bluuebunny/crossref_metadata_2025 huggingface dataset:
RARE-08. MULTI-INSTITUTIONAL ANALYSIS OF PEDIATRIC RELAPSED/REFRACTORY CENTRAL NERVOUS SYSTEM GERMINOMA
Authors: McGlynn Mary Claire , Abu-Arja Mohammad H , Nagabushan Sumanth , Zaghloul Mohamed Saad , Elhemaly Ahmed , Bertrand Kelsey , Gajjar Amar , Alias Hamidah , Cappellano Andrea , Graham Richard , Baglivo Sofia Jares , Bhadri Vivek , Govender Dinisha , Abdelbaki Mohamed S
Published: June 2023

BACKGROUND

Relapsed central nervous system (CNS) germinomas are rare with no universal agreement regarding management. We explore prognostic factors that may impact the treatment of patients with relapsed CNS germinoma.

METHODS

An international multi-institutional retrospective study of relapsed/progressive CNS germinomas was conducted. Data was summarized using descriptive statistics. Overall survival (OS) was evaluated using Kaplan-Meier and Fischer’s exact test to estimate odds ratios (OR) and 95% confidence intervals (CI).

RESULTS

Analysis included 21 patients (Male 71.4%) with relapsed/progressive germinomas from 7 sites. Median age at diagnosis was 15 years (interquartile range (IQR): 9.9-19) with 5% presenting with metastatic disease. Twelve patients (57.1%) achieved complete remission (CR) after initial therapy. Nineteen children (90.5%) suffered relapse. One (4.8%) suffered progression. The median time from diagnosis to relapse/progression was 21 months (range: 10-56 months) with 90.5% occurring within 24 months. 19 (90.5%) underwent chemotherapy, 9 (42.9%) bone marrow ablative therapy (HDCx), and 13 (61.9%) radiotherapy. At last follow-up, 88.9% of HDCx and 92.3% of radiotherapy recipients were alive. Of patients receiving radiation, 45% received whole ventricular irradiation, 25% craniospinal irradiation, and 5% focal irradiation (remainder unreported). Eleven children (52.4%) achieved CR after relapse/progression therapy and 16 (76.2%) were alive at last follow-up. Median time to last follow-up was 39 months (IQR: 18.43–89.50). Re-irradiation at relapse (OR=16, 95% CI: 1.27-200.9) and achieving complete response (CR) at relapse/progression (OR=4, 95% CI: 1.04-1.78) were associated with improved OS. CR after initial therapy (OR=0.857, 95%CI: 0.11-6.62) and HDCx at relapse/progression (OR=4, 95%CI: 0.36-44.13) were not associated with improved OS.

CONCLUSIONS

Relapsed CNS germinomas are radiosensitive and salvageable by re-irradiation at relapse. This ongoing multi-institutional study will contribute to existing knowledge about relapsed/progressive CNS germinomas and inform prospective clinical trials to improve outcomes for children with relapsed/progressive disease.
OUTC-02. CASE SERIES OF HYPERMUTATED PEDIATRIC CNS TUMORS
Authors: Parisi Rose , Horowitz Emma , Patel Roshal , Rood Gavrielle , Bowden Acacia , Turco George , Korones David , Andolina Jeffrey , Comito Melanie , Barth Matthew , Weintraub Lauren
Published: June 2023

In pediatric central nervous system (CNS) tumors, high tumor mutational burden (TMB) (≥3 mutations/megabase (mut/Mb)) has been correlated with lower overall survival and higher rates of progression as compared to low TMB tumors (<3 mut/Mb). This study is the first to examine a subset of pediatric CNS hypermutated tumors (≥10 mut/Mb) in comparison to high TMB tumors. We conducted a retrospective analysis of 121 pediatric patients (61 female (50%)) with a median age of 9 years diagnosed with a primary CNS tumor (high TMB, N=34; low TMB, N=55) at four academic medical centers from 2008 to 2021. Hypermutated tumors (N=3) were exclusively high grade tumors; subtypes were ependymoma, medulloblastoma, and oligodendroglioma. Hypermutated tumors had an average TMB of 65 mut/Mb (range=11-132 mut/Mb). Most of the hypermutated tumors had TP53 mutations (N=2; 67%) as compared to 29% of high TMB patients (N=12). Sixty-seven percent of patients with hypermutated tumors experienced tumor progression (N=2) as compared to 44% (N=15) of patients with high TMB tumors. Average time to progression was 2.4 years in hypermutated tumors and 1.4 years in high TMB tumors. No patients with a hypermutated tumor experienced a death event, as compared to 41% (N=14) of patients with high TMB. Although we report a small subset of hypermutated pediatric CNS tumors, this multi-institution case series suggests that hypermutated tumors may be associated with higher rates of progression, slower time to progression, and lower mortality as compared to high TMB tumors. Future research with a larger population of hypermutated tumors is needed to better characterize outcomes to optimize treatment for this subset of patients.
OUTC-05. DIFFERENCES IN FACTORS INFLUENCING SURVIVAL IN CHILDHOOD AND ADULT CNS MALIGNANCIES
Authors: Matharoo Jashanjeet , Dux Hayden , Broaddus William
Published: June 2023

