Solid Tumor In Children Research Articles

Exploiting the Impact of Sociodemographics in the Diagnosis of Central Nervous System Tumors in Childhood

Abstract Introduction Central nervous system (CNS) tumors are the most common solid tumors in childhood, comprising 20% of all neoplasms in that age. Besides, they constitute the biggest cause of morbidity and mortality among childhood tumors, and about two thirds of the surviving patients have sequelae. The build-up of sequelae due to neoplastic growth is directly related with the time until diagnosis. Therefore, late diagnosis has a negative influence on the prognosis. Objective To analyze the journey of the pediatric patients with CNS tumors and their families to the reference center. Materials and Methods The present is a retrospective, prospective cohort study based on chart analyses and questionnaire application. Results The mean age of the patients was 8.39 years, most were male (58%), white (56%), and originated from the Southeast of Brazil (56%). A total of 83% of the patients were accompanied by their mothers, and the family income obtained was below 3 minimum wages (20%). The average time until perception of the first signs or symptoms was 48 days, the mean time from symptom perception until the first medical appointment was 30 days, and the mean time between the first medical appointment and referral to Hospital de Amor Infantojuvenil de Barretos was 315 days. The most frequently present signs and symptoms were neurological manifestations (72%), such as headaches (14.8%) and projectile vomiting (6.5%). There was an association between the medical service (public or private service) where the first medical appointment took place and the first medical specialty consulted, although it did not relate to a shorter time until diagnosis. Conclusion The difficulties in the journey of CNS tumor pediatric patients occurred mainly due to health system flaws and medical professionals' hardships. Thus, it is essential to reinforce the importance of continued medical education and to encourage new studies that may reveal precisely where these system flaws are taking place.

Quantitative Analysis of Free 3-Methoxytyramine by LC-MS/MS in Pediatric Patients with Neuroblastoma

Neuroblastomas are the most common solid tumours in early childhood. Currently, the prognosis of patients is evaluated almost exclusively on the basis of molecular-genetic markers from a biopsy sample of tumour tissue. This study is focused on evaluating the potential use of 3‑methoxytyramine as an alternative non-invasive prognostic marker for patients with neuroblastoma. For this purpose, a method was developed to determine free 3‑methoxytyramine in urine using liquid chromatography coupled with tandem mass spectrometric detection. The method was fully validated and subsequently tested on 25 pediatric urine samples. In the group of patients with a poor prognosis, the median value of free 3-methoxy­tyramine was 666.7 nmol mmol−1Krea, while in the group with a favourable prognosis, it was 168.4 nmol mmol−1Krea. The analysis of pediatric urine samples from neuroblastoma patients revealed statistically significant differences in the concentration of free 3‑methoxytyramine (P < 0,05) between the low/medium-risk group and the high-risk group.

Global and Regional Trends in Paediatric Neuroblastoma Incidence and Mortality, 1990-2021: An Inequality and Projection Analysis.

Neuroblastoma stands as the most prevalent extracranial solid tumour in children, yet its epidemiological profile on global, regional, and national scales remains insufficiently explored. Long-term trends in the incidence and mortality of paediatric neuroblastoma from 1990 to 2021 were analysed globally, regionally, and nationally using estimated annual percentage changes. Cross-national disparities in the burden of paediatric neuroblastoma were quantified through standard health equity methodologies, with projections of burden shifts extending to 2035. From 1990 to 2021, the global age-standardised death rate for paediatric neuroblastoma increased from 0.19 (95% UI, 0.16-0.23) to 0.21 (95% UI, 0.14-0.28) per 100 000 population, with an EAPC of 0.2. Regionally, both mortality and incidence rates were highest in low-middle SDI regions and lowest in Oceania. Mortality rates were highest among males aged 12-23 months and females aged 6-11 months, while incidence rates were most pronounced in children aged 2-4 years. Cross-country inequality analyses indicated a reduction in disparities between high and low SDI countries; however, the concentration index revealed an increase in the inequality of burden distribution. The global burden of paediatric neuroblastoma is projected to continue rising through 2035. Over the past 30 years, global incidence and mortality rates for paediatric neuroblastoma have risen, particularly in low-SDI regions, whereas high-SDI regions have witnessed a downward trend. Although disparities between high- and low-SDI countries have diminished, inequality in burden distribution has grown more pronounced. The global burden of paediatric neuroblastoma is expected to continue its upward trajectory over the next 15 years.

