bluuebunny/crossref_metadata_2025_split huggingface dataset:
HGG-53. MULTI-DIMENSIONAL INTEGRATIVE PROFILING IDENTIFIES BCL2L1 METHYLATION AS A PREDICTIVE BIOMARKER FOR MCL-1 ACTIVITY IN PEDIATRIC HIGH-GRADE GLIOMAS
Authors: Adjumain Shazia , Sun Claire Xin , Bradshaw Gabrielle , Chew Nicole , Tsui Vanessa , Lee Hanbyeol , Loi Melissa , Zhukova Nataliya , Habarakada Dilru , Ludlow Louise , Neeman Naama , Daniel Paul , Firestein Ron 
Published: June 2024

Abstract

BACKGROUND
Pediatric high-grade gliomas (pHGGs) pose a significant challenge as the most aggressive central nervous system tumors in children. The lack of effective treatment and poor survival rates emphasize the critical need for innovative therapies to improve the prognosis of pediatric patients with pHGG.

METHODS
We executed CRISPR-cas9 knockout (KO) screenings in 65 pediatric and 10 adult high-grade glioma (HGG) cell lines to explore unique functional dependencies associated with pHGGs. Drug assays were carried out to assess the targetability of a gene dependency of interest in pHGG cell lines. Subsequently, Random Forest machine learning algorithm was employed on ‘omics’ datasets to identify biomarkers indicative of drug response. Finally, biomarkers were confirmed through sequencing-based methods across various pediatric cancers.

RESULTS
CRISPR-cas9 KO screens revealed 8 crucial genes essential for pHGG growth, namely MCL-1, ATIC, DHFR, EED, HDAC2, PARP1, PDK1, PIK3CA and TYMS. Among these, Myeloid Cell Leukemia (MCL-1) was further characterized as it emerged as the top differential genetic dependency in pHGGs. Consistent with this, MCL1 inhibitors exhibited potent anti-cancer activity on 43% of pHGG cell lines. Multi-feature prediction analysis identified 140 features correlated to response. Strikingly, a previously undescribed methylation site within the BCL2L1 locus, cg00300298, ranked in the top 5% of features. Tissue analysis revealed a wide range of other pediatric brain cancers that harbor the BCL2L1 cg00300298 methylation mark as compared to non-malignant brain tissue. Lastly, we validated the utility of BCL2L1 methylation as a predictive biomarker of MCL1 inhibitor sensitivity across a large panel of pediatric brain cancer cell lines.

CONCLUSION
Using an integrated genomic approach, we identify MCL1 as a distinct therapeutic target in BCL2L1-methylated pediatric brain cancers. This offers a rational approach for stratifying patients who may benefit from MCL1 inhibitors.
IMG-17. CHANGES IN GRAY MATTER VOLUMES AND THEIR RELATION WITH NEUROPSYCHOLOGICAL DOMAIN SCORES IN SURVIVORS OF A CHILDHOOD POSTERIOR FOSSA TUMOR
Authors: Bullens Kristien , Blommaert Jeroen , SLeurs Charlotte , Lemiere Jurgen , Jacobs Sandra 
Published: June 2024

Abstract
Posterior fossa tumors (PFT) often need neurotoxic radiotherapy (RT). These may affect the brain and contribute to neurocognitive impairment later in life. Therefore, we investigated region-based gray matter volumes (GMV) and their relation to neurocognitive functioning (NF) in PFT survivors. T1-weighted MRI (MPRAGE, resolution=.98x.98x1.2mm) and NF composite scores based on a compressive neuropsychological test battery: total Intelligence, verbal comprehension, working memory, perceptual reasoning, processing speed, language, learning and memory, complex attention (CA), and cognitive flexibility (CF), were analyzed for 17 survivors of PFT (12males, 5females, mean age at diagnosis=8.5±4.5y) and 19 age- and sex-matched controls. Cortical- and subcortical GMV were analyzed with region-based morphometry (RBM, fastsurfer). GMV and NF-scores were compared between controls and survivors, and surgery-only versus RT. Post-hoc analyses correlated GMV with NF-scores and clinical parameters (radiotherapy-dose, time since treatment, and time since diagnosis). Comparing controls with survivors, lower GMV were found for overall subcortical GMV (pFDR=0.020) as well as for several subcortical subregions: bilateral thalamus and bilateral ventral diencephalon (pFDR&lt;0.01). Larger GMV was observed in the left inferiotemporal region (pFDR=0.027). Survivors obtained lower NF-scores on all domains (pFDR&lt;0.007) except for CA and CF. RT-survivors had lower GMV in bilateral thalamus (pFDR&lt;0.05), right ventral diencephalon (pFDR=0.033), and central corpus callosum (pFDR=0.033) compared to surgery-only. Higher GMV were found in bilateral middle temporal regions (pFDR&lt;0.05). NF-scores were lower in RT- survivors, but none reached statistical significance after multiple comparison correction. Significant, positive correlations between GMV of bilateral thalamus and right ventral diencephalon was found for the working memory. Differences in GMV and NF scores were observed in PFT survivors. In this limited group, RT-survivors showed more deviant GMV compared to surgery-only survivors and controls. These results also suggest a potential relationship between deviant GMV and worse NF. Notwithstanding, research in larger populations is needed to validate our findings.
IMG-21. HOW CAN WE BEST UTILISE HISTORICAL IMAGING DATASETS FOR RESEARCH IN PAEDIATRIC NEURO-ONCOLOGY? A REVIEW OF HISTORICAL PRE-OPERATIVE IMAGING PERFORMED FOR 92 PAEDIATRIC BRAIN TUMOUR PATIENTS WITH COMPARISON TO 2021 SIOPE GUIDELINES
Authors: Dockrell Simon , Vaughan Kate , Kilday John-Paul , Kamaly-Asl Ian , McCabe Martin , Stivaros Stavros 
Published: June 2024

