Hemispheric Tumors Research Articles

Abstract A16: Using 3D tumor simulations to determine optimal therapeutic conditions for the cold atmospheric plasma device

Abstract It has been shown that cold atmospheric plasma (CAP) can selectively treat cancer cells while leaving healthy cells relatively unharmed through both in vitro and in vivo experiments. This plasma contains reactive oxygen and nitrogen species at room temperatures, which drives the selective ability of the plasma jet to cancer cells. The translation of this therapeutic into surgical application is being limited by knowledge of its mechanism and poorly-defined standards for optimal treatments. Previous research seeks to answer these questions, including studying the tunable effect of the jet and how external parameters affect treatment outcome. Time-dependent ROS generation rates near the tissue surface provided by plasma jet are studies in 2D fluid model simulation. A specific set of balance equations for chemical species for two types of mixtures He/air and Ar/air are developed. We study additional oxygen portions effect on the ROS production. These simulations will be used to provide boundary conditions for the CAP-tumor interactions. Two types of parameters have been defined in this study that have an affect on the outcome of CAP tumor therapy [1]: (1) CAP-specific parameters and (2) tumor-specific parameters. CAP-specific parameters include the number and type of species produced, the duration of treatment and size of the treatment area. Tumor-specific parameters include the cellular response to plasma, the growth-rate of the tumor and overall tumor geometry. A 3D tumor simulation was created that can model the effect of the CAP therapy on a hemispherical tumor, using agent-based simulation techniques. Both CAP-specific and tumor-specific parameters where varied in treatment simulations to define a set of standards for optima treatment outcomes. When varying CAP-specific parameters, it was determined that the concentration of plasma species used and the percentage of the tumor surface area treated has the greatest affect on tumor treatment outcome. Likewise, the location/angle of treatment seemed to have an affect on treatment outcome with respect to the geometry of the tumor. For tumor-specific parameters, the growth rate of the tumor seemed to not have an affect on the treatment outcome, while cellular chemical reactions that increased internal ROS of the cell decreased the treatment time. Likewise, cellular chemical reactions that decreased ROS of the cell increased the treatment time. Using computational simulations, a set of standards for optimal treatment conditions that describe both the tumor-specific and CAP-specific parameters has been elucidated. This work was partially supported by National Science Foundation, grant 1465061.

Dynamics of functional MRI and speech function in patients after resection of frontal and temporal lobe tumors

There are no studies on application of functional MRI (fMRI) for long-term monitoring of the condition of patients after resection of frontal and temporal lobe tumors. The study purpose was to correlate, using fMRI, reorganization of the speech system and dynamics of speech disorders in patients with left hemisphere gliomas before surgery and in the early and late postoperative periods. A total of 20 patients with left hemisphere gliomas were dynamically monitored using fMRI and comprehensive neuropsychological testing. The tumor was located in the frontal lobe in 12 patients and in the temporal lobe in 8 patients. Fifteen patients underwent primary surgery; 5 patients had repeated surgery. Sixteen patients had WHO Grade II and Grade III gliomas; the others had WHO Grade IV gliomas. Nineteen patients were examined preoperatively; 20 patients were examined at different times after surgery. Speech functions were assessed by a Luria's test; the dominant hand was determined using the Annette questionnaire; a family history of left-handedness was investigated. Functional MRI was performed on an HDtx 3.0 T scanner using BrainWavePA 2.0, Z software for fMRI data processing program for all calculations >7, p<0.001. In patients with extensive tumors and recurrent tumors, activation of right-sided homologues of the speech areas cold be detected even before surgery; but in most patients, the activation was detected 3 months or more after surgery. Therefore, reorganization of the speech system took time. Activation of right-sided homologues of the speech areas remained in all patients for up to a year. Simultaneous activation of right-sided homologues of both speech areas, the Broca's and Wernicke's areas, was detected more often in patients with frontal lobe tumors than in those with temporal lobe tumors. No additional activation foci in the left hemisphere were found at the thresholds used to process fMRI data. Recovery of the speech function, to a certain degree, occurred in all patients, but no clear correlation with fMRI data was found. Complex fMRI and neuropsychological studies in 20 patients after resection of frontal and temporal lobe tumors revealed individual features of speech system reorganization within one year follow-up. Probably, activation of right-sided homologues of the speech areas in the presence of left hemisphere tumors depends not only on the severity of speech disorder but also reflects individual involvement of the right hemisphere in enabling speech function. This is confirmed by right-sided activation, according to the fMRI data, in right-sided patients without aphasia and, conversely, the lack of activation of right-sided homologues of the speech areas in several patients with severe postoperative speech disorders during the entire follow-up period.

