The study aimed to review the available literature on spontaneous complete regression of congenital brain tumors and report an institutional case with a posterior fossa tumor that involuted at the age of 3 months. A systematic review was conducted in accordance with PRISMA guidelines. The study protocol was registered with INPLASY. A systematic review of the articles published from inception to 5 April 2026 in Web of Science, Scopus, PubMed (MEDLINE), and Embase was conducted. Six eligible case reports were identified and included in the analysis. Initial clinical presentation varied, with neurological deficits observed in 2/7 patients, signs of intracranial hypertension in 4/7 patients, and no neurological symptoms in one neonate. Tumors were most commonly located within deep brain structures (3/7), followed by cortical regions (2/7) and extracerebral locations (1/7). Histopathological grading revealed high-grade tumors in 3/7 patients and low-grade tumors in 2/7 individuals. Tumor resection was not pursued because of risky tumor topography (2/7), presumed benign tumor biology with a wait-and-see strategy (1/7), or parental decision to pursue hospice care (1/7). In three individuals, tumor surgery had been initially planned after gaining a greater body weight. Complete spontaneous regression was achieved between 3 and 33 months of age. Spontaneous complete regression of congenital brain tumors is a rare and incompletely understood phenomenon. Our study highlights the heterogeneity of histopathological findings, lesion localization, and the subtle clinical presentation in this age group.

Inhibitors of apoptosis proteins (IAPs), coded by BIRC genes, are cellular checkpoints that can regulate and inhibit pro-apoptotic caspase signaling. Overexpression of BIRC genes has been associated with cancer progression, multidrug resistance, poor prognosis, and shorter survival in several types of cancer. Using quantitative real-time polymerase chain reaction, we examined the expression of IAP family genes and their regulators: NAIP, BIRC2, BIRC3, XIAP, BIRC5, BIRC6, BIRC7, CASP3, CASP9, DIABLO and XAF1. We also evaluated the impact of clinical parameters (programmed death receptor 1 [PD1] expression, oligodendrocyte transcription factor 2 [Olig2] expression, Ki-67 antigen expression, tumor protein p53 expression in tumor cells, patient survival time, and progression-free survival) on gene expression levels. The expression of BIRC3 (p = 0.049), NAIP (p = 0.008), and XAF1 (p = 0.032) was significantly higher in tumors negative for Ki67, whereas the remaining genes showed no significant correlation with Ki67 expression. In contrast, BIRC2 (r=-0.478 p < 0.05) and BIRC3 (r=-0.536 p < 0.05) expression levels were negatively correlated with overall survival. A similar negative association was observed between progression-free survival and the expression of BIRC2 (r=–0.481, p < 0.05) and BIRC3 (r=-0.540, p < 0.05). To our knowledge, this is the first study to comprehensively assess the relationship between the expression of IAP family genes and their regulators in a homogeneous group of patients diagnosed with pediatric high-grade gliomas (pHGGs). Our findings provide new insights into molecular mechanisms involved in the pathogenesis of pHGGs, however, these preliminary results require confirmation in larger and more detailed studies.

Introduction: The subependymal giant cell astrocytoma (SEGA) predominantly occurs in patients with tuberous sclerosis. Here, we present an unusual aggressive transformation of SEGA-imitating fibrous meningioma in a child carrying a germline CHEK2 mutation. Methods: This case study was conducted at a tertiary pediatric oncology center in accordance with current diagnostic and therapeutic standards. Tumor classification followed WHO CNS5 criteria and was complemented by genome-wide DNA methylation profiling. Comprehensive molecular workup included germline and somatic whole exome sequencing, copy number analysis, and RNA sequencing. Results: An 8.5-year-old girl presented with an intraventricular tumor initially diagnosed as SEGA based on imaging and partial resection histology. Treatment with an mTOR inhibitor led to 4 years of stability before rapid progression and death due to postoperative brain edema. Re-examination of both specimens revealed transformation into an aggressive anaplastic meningioma, while the initial lesion was reclassified as fibrous meningioma. Whole exome and microarray analyses excluded germline TSC1/TSC2 defects but identified a pathogenic germline CHEK2 variant (c.1466del, p.Asn489ThrfsTer23). Somatic alterations involving NF1 and TP53 were found in the primary tumor. Conclusions: Constitutional CHEK2 mutations combined with somatic NF1 defect may have promoted the malignant progression of SEGA-imitating fibrous meningioma and its favorable initial response to mTOR inhibitors.