Establishing a living biobank of pediatric high-grade glioma and ependymoma suitable for cancer pharmacology.

Brain tumors are the deadliest solid tumors in children and adolescents. Most of these tumors are glial in origin and exhibit strong heterogeneity, hampering the development of effective therapeutic strategies. In the past decades, patient-derived tumor organoids (PDT-O) have emerged as powerful tools for modeling tumoral cell diversity and dynamics, and they could then help defining new therapeutic options for pediatric brain tumors. Through an integrative approach based on our expertise and a careful review of the literature about glioblastoma 3D primary cultures, we set-up a standardized methodological pipeline for the establishment, characterization and biobanking of PDT-O through direct 3D in vitro culture of the deadliest pediatric glial brain tumors. To assess PDT-O fidelity and validate their pre-clinical relevance, we performed comprehensive histological, molecular and drug-response analyses. Our methodological pipeline allowed the rapid and efficient generation of PDT-O recapitulating their parental tumor features, including intra-tumoral heterogeneity, even after several passages and cryopreservation/revival as 3D cultures. Moreover, we successfully performed pre-clinical test responses on these PDT-O to standard-of-care therapies and new therapeutic options. Finally, we identified ONC201 as a selective drug for pediatric glial tumor types not restricted to H3K27M-mutant glioma, as well as combination strategies to increase the therapeutic response to ONC201. Hence, we describe a fast and robust process to biobank PDT-O for pediatric glial brain tumors. These PDT-O models have the potential for patient-specific modeling even after long-term expansion in vitro and we established the proof-of-concept of their usefulness to support powerful pre-clinical studies.

Adults and Adolescents With Neuroblastoma: An Analysis of the National Cancer Database.

Neuroblastoma, the most common extracranial solid tumor in children, is rare in adults. This study compares patient characteristics, disease patterns, and treatments among adults, adolescents, and children with neuroblastoma. We queried the National Cancer Database (2004-2019) for neuroblastoma cases. Patient and tumor characteristics, treatments, and 5-year overall survival (5-OS) were compared between adults (≥ 18 years), adolescents (10-17 years), and children (0-9 years). Kaplan-Meier curves and Cox regression assessed survival differences. Among 6350 neuroblastoma patients, 256 (4.0%) were adults, 222 (3.5%) were adolescents, and 5872 (92.5%) were children. Tumors were largest in adolescents (9.7 cm), followed by adults (8.0 cm) and children (6.7 cm) (p < 0.001). Adults were less likely to have tumors in the adrenal glands (34.0% vs. children: 54.7%, adolescents: 43.2%, p < 0.001) and had lower rates of metastasis (10.9% vs. 19.3% and 19.4%, p < 0.001). Compared to children, adults received less chemotherapy, immunotherapy, and bone marrow transplants (p < 0.001). 5-OS was worse in adults (65.8%), followed by adolescents (70.4%) and children (78.2%) (p < 0.001). After adjustment, adults (aHR: 2.27; 95% CI, 1.71-3.01) and adolescents (aHR: 2.02; 95% CI, 1.54-2.64) had higher hazards of death compared to children. Adults and adolescents with neuroblastoma have distinct clinical features and lower survival than children, underscoring the need for tailored treatment approaches for older patients. III.

Ultrasound‐guided interstitial photothermal therapy generates improved treatment responses in a 9464D model of neuroblastoma

