bluuebunny/crossref_metadata_2025 huggingface dataset:
NFS-23. ASSOCIATION OF LOCALIZED MAGNETIC RESONANCE IMAGING FEATURES IN ANTERIOR VISUAL PATHWAY WITH VISUAL ACUITY LOSS AMONG CHILDREN WITH NF1-OPG
Authors: Jiang Zhifan , Parida Abhijeet , Liu Xinyang , Tang Yucheng , Roth Holger R , Fisher Michael J , Packer Roger J , Anwar Syed Muhammad , Avery Robert A , Linguraru Marius George
Published: June 2024

BACKGROUND

Half of children with optic pathway gliomas associated with neurofibromatosis type 1 (NF1-OPG) are at risk for vision acuity (VA) loss. NF1-OPGs manifest along the anterior visual pathway (AVP), where the overall shape and volume from MRI have been recently associated with VA loss. To investigate the added value of localized features within the optic nerves (ONs) and chiasm, we propose an automatic deep-learning framework for VA loss prediction from volumetric and radiomic analysis of ONs, chiasm, and AVP.

METHODS

We collected MRIs of 60 children with NF1-OPG from Children’s National Hospital (CNH, GE platform) and 75 from Children’s Hospital of Philadelphia (CHOP, Siemens platform). MRI sequences included T1-, T2-weighted and T2-FLAIR. Experts annotated the AVP to establish ground truth. Neuro-ophthalmic evaluation identified VA loss (LogMAR >= 0.2) in 52/135 children. Automatic AVP segmentation was performed using the Swin transformer network. ONs and chiasm were split through template-based registration. Brain volume, tumor location, child age, and 1,172 radiomic features were used to predict VA loss using support vector machines. Sequential feature selection associated with risk VA loss was done using sensitivity and univariate statistical tests (ANOVA). We compared predictions based on new ON and chiasm analysis with results based on AVP alone.

RESULTS

Balanced accuracy, sensitivity, specificity, and AUROC of VA loss prediction were 0.865, 0.882, 0.857, 0.899, respectively. Significant risk factors were maximal image intensity and gray level run length entropy in T2-FLAIR for ONs, and image intensity range in T2-FLAIR for chiasm. AUROC based on analysis of AVP alone dropped to 0.728 (p-value=0.028).

CONCLUSIONS

Deep learning-based analysis indicates an association of new localized MRI features in ONs and chiasm with VA loss, which show enhanced capability in predicting VA loss. This automated framework has the potential to accelerate and guide the treatment decisions for children with NF1-OPGs.
QOL-14. EPILEPTIC SEIZURES, ANTI-SEIZURE MEDICATIONS, AND NEUROCOGNITION IN SURVIVORS OF PEDIATRIC BRAIN TUMORS
Authors: de Licht Edvard Fine , Ideland Tova , Sigurdsson Gunnar , Anastasopoulou Stavroula , Olsson Ingrid Tonning
Published: June 2024

BACKGROUND

Younger age at diagnosis and cranial radiation therapy are associated with neurocognitive late complications in survivors of pediatric brain tumors (PBT). Less is known about the association between neurocognition and epileptic seizures, with the latter affecting 27% of 5-year survivors. This study aimed to explore whether epileptic seizures exacerbate neurocognitive late complications beyond treatment and demographic factors.

METHODS

Fifty-nine survivors of PBT who had experienced at least one epileptic seizure, and a control group of survivors matched on sex, age at diagnosis, and cancer treatment, all diagnosed at Skåne University Hospital, were included in the study. Demographic and clinical variables, along with neurocognitive measures of verbal and non-verbal reasoning, cognitive processing speed, working memory, and cognitive flexibility were collected from medical records. Neuropsychological scores, assessed on average 3.68 years after diagnosis, were transformed into z-scores employing age-adjusted norms (m=0, sd=1). Generalized linear models, controlling for increased intracranial pressure at diagnosis and tumor localization, were used to analyze the association between epileptic seizures, cumulative use of anti-seizure medications (ASM), and neurocognition.

RESULTS

Experiencing any type of epileptic seizures was associated with reduced processing speed (β = -0.91z, p<0.01) and cognitive flexibility (β =-1.05z, p<0.01). Treatment with one ASM was associated with reduced cognitive processing speed (β =-0.81z, p=0.03), and treatment with two or more ASM was associated with lower scores on measures of non-verbal reasoning (β =-0.81z, p<0.01), working memory (β =-0.77z, p=0.01), processing speed (β=-1.26z, p<0.01), and flexibility (β =-1.54z, p<0.01).

CONCLUSIONS

Epileptic seizures and treatment with ASM were both associated with neurocognitive late complications. Optimal seizure management presents a potential modifiable factor for reducing cognitive burden in survivors of PBT.
QOL-19. THE SIBLING TOOLKIT: DEVELOPMENT OF A PSYCHOLOGICALLY-INFORMED TOOLKIT TO SUPPORT SIBLINGS OF CHILDHOOD CNS TUMOUR PATIENTS WITH LIMITED ACCESS TO FORMAL SERVICES
Authors: Verity Sarah J , Adey Claire , Dyson Tracy , Fifield Kate , Holman Natalie , Lewington Philippa , Marshall Kirsty , Owens Meghan , Samrai Amandeep , Tregay Jeni , Davies Kimberley , Martinez Phil , Mitchell Deborah
Published: June 2024

BACKGROUND

There is a recognised gap in service provision addressing the psychological and social needs of siblings of children with a diagnosis of brain tumour. In the absence of funding to provide direct psychological service provision for siblings, a project development group was established to identify and advance alternative methods of delivering support.

METHODS

Funding for a two year sibling-needs project was sourced from UK child brain tumour charity Tom’s Trust and led by the Neuro-Oncology psychology service at the Great North Children’s Hospital (Newcastle, UK). A development group was established of clinical psychologists and neuropsychologists representing nine UK hospital Trusts and one former school teacher. Following a comprehensive priorities exercise a toolkit was developed to support siblings of children with brain tumours. Significant further stakeholder involvement, including input from the regional Young People’s Advisory Group, resulted in positive revision to the initial draft.