Socioeconomic factors such as income and community type have shown to correlate with outcomes in neuro-oncologic care. In pediatric populations, however, fewer conclusions have been drawn on the effects of factors such as race, gender, and insurance status on survival due to the relative rarity of such cases. This analysis utilizes the National Cancer Institute’s Surveillance, Epidemiology and End Results (SEER) program database to determine differences in factors influencing survival in both pediatric and adult CNS malignancies. From the SEER Research Nov 2020 (1975-2018) dataset, 29865 patients with malignant CNS tumors (identified by ICD-0-3 code) diagnosed between 1990-2018 and directly causing patient demise were selected and data were collected on age at diagnosis, sex, race, median household income (in 2019 USD), community type (rural-urban continuum), and survival (in months). This cohort was separated into pediatric (ages 0-19, n = 1509) and adult (ages 20 and above, n = 28356) subgroups and independent survival analysis was conducted by income, community type, sex, race, and decade of diagnosis. Kaplan-Meier curves were visualized for each comparison. Log rank analysis of survival in the pediatric cohort showed greater mortality in females (p = 0.0224) and in the most recent decade (p < 0.0001). The same analysis in the adult cohort showed greater mortality in lower income groups, more rural community settings, females, patients categorized as White, and in the most recent decade (p < 0.0001 for all comparisons). Unlike in the adult population, income, community setting, and race were not associated with significant differences in survival in the pediatric population, prompting further investigation into healthcare delivery differences between pediatric and adult populations. Further study should focus on the cause of these discrepancies to improve equity in neurosurgical care.
OUTC-06. BEST PRACTICES FOR THE SUCCESSFUL ADMINISTRATION OF COMBINATION METRONOMIC ANTI-ANGIOGENIC AND INTRAVENTRICULAR THERAPY
Authors: Burnside Kasey L , Margol Ashley S , O’Halloran Katrina , Robison Nathan J , Rushing Teresa , Davidson Tom B , Rangan Kasey , Waters Kaaren
Published: June 2023

BACKGROUND

Combination metronomic anti-angiogenic and intraventricular therapy incorporates a customized administration of a five-drug oral antiangiogenic regimen with intravenous bevacizumab and intraventricular chemotherapy and is an effective treatment regimen for children with recurrent central nervous system embryonal tumors. This treatment can be administered while maintaining quality of life and avoiding severe side effects through personalized therapy schedules; however, dosing modifications, available dosage formulations, and complexity of medication administration creates challenges for families and clinical staff.

METHODS

A retrospective chart review was completed on 11 patients who received this treatment with various combinations of oral medications (thalidomide, etoposide, cyclophosphamide, celecoxib, and fenofibrate), intravenous (IV) medication (bevacizumab), and intraventricular chemotherapy (cytarabine, etoposide, and topotecan). We implemented successful nursing interventions, family education, variable scheduling options, dosage formulation selections, and innovative oral and intraventricular administration techniques.

RESULTS

Patients were able to successfully receive therapy for an average of 14 months and no patient came off for toxicity. Treatment was generally well-tolerated, with most toxicities being hematologic or gastrointestinal in nature.

CONCLUSION

Education, innovative dosing schedules, recognition of potential side effects, and medication administration allow for successful administration of this complex therapy.
OUTC-07. ANALYZING PREDICTORS OF LOSS TO FOLLOW-UP AS SEEN AMONG YOUNG SURVIVORS OF CENTRAL NERVOUS SYSTEM TUMORS FOR QUALITY IMPROVEMENT INTERVENTIONS AT DANA FARBER CANCER INSTITUTE
Authors: Cooney Tabitha , Tabatneck Mary , Stone Amelia
Published: June 2023

