bluuebunny/crossref_metadata_2025_split huggingface dataset:
HGG-47. Comparative analysis of the Histone H3 mutant protein interactome landscape in paediatric high-grade gliomas
Authors: Porter William , Sulman Joshua , Foot Katie , Rahman Ruman , Grundy Richard , Layfield Robert , Haque Farhana 
Published: June 2022

Abstract
There have been no significant improvements in the treatments for childhood and adolescent High-Grade Glioma (pHGG) and Diffuse Intrinsic Pontine Glioblastoma (DIPG), which have a very poor prognosis. These cancers harbour mutations affecting histone 3 (H3) proteins, 80% of DIPGs harbour histone H3.1 and H3.3 K27M somatic mutations whilst 30% of pHGGs exhibit H3.3 G34R or G34V mutations. Several studies have highlighted the epigenetic changes associated with these mutations, however their precise role in tumourigenesis is still unknown. We hypothesize that H3 mutations promote an aberrant interaction landscape and analysis of these interactome will highlight important pathophysiological consequences in these tumours. Two different affinity chromatographic proteomic analyses were performed using different recombinant H3 wild type (WT) and H3 mutant histone proteins (K27M, G34R and G34V) to purify their binding partners, from cell extracts of control and pHGG/DIPG patients cell lines. The purified samples were then subjected to Liquid Chromatography-Mass Spectrometry (LC-MS) to identify their co-bound partners. The results have isolated unique and common differential interaction partners of the H3 mutants and with cellular proteins in comparison to H3 WT protein, in the pHGG tumour cells. The role these altered protein interactions are being investigating in tumour initiation, progression and/or maintenance of H3 mutated pHGG/DIPG, with the aim to manipulate their function as alternate therapeutic intervention. Results of these analyses/experiments will be presented.
HGG-55. An adolescent with a High-Grade Glioma: persuing a specific diagnosis
Authors: Luz Inês Romão , Rebelo Olinda , Costa José Augusto , Carvalho Alice 
Published: June 2022

Abstract
BACKGROUND: Recognizing the value of molecular parameters provides evidence with repercussions on diseases classification. CLINICAL CASE: A thirteen-year-old girl was admitted in coma at the Intensive Care Unit due to a hemorrhagic stroke. CT revealed an expansive left frontal lobe lesion with perilesional edema and compression signs by an extensive hematoma. She underwent an emergency decompressive craniotomy for hematoma drainage, and the lesion was biopsied. The subsequent MRI showed a large heterogeneous mass with a cystic component. A first subtotal resection of the lesion was performed considering the language area. The histopathological examination showed tumor cells organized in perivascular pseudorosettes around the central hyalinized thickened blood vessel throughout the tumor, a pattern typically encountered in astroblastoma. Immunochemistry stains revealed a positive reactivity for GFAP, Olig2, and synaptophysin. The molecular study found a BRAFV600E mutation and homozygous CDKN2A e CDKN2B deletions; no TERT amplification, BCORL1, nor MN1 gene rearrangements were identified. She completed six weeks of radiotherapy without neurological signs/symptoms. A new surgical intervention was done 12 weeks later due to a slight increase of residual lesion. The rapid growth and the presence of viable tumor cells justified the therapy with irinotecan and bevacizumab, with mild adverse effects. One year after diagnosis, the adolescent is clinically well, without neurologic deficits and the MRI without evidence of residue or tumor recurrence. DISCUSSION: We began therapy based on morphological diagnosis. Complete resection and radiotherapy proved to be beneficial as in other high-grade gliomas, but the value of other therapies is still unknown. The BRAF gene variant would allow treatment with dabrafenib (in association with trametinib) or vemurafenib; however, she presents molecular findings associated with poor prognosis (CDKN2A deletion) that may impair the effectiveness of these therapies. According to the new WHO classification, the absence of MN1 alterations precludes the diagnosis of astroblastoma.
HGG-56. Spatial mapping of the tumor micro-environment in pediatric glioma
Authors: Messiaen Julie , Antoranz Asier , Van Herck Yannick , Verhaaren Ben , Nazari Pouya , Sebastian Ivey , Milli Giorgia , Bosisio Francesca , Pey Jon , Bempt Isabelle Vanden , Sciot Raf , Jacobs Sandra , De Smet Frederik 
Published: June 2022