RESULTS

A 39 page toolkit was produced for the use of any adult involved in the sibling’s life. This psychologically-informed toolkit provides guidance and support for a caring but potentially uninformed adult, such as a teacher, community leader, or member of the wider family, to be able to offer support to siblings. Guidance is included to help the adult talk about cancer, know what common issues siblings face, and to think about how to safely and appropriately undertake supportive work with this age group. The kit is associated with a website link, allowing toolkit users to download worksheets and resources for use with the sibling.

CONCLUSIONS

Early feedback on the published toolkit is highly positive, suggesting that the toolkit is considered ‘comprehensive’, ‘accessible’, and ‘practical’. We believe that this toolkit offers the potential to bridge some of the gap in service provision to siblings of a child with brain tumour.
QOL-26. SYTHESIS OF THE LITERATURE REVIEW ON PHYSICAL ACTIVITY IN PEDIATRIC NEURO-ONCOLOGY
Authors: YILDIZ Seda , TANRIVERDİ Müberra
Published: June 2024

BACKGROUND

Physical Activity plays a vital role in physical, social, phychological wellbeing of pediatric neuro-oncologic group. However, the researches investigating the effects of physical activity on this group have been sparse. The purpose of this study was to identify studies conducted about the effects of physical activity on this population.

METHODS

PRISMA statement conduct review was followed in electronic database of Journal of Neuro-oncology. Two authors (SY, MT) independently conducted systematic literature searches February 2024. Keywords/Mesh terms: “physical activity’’. Randomized controlled English clinical trials are included; Studies that were published as “review”, “protocol”, “books”, “news”, not reach full text and not related to physical activity excluded. After articles had been reached, used QUADAS-2 checklist for methodological quality.

RESULTS

29 articles were identified from 1721 articles, and 2 of them (published 2014-2023) were about pediatric age group. One of them was assessment (50%), while the other one was interventional study (50%). Assessment study was measured by using Bruininks-Osteretsky Test of Motor Performance, Second Edition (BOT-2) and online surveys. Interventional study analyzed the effects of aerobic exercises of three 90-minute sessions per week for 12 consecutive weeks primarily on cortical thickness, white matter, hippocampal volume and secondarily reaction time, accuracy across tests of attention, processing speed, and short term memory.

CONCLUSION

This abstract provides an initial scoping review of physical activity in pediatric neuro-oncology group. It demonstrates limited range of assessments, and interventions which highlights the lack of clinical evidence in this specific area. The results raise the need for further research in this field to help the development of physical activity guidelines for evaluation and physical activity methods in children with ataxia, and tumours expecially posterior fossa brain tumors. Investigation of different physical activity methods in a group of neuro-oncology children in need of support is major importance.
QOL-29. COGNITIVE DEVELOPMENT WITHIN TWO YEARS AFTER CRANIOSPINAL IRRADIATION IN CHILDREN TREATED FOR MEDULLOBLASTOMA: A COMPREHENSIVE ASSESSMENT USING AGE-APPROPRIATE SCALES
Authors: Satragno Camilla , Kieffer Virginie , Dufour Christelle , Martin Valentine , Sellami Noura , Lanfranchi Francesco , Bolle Stephanie
Published: June 2024

BACKGROUND

Medulloblastoma 5-years survival rates range from 50-95% across risk classes, underscoring the need to mitigate treatment-related neurocognitive deficits. This study evaluates cognitive outcomes within 2 years post-radiotherapy, considering treatment modalities and various influencing factors.

METHODS

We conducted a retrospective monocentric study on patients under 18 years old, treated at our hospital from 2007 to 2020, with histologically and molecularly confirmed medulloblastoma, who underwent craniospinal irradiation. Cognitive function was assessed within 24 months post-therapy using age-appropriate Wechsler scales to evaluate verbal comprehension, perceptual reasoning, working memory, and processing speed. Patients were categorized into two groups based on a threshold score of 80, indicating “neurocognitive normality” if scores were ≥80 in all domains or “neurocognitive deficient” if any domain scored <80. Statistical analyses utilized SPSS for descriptive statistics and tests for categorical and continuous variables.

RESULTS

Among 100 selected patients, 91 completed the evaluations. The average age at diagnosis was 8.47 years, and at the onset of radiotherapy was 8.83 years. Forty-four patients (48%) scored ≥80 in all domains, indicating ‘neurocognitive normality,’ while 47 patients (52%) scored <80 in at least one domain, classified as ‘neurocognitive deficient’. In the descriptive analysis identifying significant differences in the two groups, no significant differences were observed in age, WHO classification, risk class, or pre-surgical shunt. In contrast, significant differences emerged in posterior fossa syndrome frequency, kinetic (p=0.002) and static forms (p<0.001) and in parental education level(p=0.025).

CONCLUSION

Our findings highlight the multifactorial nature of neurocognitive development in children with medulloblastoma within 2 years post-radiotherapy, identifying postoperative complications and the social environment as significant factors. Notably, specifics of radiotherapy and high-dose chemotherapy did not show a significant impact in this preliminary analysis. Future studies will further investigate the roles of various variables on neurocognitive outcomes, aiming to extend our understanding beyond two years post-radiotherapy.
QOL-32. COGNITIVE AND PSYCHOLOGICAL LATE EFFECTS IN CHILDREN AND ADOLESCENTS WITH PINEAL REGION TUMORS: A 35-YEAR-LONG EXPERIENCE IN A TERTIARY REFERRAL HOSPITAL
Authors: Verrico Antonio , Pisati Angelica , Bagnasco Francesca , De Giuseppe Sara , Rossi Andrea , Piccolo Gianluca , Molteni Marta , Mercuri Claudia , Consales Alessandro , Barra Salvina , Giannelli Flavio , Satragno Camilla , Garrè Maria Luisa , Milanaccio Claudia , Profio Sonia Di
Published: June 2024

BACKGROUND

Pineal region tumors (PRT) account for 2.8% of all central nervous system tumors in children and adolescents up to 19 years of age. Modern therapies allow more than 2/3 of patients to overcome their disease, but late effects impair quality of life of survivors. This study aimed to define the prevalence of cognitive and psychological late effects in PRT-survivors.

