Pediatric Central Nervous System Research Articles

Response assessment in pediatric neurooncology (RAPNO) criteria revisited: a practical navigation guide for neuroradiologists.

The Response Assessment in Pediatric Neuro-Oncology (RAPNO) Working Group is an international, collaborative network of experts dedicated to pediatric central nervous system (CNS) tumors that was created in 2011. Since then, six RAPNO articles with imaging guidelines for response assessment in diverse pediatric tumor subgroups have been published, namely: 1) medulloblastomas and leptomeningeal seeding tumors (2018), 2) pediatric high-grade gliomas (2020), 3) pediatric low-grade gliomas (2020), 4) diffuse intrinsic pontine gliomas (2020), 5) pediatric intracranial ependymomas (2022) and 6) pediatric craniopharyngiomas (2023). The purpose of this article is to review all current available RAPNO criteria using a systematized and comparative approach centered on the role of neuroradiologists and supported by neuroimaging examples. Special emphasis will be placed on clarification of core concepts as well as practical adoption aspects of the RAPNO guidelines, namely how and when to image the brain and/or the spine; how to interpret the imaging findings; which other clinical, therapeutic and laboratory variables to consider; and finally how to apply the information to attribute the final appropriate response assessment classification.

Diagnostic aspects of pediatric embryonal tumors of the central nervous system: what should know pediatrician

Background. Early identification of pediatric central nervous system (CNS) tumors is important in relation to disease prognosis, as well as long-term treatment outcomes, which determine subsequent quality of life. The predominance of embryonal tumors (ETs) in early childhood actualizes the problem of timely verification of the diagnosis. Factors contributing to the extension of diagnostic time in the presented patient’s cohort include the inability to adequately verbalize complaints in young children, a wide range of clinical presentations, including nonspecific ones, the relatively low incidence of ET in the population and the low level of oncological alertness among specialists. This determines the need for a more careful assessment of the clinical manifestations and disease-associated symptoms by doctors of all specialties and, especially, primary care specialists. Aim. Analysis of clinical symptoms at the disease’s onset in pediatric CNS ET in order to determine their associations with the tumor’s characteristics (site, hystologic type) and the patient’s features. Materials and methods. A retrospective analysis of data from 124 pediatric patients with CNS ET who received treatment from 2010 to 2023 in the departments of pediatric oncology of the Almazov National Medical Research Center and the St. Petersburg Scientific Research Center for Medical Sciences (o) named after. N. P. Napalkov. The analyzed parameters were the age of manifestation, initial symptoms, duration of the anamnesis and the period before verification of the diagnosis, localization and histological type of tumors. For statistical analysis, Fisher’s exact test, modified Pearson test, Kruskal-Wallis and Mann-Whitney tests, as well as (to assess the duration of anamnesis) the Cox model were used. Results. The most common type of CNS ET in the study group was medulloblastoma (MB; 66.1%). The average age of patients, in general, was 61 months, boys predominated (58%). The median age varied depending on the histological tumor type: the maximum was 72 months in patients with medulloblastoma and the minimum was 9 months in children with atypical teratoid rhabdoid tumor (ATRT). Both medians are significantly different from the total median (29 months) of all other tumors (p = 6.53 ∙ 10-4 and p = 0.029, respectively). The most frequent symptoms in patients with ET were nausea and vomiting (68%), headache (50%), and gait disturbances (25.6%). Increased head circumference/bulging fontanel (p = 0.0016) and torticollis (p = 0.0057) were the most common symptoms associated with younger age. Headache (p = 1.30 ∙ 10-9), nausea and vomiting (p = 0.019), diplopia (p = 0.0057), weight loss (p = 0.017) and dizziness (p = 0.013) were associated with older age. Headache was predominated symptom in medulloblastoma (p = 2.60 ∙ 10-4) compared to other ETs, and less common in ATRT (p = 1.51 ∙ 10-4), which may be due to the patient’s age. Fontanel bulging in medulloblastoma, unlike other ET, was not observed, which is also associated with age. Seizures were observed in all cases of CNS neuroblastoma - significantly more often (p = 0.034) than in other ETs. The most common tumor location was the posterior cranial fossa (PCF) (83.6%). PCF localization was associated with headache (p = 0.05, borderline significance) and nausea/vomiting (p = 0.040). Parietal localization was associated with seizures (p = 0.041). Four patients in the cohort had asymptomatic disease’s manifestations. The diagnosis was established by a routine screening examination. The absence of symptoms was associated with location outside the PCF (p = 0.011) and with younger age (p = 0.053, borderline significance). The diagnosis was established in a significantly shorter time if children had symptoms such as nausea and vomiting (p=0.0017), paresis and paralysis (p=0.0059). Conclusion. In patients with CNS ETs, statistically significant relationships are revealed between age, histological type, tumor site and certain symptoms. Nevertheless, the absence of strictly specific clinical manifestation determines the indications for a careful assessment of the pediatric somatic and neurological status and timely neuroimaging in children when even potential symptoms typical for CNS tumors are identified.

