High-grade Pediatric Brain Tumors Research Articles

Comparison of arterial spin labeling and dynamic susceptibility contrast perfusion MR imaging in pediatric brain tumors: A systematic review and meta-analysis.

Brain tumors are a leading cause of mortality in children. Accurate tumor grading is essential to plan treatment and for prognostication. Perfusion imaging has been shown to correlate well with tumor grade in adults, however there are fewer studies in pediatric patients. Moreover, there is no consensus regarding which MR perfusion technique demonstrates the highest accuracy in the latter population. To compare the diagnostic test accuracy of dynamic-susceptibility contrast and arterial spin-labelling, in their ability to differentiate between low-and high-grade pediatric brain tumors at first presentation. Articles were retrieved from online electronic databases: MEDLINE (Ovid), Web of Science Core Collection and SCOPUS. Studies in pediatric patients with a treatment naïve diagnosed brain tumor and imaging including either ASL or DSC or both, together with a histological diagnosis were included. Studies involving adult patient or mixed age populations, studies with incomplete data and those which used dynamic contrast enhanced perfusion were excluded. The sensitivities and specificities obtained from each study were used to calculate the true-positive, true-negative, false-positive, and false-negative count. A case was defined as a histologically proven high-grade tumor. The random-effect model was used to merge statistics. Significance level was set at p < 0.05. Forest plots showing pairs of sensitivity and specificity, with their 95% confidence intervals, were constructed for each study. The bivariate model was applied in order to account for between-study variability. The SROC plots were constructed from the obtained data-sets. The AUC for the SROC of all studies was estimated to determine the overall diagnostic test accuracy of perfusion MRI, followed by a separate comparison of the SROC of ASL versus DSC studies. Small and heterogenous sample size. The diagnostic accuracy of ASL was found to be comparable and not inferior to DSC, thus its use in the diagnostic assessment of pediatric patients should continue to be supported. ASL = arterial spin labelling, DSC = dynamic susceptibility contrast, DCE = dynamic contrast-enhanced, rCBF = relative cerebral blood flow, rCBV = relative cerebral blood volume, MTT = mean transfer time, TR = repetition time, TE = echo time, SROC = summary receiver operating characteristics, HG= high-grade, LG = low-grade, AUC = area under the curve, PRISMA = Preferred Reporting Items for Systematic Reviews and Meta-Analyses.

HGG-35. SIGNIFICANT RESPONSE TO LAROTRECTINIB AS FIRST LINE THERAPY IN INFANT WITH INFANT-TYPE HEMISPHERIC GLIOMA

Abstract BACKGROUND Infant-type hemispheric gliomas represent a recent WHO classification of high grade pediatric brain tumors that are often characterized by NTRK, ROS1, MET or ALK fusions. Novel agents may target their driver mutations but are not yet considered front line therapy. METHODS Patient data was reviewed retrospectively through chart review. RESULTS A 7 day old male infant who presented with vomiting, shaking and a full fontanelle was found to have a 8.7 x 7.2 x 9.3 cm solid and cystic mass with internal hemorrhage in the right parietal and occipital lobes associated with significant mass effect and midline shift. He underwent VP shunt placement and tumor biopsy, but later developed seizures and declining mental status. Cyst decompression was used as stabilizing measure. Due to his very small size and tenuous clinical status full tumor resection was not feasible at that time. Pathology revealed an infant-type hemispheric glioma with ETV6-NTRK3 fusion. Although cytogenetic testing for NTRK alterations was negative, the fusion was confirmed by NGS. Given his age and the risks for electrolyte imbalances and cytopenias in a patient with recent hemorrhage, we elected to treat with Larotrectinib instead of traditional cytotoxic chemotherapy. He had notable disease response within 8 weeks and remains on drug 18 months later with continued response. His tumor now measures 2 x 1.5 x 1.6 cm. He has had one grade 3 toxicity with neutropenia, which was likely impacted by viral bone marrow suppression. He is currently meeting most developmental milestones but does have orthotics and sees speech therapy. CONCLUSIONS Targeted agents may represent a viable front line therapy to decrease tumor mass and temporize very young patients until they can undergo definitive resection and therapy. Future clinical trials will need to compare efficacy to current standards of care.

