bluuebunny/crossref_metadata_2025 huggingface dataset:
MDB-27. OUTCOMES FOR CHILDREN TREATED FOR MEDULLOBLASTOMA USING A RADIATION-SPARING APPROACH: A REPORT FROM THE CHILDREN’S BRAIN TUMOR NETWORK
Authors: Ronsley Rebecca , Crotty Erin E , Vitanza Nicholas A , Stevens Jeffrey , Goldstein Hannah , Cole Bonnie , Ermoian Ralph , Leary Sarah E S
Published: June 2024

OBJECTIVE

To describe real-world outcomes in children with medulloblastoma treated with radiation-sparing chemotherapy in the USA.

METHODS

Clinical and molecular data were obtained from the Children’s Brain Tumor Network (CBTN), a multi-institutional collaboration to collect and freely share biological samples and longitudinal clinical data from consented patients. Patients with medulloblastoma treated with radiation-sparing regimens were included. Clinical data included patient demographics, stage, extent of resection, treatment regimen, and survival. Three-year overall survival (OS3) was calculated from diagnosis to death from any cause or last follow-up with log-rank p-value.

RESULTS

Eighty-one patients (56% male, median age 2.51 [range 0-7.44] years) with medulloblastoma (32% metastatic) were included. Molecular group was available for 36 (44%). Patients were treated according to protocols CCG99703 (n=26), ACNS0334 Arm A (n=13), ACNS0334 Arm B (n=30), PBTC026 (n=10), and ACNS1221 (n=2). Only 29 (36%) were enrolled on a therapeutic study. Seventy-two patients had median follow-up of 2.7 years (range 0.3-13 years). OS3 was 79+6; OS3 by molecular group was 90+9 in SHH (n=14), 55+14 in Group 3 (n=16), 56+25 in Group 4 (n=6). OS3 was 92+5 for 55 patients with localized disease versus 53+12 for 26 with metastasis (p=0.001); 86+6 for 55 patients with gross total resection versus 62+11 in 26 with partial resection or biopsy (p=0.03). OS3 was not associated with upfront radiation, 80+7 for 54 patients who received no radiation before relapse versus 78+9 for 27 who received radiation before relapse (21 focal, 6 craniospinal). OS3 was 87+8 for 30 patients on a methotrexate-containing regimen versus 74+7 for 51 without methotrexate (p=0.27). Five patients developed second malignancy.

CONCLUSIONS

CBTN data report real-world survival for young children treated with radiation-sparing approaches, most not enrolled on studies. Ongoing molecular characterization of the CBTN cohort will facilitate additional analysis to improve risk stratification and therapy selection for young children.
MDB-30. ZOLPIDEM, A PROMISING DRUG TO IMPROVE POSTOPERATIVE CEREBELLAR MUTISM SYNDROME (CMS): RETROSPECTIVE STUDY OF 19 PEDIATRIC PATIENTS WITH POSTERIOR FOSSA TUMORS
Authors: Quintero-Garcia Diannet , Añon Juan , Vazquez-Gomez Felisa , Moreno-Carrasco Jose Luis , Perez-Somarriba Marta , Castellano Serafin , Ippolito Hyaissa , Rivero Belen , Arce Begoña , De Caceres-Velasco Carmen , Cartas Susana , Esteso Borja , Galas Sebastian , Alonso-Garcia Isis , Mingarro Roser , Cantarín Veronica , Lassaletta Alvaro
Published: June 2024

INTRODUCTION

Postoperative Cerebellar Mutism Syndrome (CMS) affects up to 25% of patients undergoing surgeries for posterior fossa (PF) tumors. There is no established treatment for CMS, although zolpidem has become widespread after reporting remarkable responses in some cases. However, there is very limited scientific evidence, prompting us to document our experience with zolpidem.

OBJECTIVES

To evaluate the efficacy and safety of zolpidem in patients with postoperative CMS in PF tumors.

METHODS

Observational, descriptive, retrospective study conducted at our institution. Patients <21 years diagnosed with CMS following PF tumor surgery between 2011-2023 and treated with zolpidem were included. Demographic and clinical data, therapies, CMS scales, and outcomes were collected.

RESULTS

Nineteen patients met the criteria, 84% males, median age 8 years (range, 9 months-19 years), and median follow-up time 30 months (range, 2-126). Diagnoses included 58% medulloblastoma, 21% pilocytic astrocytoma, 10.5% ependymoma, 10.5% others. CMS mutism scale was rated mild, moderate and severe in 5%, 21% and 74%, respectively. Median zolpidem administration was 31 days (range, 2-241) and median maximum dose was 0.25 mg/kg/day (range, 0.10-0.90). Mutism scores improved in 37% (7/19), 53% (8/15) and 64% (9/14) of patients that received zolpidem for at least 48h, 7 and 14 days, respectively. Subjective improvement in communication and interaction was observed in 74% (14/19). Only three patients with mild somnolence and one with initial irritability and insomnia were reported.

CONCLUSIONS

To our knowledge, this is the largest study of patients treated with zolpidem for CMS. A considerable proportion of children improved their language abilities within the first 24-48h, but some patients may even benefit from more prolonged treatment. Most children showed an adequate tolerance with very few side effects. Further studies are urgently needed, preferably within a randomized clinical trial, to find the real efficacy, appropriate dosage, and duration of zolpidem.
MDB-37. RAC1 INHIBITION FOR THE TREATMENT OF MEDULLOBLASTOMA
Authors: Ayad Nagi , Jangde Nitish
Published: June 2024