Spinal diffuse midline glioma: An unusual case presentation

Primary spinal cord neoplasms are rare, accounting for 1% of paediatric central nervous system tumours. The majority of which are low-grade gliomas (LGG). A teenage male presented with rapidly progressive lower limb paralysis. He subsequently underwent a near-total resection of an intramedullary thoracic tumour. Although the initial histopathology report suggested a LGG, closer review of the morphology and immunohistochemical staining revealed a diffusely infiltrating high-grade astrocytoma. Methylation profiling later confirmed a H3K27M-mutated spinal DMG. He underwent spinal radiation to the tumour bed soon after surgery but succumbed to his disease 8 days after completing radiation, and 3 months after presentation.Conclusion: Spinal DMGs are rare, can lead to diagnostic challenges and have a poor prognosis.

Deep Proteome Analysis of Cerebrospinal Fluid from Pediatric Patients with Central Nervous System Cancer.

The cerebrospinal fluid (CSF) is a key matrix for discovery of biomarkers relevant for prognosis and the development of therapeutic targets in pediatric central nervous system malignancies. However, the wide range of protein concentrations and age-related differences in children makes such discoveries challenging. In addition, pediatric CSF samples are often sparse and first prioritized for clinical purposes. The present work focused on optimizing each step of the proteome analysis workflow to extract the most detailed proteome information possible from the limited CSF resources available for research purposes. The strategy included applying sequential ultracentrifugation to enrich for extracellular vesicles (EV) in addition to analysis of a small volume of raw CSF, which allowed quantification of 1351 proteins (+55% relative to raw CSF) from 400 μL CSF. When including a spectral library, a total of 2103 proteins (+240%) could be quantified. The workflow was optimized for CSF input volume, tryptic digestion method, gradient length, mass spectrometry data acquisition method and database search strategy to quantify as many proteins a possible. The fully optimized workflow included protein aggregation capture (PAC) digestion, paired with data-independent acquisition (DIA, 21 min gradient) and allowed 2989 unique proteins to be quantified from only 400 μL CSF, which is a 340% increase in proteins compared to analysis of a tryptic digest of raw CSF.

Characterization of aberrant splicing in pediatric central nervous system tumors reveals CLK1 as a candidate oncogenic dependency.

Pediatric brain cancer is the leading cause of disease-related mortality in children, and many aggressive tumors still lack effective treatment strategies. We characterized aberrant alternative splicing across pediatric brain tumors, identifying pediatric high-grade gliomas (HGGs) among the most heterogeneous. Annotating these events with UniProt, we identified 11,940 splice events in 5,368 genes leading to potential protein function changes. We discovered CDC-like kinase 1 (CLK1) is aberrantly spliced to include exon 4, resulting in a gain of two phosphorylation sites and subsequent activation. Inhibition of CLK1 with Cirtuvivint significantly decreased both cell viability and proliferation in the pediatric HGG KNS-42 cell line. Morpholino-mediated depletion of CLK1 exon 4 splicing reduced RNA expression, protein abundance, and cell viability with concurrent differential expression of 78 cancer genes and differential splicing at functional sites in 193 cancer genes. Our findings highlight a dependency of pediatric HGGs on CLK1 and represent a promising therapeutic strategy.

