblastoma in three, neuroblastoma in two, and undifferentiated neuroblastoma in one. One patient was considered as stage 1 and rest of them as stage 2. Chemotherapy was provided in five cases. The OMAS protocol was applied to five patients. Our protocol is intravenous immunoglobulin (IVIG) 1 g/kg/d for 2 consecutive days once a month and dexamethasone for 5 days (20 mg/m2 /d for 1–2 days, 10 mg/m2 /d for 3–4 days, and 5 mg/m2 /d for the fifth day) once a month, alternatively by 2-week intervals. Patients were followed up for a mean of 8.1 years. Neuropsychiatric sequelae were detected in two patients. Conclusion In tumor-related cases, alternating use of corticosteroid and IVIG for suppression of autoimmunity as the OMAS protocol, total excision of the tumor as soon as possible, and chemotherapeutics in selected patients seem to be related to resolution of acute problems, long-term sequelae, and severity. [ABSTRACT FROM AUTHOR]

Objective: To investigate the long-term changes in nutritional status in children with solid tumors during treatment and the relationship between nutritional status and clinical outcomes. Methods: This study was a retrospective medical records review of data from children who were diagnosed with solid tumors and followed up for more than 3months from January 2016 to December 2021 in China. Patient demographics and clinical information, including nutritional status, parenteral nutrition use, intensive care unit (ICU) transfers, infection during hospitalization, hospitalization frequency, length of stay, hospitalization costs and antibiotic costs, were collected to analyze the nutritional status of children with different types of solid tumors, the dynamic changes in nutritional status during treatment, and the relationship between nutritional status and clinical outcomes. Results: Among the 764 patients (383 males (50.1%); 381 females (49.9%); mean age: 2.58 years), 41.6% of the solid tumors were neuroblastomas, 17.1% were hepatoblastomas, and Wilms tumors as the third most common solid tumors (8.9%). The median follow-up duration was 6months (range: 3–40months). At diagnosis, the proportion of children who were undernourished (underweight and wasting) versus overweight or obese were 26.71% versus 5.21% (25.86% vs. 2.89% in the third month; 29.77% vs. 2.28% in the sixth month; 24.77% vs. 3.27% in the 12th month). The body mass index Z scores decreased from the initial values after the first month (−0.56 (−1.47, 0.23) vs. −0.44 (−1.29, 0.41)) but improved later and decreased again at 6months. The children in the undernutrition group had longer hospital stays (p<0.001), higher hospitalization costs (p<0.001), higher antibiotic costs (p<0.001), a higher risk of neutropenia (OR=4.781 (95% CI: 1.571–14.553), p=0.006), and a higher risk of ICU transfers (OR=1.498 (95% CI: 1.010–2.224), p=0.044). No significant differences in those associations by malnutrition and infection, ICU duration, or length of parenteral nutrition were observed. Conclusion: There is a considerable prevalence of malnutrition in children with solid tumors. Malnutrition is related to adverse clinical outcomes and increases in total hospital expenses and antibiotic costs. [ABSTRACT FROM AUTHOR]

Neuroblastoma is the most common extracranial solid tumor in children. The purpose of the present study is to detect the prognostic role and potential therapeutic efficacy of the T lymphoma invasion and metastasis 1 (Tiam1) in neuroblastoma. The overexpression of Tiam1 protein is frequently observed in neuroblastoma. Tiam1 expression is closely associated with adverse prognosis of neuroblastoma and risk group classification. Knockdown of TIAM1 by lentivirus expressing short hairpin RNA against TIAM1 (sh-TIAM1) inhibited the proliferation, invasion and cell-cycle progression, and promoted apoptosis of the neuroblastoma cell lines SH-SY5Y and SK-N-AS. Additionally, downregulation of the differentiation-related protein expression and decreased Rac1 expression was observed in the sh-TIAM1-transfected SH-SY5Y cells. In vivo, nude mice bearing TIAM1 knockdown SH-SY5Y cells showed improved overall survival and tumor growth suppression. The results demonstrate that inhibition of Tiam1 expression is a potential strategy for targeted therapy in neuroblastoma. [ABSTRACT FROM AUTHOR]

Introduction: Our aim was to evaluate the lag time between the first onset of symptoms and the final diag-nosis in children with lymphoma and solid tumors. Materials and Methods: This study was carried out by retrospectively scanning the records of 759 patients admitted to the Pediatric Oncology Department of Uludağ University between January 2005 and December 2014. Demographic data of the patients, first complaints, the time to apply to a physician after the first complaint, the first application center were determined, lag time to the center that established the oncologic diagnosis, the final diagnosis, time to diagnosis at the last center, total time elapsed from the first onset of complaints to the establishment of diagnosis and the last health state of the patient were obtained from the hospital records. Results: The patients diagnosed with cancer firstly applied to a physician median 15 days. The physicianwho saw the patient for the first time referred to him/her to the center that established the final diagnosis after a median of 8 days. The median time to final diagnosis was 10 days minimum 1 days and totaly 55 days at the last center. In patients whose first symptom is fever, abdominal pain and seizures and In patients with a definitive diagnosis of germ cell tumor, neuroblastoma, kidney tumor and liver tumor, the time to the first admission was shorter than 15 days. In patients whose first symptom was a headache, and abdominal mass; in patients and central nervous system (CNS), and eyes, and in patients with the final diagnosis of CNS tumor germ cell tumor and retinoblastoma, the lag times for referrals were significantly shorter than 8 days. In patients whose first symptom was headache, nausea and vomiting, fatigue-weight loss, and visual disturbances and in patients with the final diagnosis of CNS tumors and neuroendocrine tumors, the time to diagnosis was significantly shorter than 10 days. Conclusion: Delays in diagnosis are common in children with cancer. A sustained effort should be made to raise the level of awareness of childhood cancer among parents and to sensitize all physicians, especially those who treat pediatric patients infrequently, about the warning signs of the disease. [ABSTRACT FROM AUTHOR]

The article focuses on investigating pregnancy outcomes in 230 female survivors of neuroblastoma from a Nordic register-based cohort study. Topics include the similar incidence of live births before age 30 between survivors and the general population, the decreased live birth rate by age 50 among survivors, and an increased risk of abortions among survivors compared to the general population, emphasizing the need for further research on recent cases' fertility outcomes.

