Primary Brain Tumors In Children Research Articles

Evaluation of KIAA1549::BRAF fusions and clinicopathological insights of pilocytic astrocytomas

BackgroundPilocytic astrocytoma (PAs) represents a significant portion of childhood primary brain tumors, with distinct histological and radiological features. The prevalence of KIAA1549::BRAF fusion in PAs has been well-established, this study aims to assess the prevalence of KIAA1549::BRAF fusions and explore their associations with tumor characteristics, radiological findings, and patient outcomes in PAs. MethodsHistologically confirmed cases of PAs from a 5-year period were included in the study. Demographic, histopathological, and radiological data were collected, and immunohistochemistry was performed to characterize tumor markers. FISH and qRT-PCR assays were employed to detect KIAA1549::BRAF fusions. Statistical analyses were conducted to examine associations between fusion status and various other parameters. ResultsHistological analysis revealed no significant differences in tumor features based on fusion status. However, younger age groups showed higher fusion prevalence. Radiologically, fusion-positive cases were distributed across different tumor subtypes SE, CWE and NCWE. Survival analysis did not demonstrate a significant impact of fusion status on overall survival, however most cases with recurrence and death harboured KIAA1549::BRAF fusion. Of 200 PAs, KIAA1549::BRAF fusions were detected in 64 % and 74 % of cases via qRT-PCR and FISH, respectively. Concordance between the two platforms was substantial (86 %). ConclusionKIAA1549::BRAF fusions are prevalent in PAs and can be reliably detected using both FISH and qRT-PCR assays. Cost considerations suggest qRT-PCR as a more economical option for fusion detection in routine clinical practice.

Rebound growth of BRAF mutant pediatric glioma cells after MAPKi withdrawal is associated with MAPK reactivation and secretion of microglia-recruiting cytokines

IntroductionPatients with pediatric low-grade gliomas (pLGGs), the most common primary brain tumors in children, can often benefit from MAPK inhibitor (MAPKi) treatment. However, rapid tumor regrowth, also referred to as rebound growth, may occur once treatment is stopped, constituting a significant clinical challenge.MethodsFour patient-derived pediatric glioma models were investigated to model rebound growth in vitro based on viable cell counts in response to MAPKi treatment and withdrawal. A multi-omics dataset (RNA sequencing and LC-MS/MS based phospho-/proteomics) was generated to investigate possible rebound-driving mechanisms. Following in vitro validation, putative rebound-driving mechanisms were validated in vivo using the BT-40 orthotopic xenograft model.ResultsOf the tested models, only a BRAFV600E-driven model (BT-40, with additional CDKN2A/Bdel) showed rebound growth upon MAPKi withdrawal. Using this model, we identified a rapid reactivation of the MAPK pathway upon MAPKi withdrawal in vitro, also confirmed in vivo. Furthermore, transient overactivation of key MAPK molecules at transcriptional (e.g. FOS) and phosphorylation (e.g. pMEK) levels, was observed in vitro. Additionally, we detected increased expression and secretion of cytokines (CCL2, CX3CL1, CXCL10 and CCL7) upon MAPKi treatment, maintained during early withdrawal. While increased cytokine expression did not have tumor cell intrinsic effects, presence of these cytokines in conditioned media led to increased attraction of microglia cells in vitro.ConclusionTaken together, these data indicate rapid MAPK reactivation upon MAPKi withdrawal as a tumor cell intrinsic rebound-driving mechanism. Furthermore, increased secretion of microglia-recruiting cytokines may play a role in treatment response and rebound growth upon withdrawal, warranting further evaluation.

