bluuebunny/crossref_metadata_2025_split huggingface dataset:
IMG-11. A COMPUTERISED CLINICAL DECISION SUPPORT SYSTEM FOR DIAGNOSING CHILDREN’S BRAIN TUMOURS USING FUNCTIONAL IMAGING AND MACHINE LEARNING
Authors: Rose Heather , Ahmed Arfan , Babourina-Brooks Ben , Khan Omar , MacPherson Lesley , Manias Karen , Peake Ashley , Ali Sana , Withey Stephanie , Worthington Lara , Novak Jan , Zarinabad Nilou , Grundy Richard , Arvanitis Theodoros , Peet Andrew 
Published: June 2022

Abstract
INTRODUCTION: Magnetic resonance imaging is a key investigation in the diagnosis of childhood solid tumours. Advanced techniques such as diffusion weighted imaging (DWI), magnetic resonance spectroscopy (MRS) and perfusion imaging probe the underlying cellular, chemical and vascular nature of the disease. Coupled with machine learning these scanning methods show improvement in diagnostic accuracy compared with conventional imaging. Advanced image analysis is not routinely available in hospitals. We present a clinical decision support system (CDSS) developed for advanced MR analysis and interpretation. METHOD: The CDSS was developed in house. The Children’s Cancer and Leukaemia Group Functional Imaging Group (CCLGFIG) Database, a national resource, was used to provide a repository of cases together with their advanced imaging and machine learning diagnostic classifiers. A new case is displayed alongside cases in the repository with known diagnoses, including summary statistics for relevant diagnostic categories. The CDSS was made available to radiologists, in their clinical environment for technical and clinical evaluation. Structured interviews were undertaken. The CDSS was developed as a computer app for multi-centre distribution. RESULTS: 436 MRS, 240 DWI and 85 perfusion cases were available for building repositories. Machine learning classifiers showed diagnostic accuracies for the major childhood brain tumour types of 85-95%. Comparison of MRS with a data repository was found to improve non-invasive diagnosis. Results from the CDSS can be uploaded to the CCLGFIG to support multicentre research. Positive feedback on the CDSS from clinicians included: ready access to advanced analysis; simple and efficient integration into clinical workflow; and assisted interpretation of advanced analysis. DISCUSSION: Advanced MR analysis techniques provide improved non-invasive diagnostic accuracy but are difficult to implement on clinical systems due to technical, infrastructure and training limitations. CONCLUSION: We have successfully released a CDSS for paediatric cancer within the hospital environment and assessed its suitability for clinical use.
IMMU-04. Transcriptional analysis reveals distinct microenvironmental subgroups across pediatric nervous system tumors
Authors: Nabbi Arash , Beck Pengbo , Delaidelli Alberto , Oldridge Derek A , Sudhaman Sumedha , Zhu Kelsey , Yang S Y Cindy , Mulder David T , Bruce Jeffrey P , Paulson Joseph N , Raman Pichai , Zhu Yuankun , Silll Martin , Brabetz Sebastian , Lambo Sander , Johann Pascal D , Resnick Adam C , Sorensen Poul H , Malkin David , Kool Marcel , Jones David T W , Pfister Stefan M , Jäger Natalie , Pugh Trevor J 
Published: June 2022

