History Of Brain Tumor Research Articles

A - 110 Cognitive Phenotypes in Children with a History of Brain Tumors.

Research indicates children with a history of pediatric brain tumors (PBTs) are at increased risk for cognitive impairment. Cognitive phenotyping could reveal latent cognitive profiles and ascertain the impact of clinical and sociodemographic variables in this population. There is only one such study to date. We hypothesized patients with more treatment modalities, additional medical diagnoses, and diagnosis age/time since treatment completion would impact performance. K-means clustering was used to explore 17 test scores across 9 cognitive domains in 67 children with brain tumors aged 8-17years (median age = 12; 41 male; 85.1% Caucasian) in a pediatric hospital. Exclusion criteria included failed performance validity testing, IQs < 50, and active treatment. Parametric and non-parametric tests were utilized, and effect sizes were calculated. Two clusters were identified. Cluster 2 (n = 37) had lower scores than Cluster 1 (n = 30) on all neuropsychological domains assessed except for memory and mental flexibility with large effect sizes (p's < 0.005, n2 = 0.151-0.57). Clusters differed by tumor location (p = 0.021, V = 0.340), hydrocephalus (p = 0.041, V = 0.250), and treatment type (p = 0.037, V = 0.447). Results suggest multi-domain cognitive impairment in a large subgroup of children with PBTs associated with infratentorial tumors, history of hydrocephalus, and exposure to multiple treatment modalities (i.e., surgery, radiation, and chemotherapy). Other demographic, treatment (i.e., diagnosis age, time since diagnosis/treatment completion), and medical (i.e., tumor grade, seizures, genetic diagnoses) factors did not account for clusters. Future studies should include larger samples, increased age range, and additional clinical, sociodemographic, and psychosocial variables to form more generalizable models of cognitive phenotypes in youth with PBTs.

Older patients with COVID-19 and neuropsychiatric conditions: A study of risk factors for mortality.

Little is known about risk factors for mortality in older patients with COVID-19 and neuropsychiatric conditions. We conducted a multicentric retrospective observational study at Assistance Publique-Hôpitaux de Paris. We selected inpatients aged 70 years or older, with COVID-19 and preexisting neuropsychiatric comorbidities and/or new neuropsychiatric manifestations. We examined demographics, comorbidities, functional status, and presentation including neuropsychiatric symptoms and disorders, as well as paraclinical data. Cox survival analysis was conducted to determine risk factors for mortality at 40 days after the first symptoms of COVID-19. Out of 191 patients included (median age 80 [interquartile range 74-87]), 135 (71%) had neuropsychiatric comorbidities including cognitive impairment (39%), cerebrovascular disease (22%), Parkinsonism (6%), and brain tumors (6%). A total of 152 (79%) patients presented new-onset neuropsychiatric manifestations including sensory symptoms (6%), motor deficit (11%), behavioral (18%) and cognitive (23%) disturbances, gait impairment (11%), and impaired consciousness (18%). The mortality rate at 40 days was 19.4%. A history of brain tumor or Parkinsonism or the occurrence of impaired consciousness were neurological factors associated with a higher risk of mortality. A lower Activities of Daily Living score (hazard ratio [HR] 0.69, 95% confidence interval [CI] 0.58-0.82), a neutrophil-to-lymphocyte ratio≥9.9 (HR 5.69, 95% CI 2.69-12.0), and thrombocytopenia (HR 5.70, 95% CI 2.75-11.8) independently increased the risk of mortality (all p<.001). Understanding mortality risk factors in older inpatients with COVID-19 and neuropsychiatric conditions may be helpful to neurologists and geriatricians who manage these patients in clinical practice.

Study of Association of Various Psychiatric Disorders in Brain Tumors.

Background Brain tumors may be associated with high morbidity, and psychiatric symptoms may be an early manifestation. It is important to address mental symptoms as early as possible because they are prone to develop psychiatric comorbidities in future. If untreated, these situations may worsen and lead to burden upon caregivers. Methods A total of 176 brain tumor patients between January 2021 and January 2022 constituted the sample size. All recently diagnosed cases of brain tumor with age equal to or more than 18 years who can comprehend and answer questionnaires were included. Patients with a long history of brain tumor or who had a history of a psychiatric illness other than presenting symptoms or any other serious medical illness were excluded. Results Twenty-seven percent of brain tumor patients had psychiatric symptoms. Depressive symptoms were the most common, associated with 24% of patients, followed by anxiety disorders. Psychiatric disorders were more common in supratentorial compared to infratentorial tumors. Psychiatric symptoms seem to be associated more commonly with malignant tumors and peritumoral edema. Among malignant tumors, depressive symptoms tend to be related with high-grade glioma, and among benign tumors, they were more common in meningioma. No predilection to laterality and anatomical lobe involvement is reported. Conclusion Screening of psychiatric disorders should be a routine in brain tumor patients. An integrated approach is required to treat brain tumor patients. Healthcare professionals should be more vigilant about the onset of psychiatric symptoms and the need of palliative care to improve the quality of life.

