System Tumors In Children Research Articles

Novel paediatric case of a spinal high-grade astrocytoma with piloid features in a patient with Noonan Syndrome

Noonan Syndrome (NS) is associated with an increased risk of low-grade central nervous system tumours in children but only very rarely associated with high-grade gliomas. Here we describe the first reported case of a spinal high-grade astrocytoma with piloid features (HGAP) in a child with NS. This case was a diagnostic and treatment dilemma, prior to whole-genome germline and tumour sequencing, tumour transcriptome sequencing and DNA methylation analysis. The methylation profile matched strongly with HGAP and sequencing identified somatic FGFR1 and NF1 variants and a PTPN11 germline pathogenic variant. Therapeutic targets were identified but also alterations novel to HGAP such as differential expression of VEGFA and PD-L1. The germline PTPN11 finding has not been previously described in individuals with HGAP. This case underscores the power of precision medicine from a diagnostic, therapeutic and clinical management perspective, and describes an association between HGAP and NS which has not previously been reported.

Molecular pathway of anticancer effect of next-generation HSP90 inhibitors XL-888 and Debio0932 in neuroblastoma cell line

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

HGG-38. COMBINING TARGETED THERAPY AND RADIATION OUTPERFORMS SINGLE TREATMENTS IN PEDIATRIC HIGH-GRADE GLIOMA

Abstract BACKGROUND Pediatric-type diffuse high-grade gliomas (pHGGs) are a diverse group of central nervous system tumors in children and adolescents with typically fatal outcomes. Addressing this disease requires new treatment approaches to enhance both survival and quality of life for affected patients. Recently, targeting oncogenic receptor tyrosine kinases (RTKs) has provided promising initial responses in different pHGG subtypes. However, even in these cases, the disease invariably relapses. METHODS We utilized murine tumor cell cultures carrying oncogenic alterations in different RTKs, such as an NTRK fusion, an ALK fusion and activating FGFR1 mutations to evaluate the synergy of radiotherapy and a variety of specific small molecule inhibitors using viability and apoptosis assays. By conducting pharmacokinetic analyses in murine models, we quantified the availability of selected compounds in the mouse brain in vivo, informing downstream preclinical experiments. RESULTS We found that concomitant radiation potentiated the antitumor effect of all tested targeted compounds, mostly outperforming calculated additivity of single treatments. Of note, the level of potentiation was comparable between different inhibitors targeting the same RTK, but was highly dependent on the underlying tumor genotype. Using erdafitinib or futibatinib and a dose of 2 Gy in a FGFR1-driven pHGG model, the combined treatment resulted in a remarkably high late apoptosis rate of 90%, warranting ongoing in vivo studies. Through pharmacokinetic analyses, we identified that among all tested small-molecule-inhibitors, only lorlatinib and futibatinib reach clinically relevant concentrations in the murine brain. CONCLUSIONS Our preliminary data showed that the combination of targeted therapy and radiation elicits encouraging anti-tumor effects in different pHGG cultures. We are currently performing preclinical in vivo studies using immunocompetent orthotopic mouse models to evaluate benefits of combined treatment. Our data will inform future clinical trials and hopefully improve the prognosis and quality of life for a fraction of pediatric patients diagnosed with pHGG.

LGG-20. SELUMETINIB IN PEDIATRIC PATIENTS WITH RELAPSED/REFRACTORY OPTIC PATHWAY/HYPOTALAMIC LOW GRADE GLIOMA: A MONOINSTITUTIONAL EXPERIENCE