Abstract
INTRODUCTION: Recent clinical trials of immune checkpoint inhibitors indicated 5-11% response rate in pediatric patients depending on cancer type and expression of target proteins. Currently, a systematic analysis characterizing the immune microenvironment of childhood tumors is lacking. The main objective of this study is to uncover the features of immune microenvironment in pediatric nervous system tumors (pedNST). METHODS: We compiled transcriptomes of 925 tumors from three initiatives, Therapeutically Applicable Research To Generate Effective Treatments (TARGET, n = 149), International Cancer Genome Consortium (ICGC, n = 195) and Children Brain Tumor Tissue Network (CBTN, n = 581). We analyzed the performance of immune deconvolution tools and used publicly available datasets to define immune genesets. We conducted a consensus analysis to assign genes to cell-types and identify immunological groups. RESULTS: We found wide variability in immune infiltration across and within cancer types ranging from cold tumors such as medulloblastoma (2.7% infiltrate) to infiltrated entities such as neurofibroma (22.6%). Consensus clustering revealed four distinct immune clusters. The pediatric inflamed group (10%) included MYCN non-amplified neuroblastoma and ATRT. The myeloid-predominant group (30%) showed decreased infiltration of lymphoid cells but enrichment of myeloid cell genesets. The pediatric-cold group (42%) harbored no enrichment of immune genesets and included 72% of ependymomas and 65% of medulloblastomas. The immune excluded group (18%) showed depletion of immune cell-types and included sonic-hedgehog medulloblastoma. 71% of pedNST belonged to the lymphocyte depleted or immunologically quiet clusters, indicating the cold immune microenvironment in pedNST compared to adult cancers. CONCLUSION: We report characteristics of the immune microenvironment in pedNST. We found an overall cold microenvironment with low lymphocyte infiltration in this population compared to common adult cancers. We identified ~10% of tumors harboring a relatively inflamed microenvironment. Our data uncover characteristics of immune infiltration in pediatric tumors with potential implications to guide therapy.
IMMU-18. Targeting Antigen Presenting Cells to improve virotherapy efficacy in Diffuse Midline Gliomas
Authors: Labiano Sara , Marco-Sanz Javier , Laspidea Virginia , Garcia-Moure Marc , Puigdelloses Montserrat , Ausejo Iker , Hernández-Osuna Reyes , Becher Oren , Patiño-Garcia Ana , Gomez-Manzano Candelaria , Fueyo Juan , Alonso Marta M 
Published: June 2022

Abstract
With a 2-year survival less than 20%, Diffuse Intrinsic Pontine Glioma (DIPG) is the principal cause of pediatric death. Despite recent advances in the current treatments, the outcome for children with DIPGs remains dismal. Since the approval of T-VEC for melanoma by the FDA, oncolytic adenoviruses have emerged as a promising therapeutic strategy for brain tumors. Thus, our group launched the first world clinical trial phase I with the oncolytic adenovirus Delta-24-RGD (DNX-2401 in the clinic) for newly diagnosed DIPG (NCT03178032), which has shown safety and feasibility. Despite DNX-2401 increases the recruitment of T cells into the tumor, they usually become inactive due to the non-responsive tumor microenvironment evidencing the urgent need to improve this strategy focusing on the generation of effective long-term immune responses. Therefore, we decided to combine the Delta-24-RGD with the targeting of the costimulatory molecule CD40 in immunocompetent mice bearing orthotopic DIPG. The activation of the CD40 receptor, which is expressed by antigen presenting cells (APC) such as microglia, macrophages, and dendritic cells, is known to increase antigen presentation and enable T-cell priming and activation. Here, we observed that in addition to Delta-24-RGD anti-tumor effects, the stimulation of CD40 (using an agonistic antibody) on the tumor APCs results in a remodeling of the tumor immune compartment towards a proinflammatory scenario and a more efficient T-cell infiltration. Of importance, the combination therapy extends survival of treated mice as compared to single treatments or non-treated mice. In addition, we observe a complete regression of tumors in more than 40% of treated mice and the development of long-term anti-tumor immunity. We believe that these results provide a translational breakthrough in the treatment of these lethal tumors and open the door for a future innovative clinical trial.
LGG-13. The clinical and molecular characteristics of progressive hypothalamic/optic pathway pilocytic astrocytoma
Authors: Li Xiaoyu , Moreira Daniel , Bag Asim , Qaddoumi Ibrahim , Acharya Sahaja , Chiang Jason 
Published: June 2022

