bluuebunny/crossref_metadata_2025 huggingface dataset:
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

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

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

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

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 (>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 (>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 > 1.0 log MAR in 22/43 (LP/NLP in 10). Infants < 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

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 < 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.
LGG-58. Understanding the transcriptional heterogeneity of pediatric low-grade gliomas and its implication for tumor pathophysiology
Authors: Boisvert Michelle , Perera Ashwyn A , Condurat Alexandra L , Jeang John , Tsai Jessica W , Novikov Dana , Zhou Kevin , Chacon Madison , DiGiacomo Jeromy , Kumbhani Rushil , Wang Dayle , Taylor Michael D , Hansford Jordan R , Ludlow Louise , Jabado Nada , Ligon Keith L , Beroukhim Rameen , Bandopadhayay Pratiti , Jones David T W
Published: June 2022

Pediatric low-grade gliomas (pLGGs) are the most frequent brain tumors in children and comprise a heterogeneous group of tumors with different locations, histologic subtypes, ages at presentation, and clinical behavior. Tumors frequently respond to treatment with chemotherapy or surgical removal, but they can regrow after a period of quiescence, requiring further therapy. Thus, a deeper understanding of the molecular processes involved in these tumors is required to develop therapeutic strategies that are effective against their disease mechanisms. To better understand the cellular behaviors of this heterogenous group of tumors, we have employed single-cell and single-nuclei RNA sequencing technologies to analyze a large-scale dataset (>250,000 cells) of pLGGs. Analysis of this data identified a heterogenous population of cell types and cell states, detecting mature and progenitor-like astrocytes and oligodendrocytes, as well as cells exhibiting senescence or cycling programs. Moreover, we identify a significant immune infiltrate, comprised primarily of microglia. In addition to heterogeneity within pLGG tumors, heterogeneity between LGG subtypes represents another layer that stratifies pLGG biology. We performed a compositional analysis of the cell types present in these tumors and compared transcription signatures and gene expression programs across shared cellular populations of histologically and genetically distinct pLGGs. Finally, we optimized our integration and batch correction analyses by using external 293T cells as spike in controls during our single-cell and single-nuclei data generation steps to determine the most suitable method for batch-effect removal. Our analysis of human pLGGs at the single-cell and single-nuclei resolution provides critical insight into the heterogenous biological activities that constitute these tumors.
MEDB-06. Spatial transcriptomic analysis of Sonic Hedgehog Medulloblastoma identifies that loss of heterogeneity and induced differentiation underlies the response to CDK4/6 inhibition
Authors: Vo Tuan , Balderson Brad , Jones Kahli , Crawford Joanna , Millar Amanda , Tolson Elissa , Ruitenberg Marc , Robertson Thomas , Bhuva Dharmesh , Davis Melissa , Wainwright Brandon , Nguyen Quan , Genovesi Laura
Published: June 2022

Medulloblastoma (MB) is a malignant tumour of the cerebellum which can be classified into four major subgroups on the basis of gene expression and genomic features. Single cell transcriptome studies have defined the cellular states underlying each MB subgroup, however the spatial organisation of these diverse cell states and how this impacts response to therapy remains to be determined. Here, we used spatially resolved transcriptomics to define the cellular diversity within a sonic hedgehog (SHH) patient-derived model of MB and identify how cells specific to a transcriptional state or spatial location are pivotal in responses to treatment with the CDK4/6 inhibitor, Palbociclib. We distinguish neoplastic and non-neoplastic cells within tumours and from the surrounding cerebellar tissue, further refining pathological annotation. We identify a regional response to Palbociclib, with reduced proliferation and induced neuronal differentiation in the majority of the tumours. Additionally, we resolve in cellular resolution a distinct tumour “interface” where the tumour contacts neighbouring mouse brain consisting of abundant astrocytes and microglia and continues to proliferate despite Palbociclib treatment. Our data highlight the power of this approach to characterise the response of a tumour to targeted therapy and provide further insights into the molecular and cellular basis underlying the response and resistance to CDK4/6 inhibitors in SHH MB
MEDB-27. Clinico-Radiological Outcomes in WNT-pathway Medulloblastoma: Retrospective Single Institutional Audit
Authors: Mani Shakthivel , Chatterjee Abhishek , Sridhar Epari , Sahay Ayushi , Shirsat Neelam , Moiyadi Aliasgar , Shetty Prakash , Chinnaswamy Girish , Patil Vijay , Dasgupta Archya , Bano Nazia , Gupta Tejpal
Published: June 2022