Despite considerable advances in identifying genetic and epigenetic abnormalities in medulloblastoma, many patients succumb to the disease. In addition, patients who respond to traditional therapy suffer from cognitive and intellectual deficits. Therefore, there is a dire need to identify novel therapies for treating medulloblastoma. Rho family GTPases are targets in multiple cancers including medulloblastoma. Rho, Rac1 and Cdc42 are essential mediators of cell-cell adhesion and cellular motility signaling, which are dysregulated in medulloblastoma. These GTPases are involved in the regulation of the cytoskeleton, cell migration, cellular proliferation, and developmental signaling. The small GTPase Rac1 has recently been reported as a possible therapeutic target in SHH-medulloblastoma due to its regulation of Hedgehog signaling via the GLI1 and GLI2 transcription factors. We have recently reported that GLI1/GLI2 are in a novel complex that contains the epigenetic regulators UHRF1 and DNMT1. Therefore, Rac1 may play a previously unappreciated role in epigenetic regulation of medulloblastoma by controlling the GLI1/GLI2/UHRF1/DNMT1 complex. To test this, we have utilized a novel brain penetrant Rac1 inhibitor termed GYS32661. GYS32661 treatment of medulloblastoma cells inhibits the GLI1-UHRF1 interaction. Importantly this inhibition of the interaction occurs rapidly suggesting that it is disrupting an early event in SHH signaling. GYS32661 also inhibits actin polymerization suggesting that utilizing this compound may provide a dual mechanism of inhibiting Shh signaling and cellular migration concurrently. GYS32661 is not toxic in animal models and is approximately 50% brain penetrant and therefore is an important clinical candidate for the treatment of medulloblastoma. Our studies identify an essential link between Rac1, Shh signaling, epigenetics, and cellular migration in medulloblastoma.
MDB-40. DEFORMATION-HETEROGENEITY RADIOMIC MEASURES TO RISK-STRATIFY PEDIATRIC MEDULLOBLASTOMA PATIENTS: A PRELIMINARY ANALYSIS
Authors: Ismail Marwa , Um Hyemin , Salloum Ralph , de Blank Peter , Tiwari Pallavi
Published: June 2024

BACKGROUND

A significant challenge in medulloblastoma (MB), the most frequent malignant brain tumor in children, is to accurately identify ‘average-risk’ patients who may benefit from therapy de-escalation without affecting treatment outcomes, from ‘high-risk’ patients. Unfortunately, the current clinical risk-assessment approaches (Chang/molecular stratification) are sub-optimal in reliable risk-stratification in MB. This work evaluates the hypothesis that infiltration in aggressive tumors manifests as deformations (shifts) with larger magnitudes and positive orientations (angles) in the surrounding healthy tissue, on MRI scans, compared to average-risk tumors (smaller shift magnitudes and negative orientations). The proposed imaging marker, complementary with current approaches, may allow for more reliable risk-stratification.

METHODS

T1-weighted MRI scans of MB patients (2–18 years) were collected from Cincinnati Children’s Hospital Medical Center (Site1-training) (n=42) and Children’s Hospital Los Angeles (Site2-testing) (n=45). Preprocessing and annotations for the edema sub-compartment were performed. Scans were mapped to age-specific atlases using diffeomorphic registration and inverse transformations were employed to obtain the deformations. Deformation magnitudes (DefMag) were extracted within equidistant bands outside the edema by calculating the Euclidean norm of deformations, generating a magnitude statistics vector (median, skewness, kurtosis, mean, standard-deviation). Angles/Orientations (Defθ) were computed between deformation vectors and vectors connecting each voxel to the tumor’s centroid, then quantized to 6 intervals, creating an orientation vector per band. Deformation magnitudes and angles (DefMag+θ) were employed with Chang and molecular stratification within regression models for risk-stratification.

RESULTS

Our analysis demonstrated that deformation features, complementing molecular and Chang’s stratification, yielded best results for risk-stratification. Employing DefMag+θ+Chang+molecular on training yielded Concordance-index (CI) of 0.56, p=0.0014 (CI=0.6,p=0.03 testing). DefMag+θ+Chang’s yielded CI=0.64, p<0.0001 on training (CI=0.54,p=0.04 testing). Results were not significant when employing Chang’s or molecular classification alone.

CONCLUSIONS

Our results suggest that radiomic deformation features, complementing clinical and molecular approaches, may enable reliable risk-stratification in pediatric MB.
MDB-41. TARGETING PBK IN GROUP 3 MEDULLOBLASTOMA
Authors: Shahab Shubin W , Kenney Anna M , MacDonald Tobey J
Published: June 2024

BACKGROUND

Group 3 medulloblastoma (MB) remains a challenging diagnosis especially due to a tendency for higher prevalence in infants and to develop frequent relapse. Targeted therapy remains elusive for these patients due to a lack of targetable alterations as well as poor understanding of driver mutations. PBK/TOPK has previously been identified as a hub gene in medulloblastoma and we have recently demonstrated that the LIN28B-PBK axis may be playing a crucial role in Group 3 MB development.

METHODS

Here we utilize transcriptomic profiling to identify pathways regulated by PBK in Group 3 MB to help identify potential vulnerabilities, immunofluorescence and cell viability analysis to calculate drug synergy.

RESULTS

Our analysis demonstrates that PBK knockdown leads to significant down regulation of cell cycle pathway genes. We also demonstrate that combining PBK inhibitor HI-TOPK-032 with the CDK 4/6 inhibitor palbociclib is synergistic in Group 3 MB cells.

CONCLUSION

Our investigations suggest PBK inhibition alone or in combination with other targeted agents may be a useful addition to existing therapy for these hard to treat cancers.
MDB-71. IDENTIFICATION AND DESCRIPTION OF A NOVEL TYPE OF MEDULLOBLASTOMA
Authors: Eckhardt Alicia , Meulenbroeks Chris , Geisemeyer Neal , Bockmayr Michael , Hack Karoline , Sönksen Marthe F , Thomas Christian , Schoof Melanie , Koch Arend , Green Sage , Doss David , Guney Ekin , Perry Arie , Frank Stephan , Kuzman Peter , Ratliff Miriam , Suwala Abigail , Rutkowski Stefan , Hasselblatt Martin , Taylor Michael D , Jones David , Kool Marcel , Schüller Ulrich
Published: June 2024

BACKGROUND

Medulloblastoma (MB) is one of the most frequent high-grade brain tumor types of childhood and adolescence. Based on biology, histology, and its clinical course, MB is a heterogeneous disease with four different molecular types (WNT, SHH, Group 3, and Group 4), which are most reliably distinguishable by their global DNA methylation pattern.