Abstract
High-grade glioma are the main cause of cancer-related death in children. The highly heterogeneous composition of the tumor cells and their interactions with the tumor micro-environment (TME), contribute substantially to the poor response to treatment and the high levels of morbidity and mortality. Here, we used high-dimensional, multiplexed immunohistochemistry to map the single-cell tissue architecture of 26 pediatric glioma samples covering 8 histologic diagnoses, allowing us to determine the spatial distribution of the various tumoral subtypes and how these interact with their local immune-microenvironment. Overall, this analysis showed that tumor grade anti-correlated with the amount of infiltrating cytotoxic T-lymphocytes (CTLs), which were typically more exhausted in the higher grade tumors. In addition, tumor associated macrophages were primarily infiltrating from the blood and presented an M2-like anti-inflammatory phenotype which became more extended with tumor grade. Using the spatial information, possible cell-cell interactions could be determined. In lower grade glioma, we observed an increased activation level of CTLs that were closely located to neighboring T-helper cells. In pediatric glioblastoma, on the other hand, CTLs, even though they were located close to a T-helper cell, could only minimally be activated, and showed more extended exhaustion when residing further away. Additionally, the activation of the CTLs was associated to the distance to the closest PD-L1 positive macrophage in pilocytic astrocytoma and desmoplastic infantile ganglioglioma. In conclusion, with the use of multiplex immunohistochemistry, we are able to study the tumor and TME of pediatric glioma in depth on a single-cell and spatial level, which allows us to further study the heterogeneous landscape of these tumors.
IMG-02. Improved prediction of postoperative paediatric cerebellar mutism syndrome using an artificial neural network
Authors: Sidpra Jai , Marcus Adam P , Löbel Ulrike , Toescu Sebastian , Yecies Derek , Grant Gerald , Yeom Kristen , Mirsky David M , Marcus Hani J , Aquilina Kristian , Mankad Kshitij 
Published: June 2022

Abstract
BACKGROUND: Postoperative paediatric cerebellar mutism syndrome (pCMS) is a common but severe complication which may arise following the resection of posterior fossa tumours in children. Two previous studies have aimed to preoperatively predict pCMS, with varying results. In this work, we examine the generalisation of these models and determine if pCMS can be predicted more accurately using an artificial neural network (ANN). METHODS: An overview of reviews was performed to identify risk factors for pCMS, and a retrospective dataset collected as per these defined risk factors from children undergoing resection of primary posterior fossa tumours. The ANN was trained on this dataset and its performance evaluated in comparison to logistic regression and other predictive indices via analysis of receiver operator characteristic curves. Area under the curve (AUC) and accuracy were calculated and compared using a Wilcoxon signed rank test, with p&lt;0.05 considered statistically significant. RESULTS: 204 children were included, of whom 80 developed pCMS. The performance of the ANN (AUC 0.949; accuracy 90.9%) exceeded that of logistic regression (p&lt;0.05) and both external models (p&lt;0.001). CONCLUSION: Using an ANN, we show improved prediction of pCMS in comparison to previous models and conventional methods.
IMG-03. Impact of childhood cerebellar tumor surgery on cognition: Can fMRI serve as a surrogate marker?
Authors: Dorfer Christian , Pletschko Thomas , Seiger Rene , Chocholous Monika , Kasprian Gregor , Roessler Karl , Kollndorfer Kathrin , Schöpf Veronika , Leiss Ulrike , Slavc Irene , Prayer Daniela , Lanzenberger Rupert , Czech Thomas 
Published: June 2022

Abstract
BACKGROUND: Childhood cerebellar pilocytic astrocytomas harbour excellent overall survival rates after surgical resection, but the patients may exhibit specific cognitive and behavioural problems emphasising our current understanding of the cerebellar role in cognition. Functional MRI has catalysed the mechanistic insights into brain functional systems and has already been linked with the neuropsychological performance. We aimed to exploit the question whether functional MRI can be used as a surrogate measure for the cognitive outcome assessment of these patients. METHODS: We investigated 13 patients (median age 22.0 years, range 15.2 – 31.7) after a median interval between surgery and examination of 15.0 years (range 4.2 – 20.8) and 16 matched controls. All subjects underwent a functional 3T MRI scans in a resting state condition and a battery neuropsychological tests. RESULTS: Patients showed a significantly increased functional connectivity in the precuneus compared to controls (p&lt;0.05) and at the same time impairments in various domains of neuropsychological functioning such as a lower mean WIE IQ percentile (M = 48.62, SD = 29.14), lower scores in the TMT letter sequencing (M = 49.54, SD = 30.66), worse performance on the WIE subtest Digit Symbol Coding (M = 38.92, SD = 35.29), subtest Symbol Search (M = 40.75, SD = 35,28), and TAP divided attention task (M = 783.92, SD = 73.20). CONCLUSION: Functional MRI has the potential to serve as a surrogate measure for the cognitive outcome assessment. The precuneus brain region is heavily involved in the cerebral associative oversight of cerebellar cognitive function.
IMG-12. Transient atypical brain and spine MRI features after high-dose chemotherapy may represent clumps of CD34+ hematopoietic stem cells
Authors: Ramaglia Antonia , Arkhangelskaya Elena , Sementa Angela Rita , Morana Giovanni , Rossi Andrea , Faraci Maura , Piccolo Gianluca , Crocco Marco , Milanaccio Claudia , Garrè Maria Luisa , Verrico Antonio 
Published: June 2022