Abstract

BACKGROUND
Utilisation of historical imaging is important for studying long-term outcomes in paediatric brain tumours often pooling data across multiple centres retrospectively over many years. Disparities in MRI sequence parameters, imaging planes, fields of view and resolution limit quantitative radiomic analysis and segmentation algorithms. We review historical imaging datasets, analysing the MRI scans performed assessing suitability for modern research techniques.

METHODS
Retrospective review of presenting MRI scans was performed in 92 paediatric brain tumour patients between 2006-2020. Whether imaging was performed internally at our paediatric neurosciences centre or externally at their referring hospitals was recorded. Image sequences, planes and slice thickness were compared with 2021 SIOPE guidelines for paediatric brain tumour imaging. T2 signal intensities for tumour, white and grey matter were compared for scans completed in different centres. Statistical testing was performed with T-Test and Paired T-Test.

RESULTS
75% of patients had all SIOPE essential sequences and 60.9% were in the recommended planes. Only 1 patient had the desired slice thickness in all sequences recommended for 1.5T scanners. 38.5% had T1 and 27.8% had post-contrast T1 in the ≤1mm slice thickness recommended for 3T scanners. Comparison between 62 internal and 30 external scans revealed statistically significant differences in T2 signal intensities for regions of interest (ROI) within tumour, white and grey matter (p&lt;0.01). Comparison of matched ROI for 12 patients imaged internally and externally demonstrated statistically significant differences in T2 signal intensities (p&lt;0.05). Differences persisted despite normalisation of T2 signal intensity as ratios between tumour and the weighted mean of white and grey matter (p&lt;0.01).

CONCLUSIONS
This study highlights the challenges of non-standardisation of imaging resolution and acquisition parameters in historical imaging. One approach to utilise these datasets is to use qualitative classifications where human experts label imaging features and encode data for future statistical or machine learning analysis.
IMG-22. ASL PERFUSION LIGHTBULB SIGN: A POTENTIAL PATHOGNOMONIC FEATURE OF PEDIATRIC POSTERIOR FOSSA HEMANGIOBLASTOMA
Authors: Simsek Onur , Sheth Nakul , Manteghinejad Amirreza , Wannasarnmetha Mix , Bhatia Aashim 
Published: June 2024

Abstract

INTRODUCTION
Hemangioblastoma is a rare vascular tumor which occurs within the central nervous system in children. Differentiating hemangioblastoma from other posterior fossa tumors can be challenging on imaging and preoperative diagnosis can change neurosurgical approach. We hypothesize a ‘lightbulb sign’ (diffuse homogenous intense hyperperfusion within solid component of tumor) will help differentiate hemangioblastoma from other posterior fossa tumors.

METHODS
In this retrospective case-control study, we only included pathology-proven cases of hemangioblastoma, while the control group consisted of other randomly selected pathology-proven posterior fossa tumors from January 2022 to January 2024. Two blinded neuroradiologists analyzed all applicable MRI sequences. Their perfusion analysis also included the “lightbulb sign” as an extra criterion. Disagreements between the radiologists were confirmed by a third pediatric neuroradiologist. Chi-square and Fisher’s exact test were used to analyze the data.