Background: The subependymal giant cell astrocytoma (SEGA) predominantly occurs in patients with tuberous sclerosis. Here, we present an unusual aggressive transformation of SEGA-imitating fibrous meningioma in a child carrying a germline CHEK2 mutation Methods: This case study was conducted at a tertiary pediatric oncology center in accordance with current diagnostic and therapeutic standards. Tumor classification followed WHO CNS5 criteria and was complemented by genome-wide DNA methylation profiling. Comprehensive molecular workup included germline and somatic whole-exome sequencing, copy-number analysis, and RNA-sequencing; Results: An 8.5-year-old girl presented with an intraventricular tumor initially diagnosed as SEGA based on imaging and partial resection histology. Treatment with an mTOR inhibitor led to four years of stability before rapid progression and death due to postoperative brain edema. Re-examination of both specimens revealed transformation into an aggressive anaplastic meningioma, while the initial lesion was reclassified as fibrous meningioma. Whole-exome and microarray analyses excluded germline TSC1/TSC2 defects but identified a pathogenic germline CHEK2 variant (c.1466del, p.Asn489ThrfsTer23). Somatic alterations involving NF1, and TP53 were found in the primary tumor. Conclusions: Constitutional CHEK2 mutations combined with somatic NF1 defect may have promoted the malignant progression of SEGA-imitating fibrous meningioma and its favorable initial response to mTOR inhibitors.

This study aimed to summarize the existing English-language literature on central nervous system (CNS) meningeal melanocytomas in children, and additionally describe our institutional case report. PubMed database was screened on September 2, 2024, for English-language papers reporting on pediatric patients with CNS meningeal melanocytoma. A total of 17 papers reporting on 18 patients with 19 CNS meningeal melanocytomas were found in the literature. Additionally, we reported on a 15-year-old male patient with C2-C6 meningeal melanocytoma. Pediatric cohort analysis showed nearly equal sex distribution and a mean age at diagnosis of 11.9 years. There were fifteen intracranial (75

Paediatric high-grade gliomas (pHGGs) are aggressive brain tumours and the leading cause of deaths in children. The management of pHGGs is one of the greatest challenges in paediatric oncology as those tumours are considered “cold”, immunosuppressed. Preclinical research is struggling to find new targets with the potential to revolutionise the therapeutic approach. Tumour-host interactions in the brain tumour microenvironment (TME) are poorly understood. In the HIT-GLIO project we aim to perform a comprehensive analysis of pHGG TME, define new immunological targets and compounds/strategies that would change future of those paediatric patients. We combined single-cell (sc)RNseq with 40 immune cell markers, sc-T cell receptor (TCR) profiling, Visium 10X Genomics spatial transcriptomics, multimodal CODEX (Co-detection by indexing) staining and computational approaches to define diverse immune cell types, cellular states and spatial niches that contribute to a cold TME of pHGGs. Thus far, we profiled 180,000 immune cells from biopsies and corresponding cerebrospinal fluids (CSF) of eight pHGGs, 4 diffuse midline gliomas (DMGs). We found that CD45+ cells in pHGG tissue samples predominantly comprise of CD11b+/TMEM119 microglia with less frequent immunosuppressive CD68+Gal3+macrophages, with very few CD3+ T lymphocytes. pHGG-associated microglia express transcriptomic programs related to ECM remodeling and angiogenesis, with low expression of chemokines and cytokines. Tumour-associated monocytes show low expression of inflammatory factors, and macrophages display phagocytic and immunosuppressive phenotypes. Analysis of paired scRNA/TCR sequencing data revealed the combinatorial impact of TCR utilization on phenotypic diversity and clonality of T cells in CSF and tumours. Overall, our data demonstrate the abundance of microglia, low inflammatory and chemotactic signature of pHGGs which may contribute to the lack of lymphocytes and the immunosuppressive phenotype of pHGG-associated microglia and macrophages. Studies supported by the EU Cancer Mission Horizon Europe HIT-GLIO project (101136835) founded by the European Health and Digital Executive Agency.