The heterogeneous sensitivity of pediatric brain tumors to different oncolytic viruses is predicted by unique gene expression profiles

Despite decades of research, the prognosis of high-grade pediatric brain tumors (PBTs) remains dismal, however, recent cases of favorable clinical responses were documented in clinical trials using oncolytic viruses (OVs). In the current study, we employed four different species of OVs: adenovirus Delta24-RGD, herpes simplex virus rQNestin34.5v1, reovirus R124 and the non-virulent Newcastle Disease Virus rNDV-F0-GFP against three entities of PBTs (high-grade gliomas, atypical teratoid/rhabdoid tumors and ependymomas) to determine their in vitro efficacy. These four OVs were screened on 14 patient-derived PBT cell cultures and the degree of oncolysis was assessed using an ATP-based assay. Subsequently, the observed viral efficacies were correlated to whole transcriptome data and Gene Ontology analysis was performed. Although no significant tumor type-specific OV efficacy was observed, the analysis revealed the intrinsic biological processes that associated with OV efficacy. The predictive power of the identified expression profiles was further validated in vitro by screening additional PBTs. In summary, our results demonstrate OV susceptibility of multiple patient-derived PBT entities and the ability to predict in vitro responses to OVs using unique expression profiles. Such profiles may hold promise for future OV preselection with effective oncolytic potency in a specific tumor, therewith potentially improving OV responses.

XRT-02. SINGLE-CELL RNA SEQUENCING IDENTIFIES FUNCTIONAL MACROPHAGE SUBSETS THAT ARE ENRICHED IN RESPONSE TO DIFFERENTIAL PHAGOCYTOSIS INDUCTION AGAINST GLIOMA

Abstract Pediatric diffuse midline gliomas (DMGs), are fatal brain tumors of childhood arising in the ventral pons. Currently, radiation therapy (RT) is the mainstay treatment for DIPG. However, RT is not a curative treatment and provides only temporary relief for most patients. Recent advances in immunotherapy have yielded some fantastic opportunities to effectively treat patients with high-grade pediatric brain tumors. In this study, we demonstrate that fractionated RT (4Gy X 3) induces immunogenic cell death and activates multiple damage-associated molecular patterns (DAMPs) on DMG/DIPG cells. Furthermore, combining 4Gy X 3 with anti-CD47 therapy enhances the in vitro phagocytosis of DIPG/DMG cells by peripheral blood mononuclear cell-derived macrophages. Next, using single-cell RNA sequencing (scRNA-seq), we investigated the transcriptomic profile of macrophages that were co-cultured with irradiated or non-irradiated DMG cells in the presence of anti-CD47 monoclonal antibodies for 24 hours. Our findings identified eleven distinct macrophage clusters displaying different gene expression patterns in all the treatment conditions. However, PBS treatment led to a marked increase in macrophages expressing antigen-presentation genes (HLA-DR and HLA-DQB1). 4Gy X 3 treatment led to the enrichment of macrophages expressing genes related to the oxidative phosphorylation pathway, whereas anti-CD47 treatment led to the enrichment of macrophages expressing genes related to interferon-gamma response and ERK-signaling pathway. Lastly, mice intracranially transplanted with DMG/DIPG that received 4Gy X 3 and anti-CD47 therapy showed a significant decrease in tumor growth and an increase in survival rate than those receiving either monotherapy alone. We are currently performing scRNA-seq validation studies on tumors obtained from orthotopic and syngeneic models of DMG. In summary, our results highlight the functional heterogeneity of macrophages and suggest that combining fractionated RT with anti-CD47 therapy has distinct anti-tumor effects and can be used as a therapeutic approach for treating DIPG patients.

IMG-10. MAGNETIC RESONANCE FUNCTIONAL IMAGING BIOMARKER FOR DISTINGUISHING HIGH GRADE FROM LOW GRADE PEDIATRIC BRAIN TUMORS

Abstract This study aims to show that the ratio between perfusion MRI (RCBV) and diffusion MRI (ADC - apparent diffusion coefficient) is more effective in distinguishing low-grade from high-grade pediatric brain tumors than either parameter (RCBV or ADC) alone. After IRB approval was obtained, an initial pilot prospective study was performed that included 38 patients (newborn - 18 years) (22 females and 16 males). All MRI exams were performed on a 1.5 T or 3.0 T scanner. Surgically resected tumors were classified as low grade (WHO I, II) or high grade (WHO III, IV). ROIs were selected using tumor boundaries delineated on the FLAIR sequence, excluding perilesional edema. Both standardized and normalized perfusion RCBV (sRCBV, nRCBV) as well as diffusion (ADC) mean values were acquired. Then sRCBV/ADC ratios were calculated. Statistical analysis included the Wilcoxon-Mann-Whitney t-test using an alpha=0.05 as the level of significance. The results of this preliminary study revealed that the sRCBV/ADC ratio calculations were more effective at separating high grade from low grade tumors than were RCBV or ADC values alone. As a result of this original pilot study, the calculated sRCBV/ADC ratio has occasionally been used as a clinical tool at our institution. In order to validate the results from this original pilot study, we have collected additional retrospective data to increase sample size. We plan to share the results of this additional data in order to validate that the sRCBV/ADC ratio is an easy-to-use imaging biomarker that can effectively separate high grade from low grade pediatric brain tumors. This information is useful for patient care in that it can potentially help predict prognosis which is essential for parental counseling, and potentially reduce the need for invasive tests and biopsies.