Abstract BACKGROUND Pediatric low-grade gliomas (pLGG) are the most common central nervous system tumors in children. The optic pathway and hypothalamic (OPH) frequent localizations are correlated with multiply relapses due to inoperability, thus emphasizing the need for alternative treatments. The results of activation of the BRAF oncogene through a tandem duplication resulting in a KIAA1549–BRAF fusion is the most common genetic aberration. Selumetinib is an oral mitogen-activated protein kinase (MEK) 1/2 inhibitor with promising efficacy and good tolerability on relapsed/refractory pLGG. METHODS From January 2021 to January 2024 three patients with refractory OPH-pLGG with KIIA1549-BRAF fusion were treated with Selumetinib 25 mg/sqm/day (compassionate use) all after two lines of chemotherapy. They were males, mean age at diagnosis 8 months, at starting Selumetinib 74 months. All had partial surgery at diagnosis and two of them other debulking surgeries during the treatment. All patients had numerous events of hydrocefalous with need of shunt revision. RESULTS Two patients experienced grade-3 stomatitis, one grade 3 nausea-vomiting, one grade 3 gastritis, one grade 1 increased level of CPK (CTCAE-V5.0). For grade 3 toxicity Selumetinib had to be stopped for a maximum of 7 days with clinical benefit. Two of them have completed treatment with Selumetinib, one is ongoing after 20 months, all with radiological stable disease at MRI. Median time of treatment is 26 months (range 20-30 months). All three experienced a trend in reduction of emergency room admission for ventricular-shunt problems. Median PFS at starting Selumetinib was 62 months, median OS is 97 months. CONCLUSIONS Selumetinib has a good profile of toxicity, allowing a good quality of life procrastinating radiotherapy and reducing surgery events in a context of heavily pretreated relapsed/refractory patients. Further data are needed on both visual and auxological parameters and late side effects.

QOL-32. COGNITIVE AND PSYCHOLOGICAL LATE EFFECTS IN CHILDREN AND ADOLESCENTS WITH PINEAL REGION TUMORS: A 35-YEAR-LONG EXPERIENCE IN A TERTIARY REFERRAL HOSPITAL

Abstract BACKGROUND Pineal region tumors (PRT) account for 2.8% of all central nervous system tumors in children and adolescents up to 19 years of age. Modern therapies allow more than 2/3 of patients to overcome their disease, but late effects impair quality of life of survivors. This study aimed to define the prevalence of cognitive and psychological late effects in PRT-survivors. METHODS Demographic information, medical variables, cognitive and psychological age-appropriated assessments of childhood and adolescence PRT-survivors, followed-up at Gaslini Children’s Hospital between 1988 and 2023, were retrospectively collected. Neurocognitive assessment was performed using the Wechsler scale. Psychological assessment was obtained using the Child Behavior Checklist, Beck Depression Inventory, State-Trait Anxiety Inventory, Trauma Symptom Checklist for children and Impact of Event Scale–Revised. RESULTS Sixty patients were included (53 males, 88%); median age at diagnosis was 12.8 years (Interquartile range, IQR, 9.0–15.7 years). Main entities were: germinoma (17, 28%), non-germinomatous germ cell tumor (16, 27%), bifocal germinoma (13, 22%), pineoblastoma (6, 10%), teratoma (3, 5%). 20/60 patients (33%) had neuroaxis spread, 48/60 (80%) presented hydrocephalus, 41/60 (68%) underwent surgery, 16/60 (27%) needed ventricular-peritoneal shunt, 51/60 (86%) received chemotherapy and 56/60 (93%) required radiotherapy. Median follow-up was 8.9 years (IQR 4.1–15.2). Six patients died, 5/6 died for progressive disease. Intelligence quotient (IQ) score was available for 43/60 patients with a median value of 91 (IQR 85-107). Complete cognitive and neuropsychological assessment was available for 25/60 patients showing presence of: anxiety symptoms (16/25, 64%), depression symptoms (20/25, 80%) and post-traumatic symptoms (7/25, 28%). CONCLUSIONS In our cohort, PRT-survivors showed IQ scores within expected average and a high frequency of anxiety and depression symptoms. Deeper insights into the mechanisms underlying cognitive and psychological late effects are needed, focusing on the role of demographics, treatments and disease-specific variables as well as on tumor location.

PATH-02. THE IMPACT OF EVOLVING DIAGNOSTIC METHODOLOGY ON THE CLASSIFICATION AND OUTCOME OF CENTRAL NERVOUS SYSTEM TUMOURS IN CHILDHOOD: A RETROSPECTIVE COHORT STUDY