Risk of second brain tumour after radiotherapy for pituitary adenoma or craniopharyngioma: a retrospective, multicentre, cohort study of 3679 patients with long-term imaging surveillance

Radiotherapy is a valuable treatment in the management algorithm of pituitary adenomas and craniopharyngiomas. However, the risk of second brain tumour following radiotherapy is a major concern. We assessed this risk using non-irradiated patients with the same primary pathology and imaging surveillance as controls. In this multicentre, retrospective cohort study, 4292 patients with pituitary adenoma or craniopharyngioma were identified from departmental registries at six adult endocrine centres (Birmingham, Oxford, Leeds, Leicester, and Bristol, UK and Ferrara, Italy). Patients with insufficient clinical data, known genetic predisposition to or history of brain tumour before study entry (n=532), and recipients of proton beam or stereotactic radiotherapy (n=81) were excluded. Data were analysed for 996 patients exposed to 2-dimensional radiotherapy, 3-dimensional conformal radiotherapy, or intensity-modulated radiotherapy, and compared with 2683 controls. Over 45 246 patient-years, second brain tumours were reported in 61 patients (seven malignant [five radiotherapy, two controls], 54 benign [25 radiotherapy, 29 controls]). Radiotherapy exposure and older age at pituitary tumour detection were associated with increased risk of second brain tumour. Rate ratio for irradiated patients was 2·18 (95% CI 1·31-3·62, p<0·0001). Cumulative probability of second brain tumour was 4% for the irradiated and 2·1% for the controls at 20 years. Irradiated adults with pituitary adenoma or craniopharyngioma are at increased risk of second brain tumours, although this risk is considerably lower than previously reported in studies using general population controls with no imaging surveillance. Our data clarify an important clinical question and guide clinicians when counselling patients with pituitary adenoma or craniopharyngioma on the risks and benefits of radiotherapy. Pfizer.

Neuropsychological Screening in Pediatric Multidisciplinary Clinics: Group Characteristics and Predictive Utility.

To evaluate the feasibility of administering caregiver-report neuropsychological screening measures in pediatric multidisciplinary clinics (MDCs) and investigate predictive utility for cognitive and academic difficulties on follow-up testing. The Pediatric Perceived Cognitive Functioning (Peds PCF) and Colorado Learning Difficulties Questionnaire (CLDQ) were administered to caregivers of youth with history of brain tumor (BT), non-central nervous system (CNS) cancer, or Fontan circulation as part of routine neuropsychological consultation in MDCs from 2017 to 2019. We examined cross-sectional differences on screening measures, and relationships between screening and intellectual and academic test performance in a subset who presented for follow-up neuropsychological evaluation. Receiver operating characteristic (ROC) curve analysis was used to identify suggested cut scores on screening measures for predicting who would most benefit from further evaluation. Screening was completed with 192 families. Children with history of non-CNS cancer (n = 29) had fewer parent-reported cognitive and academic concerns compared with either BT (n = 88) or Fontan (n = 75) groups. Peds PCF and CLDQ scores were related to intellectual and academic test performance in the group presenting for neuropsychological evaluation (n = 68). ROC curve analysis identified cut scores across screening measures with maximal sensitivity and specificity for detecting neuropsychological difficulties. It is feasible to utilize parent rating measures during neuropsychological consultation in pediatric MDCs. The Peds PCF and CLDQ demonstrated sensitivity to intellectual and academic difficulties in children with significant medical histories. Screening may be a helpful tool for pediatric neuropsychologists and other professionals during MDC consultation to inform clinical management.

Diagnostic testing in nontrauma patients presenting to the emergency department with recurrent seizures: A systematic review.

There is a lack of consensus regarding the role of investigations among patients presenting to the emergency department (ED) with recurrent seizures. The aim of this systematic review was to determine the frequency and utility of commonly requested investigations for nontrauma patients presenting to the ED with recurrent seizures. The MEDLINE, EMBASE, and Cochrane Library databases were searched (March 2021) for articles on this topic using search terms related to recurrent seizures, investigations, and the ED. The inclusion criteria required that articles include adult nontrauma patients presenting to the ED. Studies exclusively investigating first-episode seizures, trauma patients, and status epilepticus were excluded. Eligible studies were assessed for bias using the Newcastle-Ottawa scale. Results of studies were presented using proportions. There were six cohort studies included that contributed data from 36,595 patients. All six studies assessed at least one of our primary outcomes for computed tomography (CT) brain scans. The proportion of patients who underwent a head CT ranged from 13% to 42%. The rates of abnormal head CT findings ranged from 8% to 21%. One study reported on magnetic resonance imaging (MRI) and found it used infrequently in 0.79% of cases. The proportion and yield of nonneuroimaging investigations were not well evaluated in this patient population. Only one study reported on the utility of sodium levels or blood glucose results for this population and reported abnormalities in sodium levels for 19% of patients and abnormalities in glucose levels in 50% of patients. In this population, CT brain scans appeared to be performed uncommonly but with moderate rates of abnormal findings. In the absence of prolonged alteration of consciousness, a history of brain tumor, or positive neurologic findings, however, neuroimaging was of low yield. Given the heterogeneity and potential limitations of these studies, further research on this topic is required.

Return to play after brain tumor surgery in children.