Epidemiology and Anatomical Distribution of Primary Brain Tumors Among Children in Palestine: A 6-Year National Referral Institution Study

ObjectiveThe purpose of this research was to investigate the incidence rate of primary brain tumors (PBTs) among Palestinian children over a 6-year interval. Additionally, the study aimed to identify the predominant histopathological types identified in these children. MethodsThis retrospective epidemiologic study focused on PBTs in children (< 15 years) in Palestine. The data were collected from the registry system at Al-Makassed Hospital in Jerusalem, a prominent referral institution in Palestine and the largest center for PBTs in the region, over a 6 years period from 2018 to 2023. ResultsThe incidence rate of PBTs in children (<15 years) was 1.33 per 100,000 person-years, with a 5% mortality rate. Pilocytic astrocytoma was the most common type (24%), followed by medulloblastoma (15.2%), and glioblastoma (6.3%). About half of the tumors in children were malignant. Headaches were the most common first sign or symptom. About 20% of brain tumors in children were situated within the ventricles, making it the most prevalent location of these tumors, followed by the cerebellum (15.19%), and frontal lobe (11.39%). ConclusionThis is the first national study in Palestine investigating PBTs in children. The crude incidence rate of primary brain tumors among Palestinian children was lower than the incidence rate in many countries around the world. It is recommended that more research be done on the epidemiology and distribution of PBTs in children in Palestine.

Pediatric craniopharyngioma: a 20-year study on epidemiological features, clinical presentation, and survival outcomes in a tertiary care center from LMIC.

Craniopharyngioma constitutes approximately 10% of primary brain tumors in children. It can cause considerable morbidity and mortality due to the local aggressiveness of the tumor itself or its management affecting the hypothalamus-pituitary axis and optic pathway involvement. There is very scarce data available from LMIC which makes the management controversial where multidisciplinary teams are already not available in most of the centers. This is a single-center cross-sectional retrospective review of 20-year record of 49 patients with craniopharyngioma treated between 2001 and 2020 at Aga Khan University Hospital, a tertiary care center in Karachi, Pakistan. We have assessed the epidemiological data of children presenting with the diagnosis of craniopharyngioma, treatment modalities used, and neurological, endocrine, and hypothalamic complications in these patients. The assessment involved a retrospective review of medical records and medical follow-up. Out of a total of 49 patients, 26 (53%) were male, and 23 (46.9%) were female. The mean age was 9.5years (SD ± 4.5years). Most common symptoms at initial presentation were headache 41 (83.6%), visual deficit 40 (81.6%), nausea and vomiting 26 (53%), and endocrine abnormalities 16 (32%). Treatment modalities used at our center include gross total resection 11 (22%) and subtotal resection 38 (77%) out of total, while 6 (12.2%) patients received intracystic interferon. Histopathologic findings of the majority of patients (40 (81%)) revealed an adamantinomatous type of tumor. Only 23 (46.9%) children followed in clinic post-op. Median follow-up after craniopharyngioma presentation was 5years (± 2.1 SD, range: 2-10years). Pituitary hormone deficiencies (98%) and visual disturbances (75%) were the most common long-term health conditions observed. Since pituitary hormone deficiencies and visual disturbance were the most common long-term health conditions observed in our study, these patients require a multidisciplinary team follow-up to improve their quality of life.

Socio-demographic and antenatal risk factors of brain tumor in children and young people: A matched case-control study from Karachi, Pakistan.

Brain tumors are a common cause of morbidity, disability, cognitive deterioration and mortality in children, even after treatment. Little is know about the specific causes. The study aimed to assess potential socio-demographic and antenatal factors in primary brain tumor (PBTs) in children and young people (CYP) in Karachi, Pakistan. A single center hospital based matched case control study in Karachi, Pakistan. Cases were defined as CYP aged between 5 and 21 years with any histological type and grade of primary brain tumor of any histology, stage or grade. Data were collected from parents of 244 patients at the selected center between 2017 and 2021 via telephonic interview. Controls were 5-21 years old CYP admitted with non-oncological diagnoses matched on age and sex. Matched Odds Ratios for predictors of brain tumor in children were derived. Those of statistical significance were included in a multivariable logistic regression model. In the adjusted model, lower paternal education (matched adjusted odds ratio (maOR) 2.46; 95% CI 1.09-5.55), higher household monthly income (maOR 3.4; 95% CI 1.1-10.2), antenatal paternal use of addictive substances (maOR 19.5; 95% CI 2.1-179.8), and antenatal maternal use of analgesics during pregnancy (maOR 3.0; 95% CI 1.2-7.9) were all independently predictive of brain tumors. This matched case-control study found novel associations between maternal use of analgesics, paternal use of addictive substances, higher household income, and lower paternal education and Primary Brain Tumors in Children and Young People. Longitudinal multicenter studies will be required to test these associations prospectively.