Abstract INTRODUCTION Infants constitute approximately 5% of all pediatric LGG. This group is identified as having aggressive course and worse prognosis as compared to older children. No specific therapeutic guidelines are yet available for this specific age group. AIM: Retrospective analysis of infants diagnosed and treated for LGG. METHODOLOGY: 25 patients treated between 2001-2023 were analyzed for: sex, age, tumor location, pathology, treatment and outcome. NF1 patients were excluded. RESULTS There were 13 boys and 12 girls, aged 3 months-11 months, median 6 months. 12 had optic chiasm tumors, 6 of visual pathway, 3 had tumors of posterior fossa, 2 of pineal region and 1 spinal tumor. Pathology was available for 16 children revealing Pilocytic astrocytoma in 9, Pilomyxoid astrocytoma in 6, ganglioglioma in 1. Resection as first line treatment was performed in posterior fossa and spinal locations, in 4 cases of visual tracts tumors. All patients were treated with chemotherapy with a maximum of 6 subsequent episodes in a patient with visual pathway tumor. MEK inhibitors were given to 3 pts (in 2 discontinued due to cardiotoxicity). Radiotherapy was applied in 5 (older than 4 years). Twenty two patients are alive, from 4 months to 22 years 4 months (median 8 years 11 months) from diagnosis. Three patients died (midline tumors) 2 from electrolyte disorders and 1 from radiation related cerebral bleeding with observation time of 3, 10, 9 years. Among children with visual tract tumors 5 are blind, 3 have impaired vision. Five patients with very good response to first line treatment have excellent quality of life. Ten patients are disabled, requiring help in everyday life. CONCLUSIONS The risk of disability or death is highest in infants of all LGG patients, those who respond the first line treatment have very good quality of life.

Diffuse intrinsic pontine gliomas (DIPGs) are deadly pediatric brain tumors, non-resectable due to brainstem localization and diffusive growth. Over 80% of DIPGs harbor a mutation in histone 3 (H3.3 or H3.1) resulting in a lysine-to-methionine substitution (H3K27M). Patients with DIPG have a dismal prognosis with no effective therapy. We show that histone deacetylase (HDAC) inhibitors lead to a significant reduction in the H3.3K27M protein (up to 80%) in multiple glioma cell lines. We discover that the SB939-mediated H3.3K27M loss is partially blocked by a lysosomal inhibitor, chloroquine. The H3.3K27M loss is facilitated by co-occurrence of H2A.Z, as evidenced by the knockdown of H2A.Z isoforms. Chromatin immunoprecipitation sequencing (ChIP-seq) analysis confirms the occupancy of H3.3K27M and H2A.Z at the same SB939-inducible genes. We discover a mechanism showing that HDAC inhibition in DIPG leads to pharmacological modulation of the oncogenic H3.3K27M protein levels. These findings show the possibility of directly targeting the H3.3K27M oncohistone.

Pediatric ependymomas are aggressive central nervous system malignancies arising from the ependymal linings of ventricles and spinal canal. Despite better understanding of tumor biology ependymomas remain therapeutic challenge in pediatric neurooncology. The role of chemotherapy remains controversial. Herein, we describe the outcomes of patients treated at the largest center in Poland who underwent surgery, pre-irradiation chemotherapy and irradiation regardless of extent of surgical resection. This retrospective review includes pediatric patients with ependymoma treated according to national protocol at the Children’s Memorial Health Institute. We reviewed histology, disease extent, treatment, and report on overall survival (OS) and progression free survival rates (PFS). Descriptive statistics were analyzed using SPSS software. Forty-nine patients were included (median age: 84 months). Most patients (96%) had cranial ependymomas (43% supratentorial and 57% posterior fossa lesions). Disseminated disease was found in 16% of cases. Complete resection was achieved in 43%. All patients received pre-irradiation chemotherapy; 6.1% had progressive disease and 41% achieved complete response (CR). All patients, except one, underwent irradiation (67% focal, 2% focal/ventricular, 29% craniospinal, and 2% whole brain). Thirty-five percent of patients relapsed. Five-year PFS and OS were 69% and 80% respectively. Comparing posterior fossa to supratentorial lesions, there was no difference in response after surgery and pre-irradiation chemotherapy (CR 37% versus 50% (p=0.51)) or irradiation (CR 42% versus 55% (p=0.37)). However, relapse was more likely in posterior fossa ependymomas (OR 0.30 IQR (0.70, 1.29), p=0.03) with lower 5-year PFS (56% versus 85%, p=0.03) and 10-year PFS (52% versus 85%, p=0.02). The benefit of chemotherapy was marked in patients with Grade 3 (5-year OS 82% versus 69%) We describe a large cohort of pediatric ependymoma patients who received pre-irradiation chemotherapy. This strategy did not negatively impact the incidence of progression before irradiation.