AbstractWe describe the use of ultrasound image guidance to improve treatment outcomes when administering interstitial photothermal therapy (I‐PTT), an experimental cancer treatment modality. I‐PTT is a promising thermal therapy for tumors using intratumorally injected nanoparticle‐based photothermal agents activated by an interstitially placed laser diffuser. We hypothesized that ultrasound‐based image guidance yields improved tumor treatment outcomes in terms of tumor regression and survival by improving the accuracy of the placement of the laser fiber and nanoparticles within a tumor and facilitating more precise PTT delivery. To test this hypothesis, we assessed the effect of ultrasound‐guided I‐PTT (US I‐PTT) on neuroblastoma, an aggressive solid tumor of childhood, using the 9464D syngeneic model in C57BL/6 mice. US I‐PTT using Prussian blue nanoparticles activated by an interstitial cylindrical laser diffuser generated an equivalent in vivo thermal dose as blinded, non‐image‐guided I‐PTT (B I‐PTT). However, US I‐PTT resulted in significantly higher treatment accuracy compared to B I‐PTT, attributable to the image guidance. Importantly, this improved accuracy translated to improved treatment outcomes wherein mice treated with US I‐PTT exhibited significantly improved tumor regression, tumor‐free survival, and long‐term survival compared to mice treated with B I‐PTT. Further, histological analyses of the tumors post‐PTT confirmed the advantages conferred by US I‐PTT over B I‐PTT for tumor control. These proof‐of‐concept results demonstrate the value of using ultrasound guidance for I‐PTT treatment and the translational implications of this approach to provide a more accurate and effective treatment for neuroblastoma.

YY1 drives PARP1 expression essential for PARylation of NONO in mRNA maturation during neuroblastoma progression

BackgroundNeuroblastoma (NB), the most prevalent solid tumor in children, arises from sympathetic nervous system and accounts for 15% of pediatric cancer mortality. This malignancy exhibits substantial genetic and clinical heterogeneity, thus complicating treatment strategies. Poly(ADP-ribose) polymerase 1 (PARP1), a key enzyme catalyzing polyADP-ribosylation (PARylation), plays critical roles in various cellular processes, and contributes to tumorigenesis and aggressiveness. However, the functions and regulatory mechanisms of PARP1 in NB progression still remain to be determined.MethodsThe association of PARP1 expression with NB patients’ survival was analyzed by mining of R2 database. Western blotting, reverse transcription-polymerase chain reaction, MTT colorimetric, soft agar, and matrigel invasion assays were utilized to assess PARP1 expression and its effects on aggressiveness of NB cell lines. Chromatin immunoprecipitation (ChIP) sequencing and ChIP assays were employed to investigate the binding of Yin Yang 1 (YY1) to PARP1 promoter. Protein interactions were explored by BioGRID database analysis, molecular docking, and co-immunoprecipitation assay. RNA sequencing and crosslinking-immunoprecipitation high throughput sequencing datasets were used to identify precursor mRNA splicing targets of non-POU domain containing octamer binding protein (NONO).ResultsHigh PARP1 expression was associated with poor survival of NB patients. PARP1 over-expression enhanced the proliferation and invasion of NB cell lines, confirming its oncogenic roles. YY1 was identified as a key transcriptional regulator facilitating PARP1 expression. Additionally, PARP1 interacted with NONO to induce its PARylation, resulting in stabilization of NONO protein via preventing ubiquitin-mediated degradation. NONO facilitated the splicing and mRNA maturation of target genes a disintegrin and metalloproteinase domain 8 (ADAM8) and testis-expressed gene 14 (TEX14) in a PARylation-dependent manner. Rescue experiments indicated that YY1 facilitated PARP1-mediated PARylation of NONO and subsequent mRNA maturation of ADAM8 and TEX14 in NB cells. In clinical NB cases, high expression of YY1, PARP1, NONO, ADAM8, or TEX14 was associated with poor survival of patients.ConclusionsThese findings indicate that YY1 drives PARP1 expression essential for PARylation of NONO in mRNA maturation during NB progression.

Effects of Pelargonium Sidoides Extract on Apoptosis and Oxidative Stress in Human Neuroblastoma Cells.