Abstract
Unresectable hypothalamic/optic pathway pilocytic astrocytoma (PA) can be challenging to manage due to repeated progressions despite multiple lines of therapy. To identify clinical and biologic factors associated with tumor progression, we retrospectively identified 72 unresectable non-NF1-associated hypothalamic/optic pathway PA. Tumors were classified as high-risk (50%) if they progressed after three or more lines of chemotherapy/targeted therapy, progressed after radiation, developed metastatic disease, or died of disease. DNA methylation profiling and transcriptome analysis (RNA sequencing) were performed on treatment-naïve tumors with available tissue (n=40), and the findings were validated by immunohistochemistry (IHC) on additional tumor tissue. The median follow-up of the entire cohort was 12.3 years. High-risk tumors were associated with male sex (M:F = 2.6:1), younger age at diagnosis (median 3.2 years vs. 6.7 years, P = 0.005), and high incidence of KIAA1549-BRAF fusion (81.5% vs. 38.5%, P = 0.0032). High-risk tumors demonstrated decreased CpG methylation and increased RNA expression in many mitochondrial genes and genes downstream of E2F and NKX2.3 transcription factors. Transcriptome analysis identified transcription factor TBX3 and proto-oncogene serine/threonine protein kinase PIM1 as common downstream targets of both E2F and NKX2.3 and potential drivers of tumor progression. IHC confirmed increased expression of TBX3 and PIM1 in high-risk tumors. PIM1 is known to increase the stability and transcriptional activity of MYC, and gene enrichment analysis identified enrichment of MYC targets. Signaling pathways known to be implicated in PA, such as MAPK and PI3K/AKT/mTOR, were also enriched, in addition to pathways related to mitochondrial biogenesis and oxidative phosphorylation. Our results support the model in which the p53-PIM1-MYC axis and TBX3 act alongside MAPK and PI3K/AKT/mTOR pathways to promote tumor progression, highlighting potential new targets for combination therapy and refining disease prognosis.
LGG-21. Durability of response to targeted therapies in pediatric low-grade gliomas: A multi-institution retrospective review
Authors: Cantor Evan , Chaturvedi Sneha , Reiners Stephanie , Ogle Andrea , Meyer Ashley , Cluster Andrew , Brossier Nicole M , Dholaria Hetal , Govender Dinisha , Nagabushan Sumanth , Schwartz Johnathan , Abdelbaki Mohamed S , Navalkele Pournima , Shatara Margaret 
Published: June 2022

Abstract
Background: The discovery of the driving oncogenic alterations in pediatric low-grade gliomas (pLGGs) has shifted our focus towards management with targeted therapies, especially in relapsing or progressive disease. Limited data is available on the durability of response to targeted therapy in pLGGs once the therapy has ceased. Methods: Multi-institutional retrospective chart review of patients with pLGGs younger than 25 years, between 2010-2021, was undertaken to evaluate the durability of response to targeted therapy and determine risk factors associated with disease progression after cessation of therapy. Results: Current analysis included 18 patients from two centers. Seven (39%) had neurofibromatosis type-1 (NF-1). Diagnoses included: optic pathway glioma (OPG) (6/18, 33%), pilocytic astrocytoma (8/18, 44%), diffuse fibrillary astrocytoma (1/18), ganglioglioma (1/18), glioneural neoplasm (2/18). Sixteen patients received at least one prior line of chemotherapy (range 1-5). Targeted agents included trametinib (50%), selumetinib (5%), binimetinib (22%), vemurafenib (11%) and everolimus (11%). Median time on therapy was 351 days (range 29-979 days). All, but one patient had residual intracranial findings at the end of therapy: eight patients (44%) had stable disease, while ten required additional therapy; 50% were NF-1 patients with OPG. Median time to progression was 203 days (range 29-615 days). Of those who did not require any additional therapies, 50% had suprasellar tumors. Genomic data was available for twelve patients; BRAF-KIAA1549 fusion was the most common genomic alteration. Others included mutations in KRAS, BRAF (V600E), PTPN11, SOX6-RAF1 fusion, NF-1, and a patient with FGFR1, KMT2C, and PTPN11 alterations. Conclusion: Preliminary analysis demonstrates that despite initial response, the majority of patients required additional line of therapy. Patients with NF-1 and OPGs tend to progress after discontinuing therapy, while suprasellar non-NF1 pLGGs tend to develop sustained response to targeted therapies. Additional multi-institutional analysis is underway and will be presented at the meeting.
LGG-26. Predicting MAPK inhibitor sensitivity in pediatric low-grade gliomas with novel gene expression-derived signatures
Authors: Sigaud Romain , Heß Caroline , Hielscher Thomas , Winkler Nadine , Selt Florian , Kocher Daniela , Nonnenbroich Leo , Usta Diren , Sommerkamp Alex , Büdenbender Isabel , Capper David , Thomale Ulrich W , Driever Pablo Hernáiz , le Simon Michè , Koch Arend , Jabado Nada , Andrade Augusto F , van Meeteren Netteke Schouten- , Hoving Eelco , van Tilburg Cornelis M , Pfister Stefan M , Witt Olaf , Jones David T W , Milde Till 
Published: June 2022