Abstract BACKGROUND Central nervous system tumours are the second most common childhood tumours and the largest cause of childhood cancer death in Australia. Tumours arise from many cell types within the developing and mature CNS, leading to a wide spectrum of clinical behaviour despite overlapping histological appearances. Emerging molecular testing methods allow more precise determination of cell lineage as well as genetic and epigenetic changes driving tumour development. Particularly since 2016, molecular findings have been incorporated into international classification schema, potentially impacting the frequency of individual diagnoses and their observed prognosis. METHODS We performed a retrospective cohort study including patients with newly diagnosed CNS tumours at Royal Children’s Hospital, Melbourne between 2011 and 2020 (total 473). The first and last 100 eligible patients in the data set were reviewed for diagnosis, survival and recorded use of molecular testing. Reviewed patients were assigned to one of two cohorts, Cohort 1 2011-2013 (pre-2016 WHO revision) or Cohort 2 2018-2020 (post-2016 WHO revision). RESULTS The frequency of diagnoses on biopsy rather than imaging alone was stable (81% Cohort 1 vs 83% Cohort 2). Molecular testing utilization increased markedly over time (10 molecular investigations in Cohort 1 vs 348 in Cohort 2). The incidence of astrocytic and oligodendroglial diagnoses was stable. The incidence of embryonal and neuronal/ mixed glial neuronal diagnoses increased in Cohort 2, and the incidence of ependymal diagnoses decreased (p=0.0122). There were no event free or overall survival differences between the whole of Cohorts 1 and 2, with numbers of individual diagnoses too small for meaningful comparisons over time. CONCLUSIONS Access to molecular testing has impacted on the pattern of reported diagnoses of central nervous system tumours in children. Although outcomes have not changed, it is hoped that over time, improved molecular understanding will lead to more effective therapy selection.

MODL-13. ORGANOTYPIC BRAIN SLICE CULTURE PLATFORM AS A MODEL OF PEDIATRIC LOW GRADE GLIOMAS

Abstract BACKGROUND Pediatric low grade glioma (pLGG), the most common subgroup of central nervous system tumors in children, suffers from a paucity of models that support pLGG biological discovery, preclinical target identification, and drug screening studies. METHODS We propose the use of an organotypic brain slice culture (OBSC) platform as a novel model in which we are able to reliably support fresh, zero-passage pLGG patient tumor tissue for preclinical testing. We performed individualized drug screening with the frequently used up-front agents: carboplatin, vincristine, trametinib, and dabrafenib. RESULTS We have collected and established on OBSCs 100% (3/3) pLGGs since 2023. With these three patient samples, we have applied our quantitative drug screening algorithm, which combines tumor killing efficacy with healthy tissue toxicity, and yielded resultant drug sensitivity scores (DSS) to quantify patient-specific treatment efficacies. CONCLUSIONS Overall, these early results suggest that the OBSC platform may serve as a novel and reliable model for pLGG, filling a critical void in representative models for this common and often highly morbid pediatric tumor.

HGG-53. MULTI-DIMENSIONAL INTEGRATIVE PROFILING IDENTIFIES BCL2L1 METHYLATION AS A PREDICTIVE BIOMARKER FOR MCL-1 ACTIVITY IN PEDIATRIC HIGH-GRADE GLIOMAS

Abstract BACKGROUND Pediatric high-grade gliomas (pHGGs) pose a significant challenge as the most aggressive central nervous system tumors in children. The lack of effective treatment and poor survival rates emphasize the critical need for innovative therapies to improve the prognosis of pediatric patients with pHGG. METHODS We executed CRISPR-cas9 knockout (KO) screenings in 65 pediatric and 10 adult high-grade glioma (HGG) cell lines to explore unique functional dependencies associated with pHGGs. Drug assays were carried out to assess the targetability of a gene dependency of interest in pHGG cell lines. Subsequently, Random Forest machine learning algorithm was employed on ‘omics’ datasets to identify biomarkers indicative of drug response. Finally, biomarkers were confirmed through sequencing-based methods across various pediatric cancers. RESULTS CRISPR-cas9 KO screens revealed 8 crucial genes essential for pHGG growth, namely MCL-1, ATIC, DHFR, EED, HDAC2, PARP1, PDK1, PIK3CA and TYMS. Among these, Myeloid Cell Leukemia (MCL-1) was further characterized as it emerged as the top differential genetic dependency in pHGGs. Consistent with this, MCL1 inhibitors exhibited potent anti-cancer activity on 43% of pHGG cell lines. Multi-feature prediction analysis identified 140 features correlated to response. Strikingly, a previously undescribed methylation site within the BCL2L1 locus, cg00300298, ranked in the top 5% of features. Tissue analysis revealed a wide range of other pediatric brain cancers that harbor the BCL2L1 cg00300298 methylation mark as compared to non-malignant brain tissue. Lastly, we validated the utility of BCL2L1 methylation as a predictive biomarker of MCL1 inhibitor sensitivity across a large panel of pediatric brain cancer cell lines. CONCLUSION Using an integrated genomic approach, we identify MCL1 as a distinct therapeutic target in BCL2L1-methylated pediatric brain cancers. This offers a rational approach for stratifying patients who may benefit from MCL1 inhibitors.