METHODS

We analyzed DNA methylation (n=47), copy number variants, transcriptomic data (n=7) and histology (n=28) of a previously unrecognized type of MB.

RESULTS

As a result of integrating DNA methylation data of >2,600 MB and screening of >140,000 data sets uploaded to the DKFZ brain tumor classifier (www.molecularneuropathology.org), we identified a small group of MB that displayed a homogeneous DNA methylation pattern, which was clearly distinct from previously known MB types. Tumors within this group have also been recognized as a separate methylation class by latest versions of the classifier, which has provisionally been named medullomyoblastoma (MB_MYO). Transcriptomic data were similarly distinct from other MB types. Comparison of these data to various cell types of the developing hindbrain revealed transcriptional similarities to precursor cells of the rhombic lip with signatures of WNT signaling and myogenic differentiation. In line with the latter findings, 2/11 cases with DNA sequencing data harbored hotspot CTNNB1 mutations and 5/28 cases showed a myogenic differentiation based on histology. MYC amplifications were present in 11/47 cases, corresponding to a higher fraction of MYC-amplified tumors compared to all known MB types. Median age at diagnosis in this cohort was 16 years, and five-year overall survival was ~75 %.

CONCLUSIONS

In summary, we describe a novel type of MB identified by DNA methylation profiling that likely needs to be addressed separately during the retrospective analyses of MB patient cohorts, for the design of future clinical trials, and when evaluating targeted therapies.
MDB-100. RETROSPECTIVE ANALYSIS OF CUMULATIVE DOSING OF CHEMOTHERAPY AGENTS AND THE EFFECT ON SURVIVAL IN PATIENTS WITH AVERAGE RISK MEDULLOBLASTOMA TREATED ON CHILDRENS ONCOLOGY GROUP STUDY ACNS0331
Authors: Wright Erin N , Billups Catherine , Li Yimei , Rush Sarah , Salloum Ralph , de Blank Peter
Published: June 2024

BACKGROUND

Although survival outcomes for average risk (AR) medulloblastoma remain good, patients may experience significant acute and long-term toxicities from therapy. To evaluate the effect of dose modifications among children with AR medulloblastoma, we examined the effect of cumulative chemotherapy dose on overall and event-free survival.

METHODS

We retrospectively examined the association between the proportion of scheduled chemotherapy dose received on survival outcomes (OS and EFS) using Cox regression models and log-rank tests for patients treated on ACNS0331. We evaluated all chemotherapy agents for the group as a whole and within the four major subgroups. Dose intensity was analyzed continuously and categorically (>75% or <75% of planned dose) for each agent.

RESULTS

274 evaluable children (medulloblastoma by methylation, received standard dose craniospinal radiation and chemotherapy) were followed for a median of 9.3 years (range, 7.0-10.4 years). Vincristine and cisplatin showed the most variable dose intensity (25.2% and 31.8% of patients received <75% of expected dosing, respectively). Cyclophosphamide and lomustine were not examined due to low dose variability (17.2% and 11.7%, respectively). The effect of dose intensity was evaluated in 235 patients who completed planned therapy. Molecular subgroup remained a significant predictor of outcome in AR medulloblastoma (EFS (p=0.012) and OS (p=0.008)). Although survival curves were lower for less dose intense treatments, no significant difference in EFS or OS was found due to reduced dose intensity for vincristine (p=0.36 EFS, p=0.35 OS) or cisplatin (p=0.49 EFS, p=0.52 OS). The hazard ratio [95% confidence interval] for chemotherapy proportion and EFS was 0.998[0.977-1.019] (vincristine) and 0.989[0.966-1.012] (cisplatin). There was no difference in the effect of dose reductions by molecular subgroup.

CONCLUSIONS

Moderate reductions in vincristine and cisplatin dose intensity do not significantly affect survival in AR medulloblastoma. It is unknown whether this reduction would reduce chemotherapy-related toxicity.
MDB-102. CDK8 IS A DEPENDENCY IN GROUP 3 MEDULLOBLASTOMA AND COMBINES WITH BET BROMODOMAIN INHIBITION
Authors: Terrones Isabella , Jagana Hawa , Hathaway Matthew , Hemenway John , Rajendran Ashmitha , Conrad Jay , Evans Myron
Published: June 2024

Medulloblastoma (MB) is the most common pediatric CNS malignancy with varying prognoses depending on subgroup diagnosis. Group 3 MB displays the poorest overall prognosis, specifically in cases characterized by MYC hyperactivation. Current standard treatment can cause lifelong debilitating side effects, therefore the identification of targeted therapeutic agents will be critical in enhancing patient survival and bypassing therapy-induced aftereffects. We utilized the Pediatric Cancer Dependency Map to identify CDK8 as the most striking dependency in MB compared to all other pediatric malignancies. Further analysis revealed dependencies on its cognate cyclin, Cyclin C, and other members of the CDK8 kinase module (CKM). The CKM functions as a transcriptional regulator, phosphorylating RNAPol2 and other transcription factors. Interestingly, CDK8 dependency correlates with MYC amplification status in cell lines suggesting it to be a strong dependency in G3 MB. CDK8 expression, both RNA and protein, is highest in G3 tumors. We depleted CDK8 both genetically and pharmacologically and demonstrated downregulation of MYC expression in tumor cells and decreased cell survival. We next tested the efficacy of a CDK8 kinase inhibitor currently in clinical trials. Treatment with SEL-120 reduced cell proliferation and viability in vitro and inhibited tumor growth in vivo. This effect was limited to G3 models, as SEL120 showed little efficacy in SHH MB. Analysis of gene expression revealed that targeting CDK8 did not affect MYC-dependent gene expression but led to de-repression of differentiation genes regulated by PRC2. We further observed a global de-repression of H3K27me3 in cells treated with CDK8i. Finally, we tested the first ever blood-brain barrier penetrant CDK8i which mimics the activity of SEL-120 and potently synergizes with BETi, which antagonizes MYC signaling. In summary, we have identified and validated CDK8 as a novel target in G3 MB and identified a possible synergistic combination to move forward in clinical trials.
MDB-105. CONSTRUCTION OF AN INTERACTIVE MEDULLOBLASTOMA VISUALIZATION PORTAL FROM MOLECULAR AND CLINICAL DATA DERIVED FROM THREE MULTI-INSTITUTIONAL PROTOCOLS (ACNS0331, SJMB03, ACNS0332) TO COMPARE, CONTRAST, AND INVESTIGATE COHORTS AS A MEANS TO REFINE THERAPY
Authors: Robinson Giles W , Dhanda Sandeep K , Lu Congyu , Sioson Edgar , Gangwani Karishma , Peraza Airen Zaldivar , Li Qian , Smith Kyle S , Billups Catherine , Onar-Thomas Arzu , Northcott Paul A , Zhou Xin
Published: June 2024