Language in individuals with left hemisphere tumors: Is spontaneous speech analysis equally good as formal testing?

Language in individuals with left hemisphere tumors: Is spontaneous speech analysis equally good as formal testing?

Enhancing Predicted Efficacy of Tumor Treating Fields Therapy of Glioblastoma Using Targeted Surgical Craniectomy: A Computer Modeling Study.

ObjectiveThe present work proposes a new clinical approach to TTFields therapy of glioblastoma. The approach combines targeted surgical skull removal (craniectomy) with TTFields therapy to enhance the induced electrical field in the underlying tumor tissue. Using computer simulations, we explore the potential of the intervention to improve the clinical efficacy of TTFields therapy of brain cancer.MethodsWe used finite element analysis to calculate the electrical field distribution in realistic head models based on MRI data from two patients: One with left cortical/subcortical glioblastoma and one with deeply seated right thalamic anaplastic astrocytoma. Field strength was assessed in the tumor regions before and after virtual removal of bone areas of varying shape and size (10 to 100 mm) immediately above the tumor. Field strength was evaluated before and after tumor resection to assess realistic clinical scenarios.ResultsFor the superficial tumor, removal of a standard craniotomy bone flap increased the electrical field strength by 60–70% in the tumor. The percentage of tissue in expected growth arrest or regression was increased from negligible values to 30–50%. The observed effects were highly focal and targeted at the regions of pathology underlying the craniectomy. No significant changes were observed in surrounding healthy tissues. Median field strengths in tumor tissue increased with increasing craniectomy diameter up to 50–70 mm. Multiple smaller burr holes were more efficient than single craniectomies of equivalent area. Craniectomy caused no significant field enhancement in the deeply seated tumor, but rather a focal enhancement in the brain tissue underlying the skull defect.ConclusionsOur results provide theoretical evidence that small and clinically feasible craniectomies may provide significant enhancement of TTFields intensity in cerebral hemispheric tumors without severely compromising brain protection or causing unacceptable heating in healthy tissues. A clinical trial is being planned to validate safety and efficacy.

Preoperative neurocognitive evaluation as a predictor of brain tumor grading in pediatric patients with supratentorial hemispheric tumors.

The objective of the present study was to retrospectively evaluate the relationship between tumor grading and a selective evaluation of neurocognitive and behavioral functions in children with supratentorial hemispheric brain tumors. Children admitted with a diagnosis of supratentorial hemispheric tumors involving the cerebral hemispheres or the thalamus at the Pediatric Neurosurgery Unit of the Catholic University of Rome between January 2008 and January 2014 were considered for the present study. Exclusion criteria were represented by age less than 2years, severe neurological deficits, seizures, and a metastatic disease. A selective neurocognitive and behavioral workout was used for children aged less and more than 5years. Global cognitive functions as well as selective neurocognitive and behavioral profiles were found to be significantly worse in children with low-grade tumors, compared with those affected by higher-grades histotypes. Frontal locations for cortical tumors and thalamic lesions were significantly related with worse results, with a clear contribution of dominant vs. nondominant hemisphere involvement and an age higher than 5years. Preoperative global and selective neurocognitive evaluation might contribute to the prediction of the tumor aggressiveness. Due to a longer clinical history, more benign tumors more frequently arrive to the diagnosis with a neurocognitive compromise in spite of an apparently mild presence of neurological symptoms and signs.