Overview of European standard clinical practice recommendations for multidiscplinary teams involved in the treatment of central nervous system tumours in children and adolescents – SIOPE Brain Tumour Group

Tumours of the central nervous system (CNS) represent the most common group of solid tumours in children and adolescents up to the age of 18 years. They comprise several biological entities, subgroups, and subtypes. These subtypes and additional factors, including age at diagnosis, location, stage, or genetic characteristics of the tumours result in a very heterogeneous spectrum of treatment-relevant strata for risk-adapted multimodal treatment recommendations, clinical courses, and long-term outcomes. Multidisciplinary teams with highly experienced members are needed to treat these children and adolescents to achieve the best possible outcome in the short and long-term. This is particularly important for the new CNS tumour entities with no established standard of care. On behalf of the Brain Tumour Group of the European Society for Paediatric Oncology, we summarize the key statements of the involved disciplines that need to cooperate in the diagnosis and risk-adapted treatment of children with CNS tumours: neuroradiology, neurosurgery, neuropathology, radiotherapy, endocrinology, neuro-ophthalmology, and quality of survival professionals, covering what should be considered standard clinical practice for diagnostic assessments, treatment modalities, and follow-up of children with CNS-tumours.

Поліморфізм клінічних проявів орфанних захворювань у дітей із мутаціями генів ARID1A та ARID1B

The Department of Psychoneurology for Children with Perinatal Pathology and Orphan Diseases at the SI “Institute of Pediatrics, Obstetrics and Gynecology named after academician O.M. Lukyanova of the NAMS of Ukraine” has a multidisciplinary team which provides care to children with orphan diseases from all over Ukraine. Thanks to modern methods of clinical, instrumental and genetic diagnostics, it is possible to establish a definitive diagnosis. Aim - to provide a literature review and a clinical case of a child with pathogenic variants of the ARID family genes, which, in particular, lead to the development of Coffin-Circe syndrome (CCS), autism spectrum disorder and intellectual disability, as well as the development of nervous system tumors in children. The article presents a clinical case of a child with a rare disease - CCS, which is part of the ARID gene mutation spectrum. The general clinical and neurological examination, electroencephalographic sleep monitoring, magnetic resonance imaging, whole-exome sequencing, and pathological examination were performed. The difficulty of diagnosis was that a child with skin manifestations of phacomatosis was diagnosed with subependymal giant cell astrocytoma (SGСA) by magnetic resonance imaging, but there were no mutations characteristic of tuberous sclerosis (TSC1, TSC2). Pathologically, the patient was confirmed to have grade I SGСA according to the World Health Organization classification. Two pathogenic mutations of the ARID1A gene in the compound heterozygous state were detected by whole-exome sequencing. After combining the combined clinical and instrumental signs, the diagnosis of CCS with grade I SGСA was established. Conclusions. The disorders caused by ARID1A and ARID1B mutations belong to a spectrum that includes syndromic and non-syndromic cases of intellectual disability, autism spectrum disorder, and CCS with or without a variety of somatic and neurological symptoms, and are grouped under the general term “ARID-related disorders”. Only a thorough medical history, clinical examination, and modern methods of instrumental and genetic diagnostics can make a diagnosis. The research was carried out in accordance with the principles of the Declaration of Helsinki. Informed consent of the women was obtained for the research. No conflict of interests was declared by the authors.