BCOR expression in paediatric pineoblastoma.

BCOR is expressed in a new brain tumour entity, i.e. 'CNS tumour with BCOR internal tandem duplication' (HGNET BCOR) but not in several other high grade paediatric brain tumours investigated. Immunohistochemical detection of BCOR expression may therefore serve as a potential diagnostic marker. Nevertheless, in rare paediatric glioma cases recurrent EP300-BCOR fusions were detected, which resulted in strong BCOR immunopositivity. We have therefore examined other, not analysed so far, types of central nervous system (CNS) tumours, pineoblastoma and germinoma, to assess a potential involvement of BCOR in these tumours. Levels of BCOR RNA expression were investigated by NanoString nCounter system analysis in a series of altogether 66 high grade paediatric tumours, including four pineoblastoma cases. Immunohistological detection of BCOR was performed in eight pineoblastoma, five germinoma and four atypical teratoid rhabdoid tumours (ATRTs), all located in the pineal region. We detected BCOR expression in all pineoblastomas, at the RNA and protein levels, but not in germinomas and ATRTs. Further analysis of pineoblastoma samples did not reveal the presence of either BCOR internal tandem duplication or BCOR fusion involvement. Positive immunohistological BCOR nuclear reaction in pineoblastoma may therefore differentiate this type of tumour from other high grade tumours located in the pineal region.

IMMU-04. SINGLE-CELL RNA-SEQUENCING IDENTIFIES FUNCTIONAL MACROPHAGE SUBSETS THAT ARE ENRICHED IN RESPONSE TO DIFFERENTIAL PHAGOCYTOSIS INDUCTION AGAINST GLIOMA

Abstract Pediatric diffuse midline gliomas (DMGs), are fatal brain tumors of childhood arising in the ventral pons. Currently, radiation therapy (RT) is the mainstay treatment for DIPG. However, RT is not a curative treatment and provides only temporary relief for most patients. Recent advances in immunotherapy have yielded some fantastic opportunities to effectively treat patients with high-grade pediatric brain tumors. In this study, we demonstrate that fractionated RT (4Gy X 3) induces immunogenic cell death and activates multiple damage-associated molecular patterns (DAMPs) on DMG/DIPG cells. Furthermore, combining 4Gy X 3 with anti-CD47 therapy enhances the in vitro phagocytosis of DIPG/DMG cells by peripheral blood mononuclear cell-derived macrophages. Next, using single-cell RNA sequencing (scRNA-seq), we investigated the transcriptomic profile of macrophages that were co-cultured with irradiated or non-irradiated DMG cells in the presence of either phosphate-buffered solution (PBS) or anti-CD47 monoclonal antibody for 24 hours. Our findings identified eleven distinct macrophage clusters displaying different gene expression patterns in all the treatment conditions. However, PBS treatment led to a marked increase in macrophages expressing antigen-presentation genes (HLA-DR and HLA-DQB1). 4Gy X 3 treatment led to the enrichment of macrophages expressing genes related to the oxidative phosphorylation pathway, whereas anti-CD47 treatment led to the enrichment of macrophages expressing genes related to interferon-gamma response and ERK-signaling pathway. Lastly, mice intracranially transplanted with DMG/DIPG that received 4Gy X 3 and anti-CD47 therapy showed a significant decrease in tumor growth and an increase in survival rate than those receiving either monotherapy alone. We are currently performing scRNA-seq validation studies on tumors obtained from orthotopic and syngeneic models of DMG. In summary, our results highlight the functional heterogeneity of macrophages and suggest that combining fractionated RT with anti-CD47 therapy has potent anti-tumor effects and may be used as a novel therapeutic approach for treating Glioma patients.

RBIO-08. MEMANTINE INCREASES DENDRITIC ARBORIZATION OF IMMATURE NEURONS AFTER IRRADIATION WITH NO EVIDENCE OF DISRUPTION IN THE NORMAL BRAIN FUNCTION