Background and Objectives: Neuroblastoma is the most common extracranial solid tumor in children, often presenting challenges in treatment due to its clinical and genetic heterogeneity. This study investigated the anticancer potential of Pelargonium sidoides root extract on the human neuroblastoma cell line (SH-SY5Y). Using XTT assays, ELISA-based oxidative stress markers, and RT-PCR analysis of apoptotic genes, the study explored the extract's effects on cell proliferation, oxidative stress, and apoptosis. Materials and Methods: For the cell culture, SH-SY5Y human neuroblastoma cells were thawed, cultured, and maintained under appropriate conditions for experiments. The dose- and time-dependent activity of Pelorgonium sidoides extract on SH-SY5Y neuroblastoma cells was investigated by XTT assay. The change in the oxidative stress marker 8-Hydroxy-2'-deoxyguanosine (8-OhDG) level was determined by ELISA for the doses applied to the control group root extract at a concentration of 25 μg/mL. Total antioxidant status (TAS) and total oxidant status (TOS) were measured from the cells in the study group with the help of a commercial kit. The oxidative stress index (OSI) was calculated by dividing the TAS by the TOS and multiplying by 100. In order to evaluate the expression levels of apoptosis-related Bax, Bcl-2, Caspase-3, Caspase-8, and Caspase-9 genes at the mRNA level in control and dose group cells, RNA isolation was performed from the SH-SY5Y control and dose group cells (IC50 value). Results: It is observed that the P. sidoides substance inhibits proliferation in cells at 24 h (p < 0.05). As the dose increases, cell proliferation decreases (p < 0.05). The IC50 value was calculated to be 113.83 μg/mL at 24 h. The concentration of 8-OhDG increased in neuroblastoma cells as a result of P. sidoides extract treatment (p < 0.05). TOS levels increased in neuroblastoma cells treated with P. sidoides extract (p < 0.01). OSI levels increased in cells treated with P. sidoides extract (p < 0.001). BAX and Caspase-8 expression increased are statistically significant in the P. sidoides dose group (p < 0.05). Conclusions: P. sidoides extract induces apoptosis in neuroblastoma cells through oxidative stress and mitochondrial- and death receptor-mediated pathways. This study highlights the potential of P. sidoides as a complementary therapeutic agent for neuroblastoma, warranting further in vivo and clinical investigations to assess its safety and efficacy.

DNAJC12 downregulation induces neuroblastoma progression via increased histone H4K5 lactylation

Abstract Neuroblastoma (NB) is the most common extracranial solid tumor in children. Despite treatment advances, the survival rates of high-risk NB patients remain low. This highlights the urgent need for a deeper understanding of the molecular mechanisms driving NB progression to support the development of new therapeutic strategies. In this study, we demonstrated that the reduced levels of DNAJC12, a protein involved in metabolic regulation, are associated with poor prognosis in NB patients. Our data indicate that low DNAJC12 expression activates glycolysis in NB cells, leading to increased lactic acid production and histone H4 lysine 5 lactylation (H4K5la). Elevated H4K5la upregulates the transcription of COL1A1, a gene implicated in cell metastasis. Immunohistochemistry staining of NB patient samples confirmed that high H4K5la levels correlate with poor clinical outcomes. Furthermore, we showed that inhibiting glycolysis, reducing H4K5la, or targeting COL1A1 can mitigate the invasive behavior of NB cells. These findings reveal a critical link between metabolic reprogramming and epigenetic modifications in the context of NB progression, suggesting that H4K5la could serve as a novel diagnostic and prognostic marker, and shed light on identifying new therapeutic targets within metabolic pathways for the treatment of this aggressive pediatric cancer.

Stratified Medicine Paediatrics: Cell free DNA and serial tumour sequencing identifies subtype specific cancer evolution and epigenetic states.

We profiled a large heterogenous cohort of matched diagnostic-relapse tumour tissue and paired plasma-derived cell free DNA (cfDNA) from patients with relapsed and progressive solid tumours of childhood. Tissue and cfDNA sequencing results were concordant, with a wider spectrum of mutant alleles and higher degree of intra-tumour heterogeneity captured by the latter, if sufficient circulating tumour-derived DNA (ctDNA) was present. Serial tumour sequencing identified putative drivers of relapse, with alterations in epigenetic drivers being a common feature. In keeping with epigenetic alterations being a common driver of many childhood cancers, fragmentomics analysis of cfDNA identified tumour-specific epigenetic states and transcription factor binding sites accessible in chromatin. This study leverages a large and well-annotated genomic dataset of aggressive childhood malignancies, identifies genomic and epigenetic drivers of childhood cancer relapse, and highlights the power and practicality of cfDNA analysis to capture both intra-tumoural heterogeneity and the epigenetic state of cancer cells.