BACKGROUND

Medulloblastoma (MB) patients display a heterogeneous mix of molecular and clinical characteristics that influence tumor behavior and survival. We hypothesized that if these multiple characteristics could be incorporated into an organized, searchable, and interactive dataset, this would advance our understanding and improve treatment of this disease. Consequently, we organized multifaceted datasets into an interactive portal equipped with cutting-edge visualization tools.

METHODS

Clinical and molecular data from the ACNS0331, SJMB03, and ACNS0332 protocols were collated and harmonized. A data dictionary was built to capture demographics, treatment, histology, methylation classification, mutations, chromosomal copy number variations and outcomes. To display the data, a software framework was applied. Five visualization methods were implemented (summary plots, sample view, scatter plots, sample matrix, and survival plots) in an interconnected manner such that these “cross-talk” with each other.

RESULTS

Data from 898 patients with MB were incorporated: 131 WNT, 151 SHH, 220 G3, 396 G4. The portal features enabled the creation of custom cohorts that could be instantly queried by any of the dictionary terms. For example, cohorts could be customized to include only cases with a mutation of the user’s choice and analyzed by molecular group, gender, age at diagnosis, or treatment given. Survival of patients with SHH-MB harboring TP53 mutations could be compared to patients with WNT-MB harboring TP53 mutations. Moreover, the influence of MB subtype (e.g. G34_I-VIII), focal amplifications (MYC, MYCN) and whole chromosome aberration phenotype on survival could be queried across treatment regimens accounting for metastatic status and/or additional variables of the user’s choice.

CONCLUSION

The integration of molecular and clinical data from multiple trials into an interactive visualization data portal presents an unprecedented resource for research and clinical practice. This portal facilitates answering highly specific questions about mutational frequency and patient outcome by molecular and clinical risk factors.
MDB-108. MRI-GUIDED FOCUSED ULTRASOUND BLOOD BRAIN/TUMOR BARRIER DISRUPTION FOR AUGMENTATION OF ANTIBODY DELIVERY TO HIGH-RISK MEDULLOBLASTOMAS
Authors: Maslova Stefanyda , Demir Zehra , Sherlock Thomas , Ak Beyzanur , Yaacoub Serge , Haydar Dalia , Sheybani Natasha
Published: June 2024

BACKGROUND

Medulloblastoma is the most common pediatric brain cancer, and among its four molecular subgroups, group 3 (G3MB) harbors the worst prognosis (5-year survival rate <50%). Effective treatment of G3MB remains difficult due to disease complexity, its challenging niche within the immunologically- and pharmacologically-privileged central nervous system, and significant risk of long-term developmental deficits due to treatment toxicities. MRI-guided focused ultrasound (MRgFUS) holds the potential to revolutionize care as a non-invasive, non-ionizing approach for spatially precise intervention in G3MBs. Given that the utility of FUS in MBs remains unknown, we implemented FUS-mediated blood brain/tumor barrier disruption (BBB/BTB-D) in a high-fidelity model of G3MB and evaluated its impact on localized antibody delivery – with an eye toward future applications in immuno-oncology.

METHODS

An orthotopic syngeneic model was established via stereotactic implantation of G3MB cells (Gfi1/c-MYC driven) into the cerebellum. G3MB growth kinetics were validated via serial MRI. Multiple protocols for naive cerebellum or G3MB BBB/BTB-D were established with a 1.15 MHz FUS system under 9.4T MRI guidance. Across both settings, mice were sonicated with concomitant intravenous administration of microbubbles and fluorescently-labeled IgG. Safety was confirmed by acoustic emissions monitoring, susceptibility-weighted imaging, histology, and acute activity monitoring. Antibody delivery was evaluated via ex vivo epifluorescence imaging.

RESULTS

Post-contrast T1w-MRI depicted clear evidence of localized BBB/BTB-D in naive and G3MB mice. No damage was noted by imaging or histopathologic analysis, and mice displayed normal cardiorespiratory and motor functions following FUS. FUS conferred significantly increased epifluorescence signal in targeted cerebellum (1.3x) and G3MBs (1.5x) relative to controls, indicating improved antibody access.

