Primary Brain Tumors In Children Research Articles

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.

The contribution of ketone bodies to glycolytic inhibition for the treatment of adult and pediatric glioblastoma.

Glioblastoma (GBM) remains one of the most lethal primary brain tumors in children and adults. Targeting tumor metabolism has emerged as a promising-targeted therapeutic strategy for GBM and characteristically resistant GBM stem-like cells (GSCs). Gene expression data was obtained from the online patient-histology database, GlioVis. GSC mitochondria morphology was examined by TEM. Cell viability and effect on GSC self-renewal was determined via MTS assay and neurosphere assay, respectively. Proteins were evaluated by Western Blot. Enzymes necessary for ketone catabolism (BDH1, OXCT1 and ACAT1) are significantly downregulated in adult and pediatric GBM. GSC mitochondrial ultrastructure suggested defects in oxidative phosphorylation. Treatment of both GBM and GSC cell lines resulted in dose-dependent decreases in viability in response to glycolytic inhibitor 2-deoxy-D-glucose (2-DG), and ketone body Acetoacetate (AA), but not β-hydroxybutyrate (βHB). AA induced apoptosis was confirmed by western blot analysis, indicating robust caspase activation and PARP cleavage. AA reduced neurosphere formation at concentrations as low as 1mM. Combined treatment of low dose 2-DG (50μM) with AA resulted in more cell death than either treatment alone. The effect was greater than additive at low concentrations of AA, reducing viability approximately 50% at 1mM AA. AA was found to directly upregulate mitochondrial uncoupling protein 2 (UCP2), which may explain this potential drug synergism via multi-faceted inhibition of the glycolytic pathway. Targeting the metabolic pathway of GBM via glycolytic inhibition in conjunction with ketogenic diet or exogenous ketone body supplementation warrants further investigation as a promising adjunctive treatment to conventional therapy.

Abstract 3485: PELP1 is a novel mediator of medulloblastoma progression

Abstract Background: Medulloblastoma (MB) is the most common and deadliest primary brain tumor in children that accounts for 15-20% of all pediatric brain tumors. Despite recent advances in multimodal treatment, the 5-year overall survival of MB patients is approximately 60-70%. Unfortunately, improved outcome have been associated with significant long-term toxicities. Identifying novel targets that drive MB progression is urgently needed. Proline-, glutamic acid-, and leucine-rich protein 1 (PELP1) is a scaffolding protein that functions as a coregulator of several nuclear receptors. Oncogenic PELP1 signaling is implicated in the progression of several cancers including breast, ovarian, prostate, lung, pancreas and colon. However, its role in the progression of medulloblastoma remains unknown. Here, we examined the role of proto-oncogene PELP1 in the progression of MB. Methods: The expression of PELP1 in tumor micro arrays was analyzed using validated PELP1 antibodies for immunohistochemistry. PELP1 expression was determined in vitro by western blotting. PELP1 knockdown cells were generated using PELP1 shRNA lentiviral particles or PELP1 siRNA. The effect of PELP1 knockdown or overexpression was studied using cell proliferation, colony formation and migration using established in vitro assays. Mechanistic studies were conducted using RNA-seq, RT-qPCR, immunohistochemistry, reporter gene assays and signaling analysis. Interaction of PELP1 with NF-κB was examined by immunoprecipitation. Mouse orthotopic xenografts models were used for preclinical evaluation of PELP1 knock down. Results: Immunohistochemical analysis of MB tissue microarrays revealed that PELP1 is overexpressed in MB specimens compared to normal brain specimens. Knockdown of PELP1 using PELP1 specific siRNA or shRNA significantly reduced cell proliferation, cell survival, and cell migration of MB cell lines. RNA-seq analysis revealed that PELP1 knockdown significantly downregulated the pathways related to inflammation, angiogenesis and extracellular matrix. Further, gene set enrichment analysis (GSEA) confirmed that the PELP1-regualted genes were negatively correlated with NF-κB, extracellular matrix and angiogenesis. Mechanistic studies showed that PELP1 knockdown reduced the expression of NF-κB reporter gene activity and its target genes. Additionally, knockdown of PELP1 significantly reduced in vivo MB tumor progression in orthotopic models, and improved overall mice survival. IHC analysis demonstrated that the proliferation marker Ki67 and NF- κB targets were significantly downregulated in PELP1 knockdown tumors compared to controls. Conclusions: Taken together, these results provide the evidence that PELP1 could be a potential therapeutic target for therapeutic intervention in medulloblastoma. Citation Format: Yiliao Luo, Gangadhara Reddy Sareddy, Uday P. Pratap, Mengxing Li, Junhao Liu, Prabhakar Pitta-Venkata, Suryavathi Viswanadhapalli, Xiaonan Li, Manjeet Rao, Rajeshwar Rao Tekmal, Ratna K. Vadlamudi. PELP1 is a novel mediator of medulloblastoma progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3485.