Treatment of scoliosis in children after resection of neuroblastoma—A report of five cases

Purpose: Neuroblastoma (NB) is a common extracranial solid tumor in children, often requiring surgical resection. Post-resection NB near the spine can lead to spinal deformities, but treatment strategies are not well-documented. Methods: We retrospectively reviewed our patients who developed spinal deformities after NB resection at our hospital from 2013 to 2021. Treatment included the traditional growing rod (TGR) technique for patients with growth potential, posterior spinal fusion (PSF) for skeletally mature patients, and intermittent cast therapy for infants. Results: Five female patients underwent chemotherapy and surgical resection for NB, with no recurrence during follow-up. Single curves were seen in Cases 1, 2, 4, and 5, and Case 3 had double curves. NB tumors were on the convex side in Cases 1, 3, and 5, and on the concave side in Cases 2 and 4. TGR was used for Cases 1 and 2 due to growth potential and inadequate height. PSF was chosen for Cases 3 and 4, achieving satisfactory scoliosis and kyphosis correction. Case 5, diagnosed with scoliosis at 16 months, underwent intermittent cast therapy for 2 years, significantly correcting scoliosis and avoiding surgery. The average time from NB resection to scoliosis onset was 65.2 ± 49.3 months, with scoliosis treatment starting at 82.6 ± 58.1 months. The mean follow-up was 38.2 ± 12.1 months. All patients showed significant improvement in spinal deformities, with no significant correction loss at the last follow-up. Conclusions: After NB resection, spinal deformities should be closely monitored, with intervention preferably within 6 months of discovery. TGR, PSF, and casting are effective interventions, with the treatment modality based on the patient's skeletal maturity and height.

Multicellular model of neuroblastoma proposes unconventional therapy based on multiple roles of p53.

Neuroblastoma is the most common extra-cranial solid tumour in children. Over half of all high-risk cases are expected to succumb to the disease even after chemotherapy, surgery, and immunotherapy. Although the importance of MYCN amplification in this disease is indisputable, the mechanistic details remain enigmatic. Here, we present a multicellular model of neuroblastoma comprising a continuous automaton, discrete cell agents, and a centre-based mechanical model, as well as the simulation results we obtained with it. The continuous automaton represents the tumour microenvironment as a grid-like structure, where each voxel is associated with continuous variables such as the oxygen level therein. Each discrete cell agent is defined by several attributes, including its cell cycle position, mutations, gene expression pattern, and more with behaviours such as cell cycling and cell death being stochastically dependent on these attributes. The centre-based mechanical model represents the properties of these agents as physical objects, describing how they repel each other as soft spheres. By implementing a stochastic simulation algorithm on modern GPUs, we simulated the dynamics of over one million neuroblastoma cells over a period of months. Specifically, we set up 1200 heterogeneous tumours and tracked the MYCN-amplified clone's dynamics in each, revealed the conditions that favour its growth, and tested its responses to 5000 drug combinations. Our results are in agreement with those reported in the literature and add new insights into how the MYCN-amplified clone's reproductive advantage in a tumour, its gene expression profile, the tumour's other clones (with different mutations), and the tumour's microenvironment are inter-related. Based on the results, we formulated a hypothesis, which argues that there are two distinct populations of neuroblastoma cells in the tumour; the p53 protein is pro-survival in one and pro-apoptosis in the other. It follows that alternating between inhibiting MDM2 to restore p53 activity and inhibiting ARF to attenuate p53 activity is a promising, if unorthodox, therapeutic strategy. The multicellular model has the advantages of modularity, high resolution, and scalability, making it a potential foundation for creating digital twins of neuroblastoma patients.

Validation of the biological function and prognostic significance of AURKA in neuroblastoma.