Cerebral hemispheric low-grade glial tumors in children: preoperative anatomic assessment with MRI and DTI.

The aims of this study are to analyze how the nature and the behavior of low-grade glial tumors (LGGT) in children may correlate with the anatomy of the cerebral hemispheres and to evaluate the consequent impact of diffusion tensor imaging (DTI) techniques in the presurgical assessment. This is a combined review of a series of 155 cases of LGGT and of the recent literature on the subject. The cases retrieved from our data bank were divided in central hemispheric tumors (basal ganglia and thalami) (36 cases), glioneuronal cortical-based tumors (49 cases), and glial tumors of the cerebral mantle (70 cases). A close correlation was found in the thalamus between the primary location of the tumor (juxta-ventricular, inferior, lateral, bilateral) and its extension (ventricular lumen, midbrain and mesial temporal, globus pallidus, respectively) which may relate to the connectivity. Among the glioneuronal tumors, most gangliogliomas were located in the temporal lobe and especially in the mesial temporal structures. In addition, the morphologic feature of the ganglioglioma was different there from the neocortical areas. As a complementary approach, DTI data may assist in evaluating the structure and the extension of the LGGT, in addition to planning the surgical strategy. In the cerebral hemispheres like in the rest of the central nervous system, there is some degree of correlation between the anatomy and the nature, appearance, and behavior of the LGGT in children.

Relationships between the Dark Triad and PTSD symptoms

The present study aimed to describe the quality of life (QoL) changes of survivors of low-grade gliomas (LGGs) 1 year after surgery and to identify determinants of QoL with an emphasis on the role of perceived posttraumatic growth (PTG). We also tried to examine the linear and quadratic relationship between QoL and PTG.Two hundred sixty participants were included in the final data analysis. The Chinese version of posttraumatic growth inventory and the Functional Assessment of Cancer Therapy–Brain scale were used to measure PTG and QoL. Hierarchical linear models were fitted to explore the individual time trajectories in change of QoL and examine the relationship between demographics, clinical features, PTG, and QoL.All dimensions of QoL and PTG increased over time except physical well-being, social well-being in QoL, and new possibilities in PTG. Time, PTG score, insurance, socioeconomic status, and right hemisphere tumor position were positive predictors of QoL. Seizure and depression negatively predicted QoL. The quadratic of PTG predicted QoL; however, the coefficient of quadratic PTG approached zero.In general, PTG and QoL increased over time. Perceived PTG could significantly predict QoL of LGGs survivors 1 year after surgery. A quadratic relation between PTG and QoL was not found. Although our data suggested that the growth of QoL may vary across different patients, there were only 2 time points in this study. Future studies should set more time points to examine this relationship.

Variability of intraoperative electrostimulation parameters in conscious individuals: language cortex.

OBJECTIVE Electrostimulation in awake brain mapping is widely used to guide tumor removal, but methodologies can differ substantially across institutions. The authors studied electrostimulation brain mapping data to characterize the variability of the current intensity threshold across patients and the effect of its variations on the number, type, and surface area of the essential language areas detected. METHODS Over 7 years, the authors prospectively studied 100 adult patients who were undergoing intraoperative brain mapping during resection of left hemisphere tumors. In all 100 cases, the same protocol of electrostimulation brain mapping (a controlled naming task-bipolar stimulation with biphasic square wave pulses of 1-msec duration and 60-Hz trains, maximum train duration 6 sec) and electrocorticography was used to detect essential language areas. RESULTS The minimum positive thresholds of stimulation varied from patient to patient; the mean minimum intensity required to detect interference was 4.46 mA (range 1.5-9 mA), and in a substantial proportion of sites (13.5%) interference was detected only at intensities above 6 mA. The threshold varied within a given patient for different naming areas in 22% of cases. Stimulation of the same naming area with greater intensities led to slight changes in the type of response in 19% of cases and different types of responses in 4.5%. Naming sites detected were located in subcentimeter cortical areas (50% were less than 20 mm2), but their extent varied with the intensity of stimulation. During a brain mapping session, the same intensity of stimulation reproduced the same type of interference in 94% of the cases. There was no statistically significant difference between the mean stimulation intensities required to produce interfereince in the left inferior frontal lobe (Broca's area), the supramarginal gyri, and the posterior temporal region. CONCLUSIONS Intrasubject and intersubject variations of the minimum thresholds of positive naming areas and changes in the type of response and in the size of these areas according to the intensity used may limit the interpretation of data from electrostimulation in awake brain mapping. To optimize the identification of language areas during electrostimulation brain mapping, it is important to use different intensities of stimulation at the maximum possible currents, avoiding afterdischarges. This could refine the clinical results and scientific data derived from these mapping sessions.