METHODS

Demographic information, medical variables, cognitive and psychological age-appropriated assessments of childhood and adolescence PRT-survivors, followed-up at Gaslini Children’s Hospital between 1988 and 2023, were retrospectively collected. Neurocognitive assessment was performed using the Wechsler scale. Psychological assessment was obtained using the Child Behavior Checklist, Beck Depression Inventory, State-Trait Anxiety Inventory, Trauma Symptom Checklist for children and Impact of Event Scale–Revised.

RESULTS

Sixty patients were included (53 males, 88%); median age at diagnosis was 12.8 years (Interquartile range, IQR, 9.0–15.7 years). Main entities were: germinoma (17, 28%), non-germinomatous germ cell tumor (16, 27%), bifocal germinoma (13, 22%), pineoblastoma (6, 10%), teratoma (3, 5%). 20/60 patients (33%) had neuroaxis spread, 48/60 (80%) presented hydrocephalus, 41/60 (68%) underwent surgery, 16/60 (27%) needed ventricular-peritoneal shunt, 51/60 (86%) received chemotherapy and 56/60 (93%) required radiotherapy. Median follow-up was 8.9 years (IQR 4.1–15.2). Six patients died, 5/6 died for progressive disease. Intelligence quotient (IQ) score was available for 43/60 patients with a median value of 91 (IQR 85-107). Complete cognitive and neuropsychological assessment was available for 25/60 patients showing presence of: anxiety symptoms (16/25, 64%), depression symptoms (20/25, 80%) and post-traumatic symptoms (7/25, 28%).

CONCLUSIONS

In our cohort, PRT-survivors showed IQ scores within expected average and a high frequency of anxiety and depression symptoms. Deeper insights into the mechanisms underlying cognitive and psychological late effects are needed, focusing on the role of demographics, treatments and disease-specific variables as well as on tumor location.
QOL-43. COMPARISON OF SOCIAL DETERMINANTS OF HEALTH MEASURES ON IQ AND ACADEMIC OUTCOMES IN PEDIATRIC BRAIN TUMORS
Authors: Gioia Anthony R , Jacobson Lisa A , Acharya Sahaja , Peterson Rachel K
Published: June 2024

BACKGROUND

Treatment for pediatric brain tumors impacts IQ and academic achievement; fewer studies have examined the role of social determinants of health (SDoH). To date, studies have primarily focused on family-based SDoH such as insurance type or parental education as predictors of cognition. Limited studies have examined community factors, though our work highlighted the role of education quality on IQ and academics in pediatric brain tumors. To our knowledge, no study has examined the predictive value of family and community-based SDoH.

METHODS

Participants included 151 pediatric brain tumor patients (M age at diagnosis=8.82) seen for a clinical neuropsychological evaluation (M age at evaluation=13.71). IQ was obtained from age-appropriate intelligence measures (WISC>6 years, DAS-II<6 years); untimed reading and math calculation were examined via WIAT/KTEA/WJ subtests. Family-based SDoH included insurance type (public, private) and maternal education (college degree). Community-based SDoH included the Area Deprivation Index (ADI) and Education, Health-Environment, and Social-Economic indices from the Childhood Opportunity Index (COI). Multiple regressions examined variance in IQ, reading, and math accounted for by each of the SDoH measures, after controlling for treatment exposures using the Neurological Predictor Scale (NPS).

RESULTS

Insurance [β=-.302, t(151)=-4.00; p<001] and Education [β=.235, t(151)=3.14; p=.002] accounted for 14.9% and 19.7% of the IQ variance, respectively. Education also accounted for 12.8% of the reading variance (β=.304, t(109)=3.40; p<.001). Both the Education [β=.570, t(107)=3.41; p<.001] and Social-Economic [β=-.381, t(107)=-2.28; p=.03] indices accounted for 7.7% and 11.3% of the math calculation variance, respectively.

CONCLUSIONS

Community, particularly those related to education and social & economic resources, and family factors (e.g., insurance status) were associated with IQ and academic performance. Findings indicate the importance of investigating both family and community factors that may contribute to outcomes in pediatric brain tumors.
QOL-44. EARLY SEVERE HEARING LOSS IN CANADIAN CHILDREN WITH CENTRAL NERVOUS SYSTEM TUMORS: A POPULATION-BASED COHORT STUDY
Authors: Coltin Hallie , Trudeau-Ferrin Ofélie , Perreault Sébastien , Lafay-Cousin Lucie , Renzi Samuele , Larouche Valérie , Erker Craig , Bouffet Eric , Ramaswamy Vijay
Published: June 2024

BACKGROUND

Severe treatment-related hearing loss (HL) is associated with devastating psychosocial/neurocognitive outcomes. Children with central nervous system (CNS) tumors are highly vulnerable to severe HL due to tumor location and treatment exposures. This is the first study to report national CNS tumor-specific rates and predictors of early severe HL.

METHODS

We conducted a retrospective, population-based cohort study of all children ≤15yrs at diagnosis with CNS tumors between 2001-2019 using the Cancer in Young People in Canada registry. The primary outcome was Common Terminology Criteria for Adverse Events grade 3/4 HL ≤5yrs following diagnosis. We determined prevalence and probabilities of early HL; predictors were determined using multivariable logistic regression models.