Prognostic Values of Core Genes in Pilocytic Astrocytom

Pilocytic astrocytoma (PA) is the most common primary brain tumor in children and adolescents. Treatment strategy largely depends on its key genes and molecular mutations. This study aimed to identify potential biomarkers of PA closely related to its prognosis. The gene expression profiles (series numbers GSE50161, GSE66354, and GSE86574) of PA and normal brain tissues were downloaded from the Gene Expression Omnibus database. The Gene Expression Omnibus2R was used to identify differentially expressed genes. The overlapping differentially expressed genes were subjected to Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses using the Database for Annotation, Visualization, and Integrated Discovery (DAVID) database. A protein-protein interaction network was constructed using Search Tool for the Retrieval of Interacting Genes (STRING) and Cytoscape. The Gene Expression Profiling Interactive Analysis 2 (GEPIA2) tool analyzed the impact of hub genes on PA prognosis based on the Kaplan-Meier curves. Compared with normal brain tissues (n= 36), a total of 37 upregulated and 144 downregulated genes were identified in PA (n= 40). In the protein-protein interaction network construction and GEPIA2 survival analysis, 2 of the top 10 hub genes were significantly associated with decreased overall survival of PA patients, namely Gamma-aminobutyric acid A receptor alpha 2 (hazard ratio = 2.8, P < 0.01) and regulating synaptic membrane exocytosis protein 1) (hazard ratio= 3.2, P < 0.01). This bioinformatics analysis reveals that low expression of Gamma-aminobutyric acid A receptor alpha 2 and regulating synaptic membrane exocytosis protein 1 is associated with a favorable prognosis for PA patients. These 2 hub genes could be novel biomarkers for prognosis assessment, furthermore a key element for treatment decisions in the future.

Targeting the IGF-Axis in Cultured Pediatric High-Grade Glioma Cells Inhibits Cell Cycle Progression and Survival.

Pediatric high-grade gliomas (pHGG) accounts for approximately 8-12% of primary brain tumors in children. Prognosis is poor, with a median survival of 9-15 months. Insulin-like growth factor 1-receptor (IGF-1R) gene amplifications have been identified in high-grade gliomas and may contribute to its highly aggressive phenotype, but the effect of IGF inhibitors on pHGG is yet to be determined. In the present study, we analyzed the response of patient-derived pediatric high-grade glioma cells to a novel IGF-1R inhibitor, the IGF-Trap. Using immunohistochemistry, we found that IGF-1R was localized to both the nucleus and cell membrane in different pHGG patient-derived xenograft (PDX) lines under basal conditions. In response to ligand binding, nuclear levels of the receptor increased, and this was associated with the transcriptional upregulation of both the receptor and cyclin D1, suggesting that IGF-1R could regulate its own expression and cell cycle progression in these cells. Insulin-like growth factor-1 (IGF-1) increased the proliferation of the pHGG cells DIPG13 and SGJ2, and this could be blocked by the addition of the IGF-Trap. The IGF-Trap reduced the colony formation of these cells in an optimal growth medium and impeded the ability of IGF-1 to rescue DIPG13 cells from starvation-induced apoptosis. Collectively, these results implicate the IGF-1 axis in the regulation of cell cycle progression, cellular proliferation, and cell survival in pHGG, and identify the IGF-axis as a target and the IGF-Trap as a potential inhibitor of this axis in pHGG.

Characterizing the biology of primary brain tumors and their microenvironment via single-cell profiling methods.