Exploratory study of the effect of brain tumors on the default mode network.

Resting state functional magnetic resonance imaging (RS-fMRI) is a popular method of visualizing functional networks in the brain. One of these networks, the default mode network (DMN), has exhibited altered connectivity in a variety of pathological states, including brain tumors. However, very few studies have attempted tolink the effect of tumor localization, type and size on DMN connectivity. We collected RS-fMRI data in 73 patients with various brain tumors and attempted to characterize the different effects these tumors had on DMN connectivity based on their location, type and size. This was done by comparing the tumor patients with healthy controls using independent component analysis (ICA) and seed based analysis. We also used a multi-seed approach described in the paper to account for anatomy distortion in the tumor patients. We found that tumors in the left hemisphere had the largest effect on DMN connectivity regardless of their size and type, while this effect was not observed for right hemispheric tumors. Tumors in the cerebellum also had statistically significant effects on DMN connectivity. These results suggest that DMN connectivity in the left side of the brain may be more fragile to insults by lesions.

Othello syndrome in a patient with two left hemispheric tumors

We report a case of a patient with Othello syndrome caused by two left hemispheric tumors. This 50-year-old female had experienced seizures for 10 years and developed manic-like symptoms, delusions of jealousy, persecution and being watched, auditory hallucinations, irritable mood, and violent and disorganized behavior for the past 3 years. Brain imaging studies revealed two left frontal tumors, the larger of which was causing a mass effect. The delusions of jealousy in Othello syndrome resolved after removing the larger tumor, and the other psychiatric symptoms improved after treatment with psychotropic medications. This report aims to raise awareness of Othello syndrome related to disruptions in cortico-subcortical connections in the left orbitofrontal region. Timely surgical treatment may prevent associated psychiatric comorbidities and increase the likelihood of a good outcome.

Abstract B06: Knock-down of H3.3 K27M mutant protein in DIPG cells delays, but does not abrogate, tumor growth in vivo