Exploiting metabolic susceptibilities in glioblastoma via glycolytic inhibition and ketogenic therapy.

e13558 Background: Glioblastoma (GBM) remains one of the most lethal primary brain tumors in children and adults. Despite enormous efforts to elucidate the genetic and epigenetic drivers of this disease, the prognosis for patients diagnosed with GBM remains dismal. Because tumor cell metabolism differs greatly from that of normal non-cancerous cells, it is possible to develop therapies which more effectively target the cancer cell while sparing normal cells. Growing in popularity is the ketogenic diet, which is a high fat, very low carbohydrate diet resulting in the production of ketone bodies, acetoacetate (AA) and β-hydroxybutyrate (βHB) to generate ATP. Methods: Analysis conducted by open-access GBM patient database, mts assay, Western blot, neurosphere assay, and TEM. Results: Enzymes required for ketone metabolism (BDH1 and OXCT1) were significantly downregulated in GBM while glycolytic enzymes were significantly upregulated (HK2, HK1, SLC2A3, NAMPT, G6PD). GBM stem cell (GSC) markers (CD44, STAT3) positively correlated with glycolytic enzymes. Ultrastructural analysis of GSCs indicated that about half of the mitochondria were missing cristae, highly suggestive of an increased glycolytic dependency. Treatment of patient-derived GSC lines as well as non-stem cell lines SJGBM2 (pediatric) and U87 (adult) resulted in a dose-dependent decrease in viability in response to the glycolytic inhibitor 2-deoxy-D-glucose (2-DG). When cells were exposed to ketone bodies, AA but not βHB induced a dose-dependent decrease in cell viability with 10 mM reducing viability ranging from 20-80% of non-treated controls. Western blot analysis demonstrated robust caspase activation and PARP cleavage in response to AA. Furthermore, AA significantly reduced GSC neurosphere formation at 2.5 mM suggesting inhibition of GSC self-renewal pathways. Combined treatment of low dose 2-DG (50 μM) with increasing concentrations of AA resulted in more cell death than either treatment. The effect was more than additive at the low concentrations of AA (1- 5 mM) suggesting synergy. Conclusions: Glycolytic inhibition in conjunction with the ketogenic diet may be a promising therapeutic route for this difficult-to-treat cancer.

Patient with Refractory Epilepsy Associated with Oligondendroglioma

Oligodendroglioma is a rare form of primary brain tumor, accounting for about 2-5% of intracranial tumors, being more common in adult males but rare in children, accounting for about 1-2% of all primary brain tumors in children. It originates from oligodendrocytes or glial precursor cells and exhibits infiltrative and slow growth. They can be classified in two grades (Grade II and Grade III), where Grade II are low grade tumors and have tumor cells that grow slowly and invade nearby normal tissue, and Grade III are malignant and have rapidly growing tumors. It has low growth and 50-80% of cases first symptom is seizures. A seizure is a symptom that requires a rapid solution usually requiring empirical treatment at the initial time to cease seizures and promote some well-being for the patient's routine. Seizures can cause a lot of damage to the patient's life, especially if the patient is a child who does not know what to do and what to do. Depending on the intensity and frequency of seizure episodes, the patient may experience fractures with falls, may suffer discrimination and prejudice at school. The causes behind refractory epilepsy are diverse, so whenever a patient is found to be refractory to drug treatment, the origin of seizures should be investigated early, it is not enough to stop at empirical treatment.