RESULTS

Among 3,201 children with CNS tumors, 5.1% experienced early HL. Children with medulloblastoma (N=570) and ATRT/other embryonal tumors (N=269) experienced disproportionate rates (16.1%, 15.2%, respectively); 85.4% (medulloblastoma) and 68.8% (ATRT/other embryonal) received cisplatin, 74.6% (medulloblastoma) and 52.1% (ATRT/other embryonal) were irradiated. In children with medulloblastoma, when controlling for follow-up, age <=5yrs at diagnosis [odds ratio (OR) 2.4, 1.5-3.8], radiation (OR 3.5, 1.6-7.6), and cisplatin (OR 20.4, 1.3-329.7) predicted early HL. In children with medulloblastoma post cisplatin, age ≤5yrs at diagnosis doubled the probability of early HL in both irradiated (29.8%, vs 15.3% if >5yrs at diagnosis) and non-irradiated patients (10.6% vs 4.8% if >5yrs at diagnosis). In children with ATRT/other embryonal, cisplatin (OR 28.2, 1.7-472.1) was the only predictor of early HL.

CONCLUSIONS

In the largest population-based study of early severe HL in children with CNS tumors, we report striking rates in children with embryonal tumors. Younger irradiated children had disproportionate probabilities of early HL, suggesting a novel additive interaction between age at diagnosis and radiation. Standardized otoprotection and research focusing on therapy de-escalation in young children with embryonal tumors are urgently needed.
QOL-52. SOCIOECONOMIC METRICS AND THEIR UNIQUE ROLE IN PREDICTING COGNITIVE AND FUNCTIONAL MORBIDITY IN RACIALLY AND ETHNICALLY DIVERSE PATIENTS WITH PEDIATRIC BRAIN TUMOR (PBT)
Authors: Chiang Jenna A , Mendoza Leanne , Whitaker Ashley M
Published: June 2024

BACKGROUND

Caregivers from more advantaged backgrounds have better understanding of their child’s needs, access to resources, and medical adherence, contributing to higher survival and neuropsychological (NP) outcomes in PBT, above and beyond diagnostic/treatment-related factors. Children with PBT from disadvantaged neighborhoods have increased medical morbidity, though cognitive morbidity is unknown. This study examines area deprivation index (ADI) quintiles (neighborhood disadvantage) in relation to established proxies for socioeconomic status (SES) and NP outcomes following PBT diagnosis.

METHODS

Parental education and median household income (SES proxies), as well as ADI quintiles (1-5, 5=most disadvantaged) were estimated for 120 PBT patients (ages 5-21; x̄=13.6 years, SD=3.8 years; 50% female). NP outcomes included estimated IQ (calculated from Wechsler Vocabulary/Matrix Reasoning) and/or the Adaptive Behavior Assessment System-Third Edition (ABAS-3).

RESULTS

Over 75% identified as minorities (53% Latinx, 10% Asian American, 5% Black, 8% multi/other). Findings revealed significant racial/ethnic disparities in household income [F(4,115)=11.208, p<.001] and ADI [F(4,108)=9.663, p<.001]. Parental education was correlated with household income [rs(80)=.490, p<.001] and ADI [rs(76)=-.477, p<.001]. Interestingly, household income [F(1,74)=7.498, p=.008] and parental education [F(1,49)=10.084, p=.003] significantly predicted IQ (SS=44-132; x̄=99.78, SD=14.66), while ADI did not. Neither SES proxy nor ADI predicted adaptive functioning (SS=51-120; x̄=90.12, SD=13.927), despite the relationship between IQ and adaptive functioning, r(47)=.273, p=.032.

CONCLUSIONS

The predictive value of household income (which varies by race/ethnicity) and parental education on cognition following PBT diagnosis continues to inform neuropsychological practice. While ADI is correlated with both established SES proxies, higher neighborhood disadvantage does not predict cognitive concerns in the same way, indicating potential unique housing factors (e.g., persons per room ratio) that may protect against cognitive morbidity (e.g., multigenerational living). Additional investigation is needed to understand why adaptive functioning is less susceptible to SES/ADI than cognition.
NURS-18. GERMINOMA PATIENTS – MORE PRONE TO PSYCHIATRIC DISORDERS, ALLERGIES, AND WEIGHT PROBLEMS? AN INSTITUTIONAL REVIEW
Authors: McKeown Tara , Chun Foo Jen , Li Amanda , Dutton Jordann , Rowe Rachel , Hawkins Cynthia , Janzen Laura , Bartels Ute
Published: June 2024

BACKGROUND

Germinoma are the most frequent type of intracranial germ cell tumour. Within nursing clinical practice an increased prevalence of psychiatric manifestations, allergies, and weight gain throughout treatment and into survivorship within the germinoma population has been observed. There is only limited literature about these problems available.

METHODS

A retrospective review of clinical presentation, psychiatric co-morbidity, therapeutic course, and follow-up of 27 Germinoma patients (6.2-17 years) diagnosed and treated at a tertiary care center from 2008-2021 was performed. In addition, the presence and occurrence of allergies and weight changes throughout their therapy was reviewed.

RESULTS

Nearly half of the Germinoma patients (n=11) (suprasellar, pineal, basal ganglia) were diagnosed with pre-existing psychiatric co-morbidity (anxiety, depression, mood disorder and eating disorder) as per DSM-5 criteria, more commonly verified after their brain tumour diagnosis and persistent beyond treatment. Three of 27 (11%) patients indicated allergies (medication, food) at diagnosis. Seventeen of the 27 (63%) patients presented with allergies throughout their therapy (medication, tape, cleaning products, blood products). Six (35%) of those patients developed anaphylactic reaction to Etoposide and/or blood products. Eight of the patients (suprasellar & pineal) were found to have a significant weight gain throughout their treatment and two (pineal & suprasellar) were found to have significant weight loss, the rest of the cohort remained stable. The impact of tumour location (suprasellar, pineal) on the specific problems is ongoing.