Introduction: Neuroblastoma (NB) is a common extracranial tumor in children and is highly heterogeneous. The factors influencing the prognosis of NB are not simple. Methods: To investigate the effect of cell senescence on the prognosis of NB and tumor immune microenvironment, 498 samples of NB patients and 307 cellular senescence-related genes were used to construct a prediction signature. Results: A signature based on six optimal candidate genes (TP53, IL-7, PDGFRA, S100B, DLL3, and TP63) was successfully constructed and proved to have good prognostic ability. Through verification, the signature had more advantages than the gene expression level alone in evaluating prognosis was found. Further T cell phenotype analysis displayed that exhausted phenotype PD-1 and senescencerelated phenotype CD244 were highly expressed in CD8+ T cell in MYCNamplified group with higher risk-score. Conclusion: A signature constructed the six MYCN-amplified differential genes and aging-related genes can be used to predict the prognosis of NB better than using each high-risk gene individually and to evaluate immunosuppressed and aging tumor microenvironment. [ABSTRACT FROM AUTHOR]

Simple Summary: Copy number abnormalities (CNAs) are frequent in neuroblastoma and used to determine treatments. Little is known about the role of structural variants (SVs) in disease progression. Optical genome mapping (OGM) uses label patterns to scan the genome which can be used to identify SVs in cancer. Currently, the detection of SVs still relies on standard cytogenetic techniques. We investigated the utility of OGM to detect SVs in neuroblastoma cell lines and tumours and compared it with standard cytogenetic techniques. OGM confirmed known CNAs and identified novel SVs of potential clinical significance. Background: Neuroblastoma is the most common extracranial solid tumour in children, accounting for 15% of paediatric cancer deaths. Multiple genetic abnormalities have been identified as prognostically significant in neuroblastoma patients. Optical genome mapping (OGM) is a novel cytogenetic technique used to detect structural variants, which has not previously been tested in neuroblastoma. We used OGM to identify copy number and structural variants (SVs) in neuroblastoma which may have been missed by standard cytogenetic techniques. Methods: Five neuroblastoma cell lines (SH-SY5Y, NBLW, GI-ME-N, NB1691 and SK-N-BE2(C)) and two neuroblastoma tumours were analysed using OGM with the Bionano Saphyr® instrument. The results were analysed using Bionano Access software and compared to previous genetic analyses including G-band karyotyping, FISH (fluorescent in situ hybridisation), single-nucleotide polymorphism (SNP) array and RNA fusion panels for cell lines, and SNP arrays and whole genome sequencing (WGS) for tumours. Results: OGM detected copy number abnormalities found using previous methods and provided estimates for absolute copy numbers of amplified genes. OGM identified novel SVs, including fusion genes in two cell lines of potential clinical significance. Conclusions: OGM can reliably detect clinically significant structural and copy number variations in a single test. OGM may prove to be more time- and cost-effective than current standard cytogenetic techniques for neuroblastoma. [ABSTRACT FROM AUTHOR]

Neuroblastoma is the most common extracranial solid tumor in children. Patients with neuroblastoma have a poor prognosis. The development of therapy targets and the ability to predict prognosis will be enhanced through further exploration of the genetically related genes of neuroblastoma. The present investigation utilized CRISPR-Cas9 genome-wide screening based on the DepMap database to determine essential genes for neuroblastoma cells' continued survival. WGCNA analysis was used to determine the progression-related genes, and a prognostic signature was constructed. The signature gene, NCAPG, was downregulated in neuroblastoma cells to explore its impact on various cellular processes. This research used DepMap and WGCNA to pinpoint 45 progression-related essential genes for neuroblastoma. A risk signature comprising NCAPG and MAD2L1 was established. The suppression of NCAPG prevented neuroblastoma cells from proliferating, migrating, and invading. The results of flow cytometric analysis demonstrated that NCAPG inhibition caused cell cycle arrest during the G2 and S phases and the activation of apoptosis. Additionally, NCAPG downregulation activated the p53-mediated apoptotic pathway, inducing cell apoptosis. The present work showed that NCAPG knockdown reduced neuroblastoma cell progression and may serve as a basis for further investigation into diagnostic indicators and therapy targets for neuroblastoma. [ABSTRACT FROM AUTHOR]

Background: The Toronto Paediatric Cancer Stage Guidelines are a compendium of staging systems developed to facilitate collection of consistent and comparable data on stage at diagnosis for childhood cancers by cancer registries. Material and Methods: This retrospective, observational cohort study investigated changes in stagespecific incidence and survival for children diagnosed between 2000-2008 compared to 2009-2017 using the population-based Australian Childhood Cancer Registry. Information on mortality for each patient was available to 31st December 2020. Shifts in incidence by stage were evaluated using chisquare tests, and differences in stage-specific five-year observed survival for all causes of death over time were assessed using flexible parametric models. Results: Stage was assigned according to the Toronto Guidelines for 96% (n=7944) of the total study cohort (n=8292). Changes in the distribution of incidence by stage between the two diagnosis periods were observed for retinoblastoma, with stage 0 increasing from 26% to 37% of cases (p=0.02), and hepatoblastoma, with metastatic disease increasing from 22% to 39% of cases (p = 0.04). There were large gains in stage-specific survival over time for stage IV rhabdomyosarcoma (five-year adjusted mortality hazard ratio for 2009-2017 compared to 2000-2008 of 0.38, 95% CI 0.19-0.77; p=0.01), stage M3 for medulloblastoma (HR = 0.41, 95% CI 0.21-0.79; p=0.01) and metastatic neuroblastoma excluding stage MS (HR = 0.61, 95% CI 0.44-0.84; p<0.01). Conclusion: These results indicate that improvements in childhood cancer survival in Australia are most likely due to refined management rather than changes in stage at diagnosis, particularly for metastatic solid tumours. Wide international uptake of the Toronto Guidelines will allow comprehensive evaluation of differences in survival between countries. Abbreviations: ACCR: Australian Childhood Cancer Registry; CI: confidence interval; CNS: central nervous system; HR: hazard ratio; ICCC-3: International Classification of Childhood Cancers, 3rd edition; RCC: renal cell carcinoma; TNM: tumour-node-metastasis staging system. [ABSTRACT FROM AUTHOR]