Abstract Genome-wide sequencing efforts of pediatric high grade gliomas (HGG) identified recurrent and hotspot mutations in the N-terminal regulatory tail of histone H3 variants H3.3 (H3F3A) and H3.1 (HIST1H3B/C). K27M histone mutations are mainly observed in midline tumors, including 78% of diffuse intrinsic pontine gliomas (DIPGs). By contrast, G34R/V mutations are predominantly restricted to 15% of the hemispheric tumours. This illustrates a highly specific selective pressure for each mutation in different cell types during brain development. The K27M mutation induces a dominant negative loss of trimethylated K27 (H3K27me3) marks in the bulk H3 pool. H3K27me3 interacts with Polycomb repressive complex 2 (PRC2) to repress transcription of target genes, a key process in the regulation and development of stem cells. Global gene expression analysis revealed that many significant differences between DIPGs (mostly K27M mutants) and non-brainstem pediatric HGG (mostly wild-type) are in genes that encode transcription factors and genes associated with developmental processes. Importantly, there was particular enrichment of genes exclusively expressed in distinct developing brain locations. Hence, it is challenging to define a clear gene expression signature associated with K27M mutations in DIPGs. In this study, in order to identify factors directly regulated by K27M, we aimed to knock-down the mutated protein in a DIPG-derived xenograft line. This H3.3 K27M line is maintained by successive implants of luciferase+/YFP+ tumor cells in the cortex of CD-1 nude immunocompromised mice. Resected tumor cells were transduced with lentiviral vectors expressing H3F3A specific shRNAs, selected with puromycin in neural stem cell culture conditions, and either kept under culture or re-implanted into mice. Cells in culture expressing any of three distinct shRNAs showed 92-96% H3F3A mRNA knock-down, 82-90% K27M protein knock-down and a 4-7 fold increase in H3K27me3 levels. Knock-down of H3F3A with any of three shRNAs in vivo significantly extended the time for tumor growth and the survival of xenografted mice. Notably, tumor growth was not completely abrogated. We observed an average of 79% H3F3A mRNA knock-down and increased levels of H3K27me3 by immunofluorescence in experimental tumors. Global gene expression profiling revealed modulation of a common subset of genes by all three shRNAs in vivo. We will present analysis of the gene expression changes associated with loss of the K27M mutation in DIPG cells. Overall, we show efficient knock-down of H3F3A in a H3.3 K27M mutant DIPG-derived xenograft line, leading to increased accumulation of H3K27me3, modulation of gene expression, and increased survival in vivo. Citation Format: André B. Silveira, Xiaoyan Zhu, Chunxu Qu, Suzanne Baker. Knock-down of H3.3 K27M mutant protein in DIPG cells delays, but does not abrogate, tumor growth in vivo. [abstract]. In: Proceedings of the AACR Special Conference: Advances in Brain Cancer Research; May 27-30, 2015; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2015;75(23 Suppl):Abstract nr B06.

Successful treatment of primary intracranial sarcoma with the ICE chemotherapy regimen and focal radiation in children.

OBJECT Primary CNS sarcomas are very rare pediatric tumors with no defined standard of care. METHODS This study was a retrospective review of children diagnosed with a primary CNS sarcoma and treated at 2 Canadian tertiary care centers between 1995 and 2012. This report focuses on patients with cerebral hemispheric tumor location due to their specific clinical presentation. RESULTS Fourteen patients with nonmetastatic primary CNS sarcoma were identified; in 9 patients, tumors were located in the cerebral hemisphere and 7 of these patients presented with intratumoral hemorrhage. One infant who died of progressive disease postoperatively before receiving any adjuvant therapy was not included in this study. The final cohort therefore included 8 patients (4 males). Median patient age at diagnosis was 11.8 years (range 5.8-17 years). All tumors were located in the right hemisphere. Duration of symptoms prior to diagnosis was very short with a median of 2 days (range 3-7 days), except for 1 patient. Three (37.5%) patients had an underlying diagnosis of neurofibromatosis Type 1 (NF1). Gross-total resection was achieved in 5 patients. The dose of focal radiation therapy (RT) ranged between 54 Gy and 60 Gy. Concomitant etoposide was administered during RT. ICE (ifosfamide, carboplatin, etoposide) chemotherapy was administered prior to and after RT for a total of 6-8 cycles. Seven of the 8 patients were alive at a median time of 4.9 years (range 1.9-17.9 years) after treatment. CONCLUSIONS In this retrospective series, patients with primary CNS sarcomas located in the cerebral hemisphere most commonly presented with symptomatic acute intratumoral hemorrhage. Patients with NF1 were overrepresented. The combination of adjuvant ICE chemotherapy and focal RT provided encouraging outcomes.

Neurocognitive effects of proton radiation therapy in adults with low-grade glioma.