Genomic and transcriptional heterogeneity is prevalent among the most common and aggressive primary brain tumors in children and adults. Over the past 20 years, advances in bioengineering, biochemistry and bioinformatics have enabled the development of an array of techniques to study tumor biology at single-cell resolution. The application of these techniques to study primary brain tumors has helped advance our understanding of their intra-tumoral heterogeneity and uncover new insights regarding their co-option of developmental programs and signaling from their microenvironment to promote tumor proliferation and invasion. These insights are currently being harnessed to develop new therapeutic approaches. Here we provide an overview of current single-cell techniques and discuss relevant biology and therapeutic insights uncovered by their application to primary brain tumors in children and adults.

Pilocytic astrocytoma of the cerebellopontine angle: a rare case

BackgroundPilocytic astrocytomas are the most common primary brain tumors in children. Most of the lesions occur in or near the midline. They are rare in extra-axial locations.Case presentationWe report a 23-year-old lady who was found to have progressive right-sided sensorineural hearing loss and features of raised intracranial pressure due to a pilocytic astrocytoma of the right cerebellopontine angle. After an extensive Medline search, we could find only three cases of primary extra-axial pilocytic astrocytoma of the cerebellopontine angle (CPA) reported till now.ConclusionEven a rare occurrence, primary pilocytic astrocytoma, and in general gliomas, should be kept in mind in the differential diagnosis of CPA lesions.

LGG-17. Preventing recurrence: targeting molecular mechanisms driving tumor growth rebound after MAPKi withdrawal in pediatric low-grade glioma

Pediatric low-grade gliomas, a diverse group of WHO grade 1 and 2 glial or glioneural tumors, comprise the most common category of primary brain tumors in children. The majority of these tumors are driven by alterations in the MAPK pathway, making them in principle susceptible to MAPKi therapy. While patients often benefit from MAPKi during treatment, tumor rebound may occur once treatment is stopped, constituting a significant clinical challenge. BT-40, patient-derived cells with molecular features of pleomorphic xanthoastrocytoma (BRAFV600E, CDKN2Adel), were used to model the rebound growth in vitro, based on viable cell counts in response to treatment and withdrawal of the clinically relevant BRAFV600E specific inhibitor dabrafenib. Standard-of-care chemotherapy (vincristine and carboplatin) was used as a reference. MAPK pathway reactivation upon withdrawal was assessed by WB and qPCR analysis. Based on the observed cell-regrowth and MAPK-reactivation pattern, key-timepoints during withdrawal were identified, which are currently being further analyzed through RNAseq and phospho-/proteomics. BT-40 cells started to proliferate again two days after dabrafenib withdrawal, and earliest five days after chemotherapy withdrawal. MAPK pathway activity, based on Mek and Erk phosphorylation, reached baseline levels three hours after dabrafenib withdrawal, this was associated with 2.5-fold increased c-Fos gene expression two hours after withdrawal. The earlier cell regrowth after dabrafenib withdrawal compared to chemotherapy withdrawal matches clinical observations, making the model suitable to study the rebound. The observed MAPK overactivation suggests the growth rebound might not only be caused by a fast reactivation of the pathway but also by other mechanisms, e.g. accumulation of upstream activators due to loss of negative feedback or parallel pathways. To investigate this, key-timepoints during treatment withdrawal will be analyzed using a multi-omics approach. Based on these findings, possible rebound-driving mechanisms will be identified and further validated using BT-40 and additional PXA models in vitro and in vivo.

Advances in Chimeric Antigen Receptor (CAR) T-Cell Therapies for the Treatment of Primary Brain Tumors.

Immunotherapy has revolutionized the care of cancer patients. A diverse set of strategies to overcome cancer immunosuppression and enhance the tumor-directed immune response are in clinical use, but have not achieved transformative benefits for brain tumor patients. Adoptive cell therapies, which employ a patient’s own immune cells to generate directed anti-tumor activity, are emerging technologies that hold promise to improve the treatment of primary brain tumors in children and adults. Here, we review recent advances in chimeric antigen receptor (CAR) T-cell therapies for the treatment of aggressive primary brain tumors, including glioblastoma and diffuse midline glioma, H3 K27M-mutant. We highlight current approaches, discuss encouraging investigational data, and describe key challenges in the development and implementation of these types of therapies in the neuro-oncology setting.