Primary Central Nervous System Burkitt's Lymphoma in a Pediatric Patient: A Case Report and Literature Review.

The objective of this research is to examine the therapy and outlook of pediatric primary central nervous system Burkitt lymphomas. This study involves a retrospective analysis of the clinical data of a child with primary central nervous system Burkitt lymphoma who underwent treatment in our department. In addition, pertinent literature was reviewed to provide a comprehensive understanding of the topic. The patient was admitted to the neurosurgery department with symptoms of headache and vomiting. Brain magnetic resonance imaging (MRI) revealed multiple lesions in the right frontal and temporal lobes, dorsal thalamus, and posterior medulla oblongata. Most of the tumor mass was surgically removed from the right ventricle and diagnosed as Burkitt lymphoma. Abnormal lymph nodes were not found outside of the central nervous system. The patient achieved complete remission (CR) after receiving 6 cycles of treatment (R-AA-BB-CC-AA-BB-CC) based on the regimen of the Southern Pediatric Non-Hodgkin Lymphoma Treatment Collaboration Group 2017. As of November 23, 2023, the patient remained alive with no evidence of recurrence. Primary central nervous system Burkitt lymphoma is rare in children, and there is no universally accepted treatment protocol. However, the regimen outlined by the South China Children's Cancer Group-Non-Hodgkin Lymphoma in 2017 (SCCCG-NHL-2017) can serve as a useful reference for treating pediatric non-Hodgkin lymphoma.

Individual- and community-level correlates of pediatric central nervous system tumor disparities in the US.

The aim of this study was, through comprehensive, multilevel models of social determinants of health (SDoH) factors, including the Yost Index socioeconomic status (SES) score, to determine whether community- or individual-level SDoH factors quantifiably influence pediatric CNS tumor disparities more in care and prognosis across the US. The authors performed a retrospective cohort study assessing specialized Surveillance, Epidemiology, and End Results data of pediatric patients (≤ 19 years old) with nonmalignant and malignant tumors of the CNS from 2010 to 2018. A census-level Yost Index SES score and rurality/urbanicity measures were incorporated with individual characteristics of age, sex, and race/ethnicity. Chi-square analyses for clinical and demographic descriptions, multivariate Cox proportional hazards logistic regressions for survival, and multivariate logistic regressions for resection, radiation treatment, treatment delay, and advanced staging on preliminary presentation were performed. Across 18,236 patients, age-adjusted analyses showed substantially increased mortality risk among 6 of 11 subtypes (highest hazard ratio [HR] 1.91, 95% CI 1.59-2.28, p < 0.001 for glioma NOS), decreased odds of first-line therapy among 7 of 18 subtypes (lowest OR 0.36, 95% CI 0.11-0.97, p = 0.043 for resection of choroid plexus papilloma), increased odds of treatment delay among 6 of 11 subtypes (highest OR 2.47, 95% CI 1.01-6.49, p = 0.047 for germinoma), increased odds of advanced staging on preliminary presentation among 3 of 10 malignant subtypes (highest OR 2.56, 95% CI 1.27-5.52, p = 0.008 for malignant ependymomas), and increased odds of receipt of radiation therapy among 3 of 10 malignant subtypes (highest OR 2.30, 95% CI 1.87-2.84, p < 0.001) observed across many disease subtypes contributed by certain individual- and community-level SDoH factors. Through comprehensive analyses combining individual- and community-level SDoH factors, this study identified detrimental interrelated SDoH associations with poorer care and prognosis of pediatric patients with CNS tumors, delineating how both levels differentially contribute to observed disparities across different subtypes.