Role of MRI in Diagnosis of Medulloblastoma

Background: Brain tumors represent the most common solid neoplasm in children and second most common pediatric malignancy overall. The majority of primary childhood brain tumors occurs in the infratentorial compartment and includes: medulloblastoma, juvenile pilocytic astrocytoma (JPA), ependymoma, brainstem/pontine glioma, and atypical teratoid rhabdoid tumor (ATRT) which is an additional rare but important primary brain tumor of early childhood. Objective: This study aims to provide an overview of the imaging features and appearances of the most common primary posterior fossa brain tumors in children and the diagnosis of medulloblastoma. Patients and Methods: The pool of our study was 25 patients (12 males and 13 females) who presented to diagnostic radiology departments at EL Demerdash Teaching Hospital and National Cancer Institute. They had been diagnosed to have posterior fossa lesions. Patients’ age ranged from 1 to 17 year with mean age of 4.73 years.Results: statistically significant difference between medulloblastoma and other posterior fossa tumors according to location and diffusion. Medulloblastoma is 4th ventricular in location and shows restriction in diffusion weighted images. Conclusion: Medulloblastoma is predominately 4th ventricular in location, Medulloblastoma is restricted in diffusion weighted images.

Role of MRI in Diagnosis of Medulloblastoma

Background: Brain tumors represent the most common solid neoplasm in children and second most common pediatric malignancy overall. The majority of primary childhood brain tumors occurs in the infratentorial compartment and includes: medulloblastoma, juvenile pilocytic astrocytoma (JPA), ependymoma, brainstem/pontine glioma, and atypical teratoid rhabdoid tumor (ATRT) which is an additional rare but important primary brain tumor of early childhood. Objective: This study aims to provide an overview of the imaging features and appearances of the most common primary posterior fossa brain tumors in children and the diagnosis of medulloblastoma. Patients and Methods: The pool of our study was 25 patients (12 males and 13 females) who presented to diagnostic radiology departments at EL Demerdash Teaching Hospital and National Cancer Institute. They had been diagnosed to have posterior fossa lesions. Patients’ age ranged from 1 to 17 year with mean age of 4.73 years.Results: statistically significant difference between medulloblastoma and other posterior fossa tumors according to location and diffusion. Medulloblastoma is 4th ventricular in location and shows restriction in diffusion weighted images. Conclusion: Medulloblastoma is predominately 4th ventricular in location, Medulloblastoma is restricted in diffusion weighted images.

Brain tumors in children: about 136 cases

Les tumeurs cérébrales sont les tumeurs solides les plus diagnostiquées chez les enfants de moins de 15 ans dans le monde. Toutefois, peu de publications ont rapporté le profil épidémiologique et anatomopathologique de ces tumeurs en Afrique et particulièrement au Maroc. Les auteurs rapportent les particularités épidémiologiques et anatomopathologiques des tumeurs cérébrales primitives de l'enfant dans la région de Marrakech (Sud du Maroc). C'est une étude rétrospective réalisée au service d'anatomie pathologique du CHU Mohammed VI de Marrakech de 2004 à 2016. Cent trente-six cas de tumeurs cérébrales primitives étaient diagnostiqués avec une moyenne de 11,33 cas par an. L'âge moyen était de 8,28 ans. Le sex-ratio (H/F) était de 1,6 avec une légère prédominance masculine. Ces tumeurs étaient infra-tentorielles dans 61,53% des cas et siégeaient en supra-tentoriel dans 38,47% des cas. A l'étage infra-tentoriel, les tumeurs des hémisphères cérebelleux occupaient le premier rang (61,4%). Parmi les dix-huit types histologiques diagnostiqués, l'astrocytome et le médulloblastome représentaient ensemble 46,32% (29,41% et 16,91% respectivement). Dans notre contexte, la majorité des tumeurs cérébrales de l'enfant prédominait dans les 2 groupes d'âge: 5-9 ans et 10-15 ans. Les résultats épidémiologiques de ces tumeurs au sud du Maroc concordent majoritairement avec ceux déjà publiés du Nord du pays et des autres pays non Africains.