Magnetic Resonance Imaging in the Contemporary Management of Medulloblastoma: Current and Emerging Applications.

Medulloblastoma, the most common malignant primary brain tumor in children, is now considered to comprise of four distinct molecular subgroups-wingless (WNT), sonic hedgehog (SHH), Group 3, and Group 4 medulloblastoma, each associated with distinct developmental origins, unique transcriptional profiles, diverse phenotypes, and variable clinical behavior. Due to its exquisite anatomic resolution, multiparametric nature, and ability to image the entire craniospinal axis, magnetic resonance imaging (MRI) is the preferred and recommended first-line imaging modality for suspected brain tumors including medulloblastoma. Preoperative MRI can reliably differentiate medulloblastoma from other common childhood posterior fossa masses such as ependymoma, pilocytic astrocytoma, and brainstem glioma. On T1-weighted images, medulloblastoma is generally iso- to hypointense, while on T2-weighted images, the densely packed cellular component of the tumor is significantly hypointense and displays restricted diffusion on diffusion-weighted imaging. Following intravenous gadolinium, medulloblastoma shows significant but variable and heterogeneous contrast enhancement. Given the propensity of neuraxial spread in medulloblastoma, sagittal fat-suppressed T1-postcontrast spinal MRI is recommended to rule out leptomeningeal metastases for accurate staging. Following neurosurgical excision, postoperative MRI done within 24-48h confirms the extent of resection, accurately quantifying residual tumor burden imperative for risk assignment. Post-treatment MRI is needed to assess response and effectiveness of adjuvant radiotherapy and systemic chemotherapy. After completion of planned therapy, surveillance MRI is recommended periodically on follow-up for early detection of recurrence for timely institution of salvage therapy, as well as for monitoring treatment-related late complications. Recent studies suggest that preoperative MRI can reliably identify SHH and Group 4 medulloblastoma but has suboptimal predictive accuracy for WNT and Group 3 tumors. In this review, we focus on the role of MRI in the diagnosis, staging, and quantifying residual disease; post-treatment response assessment; and periodic surveillance, and provide a brief summary on radiogenomics in the contemporary management of medulloblastoma.

RARE-05. ANAPLASTIC ASTROCYTOMA AND OLIGODENDROGLIOMA PRESENTING AS SIMULTANEOUS PRIMARY BRAIN TUMORS IN A PEDIATRIC PATIENT: THE FIRST KNOWN REPORT OF A RARE CONDITION

Abstract Multiple metastatic brain tumors and multiple histologically identical primary brain tumors have been reported in adults and children. The concurrent presence of multiple histologically distinct primary brain tumors is rare without prior chemotherapy, radiotherapy, or phacomatosis. Exceedingly rare are simultaneous histologically distinct primary brain tumors in children without therapeutic or genetic predisposition, with only five previously reported cases. Gliomas are the most common primary brain tumor in adults and children. Gliomas encompass a heterogenous group characterized by astrocytic, oliogodendroglial, and ependymomal histology, further subdivided into pathologic World Health Organization (WHO) grades I to IV. In children, grade I astrocytomas are the most common, with grade III astrocytomas (anaplastic astrocytomas) and oligodendrogliomas being rare. We report a case of simultaneous anaplastic astrocytoma and grade II oligodendroglioma in a pediatric patient. A previously healthy 6-year-old female presented with persistent headaches. Initial magnetic resonance imaging (MRI) demonstrated non-enhancing right frontal lobe and left peri-thalamic lesions without mass affect. Serial MRIs showed progression of both lesions, prompting frontal lobe biopsy, which revealed a grade II oligodendroglioma. The patient was started on standard low-grade glioma chemotherapy, which was stopped due to an allergic reaction. Following chemotherapy cessation, both lesions increased in size, and the peri-thalamic lesion demonstrated new heterogenous enhancement. The patient underwent gross-total resection of the peri-thalamic lesion and repeat biopsy of the frontal lobe lesion. Pathology confirmed the frontal lobe lesion to be a grade II oligodendroglioma and revealed the peri-thalamic lesion to be an anaplastic astrocytoma. The tumors were additionally proven molecularly distinct. The patient responded well to cranial radiotherapy and standard high-grade glioma chemotherapy. To the best of the authors’ knowledge, this is the first case of simultaneous anaplastic astrocytoma and oligodendroglioma in a child, increasingly unique given the histological and molecular rarity of the tumors in pediatric patients.