Rare Oncogenic Fusions in Pediatric Central Nervous System Tumors: A Case Series and Literature Review

Background and Objectives: Central Nervous System (CNS) pediatric tumors represent the most common solid tumors in children with a wide variability in terms of survival and therapeutic response. By contrast to their adult counterpart, the mutational landscape of pediatric CNS tumors is characterized by oncogenic fusions rather than multiple mutated genes. CNS pediatric tumors associated with oncogenic fusions represent a complex landscape of tumors with wide radiological, morphological and clinical heterogeneity. In the fifth CNS WHO classification, there are few pediatric CNS tumors for which diagnosis is based on a single oncogenic fusion. This work aims to provide an overview of the impact of rare oncogenic fusions (NTRK, ROS, ALK, MET, FGFR, RAF, MN1, BCOR and CIC genes) on pathogenesis, histological phenotype, diagnostics and theranostics in pediatric CNS tumors. We report four cases of pediatric CNS tumors associated with NTRK (n = 2), ROS (n = 1) and FGFR3 (n = 1) oncogenic fusion genes as a proof of concept. Cases presentation and literature review: The literature review and the cohort that we described here underline that most of these rare oncogenic fusions are not specific to a single morpho-molecular entity. Even within tumors harboring the same oncogenic fusions, a wide range of morphological, molecular and epigenetic entities can be observed. Conclusions: These findings highlight the need for caution when applying the fifth CNS WHO classification, as the vast majority of these fusions are not yet incorporated in the diagnosis, including grade evaluation and DNA methylation classification.

Current Landscape of NTRK Inhibition for Pediatric CNS Tumors.

Over the last decade, as molecular platforms have permitted the characterization of the genomic landscape of pediatric central nervous system (CNS) tumors, pediatric neuro-oncology has dramatically transformed. NTRK fusions are oncogenic driver alterations that have been found in a multitude of tumor types, including pediatric CNS tumors. In recent years, NTRK inhibitors have emerged as a promising class of targeted therapies for pediatric CNS tumors with NTRK gene fusions. The use of larotrectinib and entrectinib in the relapsed setting for pediatric CNS tumors has resulted in rapid and robust responses in an important fraction of patients. These agents are well tolerated, although close to 20% of patients have spontaneous bone fractures. Given the existing data for patients with relapsed disease, clinical trials using NTRK inhibitors in the upfront setting is the next natural progression of efficacy testing and many are currently underway. There are still several challenges that need to be addressed to optimize the use of NTRK inhibitors and identify the patients with NTRK fusion-positive CNS tumors who are most likely to benefit from them. As these agents are more broadly used, resistance will become a more pervasive issue and strategies will need to be determined for this scenario. This article summarizes the current status of NTRK inhibitors for pediatric CNS tumors and discusses the opportunities and challenges of their expanding use in the future.

CAR T cell therapy for pediatric central nervous system tumors: a review of the literature and current North American trials.

Central nervous system (CNS) tumors are the leading cause of cancer-related death in children. Typical therapy for CNS tumors in children involves a combination of surgery, radiation, and chemotherapy. While upfront therapy is effective for many high-grade tumors, therapy at the time of relapse remains limited. Furthermore, for diffuse intrinsic pontine glioma (DIPG) and diffuse midline glioma (DMG), there are currently no curative therapies. Chimeric antigen receptor T (CAR T) cell therapy is a promising novel treatment avenue for these tumors. Here, we review the preclinical evidence for CAR T cell use in pediatric brain tumors, the preliminary clinical experience of CNS CAR T cell trials, toxicity associated with systemic and locoregional CAR T cell therapy for CNS tumors, challenges in disease response evaluation with CAR T cell therapy, and the knowledge gained from correlative biologic studies from these trials in the pediatric and young adult population.

Cytokine profile of cerebrospinal fluid in pediatric patients with metastatic medulloblastoma