At Dana Farber Cancer Institute, children and young adults who have completed treatment for central nervous system tumors visit the Pediatric Neuro-Oncology Outcomes Clinic (“Empower”) for survivorship visits. By attending these long-term clinic visits, survivors can receive multidisciplinary services and undergo monitoring for disease recurrence. We used descriptive statistics and chi-square tests to investigate the relationship between loss to follow-up and sociodemographic factors among Empower patients. We reviewed medical records to gather data on 200 patients who had visited the clinic between 1-1-2015 and 1-1-2020, extracting information about sex, zip code, diagnosis, treatment received, and insurance type (private vs. public). We then indicated whether each patient had been “lost to follow-up,” defined as not returning to the clinic for >1,000 days after the recommended follow-up date. Among the 200 patients reviewed, 46 (23%) were lost to follow-up and 154 (77%) were not lost to follow-up. With respect to race and ethnicity, individuals identifying as Black, Asian, Middle Eastern, Native Hawaiian or Pacific Islander, Hispanic or Latino, or “Other” were more likely to be lost to follow-up than patients who exclusively identified as White (21% versus 39%; p=0.036). Additionally, individuals who were lost to follow-up were more likely to have been treated for low-grade gliomas as opposed to other CNS tumors (30% versus 13.6%; p=.015). Sex, the use of chemotherapy and radiation, and insurance type did not have a significant association with loss to follow-up. An analysis of the relationship between median household income and loss to follow-up is pending. The results imply that there is a significant association between non-white race, Hispanic or Latino ethnicity, a diagnosis of low-grade glioma, and loss to follow-up. The continuation of this study can provide the groundwork for interventions targeted at supporting patients who are at an increased risk of loss to follow-up.
OUTC-09. PEDIATRIC LOW GRADE GLIOMA SURVIVORS’ NEED FOR SURVIVORSHIP CARE: ‘ENGAGE’ A MULTIDISCIPLINARY, E-HEALTH INTERVENTION
Authors: McLoone Jordana , Hamayun Mashaal , Nagabushan Sumanth , Signorelli Christina , Wakefield Claire , Johnston Karen , Bell Rachael , Cohn Richard
Published: June 2023

Higher survival rates for children diagnosed with low-grade gliomas (LGG), compared to other brain cancers, often limit the survivorship resources afforded this cohort, despite potential long-term physical, functional and psychological impacts. We conducted a two-phase program of research, first evaluating LGG survivors’ need for support during the survivorship phase, followed by the development and pilot evaluation of a multidisciplinary, telehealth, survivorship program. Phase 1: We conducted a retrospective cohort study of children aged 0-16 years at diagnosis, diagnosed between 2000-2015, assessing psychosocial impact and quality of life. Phase 2: We developed ‘Engage Brain’, a multidisciplinary, telehealth program, designed to improve medical and psychosocial outcomes for childhood cancer survivors throughout their lifespan. Key components of Engage’s design include distance-delivered care to ensure access for all survivors irrespective of whether they live close to a tertiary, survivorship center; hospital-based expertise integrated with local, primary care services to ensure a model of care which is sustainable long-term; nurse-led care providing tailored education to encourage adoption of a prevention-focused healthy lifestyle to mitigate survivors’ personal risk and reduce ongoing costs to the individual and healthcare system; psychosocial focus, incorporating allied health staff (psychologist/social worker) as an integral aspect of care. Phase 1: 45 survivors participated (36% female, mean age 14.8 years, average 7.5 years post-treatment). Survivors reported high levels of anxiety (23%), depression (14%), fatigue (62%). Phase 2: 30 LGG survivors completed Engage Brain intervention (50% female, mean age 21 years, average 11.5 years post-treatment). 64% uptake, 10% attrition. Most (78%) of participants ‘agree’-‘greatly agree’ that Engage Brain provides ‘high-quality survivorship care’ and ‘help accessing survivorship care’. This program of research illustrates the long-term needs of LGG survivors, despite their lower risk status compared to other brain cancers, and the feasibility of providing a multidisciplinary, telehealth intervention to support them.
OUTC-11. RACE AND AGE ARE ASSOCIATED WITH ICD-10 DIAGNOSES IN THE POST-OPERATIVE PERIOD FOR PEDIATRIC PATIENTS WITH PRIMARY BRAIN TUMORS UNDERGOING NEUROSURGERY
Authors: Montgomery Canada , Plisiewicz Alexa , Zhao Chao , Yan Ying , Phillips Charles , Lehmann Kaitlin , Storm Phillip , Madsen Peter , Kline Cassie
Published: June 2023

BACKGROUND

Disparities in pediatric cancer care and outcomes are known to exist. This work evaluates the relationship of race, ethnicity, and social determinants of health (SDoH) on the post-operative neurosurgical course of pediatric neuro-oncology patients in a single-institution.

METHODS

Retrospective data were collected on patients undergoing initial neurosurgery for a primary central nervous system (CNS) tumor between May 2011 and April 2021. Newly attributed ICD-10 codes in the 30-day post-operative period were collected. Descriptive statistics were used to evaluate demographics, geographic region of residence, and insurance type. Logistic regression was performed to estimate the association between covariates and 30-day readmission as well as ICD-10 diagnoses that can complicate the postoperative course including cardiac/respiratory, bleeding, infection, wound, hardware implantation, and neurologic conditions. Linear regression was used to measure association of covariates and length of stay (LOS).

RESULTS

A total of 836 patients, median age 10.0 years, were included (n=368 females, 44%). Patients were predominantly white (69%) and non-Hispanic/Latino (88%). White (OR [95% CI] 0.55 [0.33,0.90], p=0.02), Native American/Indian (0.25 [0.07,0.89], p=0.03), and multiracial (0.24 [0.08,0.68], p=0.01) patients were significantly less likely to have new ICD-10 codes compared to Black patients. White patients trended toward shorter LOS (p=0.06) compared to Black patients. Younger patients were significantly more likely to have newly reported ICD-10 codes (0.95 [0.92,0.97], p<0.001), increased LOS (r=-0.59 [-0.87,-0.32], p<0.001), and 30-day readmission (0.81 [0.72,0.89], p<0.001). Sex, ethnicity, insurance type, and region had no significant association with outcomes. Income level analyses are ongoing.