Do routine questions provide reliable information about the patient’s diet: the results of the survey of parents of children with brain tumors being on the 2nd rehabilitation period

Introduction. The course of central nervous system tumors in children and their therapy are associated with nutritional disorders that persist after the end of antineoplastic treatment. It is important to determine nutritional problems, which is usually carried out in the form of a survey by a physician. He also needs to be aware and understand the degree of fulfillment of appointments by patient at home.Aim. To study the problems of organizing nutritional support for children with tumors of the central nervous system after the end of antitumor treatment.Materials and methods. A cross-sectional study was conducted, which included a survey, involving the parents of 71 patients with central nervous system tumors, aged 10 to 18 years, undergoing routine rehabilitation at the Russian Field Medical and Rehabilitation Scientific center. The survey included questions that a nutritionist usually asks during a consultation, with answer options, as well as a description of the diet and usual food intake. Anthropometry data (z-score of height-on-age, BMI) are included.Results. 45% of the children had deviations in BMI. The answers to the routine questions “What is the child’s appetite” and “Are there (any) problems with nutrition” were the most uninformative, did not coincide with the actual composition of the diet and food intake. More accurately, the parents answered the questions “Are there (any) problems with diet/regimen organization” and “... associated with eating”. 21 children were prescribed diets (gentle and “low-carb”), but only 6 followed these diets. 58% noted periodic “physical exhaustion”, only 7% are engaged in physical therapy at home. Only 2 children received nutritional support at home. An analysis of the composition of the diet and diet revealed significant problems in 61% of children.Conclusion. In a routine medical survey, simple questions about appetite and “are there any problems with nutrition” are not enough. Simple anthropometry is not enough. The survey has shown its effectiveness, but an analysis of the questionnaire is needed. Not all patients can follow dietary recommendations, it is necessary to take into account the motivation and understanding of both parents and children.

Terson’s Syndrome due to Ependymoma: A Rare Case Report

Abstract
 Introduction : Terson's syndrome is often associated with subarachnoid hemorrhage. Other reported causes, include trauma, tumors, hypertension, perioperative and postoperative intracranial hemorrhage, or increased intracranial pressure. This case demonstrates a unique pathogenesis of Terson's syndrome.
 Case Illustration : A 14-year-old boy presented with the blurred vision on both eyes 3 weeks ago, accompanied with nausea, vomiting, and headache, with normal blood pressure measurement (126/80mmHg). He also had a history of head injury. His visual acuity was 6/20 uncorrected with pinhole on both eyes. Both intraocular pressures within normal limits. The anterior segment showed bilateral mid-dilated reactive pupil. Funduscopy revealed bilateral papilledema with peripapillary hemorrhage, similar to retinal vein occlusion, which is suggestive with Terson’s Syndrome. Magnetic Resonance Imaging (MRI) scan showed an ependymoma mass. We consulted this case with Pediatric Neurosurgeon, who planned for ventriculoperitoneal shunt with craniotomy tumor removal.
 Discussion : Terson's syndrome now defined as any intraocular hemorrhage associated with intracranial hemorrhage or elevated intracranial pressures. In this case, the etiology was thought to be increased intracranial pressure, which may be caused by ependymoma. Ependymoma is one of the most common central nervous system tumors in children. Intraocular hemorrhage in Terson’s syndrome is often self-limiting, but ependymoma needs neurosurgical intervention, which has lower survival rates for children with posterior fossa tumors.
 Conclusion : There are still controversies regarding the pathogenesis of Terson's syndrome. Not the occlusion, but the compression of the central retinal vein, by the increased pressure of cerebrospinal fluid due to high intracranial pressure, which increases the retinal venous pressure and causes retinal hemorrhage.

Laser interstitial thermal therapy as a radiation-sparing approach for central nervous system tumors in children with cancer predisposition syndromes: report of a child with Li-Fraumeni syndrome. Illustrative case.