Neuroblastoma is one of the most common solid tumors in children younger than 1 year of age, with poor prognosis and survival rates. Therefore, novel molecular targets and therapeutic strategies are needed to prolong patient survival. For this purpose, we investigated the effects of rottlerin and genistein separately and in combination on neuroblastoma cells (SH-SY5Y, Kelly). First, the effects of rottlerin and genistein were investigated on cell proliferation. Different rottlerin (1–50 µM) and genistein (5–150 µM) doses were used as experimental groups compared to the control (DMSO/vehicle). The IC50 dose was found to be 5 µM for rottlerin and 30 µM for genistein (P < 0.0001). Other analyses, such as colony formation assays, annexin V/propidium iodide staining, matrigel invasion assays, and Western blot analysis, were performed with these doses and their combinations. To assess statistical significance, statistical analysis was conducted using the one-way ANOVA with the post hoc Tukey test. Our results showed that IC50 doses of rottlerin and genistein induced a significant reduction in cell proliferation, colony formation, and invasion in neuroblastoma cells (P < 0.0001). The combination of these doses increased the levels of inhibition of cell proliferation and invasion while decreasing the level of apoptosis (P 0.0001). Furthermore, these agents caused G1-cell cycle arrest in these cells. Our western blot data showed that rottlerin and genistein treatments markedly inhibit elongation factor 2 kinase (EF2K) and other pro-tumorigenic, metastatic proteins in neuroblastoma cells. These agents probably showed their anti-proliferative, anti-metastatic, and pro-apoptotic effects through EF2K downregulation. Our results suggested that rottlerin and genistein have inhibitory effects on cancer cell proliferation, invasion, and cell cycle and induce apoptosis in both cell lines. Combined treatment with rottlerin and genistein may be a viable approach and beneficial to neuroblastoma patients as the combined effect significantly suppresses the above-mentioned pathways. [ABSTRACT FROM AUTHOR]

Nonspecific gastrointestinal symptoms remain a problem for pediatricians because, out of a thousand trivial cases, there are rare diseases that require in-depth diagnostics and extensive knowledge to identify them. These complaints may be caused by a neoplastic process. We present the case of a 5-year-old boy whose diagnostic pathway lasted about 3 months. He was admitted to hospital due to severe abdominal pain. Physical examination revealed a bloated, hard, and painful abdomen. In the standing X-ray, the features of intestinal obstruction were visualized. An ultrasound examination showed a possible malignant lesion in the location of the left adrenal gland. After the surgical removal of the pathological mass and histopathological examination, the diagnosis of ganglioneuroblastoma intermixed was made. This tumor, along with neuroblastoma, ganglioneuroma, and ganglioneuroblastoma nodular, belongs to neuroblastic tumors (NTs), which originate from primitive cells of the sympathetic nervous system. NTs are quite rare, but they are still the majority of extracranial solid tumors in children, and their symptoms often appear relatively late when the neoplastic process is already advanced. The purpose of this review is to present current information about ganglioneuroblastoma, with a special emphasis on nonspecific gastrointestinal symptoms as first sign of this tumor and its diagnostics. [ABSTRACT FROM AUTHOR]

Secondary neoplasms were reported as one of the complicated complications of childhood cancer treatment. Salivary gland carcinoma is rare, and mucoepidermoid carcinoma (MEC) is the most prevalent subtype. Secondary neoplasms following neuroblastoma are not often described due to poor long‐term survival. The exact cause of these tumors in children, and adults is not clearly known, but they are often observed after head, and neck radiotherapy and mainly involve main salivary glands, especially the parotid. Hence, we report a case of MEC with telangiectasia in the salivary glands of a 20‐year‐old girl with complaint of a palatal swelling who was treated with chemotherapy (etoposide, G‐CSF, cyclophosphamide) without radiotherapy since childhood (18 months) in terms of neuroblastoma. Based on our knowledge, only three cases of MEC following neuroblastoma have been reported before, all of which involved the major salivary glands. Survivors of primary neoplasms who were treated are at risk of secondary malignant neoplasms, which usually occur at a long interval from the primary neoplasm (5–15 years), which necessitates long and close follow‐up. [ABSTRACT FROM AUTHOR]

Neuroblastoma is the most common extracranial solid tumor in children. A subgroup of high-risk patients is characterized by aberrations in the chromatin remodeller ATRX that is encoded by 35 exons. In contrast to other pediatric cancer where ATRX point mutations are most frequent, multi-exon deletions (MEDs) are the most frequent type of ATRX aberrations in neuroblastoma. 75% of these MEDs are predicted to produce in-frame fusion proteins, suggesting a potential gain-of-function effect compared to nonsense mutations. For neuroblastoma there are only a few patient-derived ATRX aberrant models. Therefore, we created isogenic ATRX aberrant models using CRISPR-Cas9 in several neuroblastoma cell lines and one tumoroid and performed total RNA-sequencing on these and the patient-derived models. Gene set enrichment analysis (GSEA) showed decreased expression of genes related to both ribosome biogenesis and several metabolic processes in our isogenic ATRX exon 2–10 MED model systems, the patient-derived MED models and in tumor data containing two patients with an ATRX exon 2–10 MED. In sharp contrast, these same processes showed an increased expression in our isogenic ATRX knock-out and exon 2–13 MED models. Our validations confirmed a role of ATRX in the regulation of ribosome homeostasis. The two distinct molecular expression patterns within ATRX aberrant neuroblastomas that we identified imply that there might be a need for distinct treatment regimens. [ABSTRACT FROM AUTHOR]