BACKGROUND: Medulloblastoma (MB) is a heterogeneous disease comprising 4 molecular subgroups - wingless (WNT), sonic hedgehog, Group 3, and Group 4 tumors - with distinct developmental origins, diverse clinico-demographic characteristics, unique transcriptional profiles, and widely varying outcomes. WNT-MB is associated with the best outcomes (5-year survival >90%) prompting attempts at treatment de-escalation to reduce late toxicity. We undertook a clinical audit of WNT-MB patients treated at our tertiary-care comprehensive cancer centre. METHODS: Patients with molecularly confirmed WNT-MB treated with maximal safe resection followed by post-operative standard-of-care risk-stratified adjuvant radio(chemo)therapy were identified retrospectively via electronic search of the neuro-oncology database. Data regarding clinico-demographic characteristics, histo-molecular features, treatment details, patterns of failure, and survival outcomes was retrieved from electronic medical records and/or hospital case files. Time-to-event outcomes were analyzed using Kaplan-Meier methods and compared with the log-rank test. RESULTS: Between 2004 to 2018, a total of 65 patients of WNT-MB were registered at our institute. Five patients treated on a prospective clinical trial of therapy de-intensification were excluded leaving 60 patients that constitute the present study cohort. Median age at presentation was 12 years (inter-quartile range 9-18 years) with male preponderance (2:1). Six patients (1 post-operative mortality and 5 without adequate details of treatment or outcomes) were excluded from the survival analysis which was restricted to 54 patients. At a median follow-up of 66 months, Kaplan-Meier estimates of 5-year progression-free survival and overall survival were 87.9% and 92.8% respectively. Traditional high-risk features such as age, residual tumor (>1.5cm2) and leptomeningeal metastases (M+) did not emerge as significant prognostic factors for survival in this molecularly-characterized WNT-MB cohort. CONCLUSION: WNT-MB patients have excellent survival outcomes irrespective of traditional high-risk features suggesting the need for more tailored and refined risk-stratification with potential de-intensification of therapy. ACKNOWLEDGEMENTS: Brain Tumor Foundation (BTF) of India
MEDB-28. CDK9 is a druggable mediator sustaining Myc-driven circuitry in medulloblastoma
Authors: Madhavan Krishna , Walker Faye , Wang Dong , Sobral Lays Martin , Balakrishnan Ilango , Pierce Angela , Serkova Natalie , Foreman Nicholas , Venkataraman Sujatha , Vibhakar Rajeev , Dahl Nathan
Published: June 2022

BACKGROUND: Though long recognized as a master regulator of cell proliferation across a wide range of cancers, Myc has proven elusive to direct therapeutic targeting. The CDK9-containing PTEFb, complexed with either BRD4 or SEC, facilitates Myc-driven transcriptional programs and is necessary for sustaining expression of Myc itself. Advances in development of clinical-grade CDK9 inhibitors creates an opportunity to examine this as a rational therapy for Myc-driven medulloblastoma. METHODS: We used both RNAi depletion and a panel of pharmacologic agents to characterize the mechanistic and functional consequences of CDK9 inhibition in Myc-driven medulloblastoma. We used a combination of clonogenic assays and live cell imaging to assess the cytotoxic effects of CDK9 activity loss. We then performed a combination of CUT&RUN and RNA-seq to evaluate alterations to Myc binding and downstream Myc-driven transcriptional programs. Finally, we employed orthotopic xenograft models of medulloblastoma to assess CNS penetration, tolerability, and anti-tumor efficacy of lead CDK9i candidate compounds. RESULTS: Genetic or pharmacologic inhibition of CDK9 leads to a loss of Myc expression and downregulation of hallmark Myc-driven transcriptional programs. This corresponds to a loss of cell fitness, as measured by decreased proliferation and clonogenic potential. Clinically relevant CDK9 inhibitors show variable efficacy in vivo, but the CNS-penetrant zotiraciclib achieved a significant prolongation in xenograft survival. CONCLUSION: CDK9 catalytic activity represents a druggable vulnerability underpinning Myc-driven transcriptional programs. The development of CNS-penetrant CDK9 inhibitors may open new avenues for rational therapy in these high-risk medulloblastomas.
MEDB-29. Application of Rotterdam Post-Operative Cerebellar Mutism Syndrome Prediction Model to Patients Operated for Medulloblastoma in a Single Institution
Authors: Khan Raja , Savannah Bush , Boop Frederick , Gajjar Amar , Patay Zoltan , Robinson Giles , Klimo Paul
Published: June 2022