To understand neurocognitive effects of proton radiation therapy (PRT) in patients with low-grade glioma, we evaluated 20 patients who received this therapy prospectively and over 5 years with a comprehensive neuropsychological battery. 20 patients were evaluated at baseline and at yearly intervals for up to 5 years with a battery of neuropsychological measures that assessed intellectual, attention, executive, visuospatial and memory functions as well as mood and functional status. We evaluated change in cognitive functioning over time. We analyzed the relationship between cognitive performance and tumor location and also examined whether patients' performance differed from that reported in a study of normative practice effects. Overall, patients exhibited stability in cognitive functioning. Tumor location played a role in performance; those with tumors in the left hemisphere versus in the right hemisphere were more impaired at baseline on verbal measures (p < .05). However, we found greater improvement in verbal memory over time in patients with left than with right hemisphere tumors (p < .05). Results of our study, the first to investigate, in depth, neurocognitive effects of PRT in adults with low-grade gliomas, are promising. We hypothesize that the conformal advantage of PRT may contribute to preservation of cognitive functioning, although larger sample sizes and a longer period of study are required. Our study also highlights the need to consider normative practice effects when studying neurocognitive functioning in response to treatment over time, and the need to utilize comprehensive neuropsychological batteries given our findings that differentiate patients with left and right hemisphere tumors.

The nondecussating pathway of the dentatorubrothalamic tract in humans: human connectome-based tractographic study and microdissection validation.

OBJECT The dentatorubrothalamic tract (DRTT) is the major efferent cerebellar pathway arising from the dentate nucleus (DN) and decussating to the contralateral red nucleus (RN) and thalamus. Surprisingly, hemispheric cerebellar output influences bilateral limb movements. In animals, uncrossed projections from the DN to the ipsilateral RN and thalamus may explain this phenomenon. The aim of this study was to clarify the anatomy of the dentatorubrothalamic connections in humans. METHODS The authors applied advanced deterministic fiber tractography to a template of 488 subjects from the Human Connectome Project (Q1-Q3 release, WU-Minn HCP consortium) and validated the results with microsurgical dissection of cadaveric brains prepared according to Klingler's method. RESULTS The authors identified the "classic" decussating DRTT and a corresponding nondecussating path (the nondecussating DRTT, nd-DRTT). Within each of these 2 tracts some fibers stop at the level of the RN, forming the dentatorubro tract and the nondecussating dentatorubro tract. The left nd-DRTT encompasses 21.7% of the tracts and 24.9% of the volume of the left superior cerebellar peduncle, and the right nd-DRTT encompasses 20.2% of the tracts and 28.4% of the volume of the right superior cerebellar peduncle. CONCLUSIONS The connections of the DN with the RN and thalamus are bilateral, not ipsilateral only. This affords a potential anatomical substrate for bilateral limb motor effects originating in a single cerebellar hemisphere under physiological conditions, and for bilateral limb motor impairment in hemispheric cerebellar lesions such as ischemic stroke and hemorrhage, and after resection of hemispheric tumors and arteriovenous malformations. Furthermore, when a lesion is located on the course of the dentatorubrothalamic system, a careful preoperative tractographic analysis of the relationship of the DRTT, nd-DRTT, and the lesion should be performed in order to tailor the surgical approach properly and spare all bundles.

Treatment outcome and patterns of failure in patients of non-pineal supratentorial primitive neuroectodermal tumor: review of literature and clinical experience form a regional cancer center in north India.