BackgroundMedulloblastoma (MB) is a malignant pediatric central nervous system tumor that is prone to leptomeningeal metastasis. Currently, apart from magnetic resonance imaging and cerebrospinal fluid (CSF) cytology, there are no reliable biomarkers for MB progression. Cytokines are key proteins in signaling pathways in the tumor microenvironment and are closely related to tumor recurrence and progression. This study aimed to investigate the CSF cytokine profile in pediatric patients with MB to identify biomarkers of tumor progression and metastasis. MethodsIn total, 10 patients were recruited for this study. Five patients had nonmetastatic MB and five had metastatic MB. A cytokine antibody array was used to detect the expression of 120 cytokines in the CSF, and differentially expressed cytokines were screened by integrated bioinformatics analysis. ResultsTwenty-seven cytokines were upregulated in patients with MB compared to control individuals. Of these, eight were upregulated by >1.5-fold (CCL2, BMP-4, beta-NGF, FGF-7, IL-12p40, eotaxin-2, M-CSF, and NT-4). Twelve cytokines were differentially expressed between patients with metastatic MB and nonmetastatic (nine cytokines were upregulated and three were downregulated). Among them, NAP-2, MIP-1α, MIP-1β, IGFBP-1, IGFBP-2 and IGFBP-3 were upregulated by more than two-fold. Gene Ontology analysis revealed that the upregulated cytokines were enriched mainly in “epithelial cell proliferation” and “chemotaxis,” and the Kyoto Encyclopedia of Genes and Genomes analysis indicated the enrichment of the “MAPK,” “PI3K-Akt,” and “Ras” signaling pathways. ConclusionsThe present study investigated cytokine profiles in the CSF of pediatric patients with MB. Our results suggest that these differentially expressed cytokines may serve as novel markers for detecting MB, especially for assessing the risk of progression and metastasis.

A Case Series of Children With Medulloblastoma Depicting the Disparities in Care and the Challenges in the Detection and Treatment of Pediatric Central Nervous System Tumors in Low-Resource Settings: A Case Study of Uganda

BackgroundPrimary central nervous system tumors are the second most common cancer among children in high-income countries (HICs). These tumors are also the leading cause of cancer-related deaths in children in this setting. Studies from HICs report gliomas as the most common pediatric cancer. However, there is paucity of data from low- and middle-income countries as not many publications have been made in this field. MethodsThe objective was to describe the disparities in detection, treatment, and survival of children with central nervous system tumors in low-income countries (LICs) when compared with HICs, using a case series. A retrospective chart review of three children treated for medulloblastoma in Uganda was done. In addition, a review of the literature about management of pediatric central nervous system tumors in both LICs and HICs was conducted. ResultsThere are no quantifiable results for this case series. ConclusionThere are notable differences in the quality of care for children with pediatric central nervous system tumors in LICs when compared with HICs. In Uganda, the challenges in management of these children include few multidisciplinary specialists, long distance from the neurosurgery centers, and difficulties in making a correct pathologic diagnosis, among others.

Imaging panorama of pediatric central nervous system tuberculosis.

Central nervous system tuberculosis (CNS TB) is the most dreaded manifestation of systemic tuberculosis in the pediatric age group. It is associated with high morbidity and mortality due to severe neurological complications and sequelae. Knowledge about the imaging spectrum of CNS TB will help in early presumptive diagnosis and prompt treatment, reducing the development of complications. Imaging also plays a vital role in monitoring the progression of disease after the initiation of antituberculosis therapy. Advanced magnetic resonance imaging (MRI) techniques have recently improved the diagnostic efficacy manifold.In this review, we describe the imaging characteristics, the role of advanced imaging techniques, and follow-up imaging in various types of CNS TB in the pediatric population.

Fertility preservation in pediatric central nervous system tumors: A report from the Children's Oncology Group.

The Oncofertility Consortium Pediatric Initiative Network has published recommendations about the risks of infertility due to gonadotoxic therapy. We abstracted gonadotoxic therapies from central nervous system (CNS) Children's Oncology Group (COG) protocols between 2000 and 2022. We assigned them as unknown, minimal, significant, or high levels of increased risk for gonadal dysfunction/infertility. Seven of 11 CNS protocols placed patients at a high level of risk in at least one treatment arm. Males (7/11) were most commonly at a high level of risk, followed by pubertal females (6/11) and prepubertal females (5/11), highlighting the importance of pre-treatment counseling regarding fertility preservation interventions in this population.