Background: Neuroblastoma is one of the common extracranial tumors in children (infants to 2 years), accounting for 8 ~ 10% of all malignant tumors. Few special drugs have been used for clinical treatment currently. Results: In this work, herbal extract ginsenosides were used to synthesize fluorescent ginsenosides carbon nanodots via a one-step hydrothermal method. At a low cocultured concentration (50 µg·mL− 1) of ginsenosides carbon nanodots, the inhibition rate and apoptosis rate of SH-SY5Y cells reached ~ 45.00% and ~ 59.66%. The in vivo experiments showed tumor volume and weight of mice in ginsenosides carbon nanodots group were ~ 49.81% and ~ 34.14% to mice in model group. Since ginsenosides were used as sole reactant, ginsenosides carbon nanodots showed low toxicity and good animal response. Conclusion: Low-cost ginsenosides carbon nanodots as a new type of nanomedicine with good curative effect and little toxicity show application prospects for clinical treatment of neuroblastoma. It is proposed a new design for nanomedicine based on bioactive carbon nanodots, which used natural bioactive molecules as sole source. [ABSTRACT FROM AUTHOR]

Simple Summary: Despite being in use for almost 50 years, monoclonal antibodies face limitations in their implementation in clinical practice, particularly in pediatrics and pediatric cancer. Although technological advancements and research into new therapeutic targets have led to the development of sophisticated and effective molecules, translational barriers still exist. Integrating monoclonal antibodies (mAbs) into current treatment protocols and ensuring accessibility for all children with cancer globally remains a challenge. This review examines the biological, clinical, economic, and social limitations hindering the global implementation of mAbs in pediatric cancer, with a particular focus on anti-GD2 mAbs. Monoclonal antibodies (mAbs), as the name implies, are clonal antibodies that bind to the same antigen. mAbs are broadly used as diagnostic or therapeutic tools for neoplasms, autoimmune diseases, allergic conditions, and infections. Although most mAbs are approved for treating adult cancers, few are applicable to childhood malignancies, limited mostly to hematological cancers. As for solid tumors, only anti-disialoganglioside (GD2) mAbs are approved specifically for neuroblastoma. Inequities of drug access have continued, affecting most therapeutic mAbs globally. To understand these challenges, a deeper dive into the complex transition from basic research to the clinic, or between marketing and regulatory agencies, is timely. This review focuses on current mAbs approved or under investigation in pediatric cancer, with special attention on solid tumors and anti-GD2 mAbs, and the hurdles that limit their broad global access. Beyond understanding the mechanisms of drug resistance, the continual discovery of next generation drugs safer for children and easier to administer, the discovery of predictive biomarkers to avoid futility should ease the acceptance by patient, health care professionals and regulatory agencies, in order to expand clinical utility. With a better integration into the multimodal treatment for each disease, protocols that align with the regional clinical practice should also improve acceptance and cost-effectiveness. Communication and collaboration between academic institutions, pharmaceutical companies, and regulatory agencies should help to ensure accessible, affordable, and sustainable health care for all. [ABSTRACT FROM AUTHOR]

Simple Summary: Children affected by high-risk tumors receive aggressive standard therapies that significantly improve their survival. Despite this, they have a low quality of life, suffer from life-threatening side effects, and a still-relevant number of them show resistance to therapy and develop fatal relapses. Immunotherapy showed exciting results and is now a promising treatment for cancer patients; targeting B7-H3 fits this scenario. B7-H3 is expressed by many cancers, promotes their growth, and blocks the antitumor responses mediated by cells of the immune system. Promising preclinical results were obtained using antibodies or genetically engineered T lymphocytes recognizing B7-H3 and, currently, different clinical trials are ongoing. Hopefully, the targeting of B7-H3 will help cure adult and pediatric cancer patients. B7-H3 is a 4Ig transmembrane protein that emerged as a tumor-associated antigen in neuroblastoma. It belongs to the B7 family, shows an immunoregulatory role toward NK and T cells, and, therefore, has been included in the growing family of immune checkpoints. Besides neuroblastoma, B7-H3 is expressed by many pediatric cancers including tumors of the central nervous system, sarcomas, and acute myeloid leukemia. In children, particularly those affected by solid tumors, the therapeutic protocols are aggressive and cause important life-threatening side effects. Moreover, despite the improved survival observed in the last decade, a relevant number of patients show therapy resistance and fatal relapses. Immunotherapy represents a new frontier in the cure of cancer patients and the targeting of tumor antigens or immune checkpoints blockade showed exciting results in adults. In this encouraging scenario, researchers and clinicians are exploring the possibility to use immunotherapeutics targeting B7-H3; these include mAbs and chimeric antigen receptor T-cells (CAR-T). These tools are rapidly evolving to improve the efficacy and decrease the unwanted side effects; drug-conjugated mAbs, bi–tri-specific mAbs or CAR-T, and, very recently, NK cell engagers (NKCE), tetra-specific molecules engaging a tumor-associated antigen and NK cells, have been generated. Preclinical data are promising, and clinical trials are ongoing. Hopefully, the B7-H3 targeting will provide important benefits to cancer patients. [ABSTRACT FROM AUTHOR]

Neuroblastoma (NB) is one of the most common extracranial solid tumors in children. MYCN gene amplification is highly associated with poor prognosis in high-risk NB patients. In non-MYCN-amplified high-risk NB patients, the expression of c-MYC (MYCC) and its target genes is highly elevated. USP28 as a deubiquitinase is known to regulate the stability of MYCC. We show here USP28 also regulates the stability of MYCN. Genetic depletion or pharmacologic inhibition of the deubiquitinase strongly destabilizes MYCN and stops the growth of NB cells that overexpress MYCN. In addition, MYCC could be similarly destabilized in non-MYCN NB cells by compromising USP28 function. Our results strongly suggest USP28 as a therapeutic target for NB with or without MYCN amplification/overexpression. [ABSTRACT FROM AUTHOR]