BACKGROUND: Post-operative cerebellar mutism syndrome (CMS) develops in up to 30% of children. The Rotterdam model (RM) predicts a 66% risk of CMS in patients with a score ≥100. However, our findings suggested that surgical experience contributes to CMS risk. The aim of this study was to retrospectively apply the RM and report incidence of CMS in high-risk patients from our institution. METHODS: Participants had to have first tumor resection at our institution and be enrolled on SJMB12 protocol (NCT01878617). All participants got structured serial neurologic evaluations. CMS, when present, was categorized into type 1 (complete mutism) and type 2 (paucity of speech with an inability to string 3-word sentence). Rotterdam score is calculated based on pre-operative imaging parameters and study neurologist (RBK) obtained it while blinded to CMS status. RESULTS: Of the 40 (14 female, 26 male) study participants, 4 (10%) had CMS (3 CMS1, 1 CMS2). Median age at tumor resection was 11.7 years (range 3.5-17.8). Tumor location was midline in 30 (75%), right lateral 6 (15%) and left lateral 4 (10%). Median Evans index was 0.3 (0.2-0.4) and 34 (85%) were ≥0.3 (indicative of hydrocephalus); 5 participants needed ventricular shunt. Median tumor volume was 50 cm3 (2-180.6). Gross total resection was achieved in 35 (87.5%), near total in 4 (10%) and subtotal in 1. Twelve tumors were SHH, 7 WNT, and 29 NWNS. Median RM score was 90 (25 – 145). Eighteen participants had a score of ≥100 and 16.7% of these (n=3) had CMS. Scores for the 4 with CMS were 85, 125, 145 and 145. CONCLUSION: At our institution, the incidence of CMS in those that had RM of ≥100 was much lower than reported risk of 66%. This data supports our hypothesis that neurosurgical experience remains a significant risk factor in the development of CMS.
MEDB-33. The landscape of ecDNA in medulloblastoma
Authors: Chapman Owen , Sridhar Sunita , Wang Shanqing , Larson Jon , Wechsler-Reya Robert , Mesirov Jill , Chavez Lukas
Published: June 2022

Extrachromosomal circular DNA (ecDNA) is an important driver of aggressive cancers, including medulloblastoma (MB), the most common malignant pediatric brain tumor. To assess the clinical importance of ecDNA in MB, we applied computational methods to detect ecDNA in the genomes of a cohort of 468 MB patients and 31 MB model systems. Among patients, ecDNA was detected in 18% of tumors and carried a threefold greater risk of mortality. Affected genomic loci harbor up to hundredfold amplification of oncogenes including MYC, MYCN, TERT, and other novel putative oncogenes. Between sequential patient biopsies at initial diagnosis and subsequent relapse, we observed structural variation at ecDNA loci and generation of new ecDNA sequences. Among model systems, ecDNA was found in 19 of 31 genomes (61%). Although ecDNA was far more prevalent among MB models than patients, the ecDNA genomic sequences were conserved between most patient-derived xenograft (PDX) models and the human tumors from which they were made. To elucidate the functional regulatory landscapes of ecDNAs in MB, we generated transcriptional (RNA-seq), accessible chromatin (ATAC-seq), and chromatin interaction (Hi-C) profiles of 6 MB tumor samples. In each case, we identified regulatory interactions that cross fusion breakpoints on the ecDNA, representing potential “enhancer rewiring” events which may contribute to transcriptional activation of co-amplified oncogenes. To test this hypothesis, we are currently conducting in vitro CRISPRi screens targeting regulatory regions on the ecDNA of a MB cell line to determine whether these enhancers promote proliferation. Using single-cell sequencing, we have also begun exploring intratumoral heterogeneity of ecDNA in a p53-mutant SHH MB patient tumor and its corresponding PDX model. In summary, our study analyzes the frequency, diversity, and functional relevance of ecDNA across MB subgroups and provides strong justification for continued mechanistic studies of ecDNA in MB with the potential to uncover new therapeutic approaches.
MEDB-46. ONC201 affects Group 3 Medulloblastoma growth by impairing cancer stem cells
Authors: Abballe Luana , Antonacci Celeste , Gianesello Matteo , Lago Chiara , Nazio Francesca , Mastronuzzi Angela , Catanzaro Giuseppina , Giannatale Angela Di , Tiberi Luca , Locatelli Franco , Miele Evelina
Published: June 2022