TAp73 is a marker of glutamine addiction in medulloblastoma

Medulloblastoma is the most common solid primary brain tumor in children. Remarkable advancements in the understanding of the genetic and epigenetic basis of these tumors have informed their recent molecular classification. However, the genotype/phenotype correlation of the subgroups remains largely uncharacterized. In particular, the metabolic phenotype is of great interest because of its druggability, which could lead to the development of novel and more tailored therapies for a subset of medulloblastoma. p73 plays a critical role in a range of cellular metabolic processes. We show overexpression of p73 in a proportion of non-WNT medulloblastoma. In these tumors, p73 sustains cell growth and proliferation via regulation of glutamine metabolism. We validated our results in a xenograft model in which we observed an increase in survival time in mice on a glutamine restriction diet. Notably, glutamine starvation has a synergistic effect with cisplatin, a component of the current medulloblastoma chemotherapy. These findings raise the possibility that glutamine depletion can be used as an adjuvant treatment for p73-expressing medulloblastoma.

139 Outcome of Stereotactic Laser Ablation of Primary Brain Tumors in Children

Abstract INTRODUCTION Stereotactic laser ablation (SLA) is an innovative minimally invasive strategy used to treat intracranial tumors. While it is applied commonly in adults as adjuvant therapy for high grade tumors, its use in children is less well understood. At Texas Children's Hospital (TCH), an interdisciplinary team considers SLA, with or without concomitant biopsy, as a diagnostic and treatment strategy in select cases. This study represents our institutional experience over 5 years using SLA for children with brain tumors. METHODS A retrospective chart review was performed for patients less than 18 years old undergoing SLA at TCH from 2012–2016. Demographics, medical history, and surgical outcomes were recorded. Biopsy diagnosis rate, adjuvant treatments, and tumor outcomes are noted. RESULTS &gt;Fourteen children (7 males), with an average age at first surgery of 11.6 years, underwent SLA for WHO I (8), WHO II (1), WHO III (1), WHO IV (2) and unknown (2) tumors. Tumor locations were deep (periventricular, midbrain) in nine cases. Antecedent biopsy was diagnostic in 5 of the 7 patients (71%). SLA without concurrent biopsy was the solo treatment in the other 7 patients (50%). Complete ablation of tumors was confirmed radiographically in 11/14 children. Follow-up time was an average of 2 years. At follow up, 11 children had stable disease, 2 had recurrences, and there was 1 death. One patient developed acute postoperative hydrocephalus requiring temporary ventricular drain placement for cerebrospinal fluid diversion. CONCLUSION SLA is an effective novel adjunctive or primary treatment modality for primary brain tumors in children, with a low complication profile, even in deep locations, and may be easily paired with diagnostic biopsy.

Birth weight and subsequent risk of childhood primary brain tumors: An updated meta-analysis.

Primary brain tumors are common in childhood, but the etiology is largely unclear. As studies on birth weight as a risk factor for the occurrence of histologically specified tumors have been inconclusive, we decided to update a 2008 meta-analysis on the subject. A search strategy was performed in Medline and EMBASE for the period 2007-2016. We included six new studies and performed further subgroup analyses for medulloblastoma and primitive neuroectodermal tumors (PNETs). Dichotomous analyses were performed for low (2,500 g) and high birth weight (4,000 g cutoff point). Our results confirmed that high birth weight increases the risk of astrocytoma (odds ratio [OR] = 1.60, 95% confidence interval [CI]: 1.23-2.09) and medulloblastoma/PNET. However, subgroup analysis revealed an increased risk of medulloblastoma (OR = 1.31, 95% CI: 1.08-1.58) but not of PNET (OR = 1.16, 95% CI: 0.92-1.46). Low birth weight was associated with an increased risk of medulloblastoma/PNET. Subgroup analysis for medulloblastoma and PNET revealed increased risk but CIs included zero. Neither low nor high birth weight was associated with the risk of ependymoma. While an association between high birth weight and astrocytoma was confirmed, more studies are needed to investigate medulloblastoma and PNET risk in children with high and low birth weight.