Children with a history of brain tumors do not appear to be at a significantly higher risk of sports-related injuries. Nevertheless, according to the systematic review and survey conducted by Perreault et al., 75% of healthcare professionals restrict their patients' participation in physical activities after brain tumor surgery. The aim of our study was to verify whether children after brain tumor surgery return to physical education (PE) classes. It was also an attempt to explore factors limiting return to physical activity. Patients after brain tumor surgery, ≤ 18 years old on admission with ≥ 1 year follow-up were included in the analysis. Data concerning the disease were collected and summarized in search of factors limiting return to physical activity. Meticulous information about return to sports and physical education at school was gathered during follow-up visits. 71.43% of patients returned to school sports activities. Children who did not return to PE had markedly higher neoplasm WHO grade. Significant differences were also found between the groups in terms of hydrocephalus occurrence and need for additional oncological treatment. In univariate analysis, we identified neoplasm WHO grade, tumor location, presence of neurological deficit after the procedure, additional oncological treatment, and occurrence of hydrocephalus needing shunting as the risk factors for not returning to school physical education. The majority of pediatric brain tumor survivors return safely to physical education. Higher neoplasm WHO grade, presence of neurological deficit after the procedure, additional oncological treatment, and occurrence of hydrocephalus are risk factors for not returning to physical education.

Methylphenidate improves weight control in childhood brain tumor survivors with hypothalamic obesity.

Hypothalamic obesity causes unrelenting weight gain for childhood brain tumor survivors. No single therapy has proven effective for treatment. We aimed to evaluate effectiveness of long-term methylphenidate therapy on body mass index (BMI) change in children with hypothalamic obesity. A retrospective analysis included children with a history of brain tumor and hypothalamic obesity receiving methylphenidate (10-60mg/day) for hypothalamic obesity. Subjects were evaluated for BMI trajectory before and after methylphenidate start. Given that z-scores can be skewed in severely obese children, we calculated BMI as a percent of the BMI at the 95th percentile for the child's age and gender (BMI% 95th). Twelve patients with hypothalamic obesity completed methylphenidate therapy for at least 6months (median 3.1years, range 1.0-5.8years). All subjects had a suprasellar tumor (nine [75%] with craniopharyngioma) and pituitary dysfunction. Pretreatment median BMI percent of the 95th percentile was 125.6% (interquartile range [IQR] 25-75: 115.3-138.3%) with BMI z-score of 2.4 (IQR 25-75: 2.1-2.6). Following methylphenidate treatment, there was a 69.9% reduction in the median slope of BMI change. Eleven of 12 patients (92%) had a reduction in the slope of their BMI change on methylphenidate treatment. Postmethylphenidate median BMI percent of the 95th percentile decrease to 115.2% (IQR 25-75: 103.6-121.2%) with median BMI z-score of 2.1 (IQR 25-75: 1.8-2.2). Mild side effects were noted in six patients. Methylphenidate use reduced and sustained BMI change in children with hypothalamic obesity. Stimulant therapy is an effective first-line agent for treatment of hypothalamic obesity.

The Severity of Growth Hormone Deficiency Does Not Predict the Presence or Absence of Brain Magnetic Resonance Imaging Abnormalities - A Retrospective Review.

The Growth Hormone Research Society recommends that all patients diagnosed with growth hormone deficiency (GHD) should undergo brain magnetic resonance imaging (MRI). This is still a point of controversy in patients with mild GHD, as the level of peak growth-hormone (GH) as a predictor of brain MRI abnormality has not yet been established. The objective of this study was to determine if peak GH level, determined by stimulation tests, can predict the presence or absence of brain MRI abnormality. This study was a retrospective chart review from 2008-2015. Patients were aged 2-18 years, and had growth failure and GHD as determined by stimulation test. Patients with history of brain tumour, chemotherapy and brain surgery, prior to the diagnosis of GHD, were excluded. A total of 386 patients were included. GH values (mild versus severe GHD) did not predict brain MRI abnormality with any agent (clonidine: p=0.07; arginine: p=0.17; glucagon: p=0.42). Abnormal MRI was apparent in 19.2% of the patients with mild GHD and 24.8% of the patients with severe GHD (p=0.17). Severe MRI abnormality was seen in 6.1% of the patients with mild GHD and 15.0% of the patients with severe GHD (p=0.009). The severity of GHD based on peak GH levels on stimulation tests did not predict the presence or absence of brain MRI abnormalities in our study population; however, severe GHD was more strongly associated with severe brain MRI abnormalities. Based on these results we recommend obtaining brain MRI in all patients with GHD.

Reduction of Computed Tomography Use for Pediatric Closed Head Injury Evaluation at a Nonpediatric Community Emergency Department