Ionizing radiation and alkylating chemotherapies increase secondary malignancy risk in patients with cancer predisposition syndromes (CPSs), such as Li-Fraumeni syndrome. Laser interstitial thermal therapy (LITT) is a minimally invasive ablation technique that has not been associated with mutagenic risks. We describe the case of a child with LFS and a history of treated choroid plexus carcinoma (CPC) who developed a second primary glial tumor that was safely treated with magnetic resonance imaging (MRI)-guided LITT. A 4-year-old male with left parietal World Health Organization grade III CPC associated with a TP53 germline mutation was evaluated. The patient underwent neoadjuvant platinum-based chemotherapy before near-total resection, followed by 131I-8H9 immunotherapy and 30 fractions of 54-Gy proton radiotherapy. He remained without evidence of disease for 2 years before developing a slow-growing mass adjacent to the left frontal ventricular horn. Stereotactic biopsy revealed a glial neoplasm. Given the nonsuperficial location and focality of the lesion, MRI-guided LITT was performed for ablative therapy. There were no complications, and 2 years of surveillance revealed continued retraction of the ablated tumor focus and no subsequent disease. Alternatives to mutagenic therapies for brain tumors should be explored for patients with CPS. LITT paired with imaging surveillance is a logical strategy to ensure durable outcomes and mitigate treatment-related secondary neoplasms.

Posterior Fossa Tumors Special Edition. Celebrating 4 years!

Posterior fossa tumors account for approximately half of the central nervous system tumors in children. Major technological advances, mainly in the fields of molecular biology and neuroimaging, have modified their classification, leading to a more detailed description of these entities. Certain modifications in the general nomenclature introduced by the 2021 WHO classification of tumors of the CNS have an impact on how we approach the posterior fossa tumors described in this study. The focus of this annual special issue is posterior fossa tumors in children. There were several emerging technologies and approaches in the diagnosis and treatment of posterior fossa tumors in children. It's important to note that medical technology and research are continually evolving, so there may have been further advancements in this field since then. Here are some promising technologies and strategies that were being explored: Advanced Imaging Techniques: Functional MRI (fMRI): This technology helps in mapping the brain's functional areas, allowing surgeons to plan their approach more accurately and minimize damage to critical brain regions. Diffusion Tensor Imaging (DTI): DTI provides information on the brain's white matter tracts, aiding surgeons in preserving essential neural pathways during surgery. Spectroscopy: It helps in identifying tumor types and differentiating between tumor tissue and healthy brain tissue. Surgical Navigation Systems: The use of advanced navigation systems during surgery allows for precise tumor localization and safer tumor removal, minimizing damage to surrounding healthy tissue. Brain Ultrasound and iMRI: Some hospitals are equipped with iMRI suites that allow real-time imaging during surgery. Most common brain ultrasound helps a lot during the posterior fossa surgery and can use simultaneously with neuronavigation system. Minimally Invasive Techniques: Minimally invasive procedures, such as endoscopic surgery, are being explored for certain types of posterior fossa tumors. These techniques can reduce recovery times and complications. Intraoperative monitoring (IOM), also known as intraoperative neurophysiological monitoring (IONM), is a critical technique used during certain surgeries to monitor the nervous system's function in real-time. It helps surgeons and medical teams assess the integrity of neural structures, particularly the brain and spinal cord, during surgical procedures. Genomic and Molecular Analysis: Advances in genomic and molecular analysis of tumors can provide insights into the specific genetic mutations driving the tumor's growth. This information can help guide treatment decisions, including targeted therapies. Radiation Therapy Advancements: Techniques like proton therapy and stereotactic radiosurgery are being used to precisely target tumors while minimizing damage to surrounding healthy tissue, which is especially important in pediatric cases. Immunotherapy: Immunotherapy approaches, such as checkpoint inhibitors, are being investigated for their potential in treating certain types of posterior fossa tumors in children. These therapies aim to harness the body's immune system to fight the tumor. Personalized Medicine: Tailoring treatment plans to the individual characteristics of each patient's tumor is becoming increasingly important. This includes considering factors such as tumor genetics, location, and the child's overall health. Telemedicine and Remote Consultations: Telemedicine technologies enable pediatric neuro-oncologists to collaborate with experts worldwide, improving the quality of care, especially in regions with limited access to specialized healthcare. This special issue covers the different aspects of posterior fossa tumors surgery. We wish to thank all the authors for their tremendous contributions, and we hope that you will have the same interest and pleasure to read this special issue as we have had to edit it.