RESULTS
95 patients were enrolled in the study, 57(60%) were male. The median age at diagnosis was 8 (IQR: 3-14). Out of the enrolled patients, 8 had hemangioblastoma, and 87 had other posterior fossa tumors, including medulloblastoma (n=31), pilocytic astrocytoma (n=23), posterior fossa ependymoma type A (n=16), and other tumors (n=17). The comparison of hemangioblastoma vs non-hemangioblastoma showed that peripheral edema (p=0.020, OR=1.8) and T2 flow void (p=0.021, OR=1.7) favors hemangioblastoma, whereas reduced diffusion (low ADC) (p=0.002, OR=2.3) and ventricular system extension (p=0.001, OR=2.4) favors non-hemangioblastoma tumors. 42 cases also had perfusion studies. While high perfusion favors hemangioblastoma (p=0.021, OR=2.9), the lightbulb sign shows a complete distinction since all the ASL series of hemangioblastoma cases (n=4) showed the lightbulb sign, whereas none of the non-hemangioblastoma cases (n=38) showed the sign (p&lt;0.001).

CONCLUSION
Lightbulb-like intense and homogenous hyperperfusion pattern on ASL allows differentiation of hemangioblastoma from other posterior fossa tumors in children.
IMG-24. MAPK-ALTERED PEDIATRIC LOW-GRADE GLIOMA: MRI HINTS TO EXPLAIN THE INTERPLAY BETWEEN GLIOMA AND IMMUNE CELLS
Authors: Ramaglia Antonia , Piccolo Gianluca , Molteni Marta , Mercuri Claudia , Gaggero Gabriele , De Marco Patrizia , Pavanello Marco , Rossi Andrea , Garrè Maria Luisa , Milanaccio Claudia , Verrico Antonio 
Published: June 2024

Abstract

BACKGROUND
In MAPK-altered pediatric low-grade glioma (pLGG), immune infiltration may be involved in treatment response. It is debated whether tumor immune cell infiltration is due to expansion of endogenous resident microglia or to the active recruitment of bone marrow-derived microglial progenitors from the bloodstream. This study aimed to investigate the relation between neuroradiological features of MAPK-altered pLGG and treatment response to MAPK-inhibitors (MAPKi).

METHODS
We conducted a retrospective analysis of all patients with unresectable BRAF-V600E mutated brain pLGG, radiotherapy naïve, treated with MAPKi at our institution since 2015. MRI studies were reviewed by two experienced neuroradiologist and tumor response assessed according to RAPNO criteria.

RESULTS
12 patients were enrolled (9 female). Median age at treatment start was 6.2 years (range 2.7–14.3 years). Four were pilocytic astrocytomas, 6 gangliogliomas, and 2 desmoplastic infantile gangliogliomas. Five patients received MAPKi as first line, 7 following other chemotherapy lines. Median follow-up was 4.1 years (range 2.5–8.7 years). Tumor response was associated with contrast enhancement (CE): 9 out of 10 patients with CE at treatment onset had at least partial response and subsequent CE resolution, while both 2 out of 2 patients without CE showed stable disease. A 4-year old contrast enhancing-ganglioglioma who reached partial response and CE resolution with MAPKi, presented disease progression four days after treatment withdrawal; treatment re-start determined tumor and CE reduction after only 7 days.

CONCLUSIONS
We hypothesize that brain-blood barrier breakage is induced by tumor infiltration of bloodstream immune cells, and that this trafficking is stimulated by tumor cell secreted products and determined by microglial progenitors shift from the bloodstream to the tumor site. MAPKi treatment may incite blood-brain barrier reconstitution as it reduces the trafficking between tumor site and bloodstream.

ACKNOWLEDGEMENT
This work was supported by grant number NET-2018-12366666 NeuroArtP3 from the Italian Ministry of Health.
IMMU-08. OUTCOME OF PATIENTS WITH RECURRENT MEDULLOBLASTOMA AND EPENDYMOMA TREATED WITH PEMBROLIZUMAB, AN IMMUNE CHECKPOINT INHIBITOR: A PEDIATRIC BRAIN TUMOR CONSORTIUM STUDY (PBTC045)
Authors: Hwang Eugene I , Kilburn Lindsay B , Mitchell Duane A , Lin Tong , Young-Poussaint Tina , Robinson Giles , Gajjar Amar , Lenzen Alicia , Dorris Kathleen , Robison Nathan , Fangusaro Jason R , Fouladi Maryam , Onar-Thomas Arzu , Dunkel Ira J 
Published: June 2024

Abstract

BACKGROUND
Children with recurrent medulloblastoma and ependymoma typically have a dismal prognosis. Immune checkpoint blockade has revolutionized treatment of some resistant cancers. PBTC045 is a safety and preliminary efficacy study of pembrolizumab, a PD-1 inhibitor, in children with recurrent/progressive brain tumors. Here we present the strata that included children with recurrent/progressive ependymoma and medulloblastoma.