The purpose of this study was to determine if implementation of a Pediatric Emergency Care Applied Research Network (PECARN)-based Closed Head Injury Assessment Tool could safely decrease computed tomography (CT) use for pediatric head injury evaluation at a nonpediatric community emergency department (ED). A quality improvement project was initiated at a nonpediatric community ED to implement an institution-specific, PECARN-based Pediatric Closed Head Injury Assessment Tool. Baseline head CT use at the participating ED was determined for children with closed head injury through retrospective chart review from March 2014 through November 2015. Head injury patients were identified using International Classification of Disease (ICD)-9 codes for head injury, unspecified (959.01) and concussion with and without loss of consciousness (850-850.9) until October 2015, after which ICD-9 was no longer used. To identify eligible patients after October 2015, lists of all pediatric patients evaluated at the participating ED were reviewed, and patients were included in the analysis if they had a physician-assigned discharge diagnosis of head injury or concussion. Exclusion criteria were age ≥ 18 years, penetrating head trauma, history of brain tumor, ventriculoperitoneal shunt, bleeding disorder, or presentation>24 hours postinjury. Medical history, injury mechanism, symptoms, head CT use, and disposition were recorded. Implementation of the Pediatric Closed Head Injury Assessment Tool was achieved through provider education sessions beginning in December 2015 and ending in August 2016. Head CT use was monitored for 12 months postimplementation, from September 2016 through August 2017. Patients were classified into low, intermediate, or high risk for clinically important traumatic brain injury (ciTBI) by chart review. ED length of stay (LOS), disposition, and ED returns within 72 hours were recorded. Categorical variables were compared using chi-square test or Fisher's exact test, and continuous variables, using Kruskal-Wallis test. A total of 252 children with closed head injury were evaluated preimplementation (March 2014 through November 2015), 132 children were evaluated during implementation (December 2015 through August 2016), and 172 children were evaluated postimplementation (September 2016 through August 2017). Overall CT use decreased from 37.7% (95% confidence interval [CI]= 31.7-43.7) preimplementation to 16.9% (95% CI= 11.3-22.5) postimplementation (p<0.001). Only 1% (95% CI= 0%-2.9%) of low-risk patients received a head CT postimplementation compared to 22.6% (95% CI= 16.1%-29.1%) preimplementation (p<0.001). CT use among patients ≥ 24 months decreased from 42.9% (95% CI= 36.5%-49.6%) to 19.6% (95% CI= 13.1%-26.1%; p<0.001) and remained low and unchanged for patients<24 months. Transfers to a pediatric trauma center and ED returns within 72 hours were unchanged, while median ED LOS improved from 1.5 to 1.3 hours (p=0.03). There were no missed ciTBIs after implementation of the guideline. Implementation of the PECARN-based Pediatric Closed Head Injury Assessment Tool reduced head CT use in a nonpediatric ED. The greatest impact was seen among children aged ≥ 24 months at very low risk for ciTBI.

Yield of Emergent CT in Patients With Epilepsy Presenting With a Seizure

Studies of emergent neuroimaging in the management of patients presenting with a breakthrough seizure are lacking. We sought to determine how often emergent computed tomography (CT) scans are obtained in patients with known epilepsy presenting with a seizure and how often acute abnormalities are found. This multicenter retrospective cohort study was performed in the emergency department at 2 academic medical centers. The primary outcomes were percentage of visits where a CT scan was obtained, whether CT findings represented acute abnormalities, and whether these findings changed acute management. Of the 396 visits included, CT scans were obtained in 39%, and 8% of these scans demonstrated acute abnormalities. Patients who were older, had status epilepticus, a brain tumor, head trauma, or an abnormal examination were all significantly more likely to undergo acute neuroimaging (P < .05). In the multivariable model, only history of brain tumor (odds ratio [OR] 5.88, 95% confidence interval [CI], 1.33-26.1) and head trauma as a result of seizure (OR 3.92, 95% CI, 1.01-15.2) reached statistical significance in predicting an acutely abnormal scan. The likelihood of an acute imaging abnormality in visits for patients without a history of brain tumor or head trauma as a result of the seizure was 2.7% (2 visits). Both of these patients had abnormal neurological examinations. Obtaining an emergent CT scan for patients with epilepsy presenting with a seizure may be avoidable in most cases, but might be indicated for patients with a history of brain tumor or head trauma as a result of seizure.

Abstract 3658: DNA methylation of circulating tumor educated leukocytes predicts IDH1/2 mutation status in adult patients with diffuse gliomas