Supplementary Tables 1-3 from A Sex-Specific Association between a 15q25 Variant and Upper Aerodigestive Tract Cancers

BACKGROUND:Adrenocortical carcinoma (ACC) accounts for 0.2% of childhood malignancies. The most common symptom in children is rapidly progressive androgenization. Herein, we report a case of a patient with symptoms of hypercortisolaemia and androgenization, who was diagnosed with ACC.CASE PRESENTATION:In a 10-year-old patient with ACC the course of the disease was complicated by 3 recurrences. She was treated with surgery, chemo-, and radiotherapy. Currently, 8 years after the end of treatment, there have been no signs of recurrence.CONCLUSIONS:A patient after ACC treatment requires regular check-ups and long-term observation. Constant supervision enables early diagnosis of disease recurrence, and the use of treatment improves the prognosis.

Nuclear localization of HIPPO-YAP fusion proteins has been implicated in supratentorial ependymoma development. Here, unexpectedly, we find that liquid–liquid phase separation, rather than nuclear localization, of recurrent patient-derived YAP fusions, YAP-MAMLD1 and C11ORF95-YAP, underlies ependymoma tumourigenesis from neural progenitor cells. Mutagenesis and chimaera assays demonstrate that an intrinsically disordered region promotes oligomerization of the YAP fusions into nuclear, puncta-like, membrane-less condensates. Oligomerization and nuclear condensates induced by YAP fusion with a coiled-coil domain of transcriptional activator GCN4 also promote ependymoma formation. YAP-MAMLD1 concentrates transcription factors and co-activators, including BRD4, MED1 and TEAD, in condensates while excluding transcriptional repressive PRC2, and induces long-range enhancer–promoter interactions that promote transcription and oncogenic programmes. Blocking condensate-mediated transcriptional co-activator activity inhibits tumourigenesis, indicating a critical role of liquid phase separation for YAP fusion oncogenic activity in ependymoma. YAP fusions containing the intrinsically disordered region features are common in human tumours, suggesting that nuclear condensates could be targeted to treat YAP-fusion-induced cancers.

ABSTRACTDiffuse intrinsic pontine gliomas (DIPG) are deadly paediatric brain tumours, non-resectable due to brainstem localisation and diffusive growth. Patients with DIPG have a dismal prognosis of 9-12 months of survival with no effective therapy. Over 80% of DIPGs harbour a mutation in histone 3 (H3.3 or H3.1) resulting in a lysine to methionine substitution (H3K27M). H3K27M causes global epigenetic alterations (a loss of H3K27 trimethylation and an increase in H3K27 acetylation) resulting in aberrant gene expression. To date, no therapeutic strategy exists to suppress the levels of oncogenic H3K27M.We show that pan-HDAC inhibitors (HDACi) lead to the temporary but significant reduction in the H3.3K27M protein (up to 80%) in multiple glioma cell lines expressing the H3.3K27M histone variant, without changes in theH3F3AmRNA expression. The H3.3K27M occupancy at the chromatin is greatly reduced upon HDACi (SB939) treatment, as shown by ChIPseq analysis. H3.3K27M loss is most striking at SB939-upregulated genes suggesting the role in repression of these genes. In addition, genes previously reported as H3K27M-dependent become downregulated in response to SB939 treatment. We discover that the SB939-mediated loss of H3.3K27M is partially blocked by a lysosomal inhibitor, chloroquine. Moreover, the loss of H3.3K27M is facilitated by co-occurrence of H2A.Z, as evidenced by the knock-down of H2A.Z histone isoforms. ChIPseq analysis confirms the occupancy of H3.3K27M and H2A.Z at the same SB939-inducible genes.Altogether, we provide new insight into disease-specific mechanism of HDAC inhibition and demonstrate pharmacological modulation of the oncogenic H3.3K27M protein levels. These findings open a new possibility to directly target the H3.3K27M oncohistone, which may be exploited in future therapies.