Abstract
High-dose chemotherapy is a therapeutic option in selected cases of pediatric high-grade brain tumor (pHGBT). Following high-dose chemotherapy, bone marrow is reconstituted by means of CD34+ peripheral blood stem cell (PBSC) infusion. Intravenously injected PBSCs have been reported to migrate to the Central Nervous System (CNS) and to persist for weeks. We report two cases of pHGBT in which, following PBSC infusion, we observed peculiar brain MRI signal alterations suggestive of clumps of CD34+ cells. A 15-month-old female underwent surgery and chemotherapy for an infratentorial, non-disseminated, Atypical Teratoid Rhabdoid Tumor. Following the second course of high-dose chemotherapy, MRI excluded residual disease, but revealed two contrast-enhancing nodules in the supratentorial ventricular system, with no evidence of diffusion restriction, unlike the primary tumor. Cerebrospinal fluid was collected by means of lumbar puncture and centrifuged: no neoplastic cells were found, while a few cells were positive when immunostained with anti-CD34 antibody. As no disease progression was documented, the patient completed her treatment with focal radiotherapy. Three months after the end of therapy, MRI showed new enhancing nodules with restricted diffusion, in keeping with leptomeningeal spread of disease; these progressively increased in size, despite subsequent lines of treatment, while the above-mentioned ventricular nodules shrank. Similar transient alterations were detected in a 4-year-old boy who had received treatment for high-risk Medulloblastoma, including high-dose chemotherapy. CONCLUSIONS: In the setting of new enhancing brain and spine findings with atypical MRI features, after high-dose chemotherapy to treat pHGBT, the hypothesis of CNS homing of CD34+ hematopoietic stem cells should be considered in the differential diagnosis.
IMG-13. Role of diffusion weighted imaging of spine in pediatric brain tumors showing diffusion restriction and CSF metastases
Authors: Sahu Arpita , Dasgupta Archya , Lad Shradha , Chatterji Abhishek , Jain Ayushi , Sridhar Epari , Gupta Tejpal 
Published: June 2022

Abstract
INTRODUCTION: Early detection of leptomeningeal metastases (LM) with paediatric brain tumors cases can change the prognosis as well as course of treatment. Conventional MR imaging and CSF (cerebrospinal fluid) analysis plays a vital role in detection of metastases, however, due to certain limitations these can be missed. In our study, diffusion weighed imaging (DWI) of spine was able to bridge this gap and increased the detection rate in MRI equivocal cases in which CSF study was negative. AIMS: To evaluate the incremental value of DWI over the conventional sequences in detection of LM. MATERIALS & METHODS: Paediatric patients with primary brain tumors known to show restriction and propensity for CSF metastasis underwent MRI on 1.5T Philip’s machine. CSF analysis and radiological follow up were used to confirm the diagnosis. RESULTS: Of the 26 patients proven to have LM, linear leptomeningeal metastases (LLP) were seen in 7 patients and nodular leptomeningeal metastases (NLM) were seen in 6 patients and both were seen in 13 patients. Of the 20 patients with LLM, 18 were detected on contrast; however, these were not detected on T2W and DWI except one patient with thick LLP. In 19 patients with NLM, a total of 84 lesions were detected. All were appreciated on contrast with additional 6 lesions which were false positive (FP). Total 96 lesions were detected on T2W, of which 80 were true positive and 16 were FP. About 80 lesions were detected on DWI. Thus, on contrast sequence FP were 6 while on T2W 16 were FP. DISCUSSION: DWI showed a lower FP rate than conventional sequences. CONCLUSION: Contrast sequence remains most reliable sequence for the detection of LM. However, DWI is useful in equivocal cases. The role of DWI in Group 3 and 4 Medulloblastoma with non-enhancing metastases needs to be further explored.
IMG-15. Radiomic Profiling of Pediatric Low-Grade Glioma Improves Risk Stratification Beyond Clinical Measures
Authors: Kazerooni Anahita Fathi , Arif Sherjeel , Haldar Debanjan , Madhogarhia Rachel , Familiar Ariana , Bagheri Sina , Anderson Hannah , Ware Jeffrey B , Vossough Arastoo , Storm Phillip B , Resnick Adam C , Davatzikos Christos , Nabavizadeh Ali 
Published: June 2022