Supra-tentorial primitive neuroectodermal tumors (SPNET) are high-grade, hemispheric tumors, which account for around 2-3 % of pediatric brain tumors. We herein intend to report the clinical features and treatment outcome of patients with nonpineal SPNET treated at our institute. Clinical data were collected by retrospective chart review from 2006 to 2012. Histopathology slides were reviewed, and relevant immunohistochemistry stains were done. Overall survival (OS), recurrence-free survival (RFS) and event-free survival (EFS) were analyzed by the Kaplan-Meier product-limit method. Fifteen patients met the study criterion (male: female = 2:1). Median age at presentation was 11 years (range 3-49 years). Surgical resection was gross total in 6 (40%) and subtotal in 8 (53.33%) patients. At presentation, two patients had leptomeningeal dissemination. Radiation therapy was delivered in 11 (73.33%) patients: craniospinal irradiation in 8 (36 Gy/20 fractions/4 weeks to the craniospinal axis followed by a local boost of 20 Gy/10 fractions/2 weeks) and focal RT in 3 patients. Systemic chemotherapy (median 6 cycles; range 1-16 cycles), given in 13 (86.67%) patients, included the VAC regimen (vincristine, adriamycin, cyclophosphamide) alternating with IE (ifosfamide,etoposide). After a median follow-up of 22.6 months (mean, 24.47 months), complete response and progressive disease were noted in 8 (53.33%) and 7 (46.67%) patients, respectively. Median OS was not reached, and estimated median EFS was noted to be 4.12 years (actuarial rate of EFS at 2 years, 55.2%). Maximal safe resection followed by craniospinal irradiation and systemic chemotherapy with 6-12 cycles of an alternating regimen of VAC and IE is a reasonable treatment strategy in patients with nonpineal SPNET.

HG-09 * INFANTILE GLIOBLASTOMA WITH SARCOMATOUS HISTOLOGY DRIVEN BY ETV6:NTRK3 FUSIONS ARE SENSITIVE TO TRK INHIBITION BY PHA-848125

Approximately 1% of all paediatric brain tumours occur at less than one year of age, and glioblastoma (GBM) account for only 2-9% of these. Their clinical presentation, location, histology, behaviour, response to therapy and outcome differ from GBMs of older children and adults, and they do not appear to be associated with known histone H3 or IDH1-driven subgroups. Recent genome and RNA sequencing data highlighted recurrent NTRK1-3 fusions in 4/10 non-brainstem GBM under the age of 3 years, including one case of ETV6-NTRK3 in a cerebral hemispheric tumour diagnosed at 1 month old. These fusions are usually associated with congenital mesoblastic nephroma and congenital infantile fibrosarcoma, and upon review of a series of cases diagnosed as glioblastoma under the age of 1yr, 6/14 were found to present with a predominant spindle cell morphology, a relatively circumscribed interface with adjacent brain, and without prominent infiltration. These tumours were positive for GFAP as well as desmin, CD56 and CD99. One case was diagnosed in utero by ultrasound, and at birth underwent surgical resection from which primary cell cultures were established under stem cell conditions on laminin-coated plates. Exome and RNA sequencing revealed the presence of the ETV6:NTRK3 fusion transcript as the sole somatic alteration, validated by RT-PCR, Sanger sequencing and FISH. 450K methylation profiling clustered the tumour with desmoplastic infantile ganglioglioma rather than subgroups of paediatric GBM. Primary cells treated with the CNS-penetrant small molecule Trk inhibitor PHA-848125, resulted in marked sensitivity (GI50 = 200nM) compared to cerebral hemispheric (H3 wild-type) and thalamic (H3.3K27M) paediatric GBM cells (GI50 = 1.8-4.6mM). A subset of infantile/congenital brain tumours classified as GBM appear to represent a distinct entity more closely related, biologically and histologically, to mesenchymal cancers. Agents targeting ETV:NTRK3 may be a useful novel treatment strategy in these children.

HG-11 * INTEGRATIVE MOLECULAR META-ANALYSIS OF 700 PEDIATRIC HIGH GRADE GLIOMA AND DIPG DEFINES WIDESPREAD INTER- AND INTRA-TUMORAL HETEROGENEITY