Exposição a agrotóxicos e o risco de tumores do Sistema Nervoso Central em crianças: revisão sistemática com metanálise

Abstract Central Nervous System (CNS) tumors represent more than half of all childhood malignant neoplasms. The aim of this study was to determine the relationship between environmental exposure to pesticides and the development of CNS tumors in children. We conducted a systematic review of the literature in the PubMed/MEDILINE, Embase, Web of Science, Scopus, and CINAHL databases. The inclusion criteria were cohort and case-control studies investigating the association between exposure to pesticides and CNS tumors (all histological types included in group III of the WHO Classification of Childhood Cancer) in children aged 0-14 years. The meta-analysis was performed using a random effects model and the Mantel-Haenszel method. Strength of association was measured using odds ratios (OR). The review was registered in the International Prospective Register of Systematic Reviews (PROSPERO) under identification number CRD42021209354. The search identified 1,158 studies, 14 of which were included in the review. There was evidence of an association between the development of astrocytomas and exposure to all classes of pesticides (OR 1.50; 95%CI 1.15-1.96; p=0.03). The synthesis of the evidence pointed to a relationship between exposure to pesticides and some histological types of CNS tumors in childhood.

Pesticide exposure and risk of Central Nervous System tumors in children: a systematic review with meta-analysis.

Central Nervous System (CNS) tumors represent more than half of all childhood malignant neoplasms. The aim of this study was to determine the relationship between environmental exposure to pesticides and the development of CNS tumors in children. We conducted a systematic review of the literature in the PubMed/MEDILINE, Embase, Web of Science, Scopus, and CINAHL databases. The inclusion criteria were cohort and case-control studies investigating the association between exposure to pesticides and CNS tumors (all histological types included in group III of the WHO Classification of Childhood Cancer) in children aged 0-14 years. The meta-analysis was performed using a random effects model and the Mantel-Haenszel method. Strength of association was measured using odds ratios (OR). The review was registered in the International Prospective Register of Systematic Reviews (PROSPERO) under identification number CRD42021209354. The search identified 1,158 studies, 14 of which were included in the review. There was evidence of an association between the development of astrocytomas and exposure to all classes of pesticides (OR 1.50; 95%CI 1.15-1.96; p=0.03). The synthesis of the evidence pointed to a relationship between exposure to pesticides and some histological types of CNS tumors in childhood.

HGG-20. NOVEL PAEDIATRIC CASE OF A SPINAL HIGH-GRADE ASTROCYTOMA WITH PILOID FEATURES IN A PATIENT WITH NOONAN SYNDROME

Abstract Noonan Syndrome (NS) is a genetic condition, known to be associated with low grade central nervous system tumours in children but only very rarely associated with high-grade gliomas. Here we describe the first reported case of a spinal high-grade astrocytoma with piloid features (HGAP) in a child with NS. This case presented as a diagnostic and treatment dilemma, prior to comprehensive molecular profiling with whole-genome germline and tumour sequencing, tumour transcriptome sequencing and DNA methylation analysis. The methylation profile was a strong match for HGAP and was critical to establish this child’s diagnosis, as this is an essential diagnostic criteria for confirmation of this relatively new tumour group. Sequencing results identified activation of the MAPK signalling pathway with somatic variants in FGFR1 and NF1 and the previously known germline pathogenic variant in PTPN11. The somatic molecular profile was consistent with those previously reported in other HGAP case series and reports, whereas the germline finding has not been previously described in individuals with this tumour type. This patient’s molecular profile adds to the small group of paediatric cases reported in the literature, continuing to expand our understanding of this new WHO diagnostic category. Confirmation of this rare diagnosis was critical to this child’s management and targetable aberrations were identified, providing alternative therapeutic options. The therapeutic targets included known drivers within the MAPK pathway, but also changes not previously associated with HGAP such as differential expression of VEGFA and PD-L1. Together this case underscores the power of precision medicine from a diagnostic, therapeutic and clinical management perspective, and describes an association between HGAP and NS which has not previously been reported.