Background: To identify radiomic features that can predict the pathological type of neuroblastic tumor in children. Methods: Data on neuroblastic tumors in 104 children were retrospectively analyzed. There were 14 cases of ganglioneuroma, 24 cases of ganglioneuroblastoma, and 65 cases of neuroblastoma. Stratified sampling was used to randomly allocate the cases into the training and validation sets in a ratio of 3:1. The maximum relevance–minimum redundancy algorithm was used to identify the top 10 of two clinical features and 851 radiomic features in portal venous–phase contrast-enhanced computed tomography images. Least absolute shrinkage and selection operator regression was used to classify tumors in two binary steps: first as ganglioneuroma compared to the other two types, then as ganglioneuroblastoma compared to neuroblastoma. Results: Based on 10 clinical-radiomic features, the classifier identified ganglioneuroma compared to the other two tumor types in the validation dataset with sensitivity of 100.0%, specificity of 81.8%, and an area under the receiver operating characteristic curve (AUC) of 0.875. The classifier identified ganglioneuroblastoma versus neuroblastoma with a sensitivity of 83.3%, a specificity of 87.5%, and an AUC of 0.854. The overall accuracy of the classifier across all three types of tumors was 80.8%. Conclusion: Radiomic features can help predict the pathological type of neuroblastic tumors in children. [ABSTRACT FROM AUTHOR]

One of the most frequent solid tumors in children is neuroblastoma, which has a variety of clinical behaviors that are mostly influenced by the biology of the tumor. Unique characteristics of neuroblastoma includes its early age of onset, its propensity for spontaneous tumor regression in newborns, and its high prevalence of metastatic disease at diagnosis in individuals older than 1 year of age. Immunotherapeutic techniques have been added to the previously enlisted chemotherapeutic treatments as therapeutic choices. A groundbreaking new treatment for hematological malignancies is adoptive cell therapy, specifically chimeric antigen receptor (CAR) T cell therapy. However, due to the immunosuppressive nature of the tumor microenvironment (TME) of neuroblastoma tumor, this treatment approach faces difficulties. Numerous tumor-associated genes and antigens, including the MYCN proto-oncogene (MYCN) and disialoganglioside (GD2) surface antigen, have been found by the molecular analysis of neuroblastoma cells. The MYCN gene and GD2 are two of the most useful immunotherapy findings for neuroblastoma. The tumor cells devise numerous methods to evade immune identification or modify the activity of immune cells. In addition to addressing the difficulties and potential advancements of immunotherapies for neuroblastoma, this review attempts to identify important immunological actors and biological pathways involved in the dynamic interaction between the TME and immune system. [ABSTRACT FROM AUTHOR]

Simple Summary: Specific recurrent segmental aberrations (SCA) have been associated with poor survival in neuroblastoma (NB). The effect of many other not recurrent SCA has not been clarified yet. Here we examined the role of the loss of chromosome 10q in a cohort of 260 NB primary tumors, observing a lower survival rate for the patients expressing this rare SCA. We identified a cluster of 75 genes in the long arm of chromosome 10, whose deletion was associated with poorer survival. Six genes, and in particular CCSER2, appeared to be good candidates to play a role as tumor suppressor genes in NB and possible targets for future therapeutic interventions. Neuroblastoma (NB) is a tumor affecting the peripheral sympathetic nervous system that substantially contributes to childhood cancer mortality. Despite recent advances in understanding the complexity of NB, the mechanisms determining its progression are still largely unknown. Some recurrent segmental chromosome aberrations (SCA) have been associated with poor survival. However, the prognostic role of most SCA has not yet been investigated. We examined a cohort of 260 NB primary tumors at disease onset for the loss of chromosome 10q, by array-comparative genomic hybridization (a-CGH) and Single Nucleotide Polymorphism (SNP) array and we found that 26 showed 10q loss, while the others 234 displayed different SCA. We observed a lower event-free survival for NB patients displaying 10q loss compared to patients with tumors carrying other SCA. Furthermore, analyzing the region of 10q loss, we identified a cluster of 75 deleted genes associated with poorer outcome. Low expression of six of these genes, above all CCSER2, was significantly correlated to worse survival using in silico data from 786 NB patients. These potential tumor suppressor genes can be partly responsible for the poor prognosis of NB patients with 10q loss. [ABSTRACT FROM AUTHOR]

Simple Summary: Pediatric malignancies rarely occur, with 12,000–15,000 cases per year in the United States. Approximately 10% of pediatric cancers are thought to be secondary to germline alterations in cancer-predisposing genes based on numerous germline genomic analyses. CHEK2 germline loss-of-function variants have been reported in certain pediatric cancer patient cohorts, including neuroblastomas, non-Hodgkin lymphomas, thyroid cancer, melanomas, sarcomas, and brain tumors. However, a paucity of data exists surrounding clinical phenotypes and outcomes. In this study, we present our single-institution experience regarding six children and adolescents with CHEK2 germline alterations and cancer or cancer-predisposing conditions, including their clinical presentations and outcomes. We also review the current body of data regarding CHEK2 germline alterations in the pediatric cancer population and future challenges with studies on these alterations. Background: Approximately 10% of pediatric malignancies are secondary to germline alterations in cancer-predisposing genes. Checkpoint kinase 2 (CHEK2) germline loss-of-function variants have been reported in pediatric cancer patients, but clinical phenotypes and outcomes are poorly described. We present our single-institution experience of pediatric oncology patients with CHEK2 germline alterations, including clinical presentations and outcomes. Methods: Pediatric oncology patients with CHEK2 germline alterations were identified among those assessed by clinical or translational research at the Institute for Genomic Medicine at Nationwide Children's Hospital. A chart review of disease course was conducted on identified patients. Results: We identified 6 patients with germline CHEK2 variants from a cohort of 300 individuals, including 1 patient with concurrent presentation of Burkitt lymphoma and neuroblastoma, 3 patients with brain tumors, 1 patient with Ewing sarcoma, and 1 patient with myelodysplastic syndrome. Three patients had a family history of malignancies. Four patients were in remission; one was undergoing treatment; one patient had developed treatment-related meningiomas. We review prior data regarding CHEK2 variants in this population, challenges associated with variant interpretation, and genetic counseling for individuals with CHEK2 variants. Conclusions: CHEK2 germline loss-of-function alterations occur in patients with a variety of pediatric tumors. Larger multicenter studies will improve our understanding of the incidence, phenotype, and molecular biology of CHEK2 germline variants in pediatric cancers. [ABSTRACT FROM AUTHOR]