Abstract INTRODUCTION: Identification of IDH1/2 mutations and association with better outcome revolutionized diagnosis and management of patients with gliomas. Liquid biopsy can detect driver mutation from blood, however, detection of circulating tumor DNA or circulating tumor cells from patients with brain tumors is difficult due to the low amount of circulating tumor material in the peripheral blood. We hypothesized that brain tumors alter the epigenetic profiles of circulating leukocytes and sought to identify specific methylation patterns in peripheral blood that would identify molecular subtypes of gliomas. METHODS: We analyzed brain tumors and matched whole peripheral blood collected in EDTA tubes from 63 patients with primary gliomas. Tumor IDH1/2 mutation status was analyzed using next-generation sequencing and DNA methylation was analyzed using Illumina Human EPIC array. A complete blood count with differential (CBC) was analyzed to control for variations in CBC profiles. Peripheral blood methylation profile was compared to blood of 40 individuals with no known history of brain tumors. DNA methylation of Acute Myeloid Leukemia (AML) samples (source: TCGA) was used to identify overlapping DNA methylation changes induced by IDH1/2 mutations. Methylation data were analyzed with the R Bioconductor package minfi, including quality control, data normalization and differentially methylated CpG site analysis. Subsequent filtering was performed using a p-value cutoff = 0.01 and a minimal mean difference of the Beta-value of 0.1. RESULTS: Peripheral blood methylation profiles of patients with brain tumors are distinctly different from normal controls. DNA methylation of IDH1/2 mutated brain tumors and AML showed significant overlap (enrichment = 3, p-value 2.2x10-16) and DNA methylation of IDH1/2 mutated AML cells showed significant overlap with circulating leukocytes from patients with IDH1/2 mutated brain tumors (enrichment = 6.5, p-value 2.2x10-8 ). Using this classifier supported by AML data, DNA methylation of circulating leukocytes was able to predict IDH1/2 mutation status of diffuse gliomas with 98% accuracy, nearly perfectly separating IDH status by clustering. CONCLUSIONS: Diffuse gliomas induce epigenetic changes in the methylome of the leukocytes, which resembles methylation changes of IDH1/2 mutated AML. IDH wildtype and mutant gliomas can be distinguished with high accuracy by profiling the epigenome of leukocytes. Our study demonstrates the potential of peripheral blood DNA methylation assessment for non-invasive diagnosis of brain tumors. Citation Format: Andreas Kloetgen, Jonathan Serrano, Seema Patel, Christopher Bowman, Guomiao Shen, David Zagzag, Matthias A. Karajannis, John G. Golfinos, Dimitris Placantonakis, Aristotelis Tsirigos, Andrew S. Chi, Matija Snuderl. DNA methylation of circulating tumor educated leukocytes predicts IDH1/2 mutation status in adult patients with diffuse gliomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3658.

Tumor after tumor in two years: A rare presentation of brain glioma, meningioma and supraclavicular meningiosarcoma

Introduction: Low-grade gliomas (LGG) and meningioma are common brain tumors but it is rare for both tumors to be diagnosed in a same patient. Furthermore, it is rare for the same patient to develop an extracranial primary or metastasis meningioma. Probably this is the first case report of a second primary with extracranial meningiosarcoma in literature. Case Report: We present a rare case of brain atypical meningioma which occurred shortly following craniotomy and radiotherapy after being diagnosed as brain glioma (diffused astrocytoma) in a 22-year-old Malay female. Tumors occurred at different sites of the brain namely the atypical meningioma at the temporal and the initial glioma at the frontal region. Subsequently, patient developed a right supraclavicular meningiosarcoma. We believe that the patient could have developed radiation-induced meningioma but the transformation period is very short. The patient's mother had history of brain tumor that added into the risk factors in this patient. However, we are unable to confirm whether the supraclavicular mass was a primary supraclavicular meningiosarcoma or metastatic meningiosarcoma progression from atypical meningioma. Conclusion: There are multiple variant revealed associations of glioma and meningioma. However, these variant could be coincidental. There is a possibility that one tumor acts locally as an irritating factor that induced another unrelated neoplasm. Relation of two or more types of cancers might lead to new therapies, provided target surveillance for cancer patients and risk factors or causal agent are identified.

478 Pharmacological disruption of the Astrocytic Elevated Gene-1 (AEG1) in anticancer intervention: PB0412_3 (PB03) as a first-in-class AEG1 interacting agent

Background: AEG1 is highly expressed in most solid tumors conferring multidrug resistance, increased proliferation, angiogenesis, metastatic potential and poor outcome. AEG1 activates multiple signal transduction pathways such as PIK3/AKT, NFKB, MAPK, WNT and is a rational target for therapeutic intervention in cancer. Our previous data in advanced EGFR mutated and EGFR wild type lung cancer patients confirmed that AEG1 overexpression is indicative of poor outcome to targeted and pleiotropic therapy. In addition, AEG1 functionality is instrumental in the natural history of brain tumors. Material and Methods: We designed an in silico model based on inhibition of the NFkB (p65) binding domain of AEG1, identifying a possible interacting interface between the two proteins that could be modeled as a 3-dimensional structure. This interface was reduced and transformed into a 3-point pharmacophore for virtual screeningcomparing both molecular interaction fields and the pharmacophore. A total of 217,000 chemical entities (CEs) were tested in this model. Each CE was scored using the Hercules affinity ranking. The top sixty CEs amongst the high scores were selected, and thus 4 compounds were proposed for in vitro screening. Twenty analogs were then synthesized, and PB03, a small molecular weight polyheterocyclic compound, was selected as the CE lead. Results: PB03 displays antitumor activity at low mM and nM concentrations. PB03-induced growth inhibition appears to be independent of EGFR, KRAS, BRAF, PIK3CA and p53 mutational status, Her2 amplification, and BRCA1 and AEG1 mRNA expression. PB03 clusters in vitro molar potency (MP) of Glial (Gliobastoma, GBM) and Neural Crest (Neuroblastoma (NBM) and Melanoma) -derived tumors as compared with PB03 profile in other solid tumors and in non-tumoral cells (p < 0.0001). A lack of impact of MGMT methylation status on PB03 (MP) sensitivity has been observed. PB03 is between 500 and 1000 fold more potent than temozolomide and MTIC in GBM and NBM (p < 0.0001). The mean PB03 IC50s in human non-tumoral cell lines is 2.08mM versus 1.22mM in the solid tumor panel vs 0.40mM in the Glial and Neural Crest-derived panel vs 0.11mM in GBM+NBM. Preliminary data in PC9 shows downregulation of AEG1 mRNA expression upon exposure to PB03. Expansion of the Glial and Neural Crest-derived tumor panel, cell kinetics, drug-induced cell death and in vivo/PK-PD studies in in vivo models is ongoing. PB03 has a negative score when screened in the SCIfinder chemical data base confirming PB03 as a first-in-class CE. Conclusions: This is the first successful attempt at the pharmacological intervention against the AEG1 pathway. The observed clustering of Glial and Neural Crest-derived malignancies is unique and a tool for rational development.