DIPG-27. DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG) CHALLENGE: FROM GENE EXPRESSION PROFILE TO DRUG

Abstract Diffuse intrinsic pontine glioma (DIPG) accounts for 80% of pediatric brainstem tumors and about 10-20% of all central nervous system tumors in childhood. Despite the adoption of aggressive therapeutic approaches, DIPG remains the leading cause of cancer-related mortality in childhood: prognosis is still poor with more than 90% of affected children dying within 18-24 months from the diagnosis.1 Decades of clinical attempts involving more than 200 trials evaluating different conventional cytotoxic drugs, targeted drugs and studies with radiation dose escalating and new radio sensitizing agents, have failed to improve the overall survival of children with DIPG. Since available drugs have proven no benefits hereto for DIPG, it is fundamental to gain insights into the gene expression profile of DIPG patients and speed up the discovery of novel therapeutics for this dismal malignancy. Only the compound ONC201 was discovered to reduce DIPG tumors size in DIPG H3K27M mutated and now is in phase III clinical trials. Given the complex molecular mechanisms underlying DIPG, it would be necessary to fully utilize gene expression profiles to build a fully knowledge of DIPG-related genes and pathways. Preliminarily, the gene expression profile of eight pediatric DIPG samples and two primary pontine tissue samples was downloaded and analyzed starting from the Gene Expression Omnibus (GEO) database2. The GEO data were used to evaluate the differentially expressed genes (DEGs) in the pediatric DIPG samples. Subsequently, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and Reactome pathways of DEGs were enriched, integrated, and analyzed to find out genes and signaling pathways involved in the biological and clinic-pathological features of DIPG. More data are being to be added to our meta-analysis.

HGG-07. OVEREXPRESSION OF A PLAG-FAMILY TRANSCRIPTION FACTOR DURING MURINE BRAIN DEVELOPMENT CAUSES BRAIN TUMOR FORMATION

Abstract Pediatric-type gliomas are the most common type of central nervous system tumors in children. They are highly diverse regarding their molecular entities and clinical associations, and they differ from their adult counterparts. A subset of pediatric-type high grade gliomas, including H3K27M mutated diffuse midline glioma, overexpresses the developmentally regulated transcription factor gene PLAG1. Two novel tumor types displaying amplifications or fusions with the related PLAGL1 and PLAGL2 genes have also recently been described (PMIDs 36437415, 34355256). How PLAG-family dysregulation drives tumor formation is currently unknown, however. We generated a novel mouse model that overexpresses hPLAG1 during brain development using a Cre-LoxP approach. Mice that overexpress hPLAG1 together with loss of trp53 in the Nestin-Cre lineage develop brain tumors by 3 months of age with 100 % penetrance. Intriguingly, tumors develop in different brain regions, with hotspots in the thalamus or inferior hypothalamus, the latter likely emerging from the brainstem. All mouse brains contain regions in the brainstem, thalamus and the prefrontal cortex with diffuse patterns of PLAG1+; KI67+ proliferating single cells. Using bulk-RNA sequencing, we identified several genes involved in embryonic brain development, which are still active in the tumors of adult mice. We hypothesize that continued overexpression of PLAG1 locks cells in an aberrant developmental state, making them susceptible for further oncogenic hits and ultimately leading to pediatric glioma formation. We are currently using single-nucleus RNA-seq to determine the developmental trajectories of single tumor cells to identify putative cells-of-origin and primary developmental pathways. Our work will elucidate the consequences of PLAG1 overexpression in pediatric brain tumors and its contribution to tumorigenesis. In the future, we hope to identify genetic dependencies of PLAG1 to generate novel treatment options.

Predictive Factors for Pediatric Craniopharyngioma Recurrence: An Extensive Narrative Review.

Despite being classified as benign tumors, craniopharyngiomas (CPs) are associated with significant morbidity and mortality due to their location, growth pattern, and tendency to recur. Two types can be identified depending on age distribution, morphology, and growth pattern, adamantinomatous and papillary. The adamantinomatous CP is one of the most frequently encountered central nervous system tumors in childhood. Our aim was to review the relevant literature to identify clinical, morphological, and immunohistochemical prognostic factors that have been implicated in childhood-onset CP recurrence. Lack of radical surgical removal of the primary tumor by an experienced neurosurgical team and radiotherapy after a subtotal excision has been proven to significantly increase the recurrence rate of CP. Other risk factors that have been consistently recognized in the literature include younger age at diagnosis (especially <5 years), larger tumor size at presentation, cystic appearance, difficult tumor location, and tight adherence to surrounding structures, as well as the histological presence of whorl-like arrays. In addition, several other risk factors have been studied, albeit with conflicting results, especially in the pediatric population. Identifying risk factors for CP recurrence is of utmost importance for the successful management of these patients in order to ultimately ensure the best prognosis.