Neuroblastoma (NB) is a highly aggressive extracranial solid tumor in children. Due to its heterogeneity, NB remains a therapeutic challenge. Several oncogenic factors, including the Hippo effectors YAP/TAZ, are associated with NB tumorigenesis. Verteporfin (VPF) is an FDA-approved drug shown to directly inhibit YAP/TAZ activity. Our study aimed to investigate VPF's potential as a therapeutic agent in NB. We show that VPF selectively and efficiently impairs the viability of YAP/TAZ-expressing NB GI-ME-N and SK-N-AS cells, but not of non-malignant fibroblasts. To investigate whether VPF-mediated NB cell killing is YAP-dependent, we tested VPF potency in CRISPR-mediated YAP/TAZ knock-out GI-ME-N cells, and BE(2)-M17 NB cells (a MYCN-amplified, predominantly YAP-negative NB subtype). Our data shows that VPF-mediated NB cell killing is not dependent on YAP expression. Moreover, we determined that the formation of higher molecular weight (HMW) complexes is an early and shared VPF-induced cytotoxic mechanism in both YAP-positive and YAP-negative NB models. The accumulation of HMW complexes, involving STAT3, GM130 and COX IV proteins, impaired cell homeostasis and triggered cell stress and cell death mechanisms. Altogether, our study shows significant in vitro and in vivo VPF-induced suppression of NB growth, making VPF a potential therapeutic candidate against NB. [ABSTRACT FROM AUTHOR]

Neuroblastoma (NB) is an extracranial tumor of the peripheral nervous system arising from neural crest cells. It is the most common malignancy in infants and the most common extracranial solid tumor in children. The current treatment for high-risk NB involves chemotherapy and surgical resection followed by high-dose chemotherapy with autologous stem-cell rescue and radiation treatment. However, those with high-risk NB are susceptible to relapse and the long-term side effects of standard chemotherapy. Polyphenols, including the sub-class of flavonoids, contain more than one aromatic ring with hydroxyl groups. The literature demonstrates their utility in inducing the apoptosis of neuroblastoma cells, mostly in vitro and some in vivo. This review explores the use of various polyphenols outlined in primary studies, underlines the pathways involved in apoptotic activity, and discusses the dosage and delivery of these polyphenols. Primary studies were obtained from multiple databases with search the terms "neuroblastoma", "flavonoid", and "apoptosis". The in vitro studies showed that polyphenols exert an apoptotic effect on several NB cell lines. These polyphenols include apigenin, genistein, didymin, rutin, quercetin, curcumin, resveratrol, butein, bisphenols, and various plant extracts. The mechanisms of the therapeutic effects include calpain-dependent pathways, receptor-mediated apoptosis, and, notably, and most frequently, mitochondrial apoptosis pathways, including the mitochondrial proteins Bax and Bcl-2. Overall, polyphenols demonstrate potency in decreasing NB proliferation and inducing apoptosis, indicating significant potential for further in vivo research. [ABSTRACT FROM AUTHOR]

Neuroblastoma (NB) is an embryonal tumor originating from the sympathetic nervous system, which occurs during fetal period or early postnatal period, and is one of the most common extracranial solid malignant tumors in children. Cytokines are pleiotropic proteins that can effectively activate tumor immune cells and counteract immune suppression, thereby suppressing tumors. Cytokine immunotherapy provides more possibilities for the application of immunotherapy through its own induction and activation of the immune system and has also been extensively studied in NB immunotherapy. This article mainly introduces the research progress of several immunotherapies based on cytokines in the treatment of children with NB. [ABSTRACT FROM AUTHOR]

Neuroblastoma is the most common extracranial solid tumor in children, accounting for 10% to 20% of deaths of pediatric malignancies. Due to the poor prognosis and significant biological heterogeneity of neuroblastoma, it is essential to develop personalized therapeutics and monitor treatment response. Circulating tumor cells (CTCs), as one of the important analytes for liquid biopsy, could facilitate response assessment and outcome prediction for patients in a non‐invasive way. Several methods and platforms have been used for the enrichment and detection of CTCs. The enumeration of CTCs counts and evaluation of tumor‐specific mRNA transcript levels could provide prognostic information at diagnosis, during or after chemotherapy, and during the process of disease progression. So far, studies into neuroblastoma CTCs are only in the preliminary stages. The quality‐controlled large prospective cohort studies are needed to evaluate the clinical significance and statistical rigor of CTC detection methods. Moreover, there remains a lot to be explored and investigated in genotyping characterization of neuroblastoma (NB) CTCs and construction of in‐vitro or in‐vivo functional models. CTCs and circulating tumor DNA (ctDNA) analysis will be complementary in understanding tumor heterogeneity and evolution over the course of therapy for patients with NB in the future. [ABSTRACT FROM AUTHOR]