Cancer stem cells (CSCs) represent a sub-population of cancer cells capable of proliferating and generating heterogeneous cancer cell types. Acquisition of stemness features may represent a strong advantage for neoplastic cells to promote tumorigenesis and progression, driving resistance to conventional therapy and promoting disease relapse. CSCs have been discovered and isolated in major pediatric brain tumors, including medulloblastoma (MB), the most common solid malignancy in childhood. The unfolded protein response (UPR) represents an adaptation mechanism to metabolic obstacles in CSCs, able to increase tumor aggressiveness. The initial activation of the UPR is cytoprotective but the acute activation led to cell death. We found that UPR is active in MB stem cells (MBSC) and particularly in group 3 (G3). ONC201 is an imipridone compound that activates p53-independent apoptosis causing changes in gene expression similar to those caused by UPR. Here, we aim to test the in vitro efficacy of ONC201 on G3 MBSC. We selected 4 G3 MBSC (D341-Med, D283-Med, Med411, and CHLA-01-Med), for the in vitro study. Cells were choosen for their “fidelity” to the MB subgroup through the analysis of global methylation profiling, were grown in stemness conditions and expressed stemness markers at high levels. We investigated the efficacy of ONC201 treatment on CSC features, by evaluating cell viability, cell death, protein synthesis, self-renewal, and cell cycle. ONC201 treatment on G3 MB cells led to an upregulation of ATF4, a key molecule of the UPR, and the induction was stronger in MB cultured in a “stem-like” medium. Moreover, in the most MBSC analyzed, ONC201 was effective against CSCs whether by reduced cell viability, protein synthesis, and self-renewal. We also observed a trend of increased cell death. Our results suggest that ONC201 is potentially effective in treating G3 MB by compromising the stem cell compartment, and thus deserving further investigations.
MEDB-68. Analysis of telomeres length and Alternative Lengthening of Telomeres (ALT) in molecular subgroups of infant medulloblastoma
Authors: Buttarelli Francesca Romana , Minasi Simone , Garrè Maria Luisa , Massimino Maura , Biassoni Veronica , Goschzik Tobias , Pietsch Torsten , Giangaspero Felice
Published: June 2022