CONCLUSIONS

Our findings support the safety and feasibility of FUS BBB/BTB-D in naive and G3MB-bearing cerebellum. We demonstrate that FUS markedly improves antibody penetrance within G3MBs. Ongoing studies are evaluating FUS in combination with novel immunotherapeutic antibodies for G3MB therapy.
NFS-02. MEDULLOBLASTOMAS WITH ELP1 PATHOGENIC VARIANTS: A WEAKLY PENETRANT SYNDROME WITH A RESTRICTED SPECTRUM IN A LIMITED AGE WINDOW
Authors: GUERRINI-ROUSSEAU Léa , Masliah-Planchon Julien , Filser Mathilde , Tauziede-Espariat Arnault , Entz-Werle Natacha , Maugard Catherine , Hopman Saskia , Torrejon-Diaz Jacob , Gauthier-Villars Marion , Simaga Fatoumata , Blauwblomme Thomas , Beccaria Kevin , Rouleau Etienne , Dimaria Marina , Grill Jacques , Abbou Samuel , Claret Béatrice , Brugières Laurence , Doz François , Bouchoucha Yassine , Faure-Conter Cécile , Bonadona Valerie , Mansuy Ludovic , de Carli Emilie , Ingster Olivier , Legrand Clémentine , Pagnier Anne , Berthet Pascaline , Bodet Damien , Julia Sophie , Bertozzi Anne-Isabelle , Wilems Marjolaine , Maurage Claude-Alain , Delattre Olivier , Ayrault Olivier , Dufour Christelle , Bourdeaut Franck
Published: June 2024

BACKGROUND

Medulloblastomas (MB) Sonic hedgehog (SHH) subtype are associated with a cancer predisposition syndrome (CPS) in about 15% of cases, the most frequent being related to ELP1 pathogenic variant (PV). The aim of our study is to better evaluate penetrance of this CPS and detail the characteristics of the related tumors.

METHODS

Twenty-nine ELP1-mutated MB identified in France were retrospectively reviewed. Molecular characteristics of the tumor and clinical features of the patients were collected; whenever possible, the germline DNA from patients and their relatives were sequenced.

RESULTS

All patients (sex ratio 16/13) presented with SHH-MB, mostly nodular desmoplastic (n=20/28), between 3 and 15 years of age (median 7.3). All mutations are found in the germline when a constitutional DNA sample was available (n=26). Most tumors (93%) showed a biallelic inactivation of PTCH1, other recurrent alterations concerned the TP53 pathway (including 1 somatic TP53 VP) and activation of MYCN/MYCL signaling. We observed that ELP1-mutated MB behave as sporadic cases, with similar distribution within clinical and molecular risk groups of MB, similar outcomes (5y-OS = 85%) and no unusual side effects of treatments. Three patients developed a second tumor (2 high-grade gliomas and 1 thyroid carcinoma) within the irradiation fields. All germline PV were inherited from one asymptomatic parent (11 trio). No specific morphological features were mentioned. Only two index cases from the 29 French patients had a previous familial history of MB (occurring in a cousin), with many asymptomatic carriers. Except the MB, no other cancer was significantly associated with the ELP1 PV.

CONCLUSIONS

the low penetrance, the ‘at risk’ age window limited to childhood and the narrow tumor spectrum, question the actual benefit of genetic screening in these patients and their family. Our results suggest restricting ELP1 germline sequencing to patients with MB, depending on the parents’ request.
NFS-14. INTERCEPTION TREATMENT STRATEGY FOR INCIDENTAL LESIONS IN CHILDREN, ADOLESCENTS AND YOUNG ADULTS (AYA) USING LASER INTERSTITIAL THERMAL THERAPY (LITT)
Authors: Nguyen Rita H , Guadix Sergio , Donzelli Maria , Sanders Colleen , Rosenblum Marc K , Bale Tejus A , Greenfield Jeffrey P , Souweidane Mark M
Published: June 2024

BACKGROUND

Due to widespread availability and lower threshold for neuroimaging, incidental brain lesions have increased. When a high index of suspicion exists for a neoplastic process, early treatment might be beneficial. This is appealing in cases of tumor predilection such as cancer predisposition syndromes or history of therapeutic irradiation. LITT may provide a means for total tumor extirpation in these otherwise surgically inaccessible lesions and intercept eventual anatomic or pathologic evolution. The aim of this study is to evaluate our evolving experience based on an early and minimally invasive strategy using LITT.

METHODS

Prospective review of pediatric and AYA patients in whom incidentally discovered lesions were treated with simultaneous stereotactic biopsy and LITT. Demographic data, presenting symptoms, adverse events and outcomes are reviewed.

RESULTS

Mean age for 9 patients is 11.8 years. 4 patients had tumor predilection: 2 with familial tumor predisposition syndrome and 2 history of cranial-sirradiation. In 4 patients imaging was performed for surveillance of other brain tumor or focal cortical dysplasia. 3 patients had imaging for headache. Mean time from initial finding to treatment was 29.7 months. Recommendation to proceed with treatment was due to interval growth, concerning features (contrast-enhancement), or high potential for malignant transformation. 1 patient had facial weakness and 1 patient had visual field deficit that resolved. Pathological diagnoses revealed low-grade tumor in 4 patients and non-diagnostic pathology in 5. No patients received additional tumor-directed therapy during a mean follow-up of 14.7 months. There was no evidence of tumor recurrence in any patient.

CONCLUSION

An early therapeutic strategy aimed at tumor interception is feasible in pediatric and AYA patients for incidental lesions. Early results might influence the design of future strategies for simultaneous or sequential diagnostic and thermal therapy. Evolving tumor control rates support the therapeutic potential of LITT in central, surgically-inaccessible incidental tumors.
NFS-15. SPECIFIC FOR NF1, BASED ON SOCIAL COGNITION DEFICITS, MALADAPTIVE BEHAVIORS AS RISK FACTORS OF DIFFICULTIES IN THE SOCIO-EMOTIONAL FUNCTIONING
Authors: Korzeniewska Justyna
Published: June 2024

BACKGROUND

The neurocognitive effects of NF1 include social cognition deficits, which are significant, because cause cognitive and social functioning. Social cognition is defined as cognitive processes related to the perception and understanding of cues in the environment that communicate social and interpersonal information and the ability to use those cues to interpret the thoughts and reactions of others and to modify one’s own behaviors to fit the social context. The purpose of the study was to describe cognitive deficits and behavioral phenotype of NF1, as well as looking for connections between deficits of social cognition and socio-emotional status in NF1.