CONCLUSION

The findings of this retrospective review could guide clinical practice. The potential higher incidence of psychiatric disorders should prompt practitioners to upfront screening and throughout therapy to ensure adequate support. Allergy prevalence in pediatrics is variable but an allergy occurrence of 35% is elevated in comparison to the general population and therefore increased awareness of allergies within this population is important for the bedside nurse. Lastly, early involvement of dieticians to aid in weight management seems crucial.
OTHR-10. PILOT STUDY TO EVALUATE AUTOMATED LABORATORY DATA TRANSFER INTO MEDIDATA RAVE ACROSS THE NATIONAL CANCER INSTITUTE (NCI)-SUPPORTED PEDIATRIC BRAIN TUMOR CONSORTIUM (PBTC) AND PEDIATRIC EARLY PHASE CLINICAL TRIAL NETWORK (PEP-CTN) COOPERATIVE GROUPS
Authors: Miler Tamara P , Aplenc Richard , Minard Charles , Lensing Shelly , Wang Yu , Velamuru Prasanna , Foster Jennifer H , Silverman Milena , Sung Cheryl , Wong Karina , Beeles Thalia , Weigel Brenda , Fox Elizabeth , Onar-Thomas Arzu
Published: June 2024

BACKGROUND

Electronic data capture (EDC) has the potential to improve data accuracy and efficiency in oncology. The PBTC and PEP-CTN cooperative groups conducted a pilot project to 1) assess the feasibility of automated transfer of laboratory data from participating institutions’ electronic health records (EHR) to the Medidata Rave EDC housed within each consortium’s Uniform Resource Locator (URL); 2) evaluate discrepancies between retrospective automated laboratory data extraction from the EHR and manual data ascertainment during the original conduct of the study (MANUAL).

METHODS

Data from patients treated on 7 completed PBTC or PEP-CTN trials at 7 hospitals were included. Each consortium created a Rave instance to receive data. Sites elected to use local methods or the ExtractEHR R package to map and extract laboratory data for designated patients. Post-extraction data were uploaded to the Rave Batch Uploader (BU)-associated file transfer protocol (FTP) and BU uploaded data into Rave. After successful upload, discrepancies between EHR and MANUAL data were categorized. Two hospitals reviewed discrepancies at their sites to identify reasons for discrepancies.

RESULTS

Automated extraction and upload required significant PBTC/PEP-CTN operational effort and close work with hospital technical teams to map and extract data. All sites successfully extracted specified laboratory data and had ≥1 complete upload via BU to Rave; 2 sites had 2 uploads. Discrepancies were most commonly due to more data in EHR datasets (>1 result on a given day, data on additional study window days) or mismatched values or units. Differences in percentages of discrepant results between hospitals were likely due to mapping differences for EHR extraction.

CONCLUSIONS

This study demonstrated that in the pediatric cooperative oncology group setting automated laboratory data ascertainment can be performed. Accomplishing this required upfront central operational and hospital-based effort to prepare for data upload and transfer. This effort varied by site.
OTHR-16. HYPERACTIVATION OF THE INTEGRATED STRESS RESPONSE VIA PROTEASOME INHIBITION KILLS DMG AND ATRT WHILE SPARING NORMAL IPSC BRAIN ORGANOIDS
Authors: Novak Orlandi V , Wu Alyssa , Eberhart Charles , Raabe Eric H
Published: June 2024

BACKGROUND

H3K27-altered diffuse midline glioma (DMG) and atypical teratoid/rhabdoid tumor (ATRT) have increased baseline activation of the integrated stress response (ISR), an evolutionarily conserved system that enables cells to tolerate stress. This activation is manifested by elevated levels of ATF4. Transient or low-level expression protects cells from stress, while persistent, high-level activation leads to cell death. Ixazomib is an orally bioavailable proteasome inhibitor that causes endoplasmic reticulum stress, which is a major upstream activator of the ISR. We hypothesized that the high baseline level of ATF4 in DMG and ATRT would make these tumors susceptible to ISR activators such as ixazomib.

METHODS

After determining the IC50, DMG and ATRT cell lines were treated with increasing concentrations of ixazomib. To evaluate if ixazomib selectively kills DMG and ATRT, we treated iPSC brain organoids in parallel with tumor cells. Combination treatment of ixazomib and idarubicin, a brain-penetrant anthracycline, was conducted to assess synergy.

RESULTS

Ixazomib significantly induced apoptosis and suppressed proliferation in multiple cell lines, as shown by western blots for cleaved PARP and phospho-Rb expression as well as cleaved caspase-3 and BrdU immunofluorescence (DMSO vs. 25nM p<0.0001 by ANOVA). Additionally, western blots detected elevated ATF4 and CHOP expression in ixazomib treated cells, indicating activation of the ISR. CC3 immunofluorescence and western blot for cleaved PARP showed significantly increased apoptosis in DMG and ATRT cell lines treated with ixazomib (JHHDIPG1 and CHLA06 – DMSO vs. 25nM p<0.0001 by ANOVA), while iPSC brain organoids were not affected. Synergy testing of ixazomib and idarubicin showed an overall zero-interaction-potency (ZIP) synergy score of 23.464 in CHLA06 and 19.084 in HSJD007 (scores of 10 or above indicate synergy).

CONCLUSIONS

By over-activating the ISR, ixazomib kills DMG and ATRT cells without impacting normal iPSC brain organoids. This effect may potentially be enhanced with the addition of idarubicin.
OTHR-18. IMPACT OF COVID-19 ON CLINICAL TRIAL ENROLLMENT IN THE DEPARTMENT OF PEDIATRIC HEMATOLOGY ONCOLOGY AT WASHINGTON UNIVERSITY SCHOOL OF MEDICINE/ST. LOUIS CHILDREN’S HOSPITAL FROM 2017 TO 2023
Authors: Roemerman Heather , Abdelbaki Mohamed , Barnwell Alison , Jones Sally , Hollingsworth Meili , Murray Lisa , Tackett Brittany
Published: June 2024

BACKGROUND

COVID-19 had a significant impact on clinical research within the healthcare system worldwide. However, there are only limited reports on its effects on clinical trials in pediatric cancer, specifically in brain tumors. We reviewed the impact of COVID-19 in the Department of Hematology and Oncology in St. Louis Children’s Hospital (SLCH). We analyzed the number of clinical trials open at our center from 2017 to 2023. We hypothesized that in 2020 there would be a significant drop in study participant enrollments at our site overall.