Abstract
Pediatric low-grade glioma (pLGG), the most common brain tumors in children, are driven by alterations in the MAPK pathway. Several clinical trials have shown the potential for MAPK inhibitor (MAPKi) treatment in pLGG. However, the range of response to MAPKi is heterogeneous, even between tumors sharing the same driving MAPK alteration. A predictive stratification tool is needed to identify tumors that will be sensitive to MAPK inhibition. We generated sensitivity gene signatures for each MAPKi class (BRAFi, MEKi, ERKi), based on MAPK-related genes differentially regulated between MAPKi sensitive and non-sensitive cell lines from the Genomics of Drug Sensitivity in Cancer (GDSC) dataset. Single sample Gene Set Enrichment Analysis was used to measure and validate the MAPKi predictive sensitivity scores in the GDSC dataset and an independent patient-derived xenograft (PDX) dataset (XevaDB). The validated signatures were tested in a pLGG-specific background, using gene expression data from pLGG cell lines and primary pLGG samples. Our MAPKi sensitivity signatures discriminated MAPKi sensitive and non-sensitive cells in the GDSC dataset, and significantly correlated with MAPKi response in the PDX dataset. The sensitivity scores discerned gliomas with varying MAPK alterations from those without MAPK alterations, and showed higher scores in pLGG compared to high-grade gliomas and normal brain tissue. MAPKi-predicted sensitivity was heterogeneous within pLGG groups with a common MAPK alteration, as observed in MAPKi clinical trials. Intriguingly, we observed a strong positive correlation between our MAPKi sensitivity signature scores and the predicted immune cell infiltration rate as determined by the ESTIMATE score. These data demonstrate the potential relevance of gene-expression signatures to predict response to MAPKi treatment in pLGG patients, worth of further investigation in a prospective manner in upcoming clinical trials. In addition, our data could support a role of immune cell infiltration in the response to MAPKi in pLGG, warranting further validation.
LGG-34. Nephrological impact of BRAF inhibitors in a pediatric population of central nervous system tumors: a single institution experience
Authors: Verrico Antonio , Crocco Marco , La Porta Edoardo , Angeletti Andrea , Verrina Enrico , Iurilli Valentina , Piatelli Gianluca , Piccolo Gianluca , Milanaccio Claudia , Garrè Maria Luisa 
Published: June 2022

Abstract
BRAF inhibitors (iBRAF) are under investigations in ongoing clinical trials for pediatric brain tumor treatment. Preliminary data regarding the pediatric population report pyrexia, hematological, dermatological, cardiac, and ophthalmic toxicities among the most common adverse events. Acute kidney injury (AKI), mainly due to tubular interstitial injury, has been reported in the adult population. With our study we want to contribute to a more comprehensive knowledge of the short- and long-term nephrological adverse effects of iBRAF in a pediatric population. We collected and reviewed clinical and laboratory data of all patients treated with iBRAF for pediatric central nervous system tumors at our Institution and available for publication. AKI was monitored through serial creatinine measurements, kidney function with estimated glomerular filtration rate (eGFR) and kidney injury with creatinuria/proteinuria ratio. Tubular injury was evaluated with fractional excretion of sodium, potassium and magnesium and with glycosuria. Moreover, urine was examined to detect presence and morphology of erythrocytes. Eight patients were identified, 3 females; median age at treatment start was 9 years (range 2,75 – 18,75). Six patients with BRAFV600E–mutated pediatric Low-Grade Glioma were treated with Vemurafenib, 1 patient with BRAFV600E-mutated pediatric High-Grade Glioma was treated with Vemurafenib and 1 patient with BRAFV600E-mutated Langerhans Cell Histiocytoses was treated with Dabrafenib. Seven patients were considered for analysis. After a median follow up of 3,83 years (range 2,25 – 6,58) no AKI was reported and all patients but two retained normal eGFR at last follow up. No tubular and glomerular injury laboratory findings were detected, and erythrocytes in the urine resulted always below the upper limit of normality. CONCLUSIONS: iBRAF were not associated with AKI and tubular injury. Nevertheless, some data, namely significative decrease of eGFR in two out of seven patients, warrants further investigations.
LGG-37. Long-term Outcome, Visual Morbidity and Prognostic Factors in Infants and Young Children with Optic Pathway Glioma from the Great Ormond Street Hospital (GOSH) LGG - Cohort
Authors: Picariello Stefania , Walters Brownen , Bowman Richard , Slater Olga , Jorgensen Mette , Dahl Christine , O'Hare Patricia , Spoudeas Helen A , Gan Hong-Wei , Aquilina Kristian , Chang Yen Ch'in , D'Arco Felice , Hargrave Darren , Opocher Enrico 
Published: June 2022