CONCLUSION

Non-black patients were less likely to have new ICD-10 diagnoses reported after surgery for primary CNS tumors. Older age was a protective factor against new post-operative diagnoses, increased LOS, and mortality. More research is necessary to understand the relationship between race, ethnicity, SDoH and post-operative risk including possible mechanisms of interaction across variables.
OUTC-12. BLACK IN CANCER: EMPOWERING AND ENCOURAGING FUTURE BLACK CANCER LEADERS WHILST REDUCING CANCER DISPARITIES THROUGH EDUCATION AND ADVOCACY
Authors: Bonner Sigourney
Published: June 2023

From its inception in 2020, Black in Cancer has been modelling an action-oriented approach to improving representation across the cancer community. Black in Cancer (BIC) was founded during the racial justice protests that swept across the globe in the midst of a number of Black professionals aiming to promote visibility and sharing of resources within their respective groups leading to “Black in X” communities on social media and in particular twitter. This network was required in the cancer community with Black cancer researchers, clinicians and patient advocates being underrepresented and Black patients underserved.

Black or African American workers make up 12% of the U.S. working population but represent just 9% of STEM workers. Dissected even further, only 3% of medical oncologists are Black and training programs such as oncology fellowships have minimally increased between 2006 and 2018. For researchers, this disparity is even more prominent, as only 1% of all professors in biology at U.S.institutions are Black and just 0.6% in the UK. Studies show that Black researchers are about 55% less likely to receive NIH funding than white researchers. Several studies from AACR and Cancer Research UK show that Black patients are diagnosed at a later stage, with more aggressive cancers and have a higher mortality rate. Our organisation has two main initiatives to tackle these challenges, through our

Cancer Awareness Project (CAP)and the Mentorship and Outreach Program (MOP). These programmes have delivered $2 million in funding for Black cancer researchers at the postdoctoral level and above, and have also supported almost 40 undergraduate students through our mentorship program. Our CAP initiative has delivered a number of informational sessions to the community in how to identify symptoms, diagnosis pathways and how patients can be informed and empowered about their healthcare decisions.
HGG-11. APPLICATION OF SHUNT IN PEDIATRIC DIFFUSE INTRINSIC PONTINE GLIOMA COMPLICATED WITH HYDROCEPHALUS: A 10-YEAR EXPERIENCE FROM A SINGLE CENTER
Authors: Cai Linbo , Lai Mingyao , Li Juan , Ai Ruyu
Published: June 2023

OBJECTIVE

Currently, there is no unified treatment protocol for pediatric diffuse intrinsic pontine glioma with hydrocephalus. The present study aims to explore the clinical characteristics and the best intervention modality for pediatric diffuse intrinsic pontine glioma with hydrocephalus.

METHODS

The detailed data of children with diffuse intrinsic pontine glioma admitted to the Department of Pediatrics of Guangdong Sanjiu Brain Hospital from January 2010 to December 2021 were retrospectively analyzed. The effect of radiotherapy and shunt on the prognosis of pediatric diffuse intrinsic pontine glioma complicated with hydrocephalus was evaluated.

RESULTS

165 children with DIPG aged ≤18 years were included in the analysis, of whom 9 (5.5%) had mild ventricular dilatation, 48 (35%) had hydrocephalus, and 11 (22.9%) underwent cerebrospinal fluid shunting, of whom 10 (90.9%) underwent ventriculoperitoneal shunt and 1 (9.1%) underwent endoscopic third ventriculostomy. After shunt and radiotherapy, 53 cases of hydrocephalus could be evaluated, of which 37 patients (69.8%) were significantly relieved, and 16 (30.2%) were not. 99 children had tumor progression after treatment, including 41 cases (41.4%) with hydrocephalus and 5 cases (12.2%) with ventriculoperitoneal shunt. A total of 138 children were included in the survival analysis, which revealed that hydrocephalus, mild ventricular dilatation, and no ventricular abnormality had no effect on the prognosis (p=0.944). The treatment of hydrocephalus at the initial diagnosis did not affect the prognosis, p=0.405. The median survival of the hydrocephalus remission group post-radiotherapy was 12 months, and 8 months for the non-remission group, p=0.042. The median survival was 20 months in the shunt group and 8 months in the untreated group (p=0.005).