PDTB-21. CD271 (p75NTR) AS A NOVEL DIAGNOSTIC MARKER AND THERAPEUTIC TARGET FOR SHH MEDULLOBLASTOMA

Medulloblastoma (MB) is the most common malignant primary brain tumor in children. Despite improved clinical outcomes, children with MB often suffer from consequences of treatment such as surgery, chemotherapy and radiation. MB is currently classified into 4 distinct molecular subtypes based on genomic alterations, gene expression profiles, response to treatment and cell of origin; WNT, SHH, Group 3, and Group 4. This extensive heterogeneity has revealed a critical need for subtype-specific, functionally validated biomarkers and therapeutic strategies. Using an unbiased high throughput flow cytometry screen, we identified CD271/p75NTR as a candidate SHH stem/progenitor cell marker. Here, we explored the functional role of CD271 in SHH MB cell lines and primary cultures, using gain/loss of function studies and treatments with a CD271 inhibitor, γ-secretase inhibitor (GSI). This was followed by cellular assays to measure sphere-forming capacity, self-renewal, proliferation and differentiation. Immunohistochemical (IHC) staining for CD271 was also conducted in formalin fixed paraffin embedded (FFPE) patient samples to assess expression of CD271 across MB subtypes. CD271 levels were high in SHH MB samples with minimal to no staining in WNT, Group 3, and Group 4 MBs. Stable overexpression of CD271 resulted in increased tumorsphere size, whereas CD271 knockdown cells exhibited a reversal of this cellular phenotype. Similarly, treatment of UI226 SHH MB primary cells with GSI also resulted in a significant decrease in tumorsphere growth and self-renewal, providing an opportunity to exploit CD271 as a therapeutic target. As CD271 appears to be specific to SHH MB, this marker may serve as a potential diagnostic tool. Further characterization of CD271 signaling in SHH MB could ultimately lead to development of targeted therapies that will lessen the broad impact of current toxic treatments, and improve the quality of life for children who survive long- term.

Abstract C195: A Wee1 inhibitor analog of AZD1775 demonstrates synergy with cisplatin with reduced single-agent toxicity in medulloblastoma

Abstract Medulloblastoma is the most common primary brain tumor in children. Current treatment for medulloblastoma includes surgical resection, radiation and cytotoxic chemotherapy. Although this approach has improved survival rates, the high doses of chemotherapy required to circumvent drug resistance mechanisms and result in clinical efficacy often give rise to lasting neurocognitive defects, stunted growth, deafness, and even secondary tumors. Therefore, synergistic drug combinations that maintain clinical efficacy, but allow dose reductions of cytotoxic agents limiting their adverse effects would be an attractive approach for patients with medulloblastoma. We identified Wee1 kinase as a new molecular target for medulloblastoma from an integrated genomic analysis using pathway analysis of gene expression and a kinome-wide siRNA screen of medulloblastoma cells and tissue. Wee1 participates in the G2-M checkpoint to prevent mitosis in the presence of DNA damage and therefore may play a role in drug resistance to DNA alkylating agents, such as cisplatin. Our data indicate that Wee1 prevents DNA damage-induced cell death by cisplatin and that the known Wee1 inhibitor AZD1775 (previously MK1775) displays synergistic activity with cisplatin. However, AZD1775 is known to have nanomolar activity with at least 8 other kinases and there is limited structure-activity relationship (SAR) data for AZD1775 as it was identified as a Wee1 inhibitor from a high-throughput screen. Therefore, we developed a small series of AZD1775 derivatives to establish a SAR and further examine the effects of Wee1 inhibition in medulloblastoma. The compounds, that inhibited Wee1 activity in a TR-FRET assay in the same nanomolar range as AZD1775, had significantly reduced single-agent cytotoxicity and displayed synergistic activity with cisplatin at lower concentrations than AZD1775 in medulloblastoma cells. Recently, it has been reported that AZD1775 has limited ability to diffuse across the blood-brain barrier (BBB) and this would limit its effectiveness in brain tumors. We have performed cell permeability and BBB permeability assays using AZD1775 and our lead Wee1 inhibitor and our studies support that AZD1775 has poor BBB penetration. Our studies have now transitioned into in vivo systems to determine the tissue distribution and pharmacokinetics of our lead Wee1 inhibitor compared with AZD1775. In addition, our studies will determine the effect of our lead Wee1 inhibitor and AZD1775 on tumor growth as single agents and in combination with cisplatin in medulloblastoma in vivo models. Citation Format: Christopher J. Matheson, Sujatha Venkataraman, Vladimir Amani, Peter Harris, Donald S. Backos, Nicholas K. Foreman, Rajeev Vibhakar, Philip Reigan. A Wee1 inhibitor analog of AZD1775 demonstrates synergy with cisplatin with reduced single-agent toxicity in medulloblastoma. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C195.