Recent molecular profiling studies of paediatric high grade (pHGG) and diffuse intrinsic pontine glioma (DIPG) have refined these tumours into age- and location-based subgroups driven by unique genetic and epigenetic alterations, however individual studies are underpowered to investigate subgroup-specific events. We have retrieved publicly available genome-wide data from ∼560 pHGG/DIPG samples and combined this with ∼140 unpublished cases including young adults up to the age of 30 years. We have integrated multiple array-based and sequencing platforms to produce DNA copy number profiles from ∼700 tumours, ∼500 with clinicopathological and histone H3 annotation, and >300 of which have full somatic sequence information. We identified subgroup-specific genetic alterations co-segregating, or mutually exclusive, with known driving histone mutations. H3.3G34R/V cerebral hemispheric tumours harbour significantly more CNAs and SNVs than other subgroups. These included novel amplified loci at 1p13.3 (KCNA) and a histone cluster at 6p22.2, though lacked key amplified loci such as MYC/MYCN. H3.1K27M DIPG were distinct from H3.3K27M primarily on the basis of whole arm chromosomal changes (enriched +2, -16q; reduced -17p and a lack of TP53 mutations). H3.3K27M tumours harboured specifically enriched known (7q31.2;MET) and novel amplicons (17p11.2;TOP3A). Integration with mutation data identified subgroup-independent, non-overlapping pathway-level recurrent alterations, such as RTK-PI3K-mTOR, dysregulated in 55% cases and conferring shorter survival in hemispheric, but not other locations. As well as inter-tumoral differences, deeper interrogation of the sequencing data also reveals substantial intra-tumoral heterogeneity. Whilst driving histone H3 mutations were found to be present in 100% of cells, mutations in genes such as PDGFRA and PIK3CA were predominantly found at subclonal levels, and tumours from all locations were inferred to be comprised of multiple subclonal populations, with H3.3G34R/V the most genetically diverse. These data improve our understanding of the underlying biology of pHGG/DIPG, and will provide rational targets for subgroup-specific and –independent therapies.

Predictors of subjective versus objective cognitive functioning in patients with stable grades II and III glioma.

Studies in cancer and noncancer populations demonstrate lower than expected correlations between subjective cognitive symptoms and cognitive functioning as determined by standardized neuropsychological tests. This paper systematically examines the association between subjective and objective cognitive functioning in patients with low-grade glioma and the associations of these indicators of cognitive function with clusters of sociodemographic, clinical, and self-reported physical and mental health factors. Multiple regression analyses with the subjective and 2 objective indicators of cognitive functioning as dependent variables and 4 clusters of predictor variables were conducted in 169 patients with predominantly low-grade glioma. Correlations between the subjective and the 2 objective cognitive indicators were negligible (0.04) to low (0.24). Objective cognitive deficits were predominantly associated with sociodemographic (older age, lower education, male sex) and clinical (left hemisphere tumor) variables, while lower ratings of subjective cognitive function were more closely related to self-reported mental health symptoms (fatigue, lower mental well-being), physical (motor) dysfunction and female sex. Self-reported communication deficits were associated significantly with both subjective and objective dysfunction. We recommend that both subjective and objective measures of cognitive functioning, together with a measure of psychological distress, be used for comprehensive neuropsychological assessments of patients with glioma to determine which areas are most affected and which specific intervention strategies are most appropriate.

Spontaneous Malignant Transformation of a Pilocytic Astrocytoma of Cerebellum

Pilocytic astrocytoma is a slowly growing neoplasia that represents the most frequent cerebral tumor in pediatric age. Malignant transformation is rare and it is usually related to previous radiotherapy. The authors describe a case of a spontaneous malignant transformation of a pilocytic astrocytoma. A 3-year-old boy was diagnosed with a cerebellar hemisphere tumor. He was submitted to a complete excision of the lesion, and histological findings were consistent with pilocytic astrocytoma. It was negative for p53. Twelve years later he presented with a local recurrence. Histopathological diagnosis was glioblastoma and it was positive for p53. Death from disease progression occurred 16 months after the diagnosis of glioblastoma. This case suggests that patients with pilocytic astrocytoma need closer follow-up and further genotypic studies in order to provide clues to clinical behavior. Such understanding can allow us to stratify treatment accordingly and to proceed to more aggressive treatment when necessary.

Cognitive outcome after awake surgery for left and right hemisphere tumours

Cognitive outcome after awake surgery for left and right hemisphere tumours