CONCLUSIONS

Asymptomatic ventricular enlargement in pediatric diffuse intrinsic pontine gliomas does not require surgical intervention. Hydrocephalus remission post-radiotherapy is a favorable prognostic indicator. Cerebrospinal fluid shunt could improve the prognosis of children with hydrocephalus when the tumor progresses post-radiotherapy.
HGG-16. COMPARATIVE ANALYSIS OF AUTOPHAGY IN DRUG RESPONSES AND AGGRESSIVE BEHAVIOR OF ADULT VERSUS PEDIATRIC GLIOMA CELL LINES
Authors: Yenidogan Irem , Peker Nesibe , Deveci Gamze , Aygun Bera , Kirmizi Dondu , Al Nathalie , Asarcikli Fikret , Oflaz Sozmen Banu , Akyoldas Goktug , Kulac Ibrahim , Solaroglu Ihsan , Gozuacik Devrim
Published: June 2023

Central nervous system tumors are the most common solid cancer and a leading cause of cancer-related deaths in children. Glioma is the most challenging pediatric CNS tumor with therapy resistance and poor prognosis in pediatric patients. Although histopathological analyses revealed similarities with adult brain glioma, emerging evidence suggests that the deregulated molecular pathways in pediatric glioma (p-GM) are different from that of adults. Autophagy, a cellular clearance system and a drug resistance mechanism, has been implicated in glioma progression, invasion, and relapse, yet its role in pediatric patients is not well documented. In this study, we compared the autophagic capacity of adult versus p-GM cell lines and evaluated the effect of autophagy manipulation on drug responses. In addition, migration, extracellular matrix invasion ability, and the metabolism of pediatric and adult gliomas were compared and the contribution of autophagy to the aggressive phenotype was evaluated.
HGG-21. ABERRANT SPLICING OF CLK1 IN PEDIATRIC HIGH-GRADE GLIOMAS DISRUPTS KEY ONCOGENIC TRANSCRIPTIONAL PROGRAMS
Authors: Naqvi Ammar , Ennis Brian , Corbett Ryan , Lahiri Aditya , Geng Zhuangzhuang , Kin Run , Gaonkar Krutika , Rathi Komal , Conkrite Karina , Seghal Priyanka , Hayer Katharina , Kraya Adam , Foster Jessica , Madsen Peter , Thomas-Tikhonenko Andrei , Storm Phillip , Resnick Adam , Rokita Jo Lynne
Published: June 2023

While the majority of somatic DNA coding alterations in pediatric brain tumors have been profiled, studies exploring transcriptional mechanisms remain underexplored. We systematically characterized aberrant splicing in primary tumors of seven broad histologies of pediatric brain tumors. We obtained RNA-seq data (n = 792) from the Open Pediatric Brain Tumor Atlas and integrated rMATs splice event calls with UniProt Knowledgebase to quantify and prioritize differential alternative splicing events with proteomic potential. We identified three splicing-driven biological clusters and found pediatric high-grade gliomas (pHGGs) to be uniquely heterogeneous, spanning all three clusters. We also discovered that tumors with high splicing burden (SB) had significantly worse overall survival than tumors with low SB (p < 1x10-4). Furthermore, pHGGs (n = 154) displayed the greatest splicing heterogeneity with 20,620 exon splicing aberrations (pval/FDR < 0.05) in 3,294 genes that resulted in a gain or loss of known functional sites. We prioritized targetable kinases and found that CDC-like kinase 1 (CLK1), a known modulator of master splicing regulators, exhibited significantly increased exon 4 inclusion (p < 0.05, ΔPSI >= |.20|), and subsequent gain of two phosphorylation sites, in tumors compared to matched non-tumor tissue. Exon 4 inclusion was significantly correlated with increased CLK1 expression (r = 0.57, p = 7.8 x10-9), which we posit results in hyper-activity of CLK1 and aberrant splicing of its targets in these tumors. Furthermore, predicted CLK1 gene targets (n = 101) were enriched for cancer-related pathways, such as DNA repair (odds ratio > 2, p < 0.005). In summary, we describe aberrant splicing in pHGGs as an alternative mechanism that could drive tumorigenesis. Future work will focus on molecular validation and therapeutic targeting of CLK1 in available pHGG models, potentially opening new therapeutic strategies in children with brain tumors.
HGG-23. DECIPHERING THE RELATIONSHIP OF MICROSATELLITE-INSTABILITY AND MUTATIONAL BURDEN IN HIGH-GRADE GLIOMA PATIENTS WITH CONSTITUTIONALLY IMPAIRED DNA DAMAGE RESPONSE
Authors: Blattner-Johnson Mirjam , Sturm Dominik , Jones Barbara C , Previti Christopher , Sievers Philipp , Jäger Natalie , Hirsch Steffen , Dikow Nicola , Sahm Felix , Kramm Christof M , Witt Olaf , Pfister Stefan M , Jones David T W
Published: June 2023