Abstract Cranial irradiation (IR) is a cornerstone in the treatment of high-grade pediatric brain tumors. While lifesaving, it is associated with severe sequalae in 50-90 % of the survivors, as they often show disabling cognitive dysfunction, declined IQ, impaired processing speed, anxiety and posttraumatic stress symptoms, resulting in poorer academic accomplishments and social isolation. Memantine (Mem) is a non-competitive NMDA receptor antagonist and a potent enhancer of neural plasticity. While an improvement in cognition in post-IR cancer survivors and in synaptic plasticity in association to hippocampal neurogenesis have been documented, the exact mechanisms underlying Mem’s actions are poorly understood. The goal of this project is to further dissect the actions of Mem and identify factors that contribute to hippocampal neurogenesis. To this end, 20-day-old C57BL6/J mice were subjected to a single dose of 7 Gy whole brain irradiation and then supplied with Mem in the drinking water (10 mg/kg/day) to obtain a steady-state plasma concentration of the drug. Two weeks after IR, Sholl analysis of the morphology of the newborn neurons of Mem treated animals showed a statistically significant increase in coverage area (500 µm2 vs. 250 µm2, p &amp;lt; 0,0001) and number of dendrites (15 vs. 5, p &amp;lt; 0,0001) compared to non-treated individuals. Bulk-RNA sequencing analysis revealed 9 differentially expressed genes (alpha=0.1) between the hippocampal cell populations of Mem and vehicle-treated IR mice, which are related to protein folding and the programmed cell death machinery. At six weeks after IR, Mem treatment maintains the gamma oscillatory dynamics in the hippocampal CA3 region (~2x10-9 V2 in non-IR, ~1x109 V2 in IR), but with no apparent recovery to the sham levels. These results emphasize the strong neurogenic effect that Mem exerts on the surviving newborn neurons, while also highlighting Mem’s low toxicity and impact on the normal function of the brain.

IMG-10. Determining brain tumour grade non-invasively using a simplified MRI perfusion protocol: single-bolus, leakage-corrected dynamic susceptibility-contrast MRI

Abstract INTRODUCTION: Perfusion is associated with grade and survival in children’s brain tumours. Dynamic susceptibility-contrast (DSC-) MRI measures perfusion non-invasively, estimating relative cerebral blood volume (rCBV). We previously showed significant differences between pre-treatment rCBV in low- and high-grade tumours in a multicentre study. Contrast agent leakage from tumour vessels during acquisition affects rCBV accuracy. A contrast agent pre-bolus can be given but this can be challenging in a clinical environment, introducing variability. Alternatively, a single bolus can be administered with leakage correction applied when processing the data. We investigated pre-treatment rCBV values in a multicentre study without pre-bolus administration. METHODS: Thirty-six patients underwent pre-treatment DSC-MRI scans at 2 centres on 4 different scanners. Protocols were variable. Pixel-by-pixel contrast agent concentration time courses were analysed. Maps of uncorrected (rCBVuncorr) and leakage-corrected rCBV (rCBVcorr) were produced. Whole-tumour regions-of-interest were defined and median whole-tumour DSC-MRI parameters calculated. Patients subsequently underwent surgery / biopsy. Tumours were classified and graded. RESULTS: Twelve tumours were classified as low-grade; 24 as high-grade. Median whole-tumour rCBVuncorr was significantly higher in high-grade tumours than in low-grade tumours (1.628 vs -0.167, p&amp;lt;0.001). Median rCBV significantly increased in low-grade tumours following leakage correction (-0.167 to 1.072, p=0.007); there was no significant change for high-grade tumours. Using the median rCBVuncorr of 1.19 to differentiate between low- and high-grade tumours resulted in sensitivity and specificity of 75% and 100%, respectively; median 1.45 for rCBVcorr resulted in sensitivity and specificity of 67% and 100%, respectively. DISCUSSION: DSC-MRI measures of perfusion can distinguish between low- and high-grade paediatric brain tumours. Contrast agent leakage correction is essential for accurate measurement of rCBV. This is robust across multiple centres despite using multiple protocols. CONCLUSION: Pre-treatment multicentre perfusion MRI acquired with a single-bolus and contrast agent leakage correction can aid with differentiating between high- and low-grade paediatric brain tumours.

LTBK-06. Memantine increases dendritic arborization and integration of immature neurons after cranial irradiation