Background Multiple studies and meta-analyses have claimed that breastfeeding is inversely correlated with maternal and childhood cancers. These results could either be causal or confounded by shared risk factors. By conducting an umbrella review, we aimed to consolidate the relationship between breastfeeding and maternal and childhood cancers. Methods We searched PubMed, Embase, Web of Science, Elsevier ScienceDirect, and Cochrane Library databases from inception to December 2022. Two reviewers independently extracted the data and assessed the quality of the studies using standardised forms. We considered two types of breastfeeding comparisons ("ever" vs "never" breastfeeding; and "longest" vs "shortest" duration). We estimated the pooled risk and 95% confidence interval (CI) for each meta-analysis. Results We included seventeen meta-analyses with 55 comparisons. There was an inverse correlation between breastfeeding and childhood leukaemia (pooled risk = 0.90, 95% CI = 0.81-0.99), neuroblastoma (pooled risk = 0.81, 95% CI = 0.71-0.93), maternal ovarian cancer (pooled risk = 0.76, CI = 0.71-0.81), breast cancer (pooled risk = 0.85, 95% CI = 0.82-0.88), and oesophageal cancer (pooled risk = 0.67, 95% CI = 0.54-0.81) for "ever" vs "never" breastfeeding; and with childhood leukaemia (pooled risk = 0.94, 95% CI = 0.89-0.98), and maternal ovarian cancer (pooled risk = 0.84, 95% CI = 0.78-0.90) and breast cancer (pooled risk = 0.92, 95% CI = 0.89-0.96) for "longest" vs "shortest" breastfeeding duration. Conclusions We found evidence that breastfeeding may reduce the risk of maternal breast cancer, ovarian cancers, and childhood leukaemia, suggesting positive implications for influencing women's decision in breastfeeding. [ABSTRACT FROM AUTHOR]

Simple Summary: Until recently, the prevalence of hereditary cancer in children was estimated to be very low. However, recent studies suggest that at least 10% of pediatric cancer patients have a germline mutation in a cancer predisposition gene. It has been shown that most of these mutations affect splicing, a process by which different transcripts of the same gene are produced. The splicing process is very important, as it regulates many aspects of cellular proliferation, survival, and differentiation. Hereditary cancer genes are highly prone to splicing alterations, and among them there are several genes that may contribute to the development of pediatric solid tumors when mutated in the germline. In this review, we analyze the importance of the splicing-disrupting mutations in pediatric solid cancer and inherited predisposition syndromes. The therapies developed to correct aberrant splicing in cancer are also discussed. The prevalence of hereditary cancer in children was estimated to be very low until recent studies suggested that at least 10% of pediatric cancer patients carry a germline mutation in a cancer predisposition gene. A significant proportion of pathogenic variants associated with an increased risk of hereditary cancer are variants affecting splicing. RNA splicing is an essential process involved in different cellular processes such as proliferation, survival, and differentiation, and alterations in this pathway have been implicated in many human cancers. Hereditary cancer genes are highly susceptible to splicing mutations, and among them there are several genes that may contribute to pediatric solid tumors when mutated in the germline. In this review, we have focused on the analysis of germline splicing-disrupting mutations found in pediatric solid tumors, as the discovery of pathogenic splice variants in pediatric cancer is a growing field for the development of personalized therapies. Therapies developed to correct aberrant splicing in cancer are also discussed as well as the options to improve the diagnostic yield based on the increase in the knowledge in splicing. [ABSTRACT FROM AUTHOR]

Neuroblastoma (NB) is an extracranial solid tumor in children with poor prognosis in high-risk patients and its pathogenesis and prognostic markers urgently need to be explored. This study aimed to explore potential biomarkers related to NB from the aspect of lipid metabolism. Fifty-eight lipid metabolism-related differentially expressed genes between high-risk NB and non-high-risk NB in the GSE49710 dataset were analyzed using bioinformatics, including 45 down-regulated genes and 13 up-regulated genes. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis identified steroid hormone biosynthesis as an abnormal metabolic pathway in high-risk NB. Survival analysis established a three-gene prognostic model, including ACHE, GDPD5 and PIK3R1. In the test data, the AUCs of the established prognostic models used to predict patient survival at 1, 3 and 5 years were 0.84, 0.90 and 0.91, respectively. Finally, in the SH-SY5Y cell line, it was verified that overexpression of GDPD5 can inhibit cell proliferation and migration, as well as affect the lipid metabolism of SH-SY5Y, but not the sugar metabolism. hsa-miR-592 was predicted to be a potential target miRNA of GDPD5 by bioinformatics. In conclusion, this study develops a lipid-metabolism-related gene-based prognostic model for NB and demonstrates that GDPD5 inhibits SH-SY5Y proliferation and migration and may be targeted by hsa-miR-592 and inhibit SH-SY5Y fat synthesis. [ABSTRACT FROM AUTHOR]

Background: Although primary abdominal tumors are rare but their diagnosis, high-cost treatment and psychological instability among both patients and parents are challenging. There are several types of abdominal tumors in pediatric age group which include neuroblastoma, Wilm's tumor, hepatoblastoma, lymphomas, soft-tissue sarcomas, and germ cell tumors. Aims and Objectives: The present study was objectively conducted to identify Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) tumors among all patients presented with abdominal tumors. In addition to this, histopatological profile, clinical profile and disease prognosis among such patients has also been analyzed. Materials and Methods: A total of 64 pediatric patients presented with primary abdominal tumors were included in the study but only 20 patients with lymphoma were identified. The study was conducted at the Department of Pediatric Division, SMHS Hospital Srinagar with effect from 2005 to 2008. Results: The Majority of NHL patients were found to have Stage II and Stage IV. Moreover, all the four cases of Hodkins lymphoma had Stage IV. Out of the 20 patients with lymphoma six died, of them five had NHL and one patient had HL, thus placing the overall survival rate as 70%. Conclusion: The present study demonstrated that both NHL and HL tumors may develop to advanced stage and even patient may die if the timely diagnosis and proper management is not there. We recommend collective team work of medicos from various departments for the precise diagnosis and optimal management of such patients. [ABSTRACT FROM AUTHOR]

Neuroblastoma (NB) is a pediatric neuroendocrine neoplasm. It arises from the sympatho-adrenal lineage of neural-crest-derived multipotent progenitor cells that fail to differentiate. NB is the most common extracranial tumor in children, and it manifests undisputed heterogeneity. Unsatisfactory outcomes of high-risk (HR) NB patients call for more research to further inter-relate treatment and molecular features of the disease. In this regard, it is well established that in the tumor microenvironment (TME), malignant cells are engaged in complex and dynamic interactions with the extracellular matrix (ECM) and stromal cells. The ECM can be a source of both pro- and anti-tumorigenic factors to regulate tumor cell fate, such as survival, proliferation, and resistance to therapy. Moreover, the ECM composition, organization, and resulting signaling networks are vastly remodeled during tumor progression and metastasis. This review mainly focuses on the molecular mechanisms and effects of interactions of selected ECM components with their receptors on neuroblastoma cells. Additionally, it describes roles of enzymes modifying and degrading ECM in NB. Finally, the article gives examples on how the knowledge is exploited for prognosis and to yield new treatment options for NB patients. [ABSTRACT FROM AUTHOR]