Neuroblastoma (NB) is the most common extracranial solid tumor in children, and the AURKA gene encodes a protein kinase involved in cell cycle regulation that plays an oncogenic role in a variety of human cancers. The aim of this study was to validate the biological function and prognostic significance of AURKA in NB using basic experiments and bioinformatics. Data obtained from Target and GEO databases were analyzed using various bioinformatic techniques. The expression of AURKA in 77 NB samples was detected by immunohistochemistry (IHC) method. The lentiviral RNA interference technique was employed to downregulate AURKA gene expression in NB cell lines. Additionally, cell counting kit-8 and flow cytometry analysis were conducted to investigate the impact of AURKA expression on cell proliferation, cell cycle progression, and apoptosis. A bioinformatic analysis showed that patients with NB in the AURKA-high-expression group had shorter OS (Overall Survival). Immune cell infiltration analysis showed that only activated CD4 T cell and type 2 T helper cell infiltration levels were higher in the AURKA-high-expression group than in the AURKA-low-expression group, with the infiltration levels of most other immune cells and cytokines lower in the high-expression group. Furthermore, the enhanced infiltration of activated CD4 T cells was associated with worse OS in patients with NB. IHC results showed that the AURKA expression was correlated with MYCN status and INSS stage. Log-rank test showed that pathological type, MYCN status, INSS stage, COG risk group, and AURKA expression was related to PFS (Progression-free survival) of NB patients, but COX regression analysis showed that none of the above factors were independently prognostic for PFS. In vitro, shRNA delivered via an AURKA-specific lentivirus significantly and consistently silenced endogenous AURKA expression in the human NB cell line SK-N-AS. This inhibited tumor cell proliferation, induced apoptosis, and caused G2/M-phase cell cycle arrest. Moreover, western blot assay showed significant reductions in the levels of mTOR, p70S6K, and 4E-BP1 phosphorylation in the AURKA-knockdown group. I found in subsequent experiments that NFYB can bind to the AURKA promoter and thus promote AURKA expression. High-level AURKA expression in NB is associated with poor patient prognosis. Silencing AURKA inhibited tumor cell proliferation, induced tumor cell apoptosis, and led to cell cycle arrest in the G2/M phase. Mechanistically, AURKA knockdown inhibited the phosphorylation and the activation of the mTOR1/p70S6K/4E-BP1 signaling pathway. In addition, AURKA was observed to regulate the infiltration levels of various immune cells in the NB tumor microenvironment, resulting in remodeling of the immunosuppressive tumor microenvironment.

Antiproliferative effects of cadmium sulfide nanoparticles obtained from walnut shells by green synthesis method on SH-SY5Y cell line

Nanoparticles are attracting attention for their potential therapeutic applications, particularly in cancer therapy, underscoring their importance in medicine. Cadmium sulfide nanoparticles, known for their robust catalytic and optical properties, are classified as chalcogenides and show promise for cancer diagnosis and treatment. Neuroblastoma, a common solid tumor in childhood, poses a significant health threat with different outcomes depending on its biological subtype. This study evaluated the antiproliferative effects of cadmium sulfide nanoparticles on the SY-SH5Y cell line. Walnut shell extract and Na2S were used to facilitate the synthesis of cadmium sulfide nanoparticles by green synthesis. Characterization of the synthesized cadmium sulfide nanoparticles was performed by Fourier transform infrared spectroscopy, scanning electron microscopy, and x-ray diffraction analyses. The SH-SY5Y cell line was cultured in a standard cell culture medium and then exposed to different cadmium sulfide nanoparticles (10–25–50–75–100 µg/mL) for 24 hours. Cell viability, oxidant, and antioxidant levels were then assessed using a 3-(4,5-dimetiltiyazol-2-il)-2,5-difeniltetrazolyum bromür, total antioxidant, and total oxidant assays. The data showed that applying 100 μg/mL cadmium sulfide nanoparticles resulted in a significant decrease in cancer cell viability of up to 40.96 % (p<0.05). The cadmium sulfide nanoparticles had a dose-dependent effect on the SH-SY5Y cell line. Furthermore, cadmium sulfide nanoparticles increased oxidative activity in neuroblastoma cells, which was consistent with the results of the 3-(4,5-dimetiltiyazol-2-il)-2,5-difeniltetrazolyum bromür assay. In conclusion, cadmium sulfide nanoparticles exhibited potent activity against the neuroblastoma cell. This study highlights the antiproliferative efficacy of green-synthesized cadmium sulfide nanoparticles with walnut shell extract on relevant cancer cell lines.