Cranial irradiation (IR) is a cornerstone in the treatment of high-grade pediatric brain tumors. While lifesaving, it is associated with severe sequalae in 50-90 % of the survivors, as they often show disabling cognitive dysfunction, declined IQ, impaired processing speed, anxiety and posttraumatic stress symptoms, resulting in poorer academic accomplishments and social isolation. Memantine (Mem) is a non-competitive NMDA receptor antagonist and a potent enhancer of neural plasticity. It is used in the clinical setting in the treatment of Alzheimer’s disease and dementias and has been shown to enhance cognition in post-IR cancer survivors. Nevertheless, while an improvement in synaptic plasticity has been documented in association to hippocampal neurogenesis, the exact mechanisms underlying Mem’s actions are yet poorly understood. The goal of this project is to further dissect the actions of Mem and identify factors that contribute to hippocampal neurogenesis. To this end, 20-day-old C57BL6/J mice were subjected to a single dose of 7 Gy whole brain irradiation and then supplied with Mem in the drinking water to obtain a steady-state plasma concentration of the drug. Animals were then sacrificed at different time points and the brains harvested for immunohistochemical staining, bulk-RNA sequencing and electrophysiological studies. Sholl analysis of the morphological data of the new-born neurons of Mem treated animals showed a statistically significant increase in coverage area (500µm2 vs. 250µm2, p= <0,0001) and number of dendrites (15 vs. 5, p= <0,0001) compared to non-treated individuals. Preliminary analysis of the electrophysiological responses revealed no changes in the gamma oscillations in Mem treated irradiated mice. The attained results will shed light on the mechanisms of action and take steps towards establishing Mem as a neoadjuvant therapy for children undergoing IR. Ultimately, we aim to ameliorate IR-associated neurocognitive impairment and improve the quality of life of pediatric cancer survivors.

The Clinical Applications of Liquid Biopsies in Pediatric Brain Tumors: A Systematic Literature Review.

Simple SummaryBrain tumors are the most common solid cancer in children and are traditionally diagnosed via a tissue biopsy or resection. Liquid biopsy offers the possibility to characterize brain tumors based on their circulating DNA in blood, cerebrospinal fluid or even urine. Moreover, disease progress can be monitored accurately and sometimes even detected before radiographic progression. More trials are needed to standardize the use of liquid biopsy in pediatric brain tumors.Background: Pediatric brain tumors are the most common solid tumor in children. Traditionally, tumor diagnosis and molecular analysis were carried out on tumor tissue harvested either via biopsy or resection. However, liquid biopsy allows analysis of circulating tumor DNA in corporeal fluids such as cerebrospinal fluid or blood. Methods: We performed a systematic review in Pubmed and Embase regarding the role of liquid biopsy in pediatric brain tumors. Results: Nine studies with a total of 570 patients were included. The preferred corporeal fluid for analysis with a relatively high yield of ct-DNA was cerebrospinal fluid (CSF). For high-grade glioma, liquid biopsy can successfully characterize H3K27mutations and predict tumor progression before it is radiographically detected. Moreover, liquid biopsy has the potential to distinguish between pseudo-progression and actual progression. In medulloblastoma, ct-DNA in the CSF can be used as a surrogate marker of measurable residual disease and correlates with response to therapy and progression of the tumor up to three months before radiographic detection. Conclusion: Liquid biopsy is primarily useful in high-grade pediatric brain tumors such as diffuse midline glioma or medulloblastoma. Disease detection and monitoring is feasible for both tumor entities. More trials to standardize its use for pediatric brain tumors are necessary.

Dynamic susceptibility-contrast magnetic resonance imaging with contrast agent leakage correction aids in predicting grade in pediatric brain tumours: a multicenter study

BackgroundRelative cerebral blood volume (rCBV) measured using dynamic susceptibility-contrast MRI can differentiate between low- and high-grade pediatric brain tumors. Multicenter studies are required for translation into clinical practice.ObjectiveWe compared leakage-corrected dynamic susceptibility-contrast MRI perfusion parameters acquired at multiple centers in low- and high-grade pediatric brain tumors.Materials and methodsEighty-five pediatric patients underwent pre-treatment dynamic susceptibility-contrast MRI scans at four centers. MRI protocols were variable. We analyzed data using the Boxerman leakage-correction method producing pixel-by-pixel estimates of leakage-uncorrected (rCBVuncorr) and corrected (rCBVcorr) relative cerebral blood volume, and the leakage parameter, K2. Histological diagnoses were obtained. Tumors were classified by high-grade tumor. We compared whole-tumor median perfusion parameters between low- and high-grade tumors and across tumor types.ResultsForty tumors were classified as low grade, 45 as high grade. Mean whole-tumor median rCBVuncorr was higher in high-grade tumors than low-grade tumors (mean ± standard deviation [SD] = 2.37±2.61 vs. –0.14±5.55; P<0.01). Average median rCBV increased following leakage correction (2.54±1.63 vs. 1.68±1.36; P=0.010), remaining higher in high-grade tumors than low grade-tumors. Low-grade tumors, particularly pilocytic astrocytomas, showed T1-dominant leakage effects; high-grade tumors showed T2*-dominance (mean K2=0.017±0.049 vs. 0.002±0.017). Parameters varied with tumor type but not center. Median rCBVuncorr was higher (mean = 1.49 vs. 0.49; P=0.015) and K2 lower (mean = 0.005 vs. 0.016; P=0.013) in children who received a pre-bolus of contrast agent compared to those who did not. Leakage correction removed the difference.ConclusionDynamic susceptibility-contrast MRI acquired at multiple centers helped distinguish between children’s brain tumors. Relative cerebral blood volume was significantly higher in high-grade compared to low-grade tumors and differed among common tumor types. Vessel leakage correction is required to provide accurate rCBV, particularly in low-grade enhancing tumors.