METHODS
Eligibility included patients aged 1-21 years old with recurrent/progressive ependymoma or medulloblastoma and with functional scores &gt;70, no greater than physiologic steroid usage and standard washout periods, among other eligibility criteria. Pembrolizumab was administered at 2mg/kg IV every three weeks. Tumor tissue (if available) and serum were collected for correlative studies. Primary endpoints included toxicity and response, and two stages were planned requiring objective responses for potential expansion.

RESULTS
Patients with progressive ependymoma (Stratum D, n=13) or medulloblastoma (Stratum E, n=14, one ineligible) were enrolled. The median age at diagnosis was 3.37 years (range, 1-12.7) and 7 years (range, 2.2-13.1), respectively. The median age at study entry was 8.5 and 11.4 years, respectively. There were no first-stage objective responses in either stratum, and thus the expansion arms were not initiated. Grade 3 or greater treatment-related adverse events included rash (n=1), anemia (n=1) and neutropenia (n=2), with no dose-limiting toxicities. The median progression-free survival (PFS) for ependymoma and medulloblastoma were 1.38 months (range, 1.08-1.51) and 1.41 months (range, 1.22-3.45), respectively. Immune correlative analyses are ongoing.

CONCLUSIONS
Immune checkpoint inhibition holds potential for CNS cancer treatment, and as a single agent, is well tolerated. However, in the current study, checkpoint inhibition monotherapy does not appear to significantly prolong survival or induce radiographic responses in children with recurrent/progressive ependymoma or medulloblastoma. Potential incorporation of checkpoint inhibitors into treatment for these patients will likely require combinatorial approaches that may be informed by the correlative science.
IMMU-12. STANDARD OF CARE PLUS INDIVIDUALIZED MULTIMODAL IMMUNOTHERAPY (IMI) TO TREAT H3.3G34 DIFFUSE MIDLINE GLIOMA
Authors: Van Gool Stefaan W , Kosmal Jennifer , Van de Vliet Peter , Stuecker Wilfried 
Published: June 2024

Abstract

BACKGROUND
The prognosis of patients with H3.3G34 diffuse midline glioma is uniformly dismal. Since approval of IO-Vac® as advanced therapy medicinal product (27/05/2015), we treated two young patients with IMI in connection to the standard of care.

METHODS
BN (male 14y, diagnosis 01/2022) and JV (female 21y, diagnosis 12/2021) received partial resection resp. biopsy. Both underwent standard radiochemotherapy.

RESULTS
BN received 3/6 TMZ/Lomustin maintenance chemotherapy before start IMI. JV started with 1/12 TMZ courses together with IMI. Five-day immunogenic cell death (ICD) immunotherapy (Newcastle Disease Virus bolus injections and local modulated electrohyperthermia) were added to each maintenance chemotherapy block. After maintenance chemotherapy plus ICD immunotherapy, both received active-specific immunotherapy with two IO-Vac® vaccinations (autologous mature dendritic cells loaded with ICD-induced antigenic extracellular microvesicles). Both started with modulatory immunotherapy (4x ipilimumab/nivolumab q3w and further 6x nivolumab q4w) in combination with maintenance ICD immunotherapy. BN had a spinal relapse 19 months after initial diagnosis. He restarted with local radiotherapy and thereafter Lomustin plus Nivolumab, ultimately stopped due to arthritis. He died 24 months after diagnosis. Because of the observation of spreading disease, JV is now further treated with maintenance ICD immunotherapy using local modulated electrohyperthermia to the brain and to the upper and lower spine. She shows no evidence of progressive disease after &gt;25 months.