Clinical Audit of Survival Outcomes and Prognostic Factors in Adolescents and Adults with Medulloblastoma.

Purpose: Medulloblastomas, comprising 20%-25% of all primary brain tumors in children are much rarer in adulthood. Disease biology varies substantially across different age groups; however, owing to rarity, adults with medulloblastoma are traditionally treated using pediatric protocols. This is a retrospective audit of adolescent and adult medulloblastoma from a comprehensive cancer center. Methods: Data regarding demography, clinical presentation, imaging characteristics, histopathological features, molecular profiling, risk stratification, treatment details, and outcomes were retrieved from medical records. All time-to-event outcomes were analyzed using Kaplan-Meier method and compared with the log-rank test. Univariate and multivariate analysis of relevant prognostic factors was done with p value <0.05 being considered statistically significant. Results: A total of 162 patients ≥15 years of age with medulloblastoma were included. The median age was 25 years (range: 15-59 years) with leptomeningeal metastases seen in 31 (19%) patients at initial diagnosis. Following surgery, patients were treated with appropriate risk-stratified adjuvant therapy comprising of craniospinal irradiation plus boost with or without systemic chemotherapy. At a median follow-up of 50 months, 5-year Kaplan-Meier estimates of progression-free survival and overall survival were 53.5% and 59.5%, respectively. The addition of adjuvant systemic chemotherapy did not impact upon survival in standard-risk medulloblastoma. High-risk (HR) disease and anaplastic histology emerged as significant and independent predictors of poor survival on multivariate analysis. Conclusion: Medulloblastoma is a rare tumor in adolescents and adults with key differences in disease biology and resultant outcomes compared with the pediatric population. Contemporary management comprising maximal safe resection followed by appropriate risk-stratified adjuvant therapy provides acceptable survival outcomes.

Imaging of brain tumors in children: the basics-a narrative review.

Primary pediatric brain tumors comprise a broad group of neoplasm subtypes that can be categorized based on their histological and molecular features according to the 2016 World Health Organization (WHO) classification of central nervous system (CNS) tumors. The majority of the pediatric brain tumors demonstrate a singular preference for this age group and have a unique molecular profile. The separation of certain tumor entities, including different types of embryonal tumors, low-grade gliomas, and high-grade gliomas, may have a significant impact by guiding appropriate treatment for these children and potentially changing their outcomes. Currently, the focus of the imaging diagnostic studies is to follow the molecular updates, searching for potential imaging patterns that translate this information in molecular profile results, therefore helping the final diagnosis. Due to the high impact of accurate diagnosis in this context, the scientific community has presented extensive research on imaging pediatric tumors in recent years. This article summarizes the key characteristics of the imaging features of the most common primary childhood brain tumors, categorizing them according to the recent WHO classification update, which is based on each of their molecular profiles. The purpose of this review article is to familiarize radiologists with their key imaging features and thereby improve diagnostic accuracy.

From sorting to sequencing in the molecular era: the evolution of the cancer stem cell model in medulloblastoma.