Constitutional mismatch repair deficiency is a childhood cancer predisposition syndrome associated with an increased risk of high grade paediatric brain tumours: report of 3 cases and review of the literature

Background: Constitutional mismatch repair deficiency syndrome (CMMRD) represents a biallelic (homozygous or compound heterozygous) mutation in one of the mismatch repair genes (MLH1, MSH2, MSH6 or PMS2), resulting in a recessively inherited childhood cancer predisposition syndrome. A broad range of tumours in infants and children have been described in the CMMRD spectrum, most commonly brain tumours, intestinal tumours, and haematological malignancies. This contrasts with the monoallelic mismatch repair defects (MMR) of Lynch syndrome, in which there is an increased risk of development of malignancies in particular involving the gastrointestinal and genitourinary tract, with onset in adulthood. Phenotypic features of CMMRD overlap with neurofibromatosis, with café-au-lait macules a common finding in this cohort. Aims: To highlight an increasingly recognised childhood cancer predisposition syndrome, and the importance of identification of these cases given significant implications for family counselling. There is an increased cancer risk in siblings, as well as for the parents, who may not yet be aware of their own associated monoallelic MMR defect (Lynch syndrome). Methods: We present three cases of childhood primary brain tumours that were subsequently confirmed in the setting of CMMRD. The histological, immunohistochemical and genetic findings of these cases are discussed, with focus on diagnostic pathologic features that suggest an underlying CMMRD. Results and conclusions: Three high grade brain tumours described include two high grade gliomas (a glioblastoma multiforme and a high grade diffuse intrinsic pontine glioma, H3K27M negative), and a medulloblastoma. These examples all showed complete absence of PMS2 staining on immunohistochemistry in both tumour cells and normal ‘internal control’ tissues of the patient, correlating with biallelic loss of gene function. Review of the literature shows brain tumours as the most frequent presentation in children with CMMRD, with an increased risk of gastrointestinal tumours (including colonic carcinoma) and haematological malignancies also reported.

Diffusion histology imaging differentiates distinct pediatric brain tumor histology

High-grade pediatric brain tumors exhibit the highest cancer mortality rates in children. While conventional MRI has been widely adopted for examining pediatric high-grade brain tumors clinically, accurate neuroimaging detection and differentiation of tumor histopathology for improved diagnosis, surgical planning, and treatment evaluation, remains an unmet need in their clinical management. We employed a novel Diffusion Histology Imaging (DHI) approach employing diffusion basis spectrum imaging (DBSI) derived metrics as the input classifiers for deep neural network analysis. DHI aims to detect, differentiate, and quantify heterogeneous areas in pediatric high-grade brain tumors, which include normal white matter (WM), densely cellular tumor, less densely cellular tumor, infiltrating edge, necrosis, and hemorrhage. Distinct diffusion metric combination would thus indicate the unique distributions of each distinct tumor histology features. DHI, by incorporating DBSI metrics and the deep neural network algorithm, classified pediatric tumor histology with an overall accuracy of 85.8%. Receiver operating analysis (ROC) analysis suggested DHI’s great capability in distinguishing individual tumor histology with AUC values (95% CI) of 0.984 (0.982–0.986), 0.960 (0.956–0.963), 0.991 (0.990–0.993), 0.950 (0.944–0.956), 0.977 (0.973–0.981) and 0.976 (0.972–0.979) for normal WM, densely cellular tumor, less densely cellular tumor, infiltrating edge, necrosis and hemorrhage, respectively. Our results suggest that DBSI-DNN, or DHI, accurately characterized and classified multiple tumor histologic features in pediatric high-grade brain tumors. If these results could be further validated in patients, the novel DHI might emerge as a favorable alternative to the current neuroimaging techniques to better guide biopsy and resection as well as monitor therapeutic response in patients with high-grade brain tumors.

Cell-surface antigen profiling of pediatric brain tumors: B7-H3 is consistently expressed and can be targeted via local or systemic CAR T-cell delivery.