Multiple large-scale genomic studies across pediatric tumors have reported an overall frequency of ~6-10% of patients with constitutional pathogenic variants, but associations of cancer predisposition with distinct tumor types vary between zero and 100%. We analyzed sequencing and DNA methylation data from 363 patients to explore the landscape of cancer predisposition in pediatric high-grade gliomas (pedHGG). Almost all pedHGG with constitutional alterations resulting in DNA mismatch repair deficiency (MMRD) were classified to IDH-mutant or pedRTK1a DNA methylation classes. Conversely, 70% of pedRTK1a and nearly 60% of IDH-mutant pedHGG (<18 years) arose in patients with either Lynch or cMMRD syndromes. Biallelic MMR inactivation (cMMRD) was found almost exclusively to affect the exchangeable part of the mismatch repair machinery complex (MSH6/PMS2; 75%), while heterozygous loss affected non-exchangeable core members MLH1 or MSH2 (93%). IDH-mutant MMRD tumors showed substantially lower overall tumor mutational burden (TMB < 40), less microsatellite instability, and frequent MSH6 mutation (60%), while pedRTK1-MMRD tumors often harbored additional alterations in POLE, leading to an ultra-mutator phenotype (TMB < 100), had higher microsatellite instability burden, and more often linked to PMS2 or MSH2 loss. Both IDH-mutant- and pedRTK1-MMRD tumors were associated with poor outcome, with MMRD-associated IDH-mutant pedHGG resulting in significantly shorter survival compared with sporadic IDH-mutant tumors (p=0.0015). We observed a nonlinear correlation between increasing numbers of point mutations, InDels and microsatellite instability. Exemplary, patients with pathogenic constitutional variants in MSH6 showed a significantly lower number of InDels compared with overall TMB, which might be due to repair ability of the replacement protein MSH3. As newer studies point towards an important role of InDels in antigen presentation and therefore as a potential biomarker for immune checkpoint inhibition, further exploration of these detailed molecular associations in conjunction with clinical outcome and response data is warranted.
HGG-24. A NOVEL ONCOGENIC ROLE FOR MENIN IN GLIOMA
Authors: Yang Yanhong , Saito Yuhki , Goldberg Elena , Mrad Zaki Abou , Larsen Alexandra Giantini , Ghita Greta , Tabar Viviane
Published: June 2023

High-grade gliomas (HGGs) represent the most common subtype of primary malignant tumors from brain or spinal cord. With about 18 months overall survival time, HGGs is the leading cause of death from primary brain tumor. Survival outcomes have not improved significantly over the past two decades despite major research and therapeutic discovery efforts. Previous work from our lab suggested a role for menin in initiation and maintenance of pediatric high-grade glioma. Here we describe a critical oncogenic role of menin (encoded by the MEN1 gene) in maintaining HGGs proliferation. Using a panel of early passage HGG lines harboring diverse genomic alterations, we demonstrate that silencing of MEN1 blocks proliferation (60%-80%) of a subset (8/12) of HGGs, independent of their genomic alteration profile. An oncogenic role of menin has been described in MLL-rearrangement leukemia, where menin complexes with MLL to affect H3K4 trimethylation and activate leukemogenic genes. However, we found that the menin-MLL interaction is not associated with glioma. Instead, our mechanistic studies suggest that menin plays a critical role in maintaining H3K27 acetylation marks across the genome. Using immunoprecipitation and mass spectrometry, we identified HMGN1 (high mobility group nucleosome-binding domain 1 protein) as a putative novel menin partner. HMGN1 is a chromatin remodeling protein associated with chromatin accessibility and H3K27 acetylation. Transcriptional studies of patient-derived HGGs revealed that knockout of MEN1 and silencing of HMGN1 both resulted in broad repression of genes associated with proliferative tumor progenitor clusters. Ongoing work is aimed at therapeutic targeting by novel menin inhibitors. Our work demonstrates the role of epigenetic remodeling in controlling glioma proliferation and identifying novel therapeutic targets.
IMG-03. HARNESSING COMPUTATIONAL IMAGING, SCALABLE CLOUD-BASED WORKFLOWS, AND MULTI-MODAL DATA ANALYTICS WITH INTEROPERABLE SOFTWARE PLATFORMS IN PEDIATRIC NEURO-ONCOLOGY; THE ROAD AHEAD FOR CHILDREN’S BRAIN TUMOR NETWORK (CBTN)
Authors: Nabavizadeh Ali , Familiar Ariana , Kazerooni Anahita Fathi , Viswanathan Karthik , Kim Meen Chul , Lubneuski Alex , Heath Allison P , Vossough Arastoo , Storm Phillip B , Resnick Adam C
Published: June 2023