METHODS

Psychological repeated testing and long-term observation was performed in 100 patients with NF1. Age at psychological diagnosis: 3 - 18 years. Full psychological outcome assessed cognitive, verbal and affective problems associated with manifestations of NF1. The patients were examined using battery of neuropsychological methods, psychological interview and analysis of medical history. For research of social functioning used subscales of Vineland Adaptive Behavior Scales (VABS-II) and Child Behavior Checklist (CBCL). We assessed also maladaptive behavior as a risk of social rejection. The main point of the assessment was to discover link between social cognition and challenging behaviors.

RESULTS

In the sample of patients with NF1 we observed specific social difficulties associated with emotional disturbances and social rejection. This specific behavioral phenotype and social cognition deficits disturbed learning process and their social life. Patients with NF1 were distinctly ineffective in interpersonal communications and establishing relations in the peer group as well as following the rules of social convention.

CONCLUSIONS

The results of our study suggest that social cognition deficits, are responsible for socio-emotional status of patients with NF1. Draft recommendations for diagnosis of specific emotional problems typical for NF1 and program of social development stimulation in NF1 will be presented and discussed.
NFS-16. NOVEL AUSTRIAN CARE AND PREVENTION GUIDE FOR CHILDREN AND ADOLESCENTS WITH NF1
Authors: Azizi Amedeo A , Baumgartner Alicia-Christina , Hedrich Cora , Seidl Markus , Zobel Joachim , Ebetsberger-Dachs Georg , Zellner Herta , Rauscher Christian , Birnbacher Robert , Pichler Ursula , Haberlandt Edda , Bergmeister-Berghoff Anna Sophie , Gruber Robert , Welponer Tobias , Hutterer Markus , Pletschko Thomas , Krottendorfer Kerstin , Röhl Claas
Published: June 2024

BACKGROUND

Unified strategies for the care of children and adolescents affected by Neurofibromatosis type 1 (NF1) are lacking in Europe. While ERN GENTURIS developed guidelines for the tumour surveillance and management in NF1, these recommendations do not cover all other aspects of the disease. This holds not only true on an international level, but also on the national level in Austria. Despite being a small country with a uniform health and social security system, approaches to patient care may be comparable but not identical.

AIM

In order to standardise and improve patient care for children with NF1 in Austria, a care and prevention sheet was developed.

METHODS

In close cooperation with the Austrian patient organisation NF Kinder the Austrian NF network was established. This network is composed of dedicated health-care providers (medical as well as psychosocial) involved in the care of patients with NF1 in ten Austrian centres as well as patient representatives, some of whom were also involved in drafting the novel ERN GENTURIS recommendations. This network undertook the task of reviewing existing guidelines and incorporate the national healthcare structure and best practice guidelines into a consensus document.

RESULTS

The recommendations were condensed into a single sheet that is divided in four sections: clinical examination, lab investigations, imaging, additional consultations. For each parameter, the document advises on the age specific intervals for screening. Furthermore, it indicates the appropriate time points during follow-up (e.g. at initial presentation, at transition, if clinically indicated, …). The recommendations thereby focus not only on the inherent tumour risk but address the broad spectrum of possible symptoms (such as orthopaedic or surgical), specifically emphasising also psychosocial and neurocognitive issues.

CONCLUSION

The novel Austrian care and prevention guide for children and adolescents with NF1 will facilitate uniform best practice care for affected kids on a national level
NFS-17. CORRELATIONS BETWEEN OPTICAL COHERENCE TOMOGRAPHY AND MAGNETIC RESONANCE IMAGING IN NEUROFIBROMATOSIS TYPE 1 – RELATED OPTIC PATHWAY GLIOMAS
Authors: Piccolo Gianluca , Luongo Ilaria , Parodi Costanza , Camicione Paola , Carlini Luca , Chelleri Cristina , Severino Maria Savina , Serafino Massimiliano , Molteni Marta , Striano Pasquale , Diana Maria Cristina
Published: June 2024

BACKGROUND

Optic pathway glioma (OPG) is a prevalent tumor affecting children with Neurofibromatosis type 1 (NF1), representing a diagnostic hallmark. OPGs, typically WHO grade 1 pilocytic astrocytomas, are characterized by an indolent course. Diagnosis and surveillance traditionally rely on Magnetic Resonance Imaging (MRI). Routine NF1 pediatric surveillance includes annual eye examinations, encompassing visual acuity (VA) and Optical Coherence Tomography (OCT), with MRI reserved for ophthalmological abnormalities. However, the precise correlation between altered OCT findings and OPG presence or size remains unclear, while the role of MRI in screening is contentious due to cost and anesthesia requirements.

METHODS

In this retrospective study, we sought to establish correlations between OCT changes and MRI-observed tumor volume in NF1-diagnosed children at a tertiary center. Clinical and ophthalmological data, including VA, fundoscopy, and OCT, were collected. Tumor volumes were assessed using the software Sophia DDMTM for Radiomics in two consecutive MRI scans in a randomly selected cohort of 50 untreated patients.

RESULTS

Among 409 NF1 patients, 132 (31%) were diagnosed with OPG (48% females = 64), revealing a significant association with plexiform neurofibroma (pNF) (p=0.03), thus indicating an elevated risk of concurrent tumor development. In the subcohort of patients in whom volumetric analysis was performed, the mean age at OPG diagnosis was 5.56 ± 3.59 years. While tumor volume on MRI correlated with VA (p=0.0007), OCT values did not: larger OPGs did not consistently result in thinner retinal nerve fiber layers, suggesting independence between OCT alterations and OPG size.