Purpose: Neuroblastoma (NB) is the most frequent extracranial tumor in children. The detection of bone marrow (BM) involvement is crucial for correct staging and risk-adapted treatment. We compared three methods regarding the detection of NB involvement in BM. Methods: Eighty-one patients with NB were included in this retrospective study. BM samples were obtained at designated time points at study entry and during treatment or follow-up. The diagnostic tools for BM analysis included cytomorphology (CM), flow cytometry (FCM) and automatic immunofluorescence plus fluorescence in situ hybridization (AIPF). Results: We analyzed 369 aspirates in 81 patients in whom AIPF, CM, and FCM were simultaneously available. During the observation period, NB cells were detected in 86/369 (23.3%) cases, by CM in 32/369 (8.7%), by FCM in 52 (14.1%), and by AIPF in 72 (19.5%) samples. AIPF and/or FCM confirmed all positive results obtained in CM and detected 11 additional positive BM aspirates in 294 CM negative samples (p < 0,001). Survival of patients with BM involvement at study entry identified solely by FCM/AIPF was 17.4% versus 0% for patients in whom BM involvement was already identified by CM. Conclusion: The combination of AIPF/FCM yielded the highest detection rate of NB cells in BM. AIPF was the single, most sensitive method in detecting these cells. Although CM did not provide any additional positive results, it is still a useful, readily available and cost-effective tool. The prognostic significance of FCM and AIPF should be confirmed in a prospective study with a larger number of patients. [ABSTRACT FROM AUTHOR]

Background: Neuroblastoma is the most common malignant extracranial tumor for children. Molecular mechanisms underpinning the pathogenesis of this disease are yet to be fully clarified. This study aimed to identify a novel oncogene that could be used as a biomarker informing the prognosis of neuroblastoma, and to predict its biological functions, using bioinformatics and molecular biology tools. Methods: Three data sets from the TARGET, GSE62564, and GSE85047 databases were used for analysis. Survivals of patients with high or low expression of bub1 were compared, using the Kaplan-Meier curve and logrank test. Immune infiltration was evaluated using ESTIMATE and MCP-counter algorithms. Synthetic small interfering RNAs (siRNAs) were employed to silence bub1 expression in neuroblastoma cell lines SH-SY5Y and SK-N-SH, in order to characterize its biological functions. Gene enrichment analyses of bub1 were carried out, using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. Results: Expression of bub1 was found to significantly affect overall survival and event-free survival of patients with neuroblastoma, positively correlate with the expressions of tpx2 and the ASPM gene, and negatively correlate with host immune infiltration. Expression of bub1 was elevated in patients with neuroblastoma. Silencing bub1 expression using siRNAs in SH-SY5Y and SKN- SH resulted in decreased cell growth (p < 0.05), reduced migration (p < 0.05), and increased apoptosis (p < 0.05). Function analysis of bub1 revealed cancerpromoting effects, probably via regulating several important downstream molecules, including that related to the apoptosis process and epithelialmesenchymal transition. Conclusion: We identified a potential tumor-promoting gene bub1 for neuroblastoma that could also serve as a prognostic biomarker. [ABSTRACT FROM AUTHOR]

Neuroblastoma is the most common extracranial solid tumor found in children and despite intense multi-modal therapeutic approaches, low overall survival rates of high-risk patients persist. Tumors with heterozygous loss of chromosome 11q and MYCN amplification are two genetically distinct subsets of neuroblastoma that are associated with poor patient outcome. Using an isogenic 11q deleted model system and high-throughput drug screening, we identify checkpoint kinase 1 (CHK1) as a potential therapeutic target for 11q deleted neuroblastoma. Further investigation reveals MYCN amplification as a possible additional biomarker for CHK1 inhibition, independent of 11q loss. Overall, our study highlights the potential power of studying chromosomal aberrations to guide preclinical development of novel drug targets and combinations. Additionally, our study builds on the growing evidence that DNA damage repair and replication stress response pathways offer therapeutic vulnerabilities for the treatment of neuroblastoma. [ABSTRACT FROM AUTHOR]

Simple Summary: Metabolic reprogramming has a central role in the initiation and progression of cancer, including high-risk neuroblastoma, a deadly childhood malignant tumor of the sympathetic nervous system. This rewiring of cellular metabolism increases the manufacture of fuel and building blocks for biomass production, which is essential to sustain the growth and proliferation of neuroblastoma cells. However, the rewiring also makes neuroblastoma cells metabolically distinct from normal sympathetic neurons, thereby offering new therapeutic opportunities. In this review, we summarize the recent progress in the study of neuroblastoma metabolic reprogramming and underlying molecular mechanisms. Neuroblastoma is a pediatric cancer responsible for approximately 15% of all childhood cancer deaths. Aberrant MYCN activation, as a result of genomic MYCN amplification, is a major driver of high-risk neuroblastoma, which has an overall survival rate of less than 50%, despite the best treatments currently available. Metabolic reprogramming is an integral part of the growth-promoting program driven by MYCN, which fuels cell growth and proliferation by increasing the uptake and catabolism of nutrients, biosynthesis of macromolecules, and production of energy. This reprogramming process also generates metabolic vulnerabilities that can be exploited for therapy. In this review, we present our current understanding of metabolic reprogramming in neuroblastoma, focusing on transcriptional regulation as a key mechanism in driving the reprogramming process. We also highlight some important areas that need to be explored for the successful development of metabolism-based therapy against high-risk neuroblastoma. [ABSTRACT FROM AUTHOR]