Abstract
INTRODUCTION: The treatment aim of childhood optic pathway glioma (OPG) is visual preservation. However, long-term outcomes and prognostic factors implicated remain largely unknown.
METHODS: We undertook a retrospective study of infants and young children (IYC) ≤3 years with OPG and logMAR visual acuity (VA) at baseline/follow-up. We derived Overall- (OS), Progression-free (PFS), Radiotherapy-free (RTFS) and Visual event-free survival (vEFS) curves and analysed prognostic factors for visual deterioration and WHO defined blindness (&gt;1.3 logMAR both eyes).
RESULTS: Of 81 IYC-OPG (147 evaluable eyes) baseline vision was below 5%ile for age in 33 (41%) and 27 (33%) in one or both eyes respectively, within normal range in 21 (26%). After observation (11), chemotherapy (66) or RT (4), radiological progression occurred in 47 (58%), multiple times in 34.6% (range 2 - 8) and 10yr-PFS was 39.8%. Twenty had RT after 4.2 years from diagnosis (10yr-RTFS 72.4%) and 12% died (10yr-OS 89%). After 8.9 years VA was better/stable/ worse in 36%/32%/32% of subjects, with median time to visual event of 1.7 years (range 0.16 - 12) and 10yr-vEFS 41.3%. Final VA was reduced (&gt;0.2 logMAR) in 23 (28.4%) and 43 (53.1%) in only one or both eyes respectively. Amongst those with unilateral impairment 13/23 affected eyes had no useful vision (light/no light perception). Amongst those with bilateral impairment best eye VA was &gt; 1.0 log MAR in 22/43 (LP/NLP in 10). Infants &lt; 1 year had significantly inferior 10-yrPFS (5.6%), post-chiasmatic involvement was associated with visual deterioration (HR 2.91, 95%CI=1.1- 7.7), and baseline bilateral abnormal for age vision predicted WHO blindness at follow-up (OR 17.9, 95%CI=3.2 – 101.1).
CONCLUSIONS: Many IYC-OPG suffer multiple progressions with significant long-term visual morbidity. Predictive factors such as age, tumor location and baseline age-adjusted vision allow patients’ selection for early sight rehabilitation and consideration for experimental strategies preventing visual loss.
LGG-56. Surgical management of pre-chiasmatic intraorbital optic nerve gliomas in children after loss of visual function – Resection from bulbus to chiasm
Authors: Zipfel Julian , Tellermann Jonas , Besch Dorothea , Bertelmann Eckart , Ebinger Martin , Driver Pablo-Hernandez , Thomale Ulrich-Wilhelm , Schuhmann Martin U 
Published: June 2022

Abstract
INTRODUCTION: Optic pathway gliomas (OPG) in children carry significant morbidity and therapeutic challenges. The subgroup of pre-chiasmatic gliomas manifest with exopthalmus are a subgroup where, after blindness has occurred, an intraorbital and intradural resection is a curative option. We present a two-center cohort using two different surgical approaches and describe indication, technique, and long term surgical outcome. METHODS: A retrospective analysis in both centers was performed to included patients &lt; 18 years at diagnosis with a pre-chiasmatic intra-orbital glioma, in whom a resection from the bulb to the chiasm was performed. RESULTS: 11 patients were included. 4 had NF1. Mean age at surgery was 7.0 years. Interval between diagnosis and surgery was 1-74 (median 10) months. Two had prior chemotherapy, one radiation, one both, one prior intraorbital surgery. In all 5 progression occurred. Indications for surgery were exophthalmos, pain, tumor progression or a combination. 8 patients (Group A) underwent an extradural trans-orbital-roof approach to resect intra-orbital tumour including the optic canal part plus intradural pre-chiasmatic resection. In 3 patients (Group B) a combined supra-orbital mini-craniotomy plus orbital frame osteotomy was used for intraorbital tumour-resection, excluding the optic canal part, plus intradural pre-chiasmatic resection. GTR was achieved in 7/8 of Group A and none had a recurrence (mean-FU 42 month). One residual behind the bulbus showed progression, treated by chemotherapy. All residuals in Group B were remnants of the optic nerve within optic canal remained stable (mean FU 11.8 months). No patient had a chiasmatic functional affection or permanent oculomotor deficits. Two after prior radiotherapy developed slight enophthalmos. CONCLUSION: In these selected patients surgical resection from bulb to chiasm (± removal of optic canal tumor) is safe without long-term sequela and with excellent cosmetic result. Surgery removes immediately exophthalmos and provides an effective long-term tumor control. It should be considered therapy of choice.