We investigated the association between the molecular profile and telomere length in a infant medulloblastoma (iMB) cohort, retrospectively studied. Activation of telomeres maintenance mechanisms was analyzed to determine whether the senescence escape triggered by telomere-elongation mechanisms could explain the aggressivity of some iMB belonging to the same molecular subgroup. Interestingly, several telomerase- and ALT-targeted therapies have recently been tested on pediatric cancers and might represent a promising strategy for the future treatment of aggressive telomerase- or ALT-positive iMB. We analyzed a cohort of 50 FFPE tissues from young MB patients (age ≤ 3); IHC, FISH, and an Illumina 850K methylation profile were used to identify molecular subgroups. Telomere length was measured using Telo-quantitative FISH, and image analysis was performed using TFL-Telo software. Three distinct telomere intensity categories (low (L), medium (M), and high (H)) were identified by comparing neoplastic- to endothelial-cell signals in each sample. ATRX loss and TERTp mutation/methylation were investigated using IHC and Sanger sequencing/methylation-specific PCR. SHH-MBs accounted for 59% of our cohort, while Group3/4-MBs accounted for 41%; no WNT-MBs were detected. ALT was found to be activated in 10% of iMBs and was not exclusive to any molecular subgroup, implying that it could be a potential mechanism associated with aggressive behaviour in a subset of iMBs. Promising results have been found in the telomere length distribution among the iMB molecular subgroups: SHH iMBs had a higher frequency of High (H) telomeres length (85%) than NON-SHH/NON-WNT iMBs (p=0.046), which were more frequently associated with Medium (M) telomeres length. CONCLUSIONS: ALT activation in infant MBs (10%) could be a novel target for risk-stratification and personalized therapy. It may be useful to examine ALT as a potential predictor of aggressive behaviour and as a promising novel therapeutic approach for a subset of these tumors in the diagnostic workup.
MEDB-74. Serial assessment of measurable residual disease in medulloblastoma liquid biopsies
Authors: Northcott Paul , Smith Kyle , Kumar Rahul , Paul Leena , Bihannic Laure , Lin Tong , Maass Kendra , Pajtler Kristian , Chintagumpala Murali , Su Jack , Bouffet Eric , Fisher Michael , Gururangan Sridharan , Cohn Richard , Hassall Tim , Hansford Jordan , Klimo Paul , Boop Frederick , Stewart Clinton , Harreld Julie , Merchant Thomas , Tatevossian Ruth , Neale Geoffrey , Lear Matthew , Klco Jeffery , Orr Brent , Ellison David , Gilbertson Richard , Onar-Thomas Arzu , Gajjar Amar , Robinson Giles
Published: June 2022

Nearly one-third of children with medulloblastoma, a malignant embryonal tumor of the cerebellum, succumb to their disease. Conventional response monitoring by imaging and cerebrospinal fluid (CSF) cytology remains challenging and a marker for measurable residual disease (MRD) is lacking. Here, we show the clinical utility of CSF-derived cell-free DNA (cfDNA) as a biomarker of MRD in serial samples collected from children with medulloblastoma (123 patients, 476 samples) enrolled on a prospective trial. Using low-coverage whole-genome sequencing, tumor-associated copy-number variations (CNVs) in CSF-derived cfDNA are investigated as an MRD surrogate. MRD is detected at baseline in 85% and 54% of patients with metastatic and localized disease, respectively. The number of MRD-positive patients decline with therapy, yet those with persistent MRD have significantly higher risk of progression. Importantly, MRD detection precedes radiographic progression in half who relapse. Our findings advocate for the prospective assessment of CSF-derived liquid biopsies in future trials for medulloblastoma.
NFB-01. Central nervous system tumors in Von Hippel-Lindau multisystem disorder: are there preventive approaches to escape tumor initiation at a young age?
Authors: Abdelmoula Nouha Bouayed , Abdelmoula Balkiss , Smaoui Walid
Published: June 2022

In pediatric neuro-oncology, the likelihood of an underlying tumor predisposition condition should be considered for all types of brain tumors. The aim of this study was to report the dramatic history of a VHL Tunisian family with many affected adolescents presenting central nervous system hemangioblastomas among wich many died in their twenties and those who survived suffered from depression and suicide attempts. To provide optimal clinical care and genetic counseling to affected patients and their young relatives, we conducted a literature review to answer the major question for this family: are there any preventive approaches to escape tumor initiation in our at-risk relatives at young age? The onset of VHL syndrome at the index case of our Tunisian family was at the age of 40 years when she presented a blurred vision on the right, related to retinal angiomatosis. The evolution was caraterised by recurrent eye lesions, the development of multiple renal tumors and hemangioblastomas at the cerebral, cerebellar and cervical spinal cord levels with neurologic symptoms and various functional nervous sequels after neurosurgical resections. Familial features of VHL were present in half of her siblings (6 among 12). Her 2 adolescent sisters, dead at the age of 20, harbored cerebral hemangioblastomas, whereas 2 of her brothers who died respectively at the age of 21 and 47 years harbored respectively ocular angiomas and vertebral angiomas. A third 48 year-old alive brother harbored cerebral hemangioblastoma as well as renal cell carcinoma. Only preimplantation genetic diagnosis (PGD) to select unaffected embryos can be applied to prevent the disease. High-throughput methods such as microarrays and sequencing are available nowadays for late-onset disorders with genetic predispositions. Long term surveillance and timely preventive treatment of lesions are crucial for VHL disease carriers. Effective psychosocial support to vulnerable children and their families is also essential.
NFB-04. Evaluating focal areas of signal intensity (FASI) in children with neurofibromatosis type-1 (NF1) treated with selumetinib on PBTC-029B
Authors: Pillay Smiley Natasha , Leach James , Lane Adam , Hummel Trent , Fangusaro Jason , de Blank Peter
Published: June 2022