Flavokawain A suppresses the malignant progression of neuroblastoma in vitro depending on inactivation of ERK/VEGF/MMPs signaling pathway

BackgroundNeuroblastoma (NB), the most common extracranial solid tumor in children, is featured by high malignancy and poor prognosis. Flavokawain A (FKA), a novel chalcone isolated from the roots of the kava plant, has been identified to exert the tumor-inhibiting properties in various cancers. The present study was formulated to tell about the anticarcinogenic effects of FKA against NB and to thoroughly elucidate the intrinsic molecular mechanisms.MethodsIn this work, for functional experiments, SK-N-SH cells were treated with various concentrations (0, 12.5, 25, 50 μM) of FKA in order to expound the tumor-inhibiting functions of FKA on proliferative ability, clone-forming ability, apoptosis, cell cycle arrest, migratory ability, invasive ability, EMT and in vitro angiogenesis of NB cells. Moreover, to probe into the intrinsic molecular mechanisms underlying the tumor-inhibiting functions of FKA in NB cells, FKA-treated SK-N-SH cells were co-treated with ERK activator LM22B-10 for rescue experiments.ResultsIn our current work, it was verified that FKA treatment suppressed the proliferative and clone-forming abilities of NB cells, facilitated NB cell apoptosis, arrested NB cell cycle as well as inhibited NB cell migration, invasion, EMT and in vitro angiogenesis in a dose-dependent manner. What’s more, molecular docking predicted the compound-protein interaction between FKA and ERK and biotin pull-down assay validated the binding of FKA to ERK. FKA targeted on ERK and acted as an inhibitor of ERK to inactivate ERK/VEGF/MMPs signaling pathway. Treatment with ERK activator LM22B-10 partially abolished the tumor-inhibiting functions of FKA in NB.ConclusionOverall, FKA may suppress the malignant behaviors of NB cells depending on inactivation of ERK/VEGF/MMPs signaling pathway.

Fine construction of gene coexpression network analysis using GTOM and RECODE detected a critical module of neuroblastoma stages 4 and 4S

BackgroundStage 4 neuroblastoma (NBL), a solid tumor of childhood, has a poor prognosis. Despite intensive molecular genetic studies, no targetable gene abnormalities have been identified. Stage 4S NBL has a characteristic of spontaneous regression, and elucidation of the mechanistic differences between stages 4 and 4S may improve treatment. Conventional NBL studies have mainly focused on the detection of abnormalities in individual genes and have rarely examined abnormalities in gene networks. While the gene coexpression network is expected to contribute to the detection of network abnormalities, the fragility of the network due to data noise and the extraction of arbitrary topological structures for the high-dimensional network are issues.ResultsThe present paper concerns the classification method of stages 4 and 4S NBL patients using highly accurate gene coexpression network analysis based on RNA-sequencing data of transcription factors (TFs). In particular, after applying a noise reduction method RECODE, generalized topological overlapping measure (GTOM), which weighs the connections of nodes in the network structure, succeeded in extracting a cluster of TFs that showed high classification performance for stages 4 and 4S. In addition, we investigated how these clusters correspond to clinical information and to TFs which control the normal adrenal tissue and NBL characters.ConclusionsA clustering method is presented for finding intermediate-scale clusters of TFs that give considerable separation performance for distinguishing between stages 4 and 4S. It is suggested that this method is useful as a way to extract factors that contribute to the separation of groups from multiple pieces of information such as gene expression levels.

Neuroblastoma cell lines display heterogeneity in differentiation responses

Background Neuroblastoma is the most common extra-cranial childhood solid tumour, arising during development from stalled neural crest-derived precursor cells. In a subset of children younger than 18 months of age, neuroblastoma can undergo spontaneous regression driven by differentiation, leading to great interest in developing differentiation therapies to re-direct neuroblastoma cells down their correct developmental pathway. Recently, we have shown that combinatorial treatment with the CDK4/6 inhibitor palbociclib and differentiation-inducing agent retinoic acid inhibits proliferation and drives neuronal differentiation of adrenergic-type neuroblastoma cell lines. Methods Here, we explore the differentiation potential of neuroblastoma cell lines in vitro in response to palbociclib and retinoic acid treatment using microscopy, transcriptomic and qRT-PCR analyses. Results We present evidence suggesting that neuroblastoma cells can give rise to mixtures of neural crest-derived adrenal gland cell types, and that differentiation responses correspond to changes in patterns of extracellular matrix substrate expression. Conclusions This study builds a case to further investigate and consider heterogeneity in neuroblastoma cell differentiation and the role of the extracellular matrix in these cell fate decisions.