Abstract Diffuse midline gliomas (DMGs) are the most challenging to treat pediatric high-grade gliomas, with a dismal prognosis of 9 to 15 months of median survival. The ones localized in the pons are not accessible to the surgery and rely on radiotherapy treatment. The majority of DMGs confer a mutation in histone 3 variants (H3.3 or H3.1), leading to lysine 27 to methionine substitution (H3K27M) and a consequent global decrease in H3K27 trimethylation (H3K27me3), increased H3K27 acetylation (H3K27ac) and oncogenic changes in gene expression. An intrinsic feature of solid tumors, including DMGs, is the occurrence of hypoxic (low oxygenated) regions, which interferes with the efficiency of radiotherapy. Identifying the vulnerabilities of hypoxia-exposed tumor cells might bring new approaches in radiosensitizing DMG tumors. Hypoxia increases histone methylation in multiple solid tumors but the consequences of hypoxia-induced histone hypermethylation in H3K27M bearing tumors are unknown. Using syngeneic patient-derived DMG cell lines, we show that the presence of H3K27M prevents the hypoxia-induced hypermethylation of H3K27me3, but also impairs the hypoacetylation of histones H3 and H4 normally caused by hypoxic stress. We show that enhancing histone acetylation in hypoxic conditions with histone deacetylase (HDAC) inhibitors has a stronger sensitization effect in cells expressing H3K27M than in H3 wild-type cells. While HDAC inhibitors have been shown problematic in pediatric DMGs due to high systemic toxicity, our data points out that HDAC inhibition in the context of hypoxia may improve the therapeutic efficacy. Recent studies showed the possibility of targeting hypoxic cells with hypoxia-activated pro-drugs, including hypoxia-activated panobinostat. Our data support that such approach might be an option to target DMGs and eliminate the radiotherapy-resistant hypoxic tumor fraction, while minimizing the systemic toxicity caused by all-time active HDAC inhibitors. Studies were supported by the grant UMO-2019/33/B/NZ1/01556 (KL) from National Science Center (Poland).

BCOR is expressed in a new brain tumour entity, i.e. 'CNS tumour with BCOR internal tandem duplication' (HGNET BCOR) but not in several other high grade paediatric brain tumours investigated. Immunohistochemical detection of BCOR expression may therefore serve as a potential diagnostic marker. Nevertheless, in rare paediatric glioma cases recurrent EP300BCOR fusions were detected, which resulted in strong BCOR immunopositivity. We have therefore examined other, not analysed so far, types of central nervous system (CNS) tumours, pineoblastoma and germinoma, to assess a potential involvement of BCOR in these tumours. Levels of BCOR RNA expression were investigated by NanoString nCounter system analysis in a series of altogether 66 high grade paediatric tumours, including four pineoblastoma cases. Immunohistological detection of BCOR was performed in eight pineoblastoma, five germinoma and four atypical teratoid rhabdoid tumours (ATRTs), all located in the pineal region. We detected BCOR expression in all pineoblastomas, at the RNA and protein levels, but not in germinomas and ATRTs. Further analysis of pineoblastoma samples did not reveal the presence of either BCOR internal tandem duplication or BCOR fusion involvement. Positive immunohistological BCOR nuclear reaction in pineoblastoma may therefore differentiate this type of tumour from other high grade tumours located in the pineal region.

Adult acute lymphoblastic leukemia (ALL) is associated with poor outcomes. ALL is initiated by primary aberrations, but secondary genetic lesions are necessary for overt ALL. In this study, we reassessed the value of primary and secondary aberrations in intensively treated ALL patients in relation to mutator enzyme expression. RT-PCR, genomic PCR, and sequencing were applied to evaluate primary aberrations, while qPCR was used to measure the expression of RAG and AID mutator enzymes in 166 adult ALL patients. Secondary copy number alterations (CNA) were studied in 94 cases by MLPA assay. Primary aberrations alone stratified 30% of the patients (27% high-risk, 3% low-risk cases). The remaining 70% intermediate-risk patients included BCR::ABL1pos subgroup and ALL lacking identified genetic markers (NEG ALL). We identified three CNA profiles: high-risk bad-CNA (CNAhigh/IKZF1pos), low-risk good-CNA (all other CNAs), and intermediate-risk CNAneg. Furthermore, based on RAG/AID expression, we report possible mechanisms underlying the CNA profiles associated with poor outcome: AID stratified outcome in CNAneg, which accompanied most likely a particular profile of single nucleotide variations, while RAG in CNApos increased the odds for CNAhigh/IKZF1pos development. Finally, we integrated primary genetic aberrations with CNA to propose a revised risk stratification code, which allowed us to stratify 75% of BCR::ABL1pos and NEG patients.