BACKGROUND: Focal Areas of Signal Intensity (FASI) are T2 hyperintense benign lesions in children with NF1. They can mimic the appearance of low-grade glioma (LGG). Selumetinib has shown efficacy in treatment of NF1-associated LGG but treatment effects on FASI have not yet been described. METHODS: Patients with NF1-associated LGG treated with selumetinib on Stratum 3 of PBTC-029B were compared to age-matched untreated children with NF1-associated LGG at Cincinnati Children’s Hospital Medical. FASI were defined by published criteria as T2 hyperintense lesions lacking mass effect, enhancement or T1 hypointensity. Lesion size was determined by cross-product of perpendicular measures in LGG and 1-3 FASI per subject. When multiple FASI were present, the sum of FASI cross-products was used. Change between baseline and the latest available measure within 4 months of control was assessed, insuring that selumetinib-treated subjects were still receiving therapy. RESULTS: Fifteen age-matched pairs were assessed (2.8-16.9 years and 60% were male). Initial FASI size was not different between groups (p=0.98; median [IQR]: 138.7mm2 [88.4-182.0] for treated subjects versus 121.6mm2 [79.6-181.9] for untreated subjects). Lesion change was measured over mean follow up of 18.9 + 5.9 months. Spider plots show decreased LGG size over time during treatment, but there was no consistent change in size among treated or untreated FASI. Comparing FASI size between paired timepoints showed no difference in change from baseline for treated subjects versus for untreated subjects (two-sided test; p=0.08). In subjects who received selumetinib, there was no correlation between change in LGG and change in FASI (r=-0.04, p=0.88). Using RANO criteria for FASI lesions, 2/30 (6.7%) subjects had partial response, 26/30 (86.7%) subjects had stable disease, and 2/30 (6.7%) subjects had progressive disease. CONCLUSIONS: While the sample size was limited, treatment with selumetinib did not reduce overall FASI size in children with NF1 and LGG.
NFB-15. "Cognitive Impairments in Children and Adolescents with Neurofibromatosis"
Authors: Mavrea Kalliopi , Kokkinou Eleftheria , Roka Kleoniki , Tsiorou Stavroula , Deligeorges Danae , Kanaka-Gantenbein Christina , Bacopoulou Flora , Pons Roser , Kattamis Antonis
Published: June 2022

INTRODUCTION-BACKGROUND: Cognitive, learning and/or behavioral disorders are common (up to 70%) complications of neurofibromatosis (NF). The first multidisciplinary-clinic for neurocutaneous-disorders was established at the Aghia Sophia Children’s Hospital in Athens, Greece, in 2016. Since then, more than 200 children and adolescents with NF have been examined. SCOPE: Acknowledging and indicating awareness on the devastating life-long consequences (poor academic performance, behavioral problems, and limited career prospectives) that can result from cognitive impairment, a research collaboration with educational specialists was recently implemented to examine the neurocognitive functions of children and adolescents with NF. MATERIALS: Children and adolescents aged 7-14 years who suffer from NF type I or type II, were eligible for study entry. The third edition of the Wechsler Intelligence Scale (WISC-III) was used to measure participants’ cognitive function. RESULTS: Preliminary results of this ongoing study are presented. Patients’ recruitment was limited by the coronavirus disease 2019 (COVID-19) restrictions. At this stage, the research involved 10 participants suffering from NF, with mean (± SD) age of 11.55 (± 1.80) years and a male-to-female ratio of 1. The mean (± SD) full-scale intelligence quotient (IQ) was 85.50 (± 18.80), corresponding to the 0.3rd to 73th percentile range. The mean (± SD) scores of performance IQ and verbal IQ were 84.90 (± 17.43) and 89.40 (± 17.23) respectively, corresponding to the 1st to 73rd percentile range for both subscales. CONCLUSION: Significant cognitive deficits, according to the percentile scores of WISC-III, were demonstrated in the small number of children and adolescents suffering from NF (type I or type II). Cognitive assessment, as part of the multidisciplinary approach of these patients is warranted, to aid timely educational interventions and improve patient learning outcomes.
QOL-19. Post-Intensive-Care Syndrome – pediatric (PICS-p) among patients with brain tumors – therapeutic strategies and preventive recommendations
Authors: Korzeniewska Justyna
Published: June 2022