Abstract 4601: Astrocytic elevated gene 1 (AEG1) a target for pharmacological anticancer intervention

Abstract AEG1 is highly expressed in solid tumors; hyperexpression confers multidrug resistance, increased tumor proliferation, angiogenesis, metastatic potential and poor outcome in most solid tumors. AEG1 activates multiple protumorogenic signal transduction pathways like PIK3/ALT, NFKB, MAMPK, WNT and is a rational target for therapeutic intervention in solid tumors.Also AEG1 functionality is instrumental in the natural history of brain tumors. Our data in NSCLCs confirm AEG1 overexpression as the main parameter (uni and multivariate analysis) indicative of outcome to targeted and cytotoxic therapy. We designed an in silico model based on inhibition of AEG1-p65 crosstalk, identifying a possible interacting interface between the 2 proteins that could be modeled as a three-dimensional structure. This interface was further reduced and transformed into a 3-point pharmacophore for virtual screening comparing both molecular interaction fields and the pharmacophore. A total of 217.000 chemical entities (CEs) were tested in this model giving a Hercules® affinity ranking. Sixty CEs with the highest Hercules® ranking were identified for a second (16 CEs) and third (5 CEs) selection to implement the first round of in vitro studies in our human solid tumor panel. Twenty analogs were generated to seek for a lead according to prospective selection criteria. PB0412-3 (PB3), a small molecule polyheterocyclic compound, was selected for further development. PB3 displays antitumor activity in the human solid tumor panel (median IC50 1.3 uM) and PB3-induced growth inhibition appears independent of EGFR, KRAS &amp; p53 mutational status, Her2 amplification, PIK3 mutations and BRCA1 expression;tumor cell lines bearing highest AEG1-mRNA expression levels were sensititive to PB3. Median IC50 in our glioblastoma (GBM) panel was 60 nM with no impact of MGMT methylation status on PB3's molar potency (MP). IC50s delta solid vs brain tumors were significant (p&amp;lt;.0001) representing a 25-fold increase in MP. Data from nitrosureas in the same GBM panel indicate PB3 is 250 times more potent than BCNU and temozolamide. Median IC50s in human non cancer lines is 2 uM. PB3 was re-screened in the in silico model; PB3 fully matches the AEG1 binder pharmacophore model and was screened in the Chemical Space web tool; results confirm PB3 as first-in-class CE. Functional studies are ongoing; preliminary data in PC9 NSCLC cell line demonstrate significant PB3-induced downregulation of AEG1 mRNA expression. Expansion of the CNS tumor panel, cell kinetics, drug-induced cell death &amp; in vivo/PK-PD studies in SC orthotopic models is ongoing. To the best of our knowledge, this is the first successful attempt at the Pharmacological intervention against the AEG1 pathway. A dual developmental plan for PB3 as local brain drug delivery and systemic therapy is proposed. Citation Format: Jose M. Jimeno, Gerardo Acosta, Miguel Ángel Molina, Nicky Karachaliou, Cristina Teixidó, Carlos Obiol, Oriol Villacañas, Jordi Bertran, María Sánchez Rouco, Ana Giménez Capitán, Santiago Ramón y Cajal, Miquel Taron, Rafael Rosell, Fernando Albericio. Astrocytic elevated gene 1 (AEG1) a target for pharmacological anticancer intervention. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4601. doi:10.1158/1538-7445.AM2014-4601

Ventriculoperitoneal (VP) Shunt Survival in Patients Developing Hydrocephalus After Cranial Surgery.

Ventriculoperitoneal (VP) shunt insertion remains the most popular method for the treatment of hydrocephalus despite its associated complications. We assessed VP shunt survival in a group of patients who had developed hydrocephalus following cranial surgery. A retrospective charts review was done over a 10-year period at our institution. Kaplan-Meier survival curves and Log-Rank (Cox-Mantel) test were used to analyze various factors affecting VP shunt survival. Among the 67 cases included, a total of 28 (46.3%) patients had undergone cranial surgery for brain tumors. The overall rate of shunt failure was 14.9% at a mean follow-up of 16 months. Shunt failure in pediatric patients (20%) was slightly higher than that in adult patients (13.5%). The median time to first shunt failure was adversely influenced by a history of brain tumor (p = 0.019), prolonged antibiotic therapy (p = 0.018) and administration of steroids (p = 0.004). Shunt survival was worse in patients who developed hydrocephalus following cranial surgery performed for brain tumors and those who received either steroids or prolonged antibiotic therapy. Thus post-cranial surgery hydrocephalus represents a unique subset of hydrocephalus.

Abstract 104: Toenail iron, genetic variation in iron status, and the risk and outcome of glioma .