Neuroimaging is acquired as part of the clinical standard of care for treatment of brain tumor patients. Capitalizing on this data and integration of imaging with other data types to perform predictive analytics is an increasing need. Here, we review the efforts at CBTN in the past couple of years to establish user-friendly workflows to support the entire imaging data lifecycle and to bridge access to multi-modal datasets with scalable analytics scale, to empower researchers to make breakthrough discoveries that will advance patient care. An automated deep learning-based brain extraction and tumor subregion segmentation model based on a multi-institutional dataset was developed that can reliably segment the MRI scans of children across a variety of brain tumor histologies. This model was subsequently integrated into an end-to-end imaging pipeline for collecting, managing, and analyzing clinically acquired radiology exams of the CBTN consortium with processing of 12,500 exams to date. A public website was also created to allow users to search and explore the dataset based on sequence labels, and clinical and imaging attributes. In addition, we established a scalable workflow and processes for de-identification, ingestion, quality control, and management of digital pathology slides on CBTN (over 8,000 slides to date). Finally, we established interoperability between imaging (Flywheel) and molecular (CAVATICA) platforms deployed in cloud ecosystems which allows streamlined, user-friendly workflows to ingest and harmonize files, perform cohort selection, prepare data using standard processing packages and cloud resources, and conduct analysis on extracted multi-modal feature sets. The described workflow lays the foundation for broad use of imaging studies and access to multi-modal datasets and analytics, with the goal of empowering researchers to make breakthroughs in patient care. The next step is to apply these tools in the context of clinical trials.
IMG-05. A MULTI-INSTITUTIONAL AND MULTI-HISTOLOGY PEDIATRIC-SPECIFIC BRAIN TUMOR SUBREGION SEGMENTATION TOOL: FACILITATING RAPNO-BASED ASSESSMENT OF TREATMENT RESPONSE
Authors: Kazerooni Anahita Fathi , Khalili Nastaran , Haldar Debanjan , Viswanathan Karthik , Familiar Ariana , Bagheri Sina , Anderson Hannah , Arif Sherjeel , Madhogarhia Rachel , Kim Meen Chul , Mahtabfar Aria , Storm Phillip B , Resnick Adam , Ware Jeffrey B , Davatzikos Christos , Vossough Arastoo , Nabavizadeh Ali
Published: June 2023

Current response assessment in pediatric brain tumors (PBTs), as recommended by the Response Assessment in Pediatric Neuro-Oncology (RAPNO) working group, relies on 2D measurements of changes in tumor size. However, there is growing evidence of underestimation of tumor size in PBTs using 2D compared to volumetric (3D) measurement approach. Accordingly, automated methods that reduce manual burden and intra- and inter-rater variability in segmenting tumor subregions and volumetric evaluations are warranted to facilitate tumor response assessment of PBTs. We have developed a fully automatic deep learning (DL) model using the nnUNet architecture on a large cohort of multi-institutional and multi-histology PBTs. The model was trained on widely available standard multiparametric MRI sequences (T1-pre, T1-post, T2, T2-FLAIR) for segmentation of the whole tumor and RAPNO-recommended subregions, including enhancing tumor (ET), non-enhancing tumor (NET), cystic components (CC), and peritumoral edema (ED). As a prerequisite step for accurate tumor segmentation, we also generated another DL model based on DeepMedic for brain extraction from mpMRIs. The models were trained on an institutional cohort of 151 subjects and independently tested on 64 subjects from the internal and 29 patients from external institutions. The trained models showed excellent performance with median Dice scores of 0.98±0.02/0.97±0.02 for brain tissue segmentation, 0.92±0.08/0.90±0.17 for whole tumor segmentation, 0.76±0.31/0.87±0.29 for ET subregion, and 0.82±0.15/0.80±0.28 for segmentation of non-enhancing components (combination of NET, CC, and ED) in internal/external test sets, respectively. The automated segmentation demonstrated strong agreement with expert segmentations in volumetric measurement of tumor components, with Pearson’s correlation coefficients of 0.97, 0.97, 0.99, and 0.79 (p<0.0001) for ET, NET, CC, and ED regions, respectively. Our proposed multi-institutional and multi-histology automated segmentation method has the potential to aid clinical neuro-oncology practice by providing reliable and reproducible volumetric measurements for treatment response assessment.
IMMU-08. SALVAGE IMMUNOTHERAPIES FOR REPLICATION REPAIR DEFICIENT (RRD) HIGH-GRADE GLIOMA FAILING ANTI-PD1 MONOTHERAPY: AN IRRDC REPORT
Authors: Das Anirban , Fernandez Nicholas R , Levine Adrian , Bianchi Vanessa , Stengs Lucie , Edwards Melissa , Nobre Liana , Pugh Trevor J , Tsang Derek S , Ertl-Wagner Birgit , Morgenstern Daniel A , Bouffet Eric , Hawkins Cynthia , Tabori Uri
Published: June 2023

BACKGROUND

Although the initial response to immune-checkpoint inhibition (ICI) for patients with DNA replication-repair deficient high-grade glioma (RRD-HGG) is encouraging, the role of immune-based salvage approaches for those progressing on anti-PD1 monotherapy is unknown.

METHODS

We performed an international registry study of patients managed using central molecular, genomic, radiological review and treatment recommendations between 2015-2021. Post-progression treatment included re-irradiation where feasible, and continuation of anti-PD1 with anti-CTLA4 (ipilimumab), or a MEK-inhibitor (MEKi). Outcomes included radiological response (iRANO), toxicity, second progression-free (PFS2) and overall survival (OS2). Companion biomarkers were performed centrally.