BACKGROUND: Patients with brain tumors needed in intensive care unit (ICU) stay due to tumors symptoms or neurosurgery, experience a complex of physical, psychological, and cognitive symptoms. This constellation of signs and symptoms has been named Post-Intensive-Care Syndrome – pediatric (PICS-p). An interesting problem emerging from this research and requires a deeper exploration are the differences between PICS-p symptoms and primary tumors effects or side effects of treatment e.g. irradiation. METHOD: Psychological repeated testing and long-term observation was performed in 350 childhood brain tumor survivors (various types and localizations of tumor) to determine PICS-p symptoms. Age at psychological diagnosis ranged from 6 to 20 years. Full psychological outcome included assessment of psychophysical, cognitive and affective problems. The patients were examined using battery of neuropsychological methods and psychological interview. Analysis of medical history was also performed. The next level of the study was distinguished between PICS-p symptoms and the effects of tumor localization and oncology treatment, including radiotherapy. RESULTS: In our sample patients presents low scores in the all PICS-p domains: physical, cognitive and mental. Low level of motor skills, impairing daily living activities are characteristic. In this group lower IQ scores, poorer visual motor integration, learning disabilities, memory and language problems persisted. Typical problems in mental area are depressive symptoms, anxiety with intrusive memories, emotional and behavioural disruptions, socialization problems with significantly low level of social contacts. CONCLUSIONS: The results of this study suggest that PICS-p well describes and explains the psychosocial problems of these patients. It allows prepare an individual psychological interventions and rehabilitative program for particular patient as well as therapeutic strategies for whole group of patients. Draft recommendations for diagnosis of PICS-p specific for patients with brain tumors, risk factors and preventive procedures will be presented and discussed.
QOL-30. Positive Effects of a psychological preparation program for MRI in children with cognitive issues – how to best meet the patients’ needs
Authors: Weiler-Wichtl Liesa Josephine , Fries Jonathan , Fohn-Erhold Verena , Schwarzinger Agathe , Holzer Angelika , Pletschko Thomas , Furtner Julia , Preyer Daniela , Baer Paul , Slavc Irene , Peyrl Andreas , Azizi Amedeo , Leiss Ulrike
Published: June 2022

BACKGROUND: A growing body of evidence has supported alternatives to sedation and general anesthesia for increasing treatment compliance of children during MRI examinations. Particularities in children with a brain tumor (frequency of examinations, neuropsychological deficits (attention, memory)) have a significant impact on methods of treatment and are given special consideration in this study. OBJECTIVE: The aim of the present study was to (1) evaluate the effectiveness of an MRI training program and to investigate the moderating factors for successful MRI examination for a group of young patients with pediatric brain tumors and/or NF1 and (2) to examine the effect of the training on the patient’s well-being. METHODS: A total of 87 in the retrospective analyses (Study 1) and a subgroup of 17 patients in the prospective analyses (Study 2, ClinicalTrials.gov: NCT04474678) of the neuro-oncology unit with a mean age of 6.83 years underwent a two-step program to prepare children for MRI, including an in vitro strategy training inside the scanner and were recorded using a process-oriented screening. RESULTS: 81 % of the children who had received MRI training managed to successfully undergo the MRI scan. Hence, the rate of successful MRI examinations without anesthesia was almost five times as high in the group that received MRI training compared to the group that did not. Memory, attentional difficulties and hyperactivity were significant neuropsychological moderators for successful or unsuccessful scanning. Furthermore, the training was effective in improving the psychological well-being of the patients. CONCLUSION: Based on the results, the MRI training is an effective alternative to sedation of young patients for MRI examinations and a promising tool for improving patient well-being related to the diagnostic procedure. However, the intervention needs to be customized according to the children’s individual neuropsychological difficulties, which requires specialized psychological staff and an interdisciplinary approach.
QOL-32. Patients treated for malignant brain tumor in the first three years of life: clinical sequelae
Authors: Giaquinta Simonetta , Rossi Bartolomeo , Pillon Marta , Carraro Elisa , Biffi Alessandra , Viscardi Elisabetta
Published: June 2022