Clinical Presentation, Treatment, and Outcomes of Pediatric Brain Tumors: A 5-Year Single-Center Experience in Istanbul

Background: Brain tumors are the most common solid tumors in childhood. With the help of increased clinical awareness, improvements in imaging methods, and the identification of molecular characteristics, advances have been made in both diagnosis and treatment. Objectives: In our study, we aimed to discuss the childhood brain tumor cases followed in our clinic, along with their clinical and epidemiological features and treatment outcomes. Methods: The study group comprised children younger than 18 years old who were followed in the Pediatric Hematology and Oncology Clinic of Istanbul Medical Faculty and diagnosed with a brain tumor over the past 5 years (2018 - 2023). Symptoms, age at diagnosis, treatment options (surgery, radiotherapy, chemotherapy), and side effects were reviewed retrospectively. Results: Thirty children were diagnosed with brain tumors. Of the patients, 14 (47%) were male and 16 (53%) were female. The mean age of the children was 8.8 ± 3.1 years, and the mean age at diagnosis was 65.6 ± 37.7 months. The most common symptom was vomiting (40%). The mean duration between the onset of symptoms and diagnosis was 3.8 months, with a median of 1 month. Of the patients, 60% were diagnosed with glial tumors and 40% with non-glial tumors. Gross total resection (GTR) was performed in 26% of patients, subtotal resection (STR) in 37%, and 37% of patients did not undergo surgery. Seventy-seven percent of the patients received chemotherapy, and 57% received radiotherapy. Of the patients, 57% were considered responsive to treatment (complete/partial), 30% had stable disease, and 13% had progressive disease. The overall brain tumor mortality rate in our clinic was 13%. While 73% of our 26 patients had no or mild neurological deficits, 27% had moderate to severe disabilities (gait impairment, hearing impairment, visual impairment). Conclusion: Although the sample size was limited, it may be speculated that the surgery rate was low and long-term side effects were notable. Insufficient surgical resection can affect the treatment response and increase the risk of neurological sequelae and functional impairment. Molecular profiling should be expanded, and a palliative care team should be involved as early as possible to address long-term side effects and improve the quality of life for patients.

Simultaneous single-nucleus RNA sequencing and single-nucleus ATAC sequencing of neuroblastoma cell lines

Neuroblastoma is the most common extracranial solid tumor in children, and a leading cause of childhood cancer deaths. All neuroblastomas arise from neural crest-derived sympathetic neuronal progenitors, but numerous mutations, the most common of which is MYCN amplification, give rise to these lesions. Epigenetic aberrations also play a role in oncogenesis and tumor progression. To better understand biologic diversity of neuroblastomas, we performed joint single-nucleus ATAC sequencing and single-nucleus RNA sequencing on six neuroblastoma cell lines, three of which are MYCN amplified. After standard filtering for high-quality nuclei, we obtained chromatin accessibility and transcript abundance data from 41,733 neuroblastoma tumor cells. Preliminary analysis reveals significant diversity in chromatin landscape and gene expression across neuroblastoma cell lines. This dataset is a valuable resource for studying the transcriptional and epigenetic mechanisms of this deadly childhood disease.

Is Serum Ferritin a Predictor of Blood Transfusions Outcome and Survival in Childhood Lymphomas and Solid Tumors?

Packed red blood cell (PRBC) transfusions are an important part of supportive treatment in oncology; however, when used frequently, they can be a result of transfusion-related iron overload. The aim of the study was to evaluate the role of ferritin as a non-specific marker of neoplastic growth and transfusion-related iron overload in children with lymphomas and solid tumors. We performed a longitudinal analysis of PRBC transfusions and changes in ferritin concentrations during oncological treatment of 88 children with lymphomas and solid tumors. A ferritin concentration above 500 ng/mL was diagnosed in 14.77% of patients at the moment of admission and 18.18% at the end of treatment. No differences were shown in serum ferritin in the context of tumor type-, sex-, and transfusion-related parameters. Those above the age of 10 demonstrated higher ferritin concentrations compared to subjects younger than 5 years of age. In addition, those over than 10 years old or above 30 kg in weight showed a tendency for better survival. All tested patients demonstrated highly significant correlations between ferritin at the 15th month of treatment or after therapy discontinuation and transfusion-related parameters. Interestingly, ferritin levels were found to lower back to the values before therapy shortly after its discontinuation. Transfusion parameters and ferritin levels had no influence on the survival of the studied cancer patients.