Abstract
PURPOSE: Treatment response is heterogeneous among patients with pediatric low-grade glioma (pLGG), the most frequent childhood brain tumor. Upfront prediction of progression-free survival (PFS) may facilitate more personalized treatment planning and improve outcomes for the pLGG patients. In this work, we explored the additive value of radiomics to clinical measures for prediction of PFS in pLGGs. We further sought associations between the derived risk groups and underlying alterations in key genomic and transcriptomic variables. METHODS: Quantitative radiomic features were extracted from pre-operative multi-parametric MRI scans (T1, T1-post, T2, T2-FLAIR) of 96 patients with newly diagnosed pLGG (median age, 8.59, range, 0.35-18.87 years; median PFS, 25.23, range, 3.03-124.83 months). Multivariate Cox proportional hazard’s (Cox-PH) regression models were fitted using 5-fold cross-validation on a training cohort of 68 subjects and tested on 28 patients. Three models were generated using (1) only clinical variables (age, sex, and extent of tumor resection), (2) radiomic features, and (3) clinical and radiomic variables. The dimensionality of radiomic features in Cox-PH models was reduced by applying Elastic Net regularization penalty to identify a subset of variables that are most predictive of PFS. The patients were then stratified into three groups of high, medium, and low-risk based on model predictions. RESULTS: Cox-PH modeling resulted in a concordance index (c-index) of 0.55 for clinical data, 0.65 for radiomics, and 0.73 for a combination of clinical and radiomic variables, highlighting the additive value of radiomics to the readily available clinical information in prediction of PFS. Radiogenomic assessments revealed significant differences in expression of BRAF, NF1, TSC1, ALK (p&lt;0.01), and RB1 (p&lt;0.05) genes in the high-risk group, compared to the medium and low-risk groups. CONCLUSION: Our results demonstrate the value of integrating radiomics with clinical measures to improve risk assessment of patients with pLGG through improved pretreatment prediction of PFS.
IMG-17. Advanced MRI On The Cellular and Vascular Phenotype of Mouse Ependymoma Models and Chemo-Radiation Treatment Response
Authors: Serkova Natalie , Manalo Jane , Steiner Jenna , Griesinger Andrea , Pierce Angela , Foreman Nicholas 
Published: June 2022

Abstract
Ependymoma (EPN) is an aggressive pediatric brain tumor, for which the benefits of chemotherapy in pediatric patients have not been defined. EPN treated with surgery and radiation recur in 23-66% of patients. Our group has previously established aggressive behaviors of EPN, including high tumor cellularity, cytological anaplasia, high mitotic index, tumor necrosis, and the presence of inflammatory cells such as M2-type myeloid cells. Here we report on an advanced 9.4 Tesla MRI protocol for characterizing the cellular and vascular phenotype and treatment response to chemo-radiation therapy (CRT) in an orthotopic mouse model of patient derived xenografts (PDX) of pediatric EPN . Female severely immune deficient (SCID) mice were used for intracranial inoculation of disaggregated tumors from pediatric EPN patients (n=22). High-resolution T2w-MRI was able to detect cerebellar microlesions as small as 0.2 mm diameter; the median tumor volumes at the baseline were 21±12 mm3. Using diffusion-weighted based cell-size imaging, iron-oxide based vessel-size imaging and quantitative T2-maps, the EPN-specific phenotype was characterized by an increased cell size (S=14 microns), increased vessel density index (Q=0.54), and low ADC values (0.63x10-3). Once the intracranial tumors reached at least 5 mm3, animals were treated with CRT (10 Gy radiation plus 30 mg/kg 5-fluorouracil, n=6). CRT resulted in a tumor shrinkage, tumor necrosis with decreased cell sizes and increased ADC values, and a dramatic vascular-inflammatory response (decreased Q and DT2 values with the injection of iron oxide nanoparticles as macrophage-specific contrast). In summary, orthotopically implanted PDX EPN in mice closely mimic histological features, anatomical location and radiological features of the primary tumors. A significant decrease in vessel size density and an increase in inflammatory cells were seen as soon as 2 days after CRT. The late response (2 weeks post CRT) is characterized by decreased cellularity, cell size, and tumor volumes.
IMMU-11. Evaluation of CAR-T cells targeting CD276 in medulloblastoma
Authors: da Silva Patricia Benites Goncalves , Sieber Laura , Mack Norman , Atar Daniel , Kutscher Lena M , Schlegel Patrick , Ebinger Martin , Kawauchi Daisuke , Seitz Christian , Pfister Stefan M 
Published: June 2022