Abstract Elevated iron stores can trigger overproduction of reactive oxygen species and induce oxidative DNA damage. To our knowledge, no studies have investigated the association of body iron stores with the risk of glioma. In this investigation, we examined single nucleotide polymorphisms (SNPs) identified as markers of iron status in genome-wide association studies, and also measured iron stores in toenail samples in a clinic-based case-control study conducted at medical centers in the southeastern US. Genotyping was performed in 622 newly diagnosed, nonrecurrent glioma cases (including 341 WHO grade IV glioblastomas (GBM); 146 WHO grade II or III astrocytomas, 94 mixed oligoastrocytomas (MOAs) and oligodendrogliomas, and 41 gliomas with unspecified histology) and 628 healthy controls with no history of brain tumors. Illumina GoldenGate and Taqman OpenArray assays were used to genotype oral DNA samples. A total of 24 SNPs associated with markers of iron status were genotyped. Iron levels in toenail samples were measured in 200 glioma cases and 200 controls using neutron-activation analysis. Logistic regression was used to estimate age and gender-adjusted odds ratios (OR) and 95% confidence intervals (CI) for glioma risk according to examined genotypes and toenail iron levels. Proportional hazards regression was used to estimate age and gender-adjusted hazard ratios (HR) for glioma-related death among 320 patients with GBM or high grade astrocytomas all treated with the current standard of care for high grade glioma (eg. surgery, radiation and temozolomide) (248 deaths; median Kaplan-Meier survival: 15.0 months). We observed no overall association with glioma risk or patient outcome for SNPs in ARSB, BTN1A1, C7ORF10, FLJ43390, GHR, GTSCR1, HFE, HIST1H2BJ, KRT18P33, LRRC16, SCGN, SLC17A1, TOPBP1, and WTAP. Among non-GBM astrocytomas, borderline risk associations were observed for rs236918 in PCSK7 (G&amp;gt;C; minor allele frequency (MAF) = 0.11) (per variant allele OR = 0.50; 95% CI: 0.29 to 0.88; p for trend = 0.01) and with rs1049296 in TF (C&amp;gt;T; MAF = 0.17) (recessive model OR = 3.03; 95% CI: 1.11 to 8.27; p = 0.03). Among oligodendrogliomas/MOAs, risk associations were observed for rs4820268 in TMPRSS6 (A&amp;gt;G; MAF = 0.43) (recessive model OR = 1.91; 95% CI: 1.14 to 3.22; p = 0.01) and rs12216125 in TRIM38 (C&amp;gt;T; MAF = 0.35) (dominant model OR = 1.67; 95% CI: 1.03 to 2.72; p = 0.04). No SNPs were associated with the risk of GBM. One SNP, rs972275 in RSPO3 (G&amp;gt;C; MAF = 0.38), was associated with shorter patient survival (dominant model HR = 1.40; 95% CI: 1.06, 1.87; p=0.02). Increasing levels of toenail iron was associated with a non-significant decrease in glioma risk (OR = 0.88; 95% CI: 0.77 to 1.02; p = 0.08). Iron levels were not associated with survival. To our knowledge this is the first report suggesting that genetically determined variation in iron status may affect glioma risk and patient outcome. Further studies are needed to confirm these results. Citation Format: Gabriella M. Anic, Reid C. Thompson, L. Burton Nabors, Jeffrey J. Olson, Melissa H. Madden, James E. Browning, John D. Brockman, Peter A. Forsyth, Kathleen M. Egan. Toenail iron, genetic variation in iron status, and the risk and outcome of glioma . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 104. doi:10.1158/1538-7445.AM2013-104

Cerebral FDG Metabolic Pattern in Pediatric Patients with Neurofibromatosis Type 1: A Retrospective Study

154 Objectives About 65% of NF1 children perform below chronologic age in school and 45% of them require special education assistance between the ages of 8 and 16 years. The cognitive phenotype of NF1 pediatric patients is not well understood. We retrospectively evaluated the cerebral FDG PET of NF1 pediatric patients using voxel-based statistical analysis. Methods Six NF1 patients (5 male, 1 female median age 13) underwent whole-body FDG PET/CT (Gemini TF, Philips Healthcare) including the brain, for evaluation of extra-cranial neoplasm. Their brain PET images were extracted from the whole-body images and compared with those of a comparison set consisting of 21 pediatric patients using Statistical Parametric Mapping SPM8 software (Wellcome Department of Cognitive Neurology, University College London, UK). The comparison set subjects underwent PET/CT for extracranial neoplasm not related to NF1, had no history of brain tumor or neurolopsychologic disease and had not received chemotherapy prior to PET/CT. SPM parameters included a 6 mm smoothing kernel, proportional scaling of global counts and a two-sample t test. Significant differences between groups were examined at p Results Compared with the comparison set, the 6 NF1 pediatric patients showed large (> 500 voxels) symmetric hypometabolic clusters in both thalami and caudate nuclei as well as large asymmetric clusters in the right medial frontal lobe and left occipital lobe. At smaller clusters (100-500 voxels), additional hypometabolic clusters were present in bilateral temporal lobe along the posterior horn, right greater than left, suggestive of the optic radiation pathway. Conclusions The striking FDG reductions of the bilateral thalamus and caudate nucleus in children is consistent with previous studies. The reduced metabolism in the occipital lobe and along the presumed bilateral optic radiations may explain the visuospacial deficits typically seen in NF1 children