METHODS

We analyzed data from our online tracking system from 2017 to 2019, pre-pandemic, and 2020-2023, post pandemic. We will also perform a literature review of the impact COVID-19 had on clinical trial enrollment involving childhood cancers in the United States. We will compare these findings to our experience at SLCH.

RESULTS

In 2020, while non-therapeutic trial enrollments declined to about half of all enrollments compared to 2019, enrollments in therapeutic trials significantly increased to almost three-fold. Overall, when combining non-therapeutic and therapeutic enrollments from 2017-2020, there was a significant decrease in 2020. By 2023, total enrollments nearly recovered to pre-pandemic levels.

CONCLUSIONS

COVID-19 negatively impacted non-therapeutic studies at SLCH as many trials permanently closed; however, the negative effect on therapeutic studies was minimal.
OTHR-23. PATIENT DESIRE TO SHARE DATA AND PARTICIPATE IN RESEARCH IN THE DIPG/DMG COMMUNITY
Authors: Lyons Nicole , Ward Lisa
Published: June 2024

Direct and reciprocal communication between patient communities and their research and care teams is essential to building trust and ensuring that all essential information is shared. Patient participation in data collection of any sort is often challenging, as patients may be hesitant or unmotivated to share their information. The DIPG/DMG patient community faces the opposite challenge. Because of the frustration of the lack of treatment options and the established trust that exists between patient families and research professionals, DIPG/DMG patient families are both willing and eager to share any information they can. Patient families have seen how their knowledge has helped other families navigate impossible situations and care teams understand how to better support their patients. The information families eagerly provide is crucial to advancing treatment and research. Patient families have repeatedly expressed willingness to participate in quality of life assessments, repeated surveys during and after treatment, and provide their medical and biological information in the hopes that it can aid research. There is a need for a centralized manner for all of this data to be shared by the patient and accessed by care teams and researchers. Patient-led initiatives are addressing this by creating a network of resources. This network helps to guide other patient families through the data-sharing process, address concerns, and find ways to provide what is needed to push research and treatments ahead. There are many benefits to having a centralized data ecosystem for researchers and care teams, such as standardizing data collection and ease of analysis. In the future, this centralized hub could inform personalized care, making options such as n-of-1 trials and matching patients to optimal clinical trials possible in a manner that is effective and efficient.
LMIC-16. PRE-IRRADIATION CHEMOTHERAPY AND DELAYED RADIATION THERAPY IN INFANTS AND YOUNG CHILDREN WITH WITH CENTRAL NERVOUS SYSTEM EMBRYONAL TUMOURS
Authors: Prasad Maya , Gollamudi Venkata Ramamohan , Dasgupta Archya , Chatterji Abhishek , Sahay Ayushi , Singh Vikas , Shetty Prakash , Moiyadi Aliasgar , Sahu Arpita , Chaudhuri Amit , Bhattacharya Kajari , Epari Sridhar , Gupta Tejpal , Chinnaswamy Girish
Published: June 2024

BACKGROUND

Established strategies for infants and young children(IYC) with embryonal tumours of the central nervous system(CNSET) - autologous stem-cell rescue(ASCT) and intraventricular chemotherapy(IVCT) – are not universally available. We report the outcomes of IYC with CNSET treated using the strategy of surgery, pre-irradiation chemotherapy and delayed radiation.

METHODS

Children <3years diagnosed with CNSET- medulloblastoma(MB), atypical teratoid/rhabdoid tumour(ATRT), embryonal tumour with multilayered rosettes(ETMR), CNS primitive neuroectodermal tumours(PNET)- and pineoblastoma(PB),underwent standard evaluation and staging, maximal safe excision, pre-irradiation chemotherapy(cyclophosphamide, etoposide and carboplatin;CEJ) upto 36months of age and either ris-adapted craniospinal with boost or focal irradiation. We performed a retrospective intention-to-treat outcome analysis.

RESULTS

Of 117children <3years with CNSET treated January2011- December2022, 72 were treated with this strategy.The median age was 25months (range6-35), 49males,histology medulloblastoma-42(58%), ATRT-9(12.5%), PNET-8(11.1%), ETMR-8(11.1%) and PB-5(6.8%); 23(32%) metastatic.The median chemotherapy cycles were 6(range 1-15). 36 children went on to receive RT; CSI in 33 (20standard-dose,13reduced-dose) and focal in 3. At last follow-up, 27children are in remission, 43 have relapsed/progressed (9 received salvage treatment) and 2 died due to chemotherapy toxicity. The 3-year and 5-year event-free-survival(EFS) are 35% and 3-year and 5-year overall-survival(OS) are 41.8% and 40.2%. The 3-year EFS/OS for MB are 51.1%/ 62.8%,PNET 25%/25%,ATRT 11.1%/11.1%,ETMR 12.5%/12.5% and PB 0%. Only metastasis was prognostic in medulloblastoma (HR 2;95% CI 0.86-4.6 for EFS and HR 1.7;95% CI 0.67-4.5 for OS); age, molecular group and histology were not prognostic. Long-term follow-up (n=17) documented >grade2 late effects in all (endocrine-16, neurocognitive-8, vision-3, hearing -8 and neurological-10).