Immunotherapy with chimeric antigen receptor (CAR) T cells is actively being explored for pediatric brain tumors in preclinical models and early phase clinical studies. At present, it is unclear which CAR target antigens are consistently expressed across different pediatric brain tumor types. In addition, the extent of HLA class I expression is unknown, which is critical for tumor recognition by conventional αβTCR T cells. We profiled 49 low- and high-grade pediatric brain tumor patient-derived orthotopic xenografts (PDOX) by flow analysis for the expression of 5 CAR targets (B7-H3, GD2, IL-13Rα2, EphA2, and HER2), and HLA class I. In addition, we generated B7-H3-CAR T cells and evaluated their antitumor activity in vitro and in vivo. We established an expression hierarchy for the analyzed antigens (B7-H3 = GD2 >> IL-13Rα2 > HER2 = EphA2) and demonstrated that antigen expression is heterogenous. All high-grade gliomas expressed HLA class I, but only 57.1% of other tumor subtypes had detectable expression. We then selected B7-H3 as a target for CAR T-cell therapy. B7-H3-CAR T cells recognized tumor cells in an antigen-dependent fashion. Local or systemic administration of B7-H3-CAR T cells induced tumor regression in PDOX and immunocompetent murine glioma models resulting in a significant survival advantage. Our study highlights the importance of studying target antigen and HLA class I expression in PDOX samples for the future design of immunotherapies. In addition, our results support active preclinical and clinical exploration of B7-H3-targeted CAR T-cell therapies for a broad spectrum of pediatric brain tumors.

Neuroimaging Appearance of Cerebral Malignant Epithelioid Glioneuronal Tumors in Children.

Malignant epithelioid glioneuronal tumor is a rare high-grade, aggressive brain tumor that shows both glial and neuronal differentiation on histopathology but is not included in the current World Health Organization classification. The neuroimaging appearance is variable but may be secondary to the size of the mass and/or location of the tumor. In our series, all epithelioid glioneuronal tumors were encountered in the supratentorial space and included pineal, temporal, and extratemporal lobar cerebral hemisphere locations. When large, the tumors demonstrate cystic degeneration and necrosis, hemorrhage, contrast enhancement, and regions of low apparent diffusion coefficient scalars consistent with patterns seen with other high-grade pediatric brain tumors. The tumors also have a propensity to spread into the meninges at presentation and for distant CSF spread on follow-up imaging.

Molecular identification of CNS NB-FOXR2, CNS EFT-CIC, CNS HGNET-MN1 and CNS HGNET-BCOR pediatric brain tumors using tumor-specific signature genes

Four molecular types of rare central nervous system (CNS) tumors have been recently identified by gene methylation profiling: CNS Neuroblastoma with FOXR2 activation (CNS NB-FOXR2), CNS Ewing Sarcoma Family Tumor with CIC alteration (CNS EFT-CIC), CNS high grade neuroepithelial tumor with MN1 alteration (CNS HGNET-MN1) and CNS high grade neuroepithelial tumor with BCOR alteration (CNS HGNET-BCOR). Although they are not represented in 2016 updated WHO classification of CNS tumors, their diagnostic recognition is important because of clinical consequences. We have introduced a diagnostic method based on transcription profiling of tumor specific signature genes from formalin-fixed, paraffin-embedded tumor blocks using NanoString nCounter Technology. Altogether, 14 out of 187 (7.4%) high grade pediatric brain tumors were diagnosed with either of four new CNS categories. Histopathological examination of the tumors confirmed, that they demonstrate a spectrum of morphology mimicking other CNS high grade tumors. However, they also exhibit some suggestive histopathological and immunohistochemical features that allow for a presumptive diagnosis prior to molecular assessment. Clinical characteristics of patients corroborated with the previous findings for CNS EFT-CIC, CNS NB-FOXR2 and CNS HGNET-MN1 patients, with a favorable survival rate for the latter two groups. Among six CNS HGNET-BCOR patients, three patients are long term survivors, suggesting possible heterogeneity within this molecular category of tumors. In summary, we confirmed the effectiveness of NanoString method using a single, multi-gene tumor specific signature and recommend this novel approach for identification of either one of the four newly described CNS tumor entities.

Integration of Neuro-Oncology and Pediatric Palliative Care at Diagnosis in the Outpatient Setting. (FR436)