The DNA methylome of pediatric brain tumors appears shaped by structural variation and predicts survival

Structural variation heavily influences the molecular landscape of cancer, in part by impacting DNA methylation-mediated transcriptional regulation. Here, using multi-omic datasets involving >2400 pediatric brain and central nervous system tumors of diverse histologies from the Children’s Brain Tumor Network, we report hundreds of genes and associated CpG islands (CGIs) for which the nearby presence of somatic structural variant (SV) breakpoints is recurrently associated with altered expression or DNA methylation, respectively, including tumor suppressor genes ATRX and CDKN2A. Altered DNA methylation near enhancers associates with nearby somatic SV breakpoints, including MYC and MYCN. A subset of genes with SV-CGI methylation associations also have expression associations with patient survival, including BCOR, TERT, RCOR2, and PDLIM4. DNA methylation changes in recurrent or progressive tumors compared to the initial tumor within the same patient can predict survival in pediatric and adult cancers. Our comprehensive and pan-histology genomic analyses reveal mechanisms of noncoding alterations impacting cancer genes.

Memantine to Reduce Cognitive Impairment After Radiation in Children: A Pilot Study Evaluating the Feasibility of Memantine in Reducing Cognitive Impairment in Pediatric Patients after Radiation Therapy for Central Nervous System Tumors

Memantine is standard in certain adults receiving brain radiation therapy (RT) to decrease cognitive impacts, but it is unknown whether pediatric patients can take, tolerate, and/or benefit from memantine. In this prospective single-arm feasibility study, we hypothesized that pediatric patients receiving central nervous system (CNS) RT would tolerate memantine with good adherence. Patients aged 4 to 18 years with a primary CNS malignancy (excluding World Health Organization grade 4 astrocytoma, glioblastoma) receiving intracranial RT were eligible. A 6-month memantine course was given during and after RT, with dose titration in 5 mg increments over 4 weeks targeting a weight-based maximum (0.4 mg/kg to the closest 5 mg), not to exceed 10 mg twice a day. The primary endpoint was to achieve 80% drug adherence rate in 80% of patients measured 1 month after RT. Secondary objectives included memantine feasibility at 3 and 6 months. Eighteen patients enrolled from 2020 to 2022 and were prescribed memantine with RT. The study closed early to avoid competing with the phase 3 randomized Children's Oncology Group study ACCL2031. No predefined stopping rules were met. One patient withdrew for cognition-altering substance use, leaving 17 patients available for analysis. One patient discontinued memantine after one dose due to nausea. For the remaining 16 patients, there was a median of 100% pill completion rate (range, 74%-100%; n = 9/17 with 100% adherence) at 1 month after RT, with 15/16 (94%) with adherence rates >80%. At the 3- and 6-month post-RT time points for secondary endpoints, the median adherence rates were 100% (range, 55%-100%) and 96% (range, 33%-100%), respectively. Grade 1 to 2 fatigue, headache, and nausea were the most common toxicity events, at least possibly related to the study drug (n = 27), without attributable grade 3+ events. Memantine is a feasible, safe, and well-tolerated addition to multimodality treatment for pediatric CNS malignancies. Results of ACCL2031 are awaited to define the value of memantine in this population.

Diagnosis of pediatric central nervous system tumors using methylation profiling of cfDNA from cerebrospinal fluid