Cerebral FDG Metabolic Pattern in Pediatric Patients with Neurofibromatosis Type 1: A Retrospective Study

154 Objectives About 65% of NF1 children perform below chronologic age in school and 45% of them require special education assistance between the ages of 8 and 16 years. The cognitive phenotype of NF1 pediatric patients is not well understood. We retrospectively evaluated the cerebral FDG PET of NF1 pediatric patients using voxel-based statistical analysis. Methods Six NF1 patients (5 male, 1 female median age 13) underwent whole-body FDG PET/CT (Gemini TF, Philips Healthcare) including the brain, for evaluation of extra-cranial neoplasm. Their brain PET images were extracted from the whole-body images and compared with those of a comparison set consisting of 21 pediatric patients using Statistical Parametric Mapping SPM8 software (Wellcome Department of Cognitive Neurology, University College London, UK). The comparison set subjects underwent PET/CT for extracranial neoplasm not related to NF1, had no history of brain tumor or neurolopsychologic disease and had not received chemotherapy prior to PET/CT. SPM parameters included a 6 mm smoothing kernel, proportional scaling of global counts and a two-sample t test. Significant differences between groups were examined at p Results Compared with the comparison set, the 6 NF1 pediatric patients showed large (> 500 voxels) symmetric hypometabolic clusters in both thalami and caudate nuclei as well as large asymmetric clusters in the right medial frontal lobe and left occipital lobe. At smaller clusters (100-500 voxels), additional hypometabolic clusters were present in bilateral temporal lobe along the posterior horn, right greater than left, suggestive of the optic radiation pathway. Conclusions The striking FDG reductions of the bilateral thalamus and caudate nucleus in children is consistent with previous studies. The reduced metabolism in the occipital lobe and along the presumed bilateral optic radiations may explain the visuospacial deficits typically seen in NF1 children

Abstract 2629: Common genetic variants in the vitamin D pathway including genome-wide associated variants in relation to glioma risk and outcome

Abstract Experimental and clinical evidence suggest that vitamin D protects against several types of cancer by promoting cell differentiation and apoptosis and by inhibiting cell proliferation and angiogenesis. In vitro evidence supports a similar protective function in glioma; however, no study has examined whether common genetic variants in the vitamin D pathway are related to glioma risk or patient outcome. We evaluated these potential associations in a clinic-based case-control study conducted at medical centers in the southeastern US. Genotyping was performed in 623 newly diagnosed (eg. nonrecurrent) glioma cases (including 343 WHO grade IV glioblastomas (GBM); 148 WHO grade II or III astrocytomas, 95 oligoastrocytomas and oligodendrogliomas, and 37 gliomas with unspecified histology) and 631 healthy controls with no history of brain tumors. A total of 7 candidate tagging single nucleotide polymorphisms (SNPs) were genotyped in the vitamin D receptor (VDR at 12q13) including rs2107301, rs2238135, rs4516035, rs731236 (Taq1), rs1544410 (Bsm1), rs11568820 (Cdx2), and rs2228570 (Fok1). SNPs associated with serum concentrations of 25-hydroxy vitamin D in genome-wide association studies (GWAS) were also evaluated including rs1155563, rs12512631, rs2282679, and rs7041 in GC (4q12-q13), rs10741657 in CYP2R1 (11p15), rs6013897 in CYP24A1 (20q13), rs3829251 in NADSYN1 (11q13), and rs6599638 at C10orf88 (10q26). Genotyping was performed in oral DNA samples using Illumina GoldenGate and Taqman OpenArray assays. Logistic regression was used to estimate age and gender-adjusted odds ratios (OR) and 95% confidence intervals (CI) for glioma risk according to vitamin D genotypes. Proportional hazards regression was used to estimate age and gender-adjusted hazard ratios (HR) for glioma-related death among 439 patients with high grade tumors including GBM and high grade astrocytomas (331 deaths; median Kaplan-Meier survival: 15.0 months). GWAS SNPs in NADSYN1, GC, and C10ORF88 were not associated with glioma risk or patient survival. Risk associations limited to GBM were observed for rs2238135 in the VDR (G&amp;gt;C; minor allele frequency (MAF) = 0.20) (per variant allele OR = 1.31; 95% CI: 1.01 to 1.71; p for trend = 0.04) and for GWAS SNP rs10741657 located near CYP2R1 (G&amp;gt;A; MAF = 0.40) (per variant allele OR = 0.79; 95% CI: 0.63 to 0.98; p for trend = 0.03). The variant allele in CYP24A1 rs6013897 (T&amp;gt;A; MAF = 0.20) was associated with prolonged survival among patients with high grade tumors (per variant allele HR = 0.79; 95% CI: 0.59 to 0.97; p for trend = 0.03) in patients uniformly treated with the current standard of care (surgery, radiation and temozolomide). To our knowledge this is the first report suggesting that genetic variation in vitamin D related genes may be a determinant of glioma risk and outcome. Further studies are needed to confirm these results and identify the putative causal variant. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2629. doi:1538-7445.AM2012-2629