BACKGROUND: Pediatric Central Nervous System tumors are the most common solid tumors in children with a higher incidence rate in the first years of life. Patients treated for brain tumor are at high risk of sequelae. In the first years of life, brain immaturity increases the risk of developing these complications. OBJECTIVE: The goal of this study was to evaluate the medium and long term sequelae of malignant brain tumor treatment in patients diagnosed in the first three years of life and to correlate these sequelae with tumor histology, localization and treatment. PATIENTS AND METHODS: Forty - nine children with aggressive brain tumor diagnosed in the first three years of life followed in the Pediatric Hematology and Oncology Department of Padua between January 2000 and December 2020 were enrolled in this study. We evaluated features, such as age at onset, tumor localization, neurosurgical resection, histology, treatment and patient outocome. From May to September 2021 we clinically evaluated 16 of them who survived to treatment and we identified the presence of visual impairment, hearing loss, endocrine dysfunctions and neurological deficits in them. RESULTS: The most common sequelae in our patient population is motor impairment (30.8%), followed by endocrine dysfunction (23%), visual impairment (19.2%), epilepsy (11.6%), cranial nerve palsy (7.7%) and hearing loss (7.7%). In this study epilepsy is significantly associated with supratentorial tumors and endocrine dysfunction with high dose chemotherapy. CONCLUSIONS: Our data and recent literature confirm the high incidence of tumor and treatment sequelae in these patients. Therefore, since diagnosis, a multidisciplinary evaluation and management are necessary for improving patients’ prognosis.
SURG-04. Robotic alignment system Cirq (Brainlab) for navigated brain tumor biopsies in children
Authors: van Baarsen Kirsten , Slot Mariam , Woerdeman Peter , Han Sen , Hoving Eelco
Published: June 2022

BACKGROUND: With the incorporation of the robotic alignment system Cirq (Brainlab, Munich, Germany) into our neurosurgical armamentarium, we deemed it important to study application accuracy of this new device. As a baseline, we retrospectively reviewed our historical data on brain tumor biopsies using the non-robotic alignment instrument Varioguide (Brainlab, Munich, Germany). Because of relatively high target registration errors in this historical series, we sought to improve our registration with the introduction of Cirq. AIMS: 1.Share our experience with the new robotic alignment system Cirq for navigated brain tumor biopsies. 2. Compare patient-to-image registration methods. 3. Evaluate the accuracy of Cirq robotic system as compared to the non-robotic instrument Varioguide. METHODS: All patients (0-19 years old) who underwent a brain tumor biopsy at the Princess Máxima Center, Utrecht, were included. Over the period 2018-2020, data were collected retrospectively (cohort “Varioguide” in which patient-to-image registration was based on preoperative MRI with adhesive scalp fiducials). From 2021 onwards, data were collected prospectively (cohort “Cirq” in which patient-to-image registration was done using 1. A preoperative MRI with adhesive scalp fiducials and 2. An intraoperative CT head scan with bone screw fiducials). For both cohorts, Euclidian distances were calculated between the intended target and the obtained target using postoperative MRI scans. PRELIMINARY RESULTS : Nineteen patients were biopsied with Varioguide and nine patients with Cirq. The Cirq robotic system was convenient and safe in use with no intraoperative complications. Patient-to-image registration was more accurate when based on bone screw fiducials as compared to scalp fiducials. The Cirq robotic system, combined with bone fiducial registration, resulted in a high target accuracy with a maximum target error of 2 millimeters. CONCLUSION: The Cirq robotic alignment system, combined with bone screw fiducial registration, provides a safe and highly accurate method for brain tumor biopsies in children.