Pediatric central nervous system tumors remain challenging to diagnose. Imaging approaches do not provide sufficient detail to discriminate between different tumor types, while the histopathological examination of tumor tissue shows high inter-observer variability. Recent studies have demonstrated the accurate classification of central nervous system tumors based on the DNA methylation profile of a tumor biopsy. However, a brain biopsy holds significant risk of bleeding and damaging the surrounding tissues. Liquid biopsy approaches analyzing circulating tumor DNA show high potential as an alternative and less invasive tool to study the DNA methylation pattern of tumors. Here, we explore the potential of classifying pediatric brain tumors based on methylation profiling of the circulating cell-free DNA (cfDNA) in cerebrospinal fluid (CSF). For this proof-of-concept study, we collected cerebrospinal fluid samples from 19 pediatric brain cancer patients via a ventricular drain placed for reasons of increased intracranial pressure. Analyses on the cfDNA showed high variability of cfDNA quantities across patients ranging from levels below the limit of quantification to 40 ng cfDNA per milliliter of CSF. Classification based on methylation profiling of cfDNA from CSF was correct for 7 out of 20 samples in our cohort. Accurate results were mostly observed in samples of high quality, more specifically those with limited high molecular weight DNA contamination. Interestingly, we show that centrifugation of the CSF prior to processing increases the fraction of fragmented cfDNA to high molecular weight DNA. In addition, classification was mostly correct for samples with high tumoral cfDNA fraction as estimated by computational deconvolution (> 40%). In summary, analysis of cfDNA in the CSF shows potential as a tool for diagnosing pediatric nervous system tumors especially in patients with high levels of tumoral cfDNA in the CSF. Further optimization of the collection procedure, experimental workflow and bioinformatic approach is required to also allow classification for patients with low tumoral fractions in the CSF.

Association of RAN and RANBP2 Gene Polymorphisms With Glioma Susceptibility in Chinese Children.

Glioma is the most prevalent pediatric central nervous system malignancy. RAN, member RAS oncogene family (RAN), is a key signaling molecule that regulates the polymerization of microtubules during mitosis. RAN binding protein 2 (RANBP2) is involved in DNA replication, mitosis, metabolism, and tumorigenesis. The effects of RAN and RANBP2 gene polymorphisms on glioma susceptibility in Chinese children are currently unknown. This study aimed to evaluate the association between RAN and RANBP2 gene polymorphisms and glioma susceptibility in Chinese children. We recruited 191 patients with glioma and 248 children without cancer for this case-control study. Polymerase chain reaction-based TaqMan was applied to gene sequencing and typing. Logistic regression model-calculated odds ratio and 95% confidence interval were used to verify whether the gene polymorphisms (RAN rs56109543 C>T, rs7132224 A>G, rs14035 C>T, and RANBP2 rs2462788 C>T) influence glioma susceptibility. Based on age, gender, tumor subtype, and clinical stage, stratified analyses of risk and protective genotypes were conducted. p values for mutant genotype analyses were all >0.05, indicating no significant correlation between these gene polymorphisms and glioma risk. RAN and RANBP2 gene polymorphisms were not found to be statistically significantly associated with glioma susceptibility in Chinese children. Other potential functional gene polymorphism loci of RAN and RANBP2 will need to be evaluated in the search for novel glioma biomarkers.

ONC206 targeting ClpP induces mitochondrial dysfunction and protective autophagy in hepatocellular carcinoma cells

Hepatocellular carcinoma (HCC) is the most common form of liver cancer, accounting for approximately 90 % of all cases. ONC201, a member of the imipridone drug family, has shown promising therapeutic potential and a good safety profile in both malignant pediatric central nervous system tumors (diffuse midline glioma [DMG]) and hematologic malignancies. ONC206 is a more potent analog of ONC201. However, the ONC206 potential and mechanism of action in HCC remain to be elucidated. We found that ONC206 hindered HCC growth by suppressing cell proliferation and inducing apoptosis. Moreover, ONC206 induced cytoprotective autophagy, and blocking autophagy enhanced the proapoptotic effect of ONC206. Additionally, ONC206 induced mitochondrial swelling, reduced the mitochondrial membrane potential (MMP), and led to the accumulation of mitochondrial ROS in HCC cells, ultimately resulting in mitochondrial dysfunction. The HCC patient samples exhibited notably elevated levels of caseinolytic protease proteolytic subunit (ClpP), which serves as a mediator of ONC206-induced mitochondrial dysfunction and the activation of protective autophagy. knockdown of ClpP reversed the cytotoxic effects of ONC206 on HCC cells. In summary, our results provide the first insight into the mechanism by which ONC206 exerts its anti-HCC effects and induces protective autophagy in HCC cells through ClpP.

Pediatric central nervous system tumor with CIC::LEUTX fusion: a diagnostic challenge

Pediatric central nervous system tumor with CIC::LEUTX fusion: a diagnostic challenge