CONCLUSION

The use of moderate-intensity pre-irradiation chemotherapy is feasible and effective in infants and young children with CNSETs. Despite inferior outcomes compared to ASCT or IVCT,this strategy could be used in resource-limited settings.
MODL-04. ZEBRAFISH: THE FUTURE OF PEDIATRIC BRAIN CANCER RESEARCH
Authors: Roy Debasish , Subramaniam Bavani , Chong Wai Chin , Nazarian Javad
Published: June 2024

Pediatric brain cancers cause the highest rate of mortality amongst all childhood cancers. Most high-grade gliomas are difficult to treat mainly due to impermeability across the blood-brain barrier, or systemic toxicity. Here, we explore the benefits of zebrafish to assess drug toxicity, orthotopic pediatric brain cancer model development and drug screening. We assessed the toxicity of eight anti-cancer drugs with diverse mechanisms of action. In addition to the survival assay (LC50), we analyzed other teratogenic characteristics to demonstrate the detrimental developmental toxicity, which was critical in determining drug safety for future human usage. To develop fast and reproducible orthotopically xenografted pediatric brain cancer models, we injected approximately 80-100 mCherry expressing JHH-NF1-PA1 and TM-31 cells into the midbrain of 2 days post-fertilization (dpf) zebrafish embryos and imaged daily for next 4 days to monitor the survival, progression, and invasion of the injected cells. Our results show that both cell types were engrafted successfully and multiplied inside the developing zebrafish brain. As compared to JHH-NF1-PA1 cells, which mostly migrated caudally within the developing spinal cord, TM-31 migrated in multiple directions and metastasized five times more rapidly. To check the efficiency of VAL-083 and AZD-1775 in high-grade glioma, 2 dpf zebrafish embryos were injected with mCherry expressing HGG cells, SF8628. At one day post-injection (dpi), the xenografted embryos were exposed to different combinations of Val-083 and AZD-1775 for 72 hours. After 4 dpi, tumor cell invasion and migration in zebrafish were quantified. We found that the combination group had the lowest tumor burden with significantly lower fluorescence intensity, total area of migration, and reduced number of metastatic cells (p<0.001) compared to single or no drug treatment groups. Our study showed that zebrafish is a valuable, rapid, and cost-effective in-vivo pediatric brain cancer pre-clinical model to assess tumor proliferation, metastasis, and rapid drug screening.
MODL-05. UNDERSTANDING THE METABOLIC VULNERABILITIES IN INFILTRATING GLIOMATOSIS CEREBRI CELLS
Authors: Bahadoor Hriday , Salmanli Chinar , Outlifah Hassiba , Hubsch Clemence , Deschuyter Marlène , Namer Izzie Jacques , Reita Damien , Martin Sophie , Dontenwill Monique , Entz-Werle Natacha
Published: June 2024

BACKGROUND

Gliomatosis cerebri (GC), a rare form of high-grade glioma, is characterized by a particularly invasive phenotype within multiple lobes of the brain and a dismal prognosis. This entity was removed in 2016 of the WHO brain tumor classification because of an absence of specific GC driving molecular signature. Its diffusive aspect on MRI is defined by an absence of cohesive tumor mass, a mild contrast enhancement and a rare neoangiogenesis. Based on those observations, our objectives were to understand how these cells are adapting to their brain environment without a physiological nutritive efflux associated to a reduced oxygen concentration and determine a metabolic signature of GC.

METHODS

Preliminary results in a large cohort of HGGs bearing several drivers (H3.3 G34V, NMYC amplified, BCOR positive) or a more “wildtype” phenotype with new entities (pedRTK 1 and 2) were underlining glucose and glutamine as major nutrients in cell metabolic suppliance. Therefore, epigenetic assessments, bulk metabolomics, and Seahorse technology, as well as labeled glucose and glutamine metabolites study, helped us in pediatric GC-derived cell lines (BT97 and BT139, PEDIAMODECAN program) to understand the role of both nutrients and their central role in GC in hypoxic microenvironment.

RESULTS

Both glucose and glutamine are involved in carbon fueling biosynthesis in those cells. Glutamine is much more involved in supplying nitrogen to fuel several specific amino acids and mitochondrial metabolisms. Meanwhile, we developed drug testing using Matrigel invasion aspects. The tested drugs were able to reduce invasiveness of GC cells and modify the intratumoral metabolism.

CONCLUSION

All those observations seem to explain GC cell adaptation into the hypoxic microenvironment, their plasticity and resistance through metabolic reprogramming based on glutaminolysis and glycolysis.
MODL-06. USING HYDROGEL MODELS TO RECAPITULATE THE TUMOUR-IMMUNE MICROENVIRONMENT OF AGGRESSIVE GROUP 4 MEDULLOBLASTOMA TUMOURS
Authors: Forder-Denham Isabelle , Kerr Ian , Jackson Andrew M , Coyle Beth
Published: June 2024

BACKGROUND

Medulloblastoma is the most common malignant childhood brain-tumour, predominantly affecting children between the ages of one and nine. It is divided into four molecular subgroups amongst which, Group 3 (G3) and Group 4 (G4) subgroups have the worst prognosis. Subgroups possess distinct extracellular-matrix (ECM) and tumour immune microenvironments (TIME) directly influencing therapy-response and metastasis. Current models of medulloblastoma fail to precisely recreate the complex, subgroup-specific TIME and do not mimic intricate immune-tumour heterotypic signalling facilitating immune-evasion. Here we use a HyStem-hydrogel which forms a hyaluronan-rich environment mimicking the natural brain architecture. This overcomes several limitations of current MB models, allowing customisation of subgroup matching of ECM components, adjustable ECM-stiffness and co-culturing of immune cells.

METHODS

HyStem-hydrogels were co-assembled with ECM components (with/without laminin) and G4 medulloblastoma cell line CHLA-01-MED. Hydrogels were imaged every three-days using an EVOS M7000 system and assessed for cell-viability with PrestoBlue every seven days. Co-culture laminin-supplemented HyStem hydrogels were established with M1-like or M2-like resting/activated macrophages and their growth tracked in the same manner. On day twenty-eight, hydrogels were fixed and stained for markers of cellular proliferation (Ki-67), ECM (laminin, vitronectin) and macrophage markers. Media from hydrogel co-cultures was collected and ELISAs permofmed to assess cytokine production.