•Gain knowledge about the common types of life-threatening brain tumors seen in children, cutting edge treatments for these tumors, and why an understanding of neuro-oncology is critical to pediatric palliative care providers.•Describe the barriers to introducing palliative care at the time of diagnosis of a high grade pediatric brain tumor and how the pediatric neuro-oncology and palliative care teams negotiated a patient/family-focused approach that overcame the barriers.•Weigh the advantages and disadvantages of several different models for overcoming the logistical challenges of integrating palliative care into a pediatric neuro-oncology clinic.•Be able to quote data that supports the benefits of early introduction of palliative care in the management of pediatric neuro-oncology patients diagnosed with life-threatening tumors. Brain tumors are the second most common tumor in children accounting for about 1 in 4 tumors. They are also the leading cause of cancer-related death in children. The tumors and their treatments are associated with significant physical symptoms, psychological strain, learning difficulties, and mortality. For these reasons, it is imperative that children with brain tumors have access to palliative care starting at the time of diagnosis. Unfortunately, access to palliative care for these children is not universal and when available is often indroduced late in the couse of disease. The prognosis and treatment of the most common life-threatening brain tumors will be reviewed by a neuro-oncology team. The neuro-oncology team will also share five years of experience embedding palliative care into the pediatric oncology clinic at a large tertiary care hospital. In this setting, it has been shown that families are very open to and appreciative of early palliative care when it is framed by the oncology team as an essential part of the care of children with brain tumors. The neuro-oncology team and the palliative care team will dialogue about the sources of resistance to early introduction of palliative care and how this resistance can be overcome. The practical considerations involved in the implementation of clinic-based palliative care will also be discussed. This will include staffing and the advantages of different clinic models including 1) embedded clinics, 2) floating clinics, and 3) free standing clinics. Finally, a retrospective review of 5 years of clinical data collected on over 60 pediatric neuro-oncology patients concurrently followed in palliative care clinic will be presented. The data will include type of brain tumor, time from diagnosis to palliative consult, symptom frequency, time from POLST completion to death, time from hospice referal to death, and location of end of life care.

İntratümöral Ve Peritümöral ADC(Apperent Diffusion Coefficient) Değerlerinin Pediatrik Beyin Tümörlerinin Tanısında Önemi Var Mıdır?

INTRODUCTION: The motion of water particles within biological tissues, which is called random Brownian motion, is detected at the microscopic level by Diffusion-Weighted Imaging (DWI) sequence of Magnetic Resonance Image technique. The Apparent Diffusion Coefficient (ADC) calculated on DWI has been used for tumor diagnosis and grading. The purpose of this study was to evaluate of ADC values in the differential diagnosis of supratentorial and infratentorial pediatric brain tumors and to reveal the difference of peritumoral ADC measurements of pediatric patients from adult patients. METHODS: All of the 56 pediatric patients included in this retrospective study had lesions &gt;1 cm in diameter on magnetic resonance image and all of the diagnosies were confirmed by histopathology. Intratumoral and peritumoral ADC values and ratios were measured in diffusion weighted Magnetic Resonance Image. RESULTS: The 58.9% (n=33) of these tumors were supratentorial and 41.1% (n=23) were infratentorial. ADC values and ADC ratios were significantly lower in high-grade tumors than low-grade tumors (p&lt;0.05). Peritumoral ADC values in high-grade tumors were lower than low grade tumors (p&lt;0.05). The cut-off value of the ADC ratio between these two groups was 1 and the ADC cut-off value was 1.1*10-3 mm2/s. DISCUSSION AND CONCLUSION: In the differentiation of low and high-grade pediatric brain tumors, cut-off values of 1.1*10_3mm2/s for ADC Value and 1.0 for ADC Ratio may be useful. Although, peritumoral ADC values differ in children compared to the adult group, both intratumoral and peritumoral ADC values can help for grading pediatric brain tumors.

Multicentre study of perfusion magnetic resonance imaging in paediatric brain tumours

Abstract Studies in adults have shown that brain tumour perfusion correlates with grade. These studies are dominated by gliomas grade II to IV which are rare in children. The standard method, Dynamic Susceptibility Contrast MRI, provides estimates of relative cerebral blood volume (rCBV) but contrast agent leakage affects rCBV accuracy. The majority of perfusion studies have been conducted at single centres and variation in acquisition protocols makes the generalizability of results questionable. The aim of this study was to compare leakage-corrected rCBV with grade in paediatric brain tumours at multiple centres. Scans were analysed from 85 patients at 4 centres on 6 scanners prior to treatment. MRI protocols varied between centres. Histological diagnoses including grade were obtained. Whole-tumour median rCBV was significantly higher in the 45 high grade than the 40 low grade tumours (2.54 ± 1.63 ml/100ml vs 1.68 ± 1.36 ml/100ml, p=0.010). Low grade tumours, particularly pilocytic astrocytomas (grade I), displayed more contrast agent leakage consistent with their appearance on contrast enhanced images and required more leakage correction than high grade tumours. This finding differs from that in adults where contrast agent uptake is usually associated with higher grade. A cut-off of 1.70 ml/100ml for rCBV gave sensitivity and specificity of 76% and 65% respectively for discriminating grade. In summary, perfusion MRI can be used to help distinguish between low and high grade paediatric brain tumours. This finding is robust across multiple centres and acquisition protocols but correction should be made for leakage of contrast agent from the vessels.