The cancer stem cell (CSC) model posits that tumors contain subpopulations that display defining features of normal stem cells including self-renewal capacity and differentiation. Tumor cells exhibiting these features are now considered to be responsible for tumor propagation and drug resistance in a wide variety of cancers. Therefore, the identification of robust CSC markers and characterization of CSC-specific molecular signatures may lead to the identification of novel therapeutics that selectively abolish this clinically relevant cell population while preserving normal tissue. Brain tumor researchers have been at the forefront of the CSC field. From initial in vitro cell sorting experiments to the sophisticated bioinformatic technologies that now exquisitely resolve primary brain tumors at a single-cell level, recent glioma and medulloblastoma (MB) studies have integrated developmental state with genomic and transcriptome data to identify the spectrum of cell types that may drive tumor progression. This review will examine the last two decades of CSC studies in the field. Seminal discoveries, emerging controversies, and outstanding questions will be covered with a particular focus on MB, the most common malignant primary brain tumor in children.

Medulloblastoma in adults - reviewing the literature from a surgeon's point of view.

Medulloblastoma is a common primary brain tumor in children but it is a rare cancer in adult patients. We reviewed the literature, searching PubMed for articles on this rare tumor entity, with a focus on tumor biology, advanced neurosurgical opportunities for safe tumor resection, and multimodal treatment options. Adult medulloblastoma occurs at a rate of 0.6 per one million people per year. There is a slight disparity between male and female patients, and patients with a fair skin tone are more likely to have a medulloblastoma. Patients present with cerebellar signs and signs of elevated intracranial pressure. Diagnostic efforts should consist of cerebral MRI and MRI of the spinal axis. Cerebrospinal fluid should be investigated to look for tumor dissemination. Medulloblastoma tumors can be classified as classic, desmoplastic, anaplastic, and large cell, according to the WHO tumor classification. Molecular subgroups include WNT, SHH, group 3, and group 4 tumors. Further molecular analyses suggest that there are several subgroups within the four existing subgroups, with significant differences in patient age, frequency of metastatic spread, and patient survival. As molecular markers have started to play an increasing role in determining treatment strategies and prognosis, their importance has increased rapidly. Treatment options include microsurgical tumor resection and radiotherapy and, in addition, chemotherapy that respects the tumor biology of individual patients offers targeted therapeutic approaches. For neurosurgeons, intraoperative imaging and tumor fluorescence may improve resection rates. Disseminated disease, residual tumor after surgery, lower radiation dose, and low Karnofsky performance status are all suggestive of a poor outcome. Extraneural spread occurs only in very few cases. The reported 5-year-survival rates range between 60% and 80% for all adult medulloblastoma patients.

EPID-01. TRENDS OF INCIDENCE IN PEDIATRIC BRAIN TUMORS IN KUMAMOTO PREFECTURE, JAPAN

BACKGROUND/PURPOSEOne of the most problematic issues Japan has is a declining birthrate resulting in an aging society. There are some reports on the trends of incidence in brain tumors in the elderly, whereas few reports on those in the children. The aim of this study is to investigate the trends of incidence in childhood primary brain tumors.METHODSThe population of children aged <15 years was available from Kumamoto Prefecture’s annual census between 1990 and 2017. During the period 301 childhood primary brain tumors (124 gliomas, including astrocytic tumors and ependymomas, 35 embryonal tumors, 34 germ cell tumors, 22 craniopharyngioma, and 86 others) were registered with the Kumamoto Brain Tumor Data Bank, and investigated.RESULTSThe average of the annual incidence rate per 100,000 child populations was 3.90 for total brain tumors, 1.63 for gliomas, 0.44 for embryonal tumors, 0.42 for germ cell tumors, 0.26 for craniopharyngioma, and 1.15 for others. Divided into the first half from 1990 to 2003 and the second half from 2004 to 2017, there was no significant difference in the incidence of brain tumors aged <15 years between the two periods. However, the average of the annual incidence rate/100,000 child populations was 3.02 in the first half, while significantly increased in the second half of 4.78 (p=0.00075, t-test). DISCUSSION &CONCLUSIONSThe average number of children aged <15 years in Kumamoto Prefecture was 31,2737.9 from 1990 to 2003, while decreased remarkably to 251460.2 from 2004 to 2017. A decrease in the number of children may affect increasing the incidence rate of pediatric brain tumors.