CONCLUSIONS

The observed lack of correlation among VA, retinal thickness (OCT), and tumor volume (MRI) underscores the importance of MRI as the gold standard for diagnosis. The strong association between pNFs and OPGs suggests considering whole-body MRI when an OPG is detected, facilitating comprehensive evaluation in NF1 patients.
NFS-30. ADJUVANT MEK INHIBITION TO PREVENT REBOUND GROWTH FOLLOWING PARTIAL RESECTION OF PLEXIFORM NEUROFIBROMAS
Authors: Chan Priya P , Hemenway Molly S , Sabus Ashley , Hrycaj Emily , Dahl Nathan A , Domeshek Leahthan F , French Brooke M , Foreman Nicholas K
Published: June 2024

BACKGROUND

Plexiform neurofibromas (PNs) are benign peripheral nerve sheath tumors that occur in patients with neurofibromatosis type I. These tumors can cause significant morbidity leading to functional impairment, pain, and disfigurement. Management of PNs is challenging. Complete surgical resection is often not possible due to tumor growth along vital structures, and rebound growth is frequently experienced following subtotal resection (STR) of PNs. The mitogen-activated protein kinase (MAPK) pathway has been implicated in the growth of PNs, and the use of MAPK enzyme (MEK1/2) inhibitors has been shown to be an effective therapy in the treatment of PNs. Herein, we described our institutional experience using a short course of adjuvant MEK1/2 inhibitors in the treatment of pediatric patients with PNs following STR to prevent rebound growth.

METHODS

A single-institution retrospective record review of pediatric patients who underwent STR of their PN.

RESULTS

A total of 35 patients with 39 separate PNs had STR of their PNs. Fourteen PNs were treated with resection alone and 25 PNs were treated with a six-month course of adjuvant MEK1/2 inhibitors following STR. The number of patients requiring additional treatment with surgical resection or medical therapy was 11 of 14 patients (79%) in the resection only group and 6 of 25 patients (24%) in the adjuvant MEK1/2 inhibitor group. The mean time to additional treatment for the resection only group was 22 months, and the mean follow-up time for patients receiving adjuvant MEK1/2 inhibition was 29 months. Skin rash was the most common adverse effect seen with adjuvant MEK1/2 inhibition, and one patient experienced a dose-limiting thrombus.

CONCLUSIONS

A short course of MEK1/2 inhibitors following STR of PNs is effective in the short-term in preventing rebound growth when compared to STR alone. Treatment is well tolerated and should be considered as adjuvant therapy in pediatric patients.
QOL-07. EFFICIENT NEUROPSYCHOLOGICAL ASSESSMENT IN PATIENTS WITH BRAIN TUMORS AND ACUTE LYMPHOBLASTIC LEUKEMIA
Authors: Hausmeister Ivana Kreft , Hafner Sandra Klašnja , Uršič Katarina , Gosar David , Kitanovski Lidija
Published: June 2024

BACKGROUND

Children treated for cancer may experience a decline in performance for a variety of reasons, one of which is the impact of treatment. Children treated for leukemias and brain tumours are at the highest risk of developing neurocognitive sequale (Daly and Brown, 2015).

METHODS

In our study we used Bayesian regression to identify assessment tools that would best predict the sequale of brain tumors (BT) and acute lymphoblastic leukemia (ALL) in children and adolescents. Using data from 15 patients with BT, 15 patients with (ALL) and 9 siblings controls we compared the predictive validity of the Wechsler Intelligence Scales for Children (WISC-V), Delis-Kaplan Executive Function System (D-KEFS), Continuous Performance Test (CPT-3), the Developmental Neuropsychological Assessment (NEPSY-II) and the parent and teacher report forms of the Achenbach Assessment System (ASEBA).

RESULTS

We found that the best predictors of ALL were d’ scores on the CPT (BF = 20.69, pd =.05) and CPT ommission scores (BF = 17.50, pd =.05), while the best predictor a BT was the WISC-IV Coding subtest (BF = 21.17, pd =.05) in addition to CPT omission scores (BF = 12.00, pd =.08) and HRT SD scores (BF = 11.91, pd =.08). CPT d’s scores were also predictive of Methotrexate treatment (MTX) (BF = 32.61, pd = 0.03), as were WISC-V Symbol Search scores (BF = 32.61, pd = 0.03) and the NEPSY-II Auditory Attention subtest (BF = 26.06, pd = 0.04). We also noted differential sensitivity of the ASEBA teacher report form for detecting deficits identified during the neuropsychological assessment.

CONCLUSIONS

We feel our findings will, together with previous meta-analyses, contribute to more efficient neuropsychological assessment in patients with BT and ALL. Neuropsychological asseessment is vital for identifying potential sequale of disease and treament in pediatric oncology.
QOL-17. LIFE AFTER PAEDIATRIC LOW-GRADE GLIOMA: THE SURVIVOR NARRATIVE. QUALITATIVE INTERVIEWS OF ADULT PLGG SURVIVORS
Authors: Green Katie L , Leyden Deirdre , Hargrave Darren , Bluebond-Langner Myra
Published: June 2024

BACKGROUND

Most patients with PLGG will survive, but long-lasting functional & Quality of Life (QOL) impairments can occur. No PLGG survivorship research has yet included individual survivor narratives. The true impact of the tumour & its treatment on lived experiences from the survivor perspective remains to be explored.

AIMS

To evaluate PLGG survivor narratives across a heterogeneous group of adult survivors atleast 5 years from PLGG treatment.

METHODS

An interview guide was created comprising topics around survivors’ past and present experiences and hopes for the future. Open-ended semi-structured interviews were completed with adult survivors diagnosed with PLGG at Great Ormond Street Hospital, UK, 1980-2005. Video interviews were completed on zoom with the same interviewer, and recordings dictated verbatim to transcripts for Framework Analysis(FA). The codebook for analysis was created according to prior literature & themes emerging within and across the transcripts.

RESULTS

10 of 26 (38%) eligible survivors (median age 21.5yrs) completed interviews 28-73 minutes long. Median duration 12 years from diagnosis (9-18yrs). FA comprised 18 codes categorised into 4 major themes: The Self, The Social World, Experiences Of A PLGG, & Survivorship. Interviews allowed novel identification that seizures universally contributed long-lasting trauma and mental health disturbance. They also demonstrated that personality, adaptation to a new normal, and both the social & practical support received significantly influenced the impact of objective functional deficits on perceived QOL.All 10 survivors directly reported considering themselves to continue to be functionally affected by their PLGG as an adult.