CONCLUSIONS
The addition of IMI to standard of care for young patients with H3.3G34 diffuse midline glioma might give a glimpse of hope, and further anecdotal experiences should be collected. Additional treatment of the spinal axis with modulated electrohyperthermia might be required for patients with DMG.
IMMU-15. CARTART: A SURFACE TARGET IDENTIFICATION TOOL FOR TUMORS
Authors: Joshi Nikhil , Murugesan Rakesh , Beaubien Ezra , McManus Olivia , Wilson Cullen , Harvey Kyra , Mishra Deepak , Hajeebu Sreehita , Madsen Peter , Foster Jessica 
Published: June 2024

Abstract

BACKGROUND
Cell surface proteins are valuable for generation of targeted and immune-based cancer therapies. While large molecular datasets are available for multiple central nervous system (CNS) tumors, identifying such targets on a tumor-level scale to generate novel therapeutics for patients is limited by a lack of analytical pipelines. Here, we present CARTarT (CAR-T Target identification Tool), a no-code, web application that utilizes user-inputted bulk transcriptomic data to identify putative surface targets for pediatric tumors.

METHODS
CARTarT was built on R 4.3.1 and performs differential gene expression between tumors and normal tissue (GTEX) utilizing an empirical bayes method. Data is then filtered based on predicted-surfaceome expression, non-immune cell expression, and limited normal tissue expression to mitigate possible off-target toxicities. Targets are finally scored using a weighted scoring metric based on RNA-level log fold change, t-value, average tumoral expression, and prevalence in oncogene databases to prioritize putative targets. Targets with a score less than 0.20 were removed from our final table. A total of 919 samples from OpenPedCan were utilized to validate the tool.

RESULTS
Amongst diffuse midline glioma specimens (n=196), we identified 100 putative surface targets. 60 (60%) of surface targets were previously identified oncogenic or cancer-associated genes. 17 surface targets (15%) are shown to have previously described immune or targeted therapeutics across cancer types, most notably identifying B7-H3, IL13RA2, EGFR, and GPC2. In addition, we identified 45 targets with potential across multiple pediatric neuro-oncologic malignancies (high grade glioma, medulloblastoma, ependymoma, atypical teratoid/rhabdoid tumor) including CHRNA5, GLP1R, B7-H3 and GPC2.

CONCLUSION
These findings highlight the potential utility of CARTarT as a no-code solution for surface target identification and describe established and novel surface targets across numerous pediatric CNS tumors. We present CARTarT to the scientific community as an open-access opportunity to advance immune-based and targeted therapies for tumors.
IMMU-17. A PHASE I STUDY OF INTRATUMORAL/PERITUMORAL HERPES SIMPLEX VIRUS-1 MUTANT HSV1716 IN PATIENTS WITH REFRACTORY OF RECURRENT HIGH-GRADE GLIOMAS: A PEDIATRIC BRAIN TUMOR CONSORTIUM STUDY
Authors: Mochizuki Aaron Y , Hummel Trent R , Cripe Timothy , Fouladi Maryam , Stevenson Charles B , Pollack Ian , Mitchell Duane , Poussaint Tina Young , Onar-Thomas Arzu , DeWire-Schottmiller Mariko , Pillay-Smiley Natasha 
Published: June 2024

Abstract

BACKGROUND
Immune-modulatory strategies, including checkpoint inhibition and tumor vaccines, have been tested in efforts to mitigate the pro-tumor microenvironment in pediatric high-grade glioma (pHGG). HSV1716 is a first-generation oncolytic virus that was previously reported safe with evidence of response in pediatric patients with relapsed or refractory extracranial tumors and in adults with high-grade glioma.

METHODS
PBTC-037 was a multicenter, phase I trial developed and performed by the Pediatric Brain Tumor Consortium (PBTC) to estimate the maximum tolerated dose or recommended phase II dose of HSV1716 administered during surgical resection. Patients aged 12 to 21 years with recurrent or refractory pHGG for whom surgical resection was clinically indicated were eligible. After maximal tumor resection, patients received one intraoperative dose of HSV1716.

RESULTS
Two patients were enrolled; one was later deemed ineligible (due to out-of-window screening evaluations) yet was continued in follow up for safety. Shortly after enrollment of the 2 patients, the study was closed to accrual due to a change in the sponsor’s investment focus. One patient completed the 8-week reporting period without toxicities. The only grade 3 or higher adverse event noted was grade 3 hyperglycemia at 2- and 3-months post injection. The second patient that was later deemed ineligible received the injection of HSV1716 and had no evidence of dose-limiting toxicity. The two patients had progressive disease 1.9 and 2.9 months after enrollment; both eventually died due to progressive disease at 7.5 months.

CONCLUSIONS
We describe the administration of HSV1716 to two pediatric patients with recurrent high-grade glioma, without evidence of dose-limiting toxicity. Oncolytic viruses are currently being tested in pediatric patients in larger trials and in combinatorial trials in other tumor types. Despite the limited numbers, the data presented here will hopefully provide incremental steps toward improved immunovirotherapy of pediatric brain tumors.