Evaluation of tumor viability in Post radiation therapy pediatric brain tumors with 99mTc- glucoheptonate single photon emission computed tomography (SPECT)

Brain single photon emission computed tomography (SPECT) with 99mTc- glucoheptonate, a blood brain barrier imaging agent, is rapidly regaining interest after it has been shown that the uptake of tumor seeking agents like thallium, tetrofosmin, sestamibi and pertechnate by brain tumors is solely dependent on disruption of the blood brain barrier. Therefore, the use of 99mTc glucoheptonate may yield the same diagnostic information as other agents such as the much more expensive 99mTc-sestamibi. The purpose of the study was to evaluate 99mTc-glucoheptonate as an imaging agent for recurrent primary brain tumors in children. Methods: Fifty-one patients aged 5-18 years were evaluated for tumor recurrence following radiotherapy for primary malignant brain tumors, using brain single photon emission computed tomographies (SPECT) with 99mTc-Glucoheptonate. Contrast enhanced computerized tomography (CT) of brain was performed in all patients within + 1 week of brain SPECT as a diagnostic standard and compared. Results: Recurrent tumors showed avid 99mTc- glucoheptonate concentration and a high 99mTc-glucoheptonate retention index (6.06 + 1.41) compared with post radiation gliosis, which showed no 99mTc-glucoheptonate concentration over the affected site and had a 99mTc-glucoheptonate retention index of 1.10 + 0.18 (p=0.001). 99mTc- glucoheptonate SPECT had a sensitivity of 79.48% and a specificity of 91.66% when compared with contrast-enhanced computed tomography as a gold standard. However, this technique did not show good performance in the differential diagnosis of lesions in posterior fossa. Conclusion: This study suggests that 99mTc-glucoheptonate brain SPECT can be used as a sensitive and specific diagnostic test to differentiate recurrent tumor from post radiation gliosis, with the exception of tumors located in posterior fossa. Further studies should address this limitation before definite protocols are established.&#x0D;

INNV-18. RECURRENT SHH MEDULLOBLASTOMA EXTRANEURAL METASTASES TO THE BONE MARROW WITHOUT CNS INVOLVEMENT

Abstract Medulloblastoma is the most common primary brain tumor in children, but is rare in adults. Because of the scarcity of adult medulloblastoma cases, treatment guidelines in the adult population are not well established, especially regarding surveillance and treatment of recurrent disease. A 47-year-old African American male presented with one month of progressive unsteady gait and dizziness. Imaging revealed a posterior fossa mass and the patient underwent gross total resection. Histology confirmed medulloblastoma and molecular subtyping revealed Sonic Hedgehog (Shh) pathway activation. No metastases were found at the time of diagnosis, and the patient received adjuvant craniospinal radiation therapy. Three years later the patient developed low back pain with severe sciatica affecting his gait and pancytopenia. Imaging revealed diffuse osseous disease without CNS recurrence and bone marrow biopsy confirmed recurrent medulloblastoma. The patient subsequently began reduced chemotherapy consisting of cisplatin and etoposide because of his severe pancytopenia. Due to a lack of response after 4 cycles, the SMO antagonist vismodegib was added. Follow-up imaging revealed improvement/stability of osseous disease, lab work demonstrated resolution of pancytopenia, and repeat bone marrow was without malignancy. Vismodegib was continued as maintenance therapy. Six months after completion of cisplatin/etoposide, follow-up imaging revealed progression of metastatic disease. Shh activated medulloblastomas have demonstrated responses to SMO inhibition. However, these responses are often transient secondary to rapid development of resistance, but may have a role to play in patients who have bone marrow involvement that limits use of cytotoxic therapy or bone marrow transplant. Due to poor survival outcomes associated with bone marrow metastases, aggressive screening for bone marrow metastases at diagnosis and in surveillance should be considered.