CONCLUSIONS

We provide novel first-hand accounts of adult PLGG survivors, representing an important first-attempt at incorporating the survivor narrative and lived experiences as a core component of the evaluation of PLGG survivor outcomes. The narrative accounts allowed us to gain a more in-depth understanding of life for PLGG survivors; and allowed identification of new themes and topics not identified by PedsQl or similar quantitative QOL instruments.
QOL-22. PARTICIPATION RESTRICTIONS IN DAILY LIVING ACTIVITIES IN CHILDHOOD CANCER SURVIVORS ACCORDING TO BODY COMPOSITON: A DOUBLE-CENTER STUDY
Authors: Tanrıverdi Müberra , Yıldırım Kardelen , Yılmaz Güleser Güney , Şahin Sedef , Çakır Fatma Betül
Published: June 2024

BACKGROUND

Impact of cancer and treatment adverse effects on daily living activities in childhood cancer survivors (CCS) are well known. In our study, we hypothesized that the participation in daily living activities is affected in CCS.

METHODS

Fifty-eight CCS (10.07±3.83 years) in the 3-97th percentile range were included in the study. Participation of CCS was evaluated by Pediatric Outcomes Data Collection Instrument (PODCI). Body compositions of CCS were grouped according to body mass index (BMI).

RESULTS

The mean z score was.64±3.22 and BMI was 17.76±3.56. The global functioning score was 80.25±15.23, upper extremity score was 86.52±12.09, transfer and basic mobility score was 92.17±10.95, sports and physical functioning score was 71.31±25.70, pain/comfort score was 72.37±23.31, and happiness score was 81.31±19.19 of PODCI. While there was no relation between PODCI global functioning score and age chemotherapy, surgery (p>0.05); there was a significant relationship between PODCI global functioning score and gender, body mass index, radiotherapy (p<0.05). The significant functional difference detected between these groups was in upper extremity, transfer basic mobility, happiness, and global functioning (p<0.05). There were no differences between the sports and physical functioning and pain/comfort (p>0.05) according to the BMI categories (underweight, normal/healthy, and overweight).

CONCLUSIONS

Survivors have participation restrictions in activities at earlier period of cessation of treatment. Patient-reported outcomes can be systematically assessed in CCS. We recommend that supportive interventions in terms of physical functioning and participation in daily living activities for CCS.
QOL-25. DETERMINING THE BURDEN OF SLEEP PATHOLOGY AMONG PEDIATRIC NEURO-ONCOLOGY PATIENTS
Authors: Yeh-Nayre Lanipua , Elster Jennifer , Sridhar Sunita , Paul Megan
Published: June 2024

BACKGROUND

Children with brain and spinal cord tumors are at higher risk for sleep disruption. The incidence and characteristics of sleep difficulties in this population is not well understood. Our aim is to use survey and chart review to retrospectively and prospectively evaluate the frequency, severity, and types of sleep difficulties experienced by pediatric patients who have brain and spine tumors.

METHODS

Pediatric patients with a diagnosis of a brain or spinal cord tumor and their parents were surveyed at three time points during routine visits with their neuro-oncology team. Parents and children completed the following self-reported standardized surveys: The San Diego Pediatric Sleep Survey (Child) and The San Diego Pediatric Sleep Survey (Parent).

RESULTS

Identified sleep disturbances include difficulty initiating sleep, excessive movement while asleep, increased incidence of nocturnal awakening, and snoring. We identified high rates of behavioral and environmental modifiers of sleep quality including sleeping in a shared bed with another family member and poor sleep hygiene.

CONCLUSIONS

Identification of sleep disruption and factors contributing to sleep difficulties in this high risk population will encourage proactive screening and recognition of these issues in future patients. Next steps include implementation of interventions such as referral to appropriate specialists, sleep hygiene modification, and parent/patient education. Early intervention may lead to overall improvement in quality of life and health, including increased academic success and job productivity in children and their caregivers.
QOL-34. POST-TRAUMATIC GROWTH AND COPING STRATEGIES AMONG ADOLESCENTS AND YOUNG ADULTS SURVIVORS OF PEDIATRIC BRAIN TUMORS
Authors: De Giuseppe Sara , Milanaccio Claudia , Verrico Antonio , Piccolo Gianluca , Molteni Marta , Robotti Sabrina , Venturino Cristina , Garrè Maria Luisa , Profio Sonia Di
Published: June 2024

BACKGROUND

Pediatric brain tumor survivors (PBTS) often report late psychosocial effects following the disease and the treatments. Recent studies have shown that PBTS can experience growth in their personal and interpersonal dimensions and develop coping strategies that allow them to deal with the stress caused by cancer diagnosis and subsequent therapies. This study aimed to describe post-traumatic growth (PTG) experiences and coping strategies among adolescents and young adults (AYA) survivors of pediatric brain tumors.

METHODS

AYA survivors were assessed using Post-Traumatic Growth Inventory (PTGI) and Coping Inventory for Stressful Situations (CISS) questionnaires. They received evaluation at a median age of 20.2 years (range 13.6-28.7), with a median of 92 months from diagnosis.

RESULTS

Among 22 AYA survivors (M =14; F=8), the diagnosed tumor types were: germ cell tumor (10/22), low-grade glioma (4/22), embryonal tumor (3/22), high-grade glioma (2/22), craniopharyngioma (2/22), and mesenchymal tumor of the meninges (1/22).The domains of PTG in which positive changes were most frequently reported were Personal Strength (25%), Appreciation for Life (25%), and New Possibilities (23%). The less impacted domain was Spiritual Growth (9%). As regards the most adopted coping style, 38% showed higher values in the Distraction scale, 31% in the Task-Oriented scale, 15% in the Avoidance scale, and 15% in the Social Diversion scale.

CONCLUSIONS

PTG and coping are important indicators of psychosocial adaptation to difficult or stressful events. To develop specific interventions that enhance PTG, it is essential to understand which factors influence growth in PBTS. Our preliminary data show that all AYA survivors report PTG after treatments, at least in some domains. Further analysis is needed to identify which coping styles may influence the development of PTG.