RESULTS

Hydrogels with/without laminin both remained viable and stable for 28 days. Laminin-supplemented hydrogels displayed a mixed laminar-nodular phenotype which mirrored the heterogenous nature of G4 patient-tumours. Co-culture of CHLA-01-MED cells with activated-macrophages led to cytokine production and altered growth patterns.

CONCLUSION

We show that HyStem hydrogels recapitulate biologically relevant behaviour of aggressive G4-MB tumours in vitro and represent a promising model for G4-tumours. Future research will involve inclusion of additional brain relevant cells/ECM components and comparisons to a fully customisable peptide-amphiphile hydrogel.
MODL-09. IMAGE-BASED SCREENING IN MEDULLOBLASTOMA REVEALS TUMOR-SUPPRESSIVE EFFECTS OF THE NEUROPROTECTIVE AGENT URMC-12K
Authors: Yan Shen , Ciraulo Bernard , Jovanovic Dejana , Hochuli Dina , Alvarez Veronica Akle , Özalp Özgün , Neuhauss Stephan C F , Allalou Amin , Baumgartner Martin
Published: June 2024

BACKGROUND

Enhanced motility and the invasive behavior of medulloblastoma (MB) influence microenvironment interactions and may promote distant spread. Current drug screening focuses on cytotoxic agents, leaving subtle but potentially therapeutically relevant drug phenotypes associated with motility and invasiveness unrecognized. The serine/threonine kinase MAP4K4 is upregulated in MB and promotes invasiveness1,2. Toxicities associated with existing MAP4K4 inhibitors in the CNS prevented further pre-clinical evaluation. URMC-12k is a novel MAP4K inhibitor identified as a motor-neuron-protective agent in ALS. Using advanced imaging approaches, we investigated URMC-12k as a tumor-suppressive drug in MB and characterized its effects at the molecular, cellular, and tissue levels.

METHODS

We use cell-based 3D invasion assays and quantitative microscopy to assess tumor-restraining activities of URMC-12k, and machine learning to detect URMC-12k phenotypes associated with repressed motility. We use tissue and zebrafish larval models to explore URMC-12k effects on cell and tissue viability and anti-invasion efficacy. We determined URMC-12k targets in MB cells using phosphoproteomics.

RESULTS

URMC-12k outcompetes existing MAP4K4 inhibitors in repressing basal and growth-factor-induced matrix invasion with no detectable effects on vertebrate developmental processes. A computational model trained to detect morphological alterations in the actin cytoskeleton associated with cell dynamics established a firm correlation between the URMC-12k-repressed motile behavior and alterations in the tumor cell actin cytoskeleton. Quantitative imaging further revealed that URMC-12k promoted increased cell clustering and reduced deposition of extracellular vesicles. Phosphoproteomics identified proteins involved in cell adhesion organization and vesicle trafficking as potential molecular effectors targeted by URMC-12k.

CONCLUSIONS

URMC-12k effectively inhibits MB cell migration and displays no toxicities at effective concentrations. The regulation of cell-cell adhesion molecules and the deposition of extracellular vesicles revealed by URMC-12k are tumor-promoting, druggable mechanisms of MAP4Ks in MB. 1. 1Migliavacca, J., et al. Commun Biol5, (2022). 2. 2Tripolitsioti, D. et al. Oncotarget9, 23220–23236 (2018).
MODL-12. REPURPOSING SSRI/SNRI TARGETING NEUROTRANSMITTER SIGNALING TO SENSITIZE DMG TO CDK9 INHIBITORS
Authors: Murdaugh Rebecca L , Eberl Brittany R , Richard Rosemary U , Tremblay Jack R , Dei-Ampeh Alfred , Olson Calla M , Anastas Jamie N
Published: June 2024

BACKGROUND

Diffuse Midline Glioma (DMG) comprise a subset of aggressive pediatric brain tumors with few effective therapies. Cyclin-dependent kinase 9 inhibitors (CDK9i) like zotiraciclib (ZTR) are in clinical trials for adult and pediatric glioma, but resistance frequently develops. In this study, we find that co-treatment with CDK9i and brain penetrant, FDA-approved drugs targeting neurotransmitter signaling alters DMG transcription and reduces DMG growth and tumorigenesis.

METHODS

We conducted drug screens to assess DMG response to a sub-threshold dose of ZTR combined with a library of ~220 bioactive and FDA-approved compounds. Combinatorial effects of CDK9i+SSRI/SNRI treatment were confirmed through in vitro dose curve studies and in orthotopic DMG xenograft models. We identified downstream targets of CDK9i+SSRI/SNRI treatment through phospho-proteomic profiling, RNAseq analysis, immunofluorescence staining, and Western blotting.

RESULTS

Our targeted drug screens identified SSRIs (selective serotonin reuptake inhibitors) and SNRIs (serotonin and norepinephrine reuptake inhibitors) that increase DMG sensitivity to a low dose of zotiraciclib (ZTR). Follow-up studies confirm that combinations of structurally distinct CDK9i (ZTR, AZD4573) and SSRI/SNRI (sertraline, duloxetine) synergistically reduce DMG growth in neurospheres, induce the apoptotic marker cleaved caspase 3, and reduce the expression of proliferation markers. Additional proteogenomic analyses define downstream targets of CDK9i+SSRI co-treatment, including differential phosphorylation of chromatin regulators and RNA Polymerase 2 (Pol2)-associated elongation factors and splicing machinery. Further RNAseq studies reveal robust transcriptional changes induced by CDK9i+SSRI treatment characterized by altered expression of developmental and synaptic signaling genes. Finally, pilot pre-clinical studies find that CDK9i+SSRI treatment reduces tumor growth and increases progression free survival in a DMG xenograft model.

CONCLUSIONS

We have identified synergistic CDK9i+SSRI drug combinations that can be applied to alter malignant gene regulation and reduce DMG growth in vitro and in xenografts. These studies provide a basis for a drug-repurposing strategy to combine SSRI/SNRI and CDK9 inhibitors for DMG treatment.