Abstract
Brain tumors are the most frequent category of solid tumors in children and have the highest mortality rate among all pediatric cancers. Although diagnosis and treatment have improved prognosis over the past decades for some childhood brain tumors, others remain lethal and current treatments are highly toxic to the developing brain, resulting in severe sequelae and considerably affecting the patient’s quality of life. Thus, new therapeutic options with reduced secondary effects are urgently needed. From this perspective, immunotherapies have gained a lot of attention due to their effectiveness in targeting tumor cells specifically. Chimeric-antigen receptor (CAR) T-cells recognize the target antigen on the surface of. CD276 is an immune checkpoint molecule that is expressed in a variety of solid tumor entities, including pediatric brain tumors. We analyzed the CD276 expression in our Patient-Derived-Xenograft (PDX) biobank of brain tumors and found that CD276 is ubiquitously expressed (ATRT, MB, EPN, GBM, ETMR, etc). Flow cytometry of MB PDX (n=4) confirmed CD276 expression of 97-99% of tumor cells, indicating that CD276 might be a good antigen target for CAR-T cell therapy of MBG3 and MBSHH. We found that second generation CAR-T cells targeting CD276 antigen significantly decreased tumor burden of the most aggressive MB subgroups (G3 and SHH-TP53mut PDX models) in NSG mice. We further treated NSG mice carrying a high tumor burden of the aggressive SHH-TP53mut PDX BT084 with second (CD28) and third generation (CD28-41BB) CD276-CAR-T cells. While both 2nd and 3rd generation improved the survival rates compared with CD19-CAR-T control cells, we found no difference in survival between the CD276 CAR-T generations, with no severe secondary effect during treatment. In conclusion, CD276 is a good antigen target for medulloblastoma, and warrants further evaluation for the treatment of medulloblastoma patients at relapse or as a maintenance therapy after standard treatment.
IMMU-14. SynNotch chimeric antigen receptor (CAR) T-cells as a potential treatment for diffuse intrinsic pontine glioma (DIPG)/diffuse midline glioma (DMG)
Authors: Ferrerosa Lauren , Simic Milos , Watchmaker Payal , Diebold David , Pineo-Cavanaugh Psalm , Deucker Jason , Lim Wendall , Okada Hideho 
Published: June 2022

Abstract
BACKGROUND: The development of effective chimeric antigen receptor (CAR) T-cell therapies for malignant pediatric brain tumors remains a challenge due to multiple barriers, including antigenic heterogeneity, on-target off-tumor toxicities, and T cell exhaustion. We have adopted a novel synthetic Notch “synNotch” receptor system and developed innovative T-cell circuits that recognize tumor cells based on the “prime-and-kill” strategy.
METHODS: We created a novel synNotch-CAR circuit in which the brain/glioma-specific antigen Brevican (BCAN) primes the T cells to induce expression of a CAR that recognizes interleukin-13 receptor α2 (IL-13Rα2) and ephrin type A receptor (EphA2), thereby eradicating glioma cells expressing either antigen. Immunocompromised mice bearing the SF8628 DIPG cell line in the frontal lobe or brain stem received a single intravenous (IV) infusion of synNotch CAR T-cells (2.5 x 106 each of CD4+ and CD8+ T cells) on day 6 following the tumor inoculation. Mice were monitored for toxicity and tumor growth.
RESULTS: Following this synNotch CAR T-cell dose, although tumors in the brainstem did not regress, 3 of the 5 mice with frontal lobe tumors demonstrated complete and sustained remission. Our histological analyses revealed primed CAR T-cells both within and surrounding the tumor in both settings. By flow cytometry, we confirmed the CAR T-cells in the CNS were primed and mostly did not express an exhaustive phenotype. In the spleen, we also found the CAR T-cells in a more naïve and central memory state.
CONCLUSIONS: Our work so far has demonstrated that synNotch-CAR T-cells are able to traffic to the tumor microenvironment even in the brainstem, are primed to express the CAR, and most do not express an exhaustive phenotype. Future work will include CAR T-cell dose optimization, continued assessments of the tumor microenvironment, and investigating for antigen escape.