RESULTS

Among 75 patients with RRD-HGG receiving PD-1 blockade, 20 are progression-free at a median follow-up of 44.6-months. For 55 patients with relapsed/progressive tumors, continuation of ICI (n=38) resulted in median OS2 of 11.6-months (51% alive) versus 1.2-months when ICI was discontinued (n=17; no survivors, p<0.001).

The combination of ipilimumab/nivolumab (n=24) resulted in response/stable disease in 75% with median OS2 of 12.1-months but high autoimmune toxicities (54%). The addition of MEKi led to response in 3/5 patients with prolonged survival. The addition of re-irradiation improved median OS2, especially in tumors with lower mutation burden (p=0.002), and those who received ipilimumab (median OS2=33-months).

Several biological insights were gained. Early radiological ‘flare’ in 33% of RRD-HGG on combined immunotherapy and radiation were associated with immunogenic radiation induced signatures. MEKi responses were associated with reinvigoration of peripheral immune response. Finally, delayed, sustained responses were observed in ultra-hypermutant RRD-HGG exhibiting changes in somatic mutational spectra.

CONCLUSION

These data suggest that the continuous mutagenesis renders hypermutant RRD-HGG susceptible to checkpoint inhibitors beyond initial progression. The combination with re-irradiation and additional immune/targeted agents can maximize survival in these children and young adults. Future research should focus on biology-driven rational immunotherapy combinations that also result in lower toxicity to maximize patient benefit.
IMMU-09. DISSECTING THE INTERPLAY BETWEEN THE ENDOGENOUS IMMUNE RESPONSE AND ONCOLYTIC VIRUS THERAPY IN PEDIATRIC BRAIN TUMORS
Authors: Hoare Owen , Jung Jangham , Inagaki Akihito , Yu Bohyeon , Collins Sara , Chuntova Polly , Barcova Maria , Patel Trishna , Kasahara Noriyuki , Müller Sabine , Diaz Aaron
Published: June 2023

Oncolytic virus (OV) elicits an antitumor immune response in addition to tumor-cell killing. However, it is unknown if a pre-existing antitumor immune response aids or hinders OV therapy. To study the interplay between the endogenous immune response and OV we profiled tumors from immunocompetent intracranial models of medulloblastoma and glioblastoma treated with measles virus (MV) and retrovirus (Toca-511), using single-cell and bulk-RNA sequencing. For both models, we assayed specimens from two treatment groups, a mid-treatment group where mice were sacrificed upon observation of treatment response, and a post-treatment group where treatment-resistant mice were sacrificed when they had succumbed to their disease. As controls, we included a cohort treated with heat-inactivated virus and a cohort treated with PBS. Both MV and Toca-511 OV therapies significantly improve survival compared to controls. From each of the MV and Toca-511 treatment/control groups, 3 mice per group were profiled via RNA sequencing. Additionally, tumors from 5 mice treated with MV alone and 4 mice treated with MV and anti-PD1 immune-checkpoint blockade (ICB) were subjected to single-cell RNA sequencing (scRNA-seq). ScRNA-seq generated 38,491 cells after filtering for quality control and successfully captured both endogenous and viral RNAs. We found that in samples treated with both OV and ICB there were higher rates of virally infected cells, depletion of M2-polarized myeloid infiltrates, and depletion of endothelial cells, compared to controls. Comparing virally infected tumor cells to non-infected controls we observed a down-regulation of translation initiation-complex genes and an upregulation of markers of oxidative phosphorylation. Infected cells from treatment-resistant tumors upregulate antigen presentation and myeloid chemotaxis genes. These studies show that OV enhances survival and anti-brain-tumor immunity. They support MV and ICB as potentially being synergistic. They suggest translation control and perturbation of the myeloid compartment as strategies for enhancing intracellular MV proliferation and infection efficiency, respectively.
IMMU-12. T CELL SEQUESTRATION IN POSTERIOR FOSSA TUMORS
Authors: Wilson Zach , Fecci Peter
Published: June 2023

INTRODUCTION

T cell dysfunction contributes to immune escape in patients with cancer and is particularly severe in CNS tumors. T cell sequestration is a contributing mechanism of T cell lymphopenia and lymphoid organ contraction occurring in treatment naive patients and mice with Glioblastoma. Our group demonstrated that this phenomenon is mediated by loss of S1P1 surface expression on T-Cells within the bone marrow. We demonstrated in murine models that reversing T cell sequestration via stabilization of surface S1P1 licenses T cell activating therapies. As pediatric brain tumors much more commonly involve the posterior fossa and brainstem, the present work set out to assess whether T cell sequestration also occurs in tumors located in the cerebellum (medulloblastoma, high grade glioma).

METHODS

CT2A murine glioma cells were orthotopically implanted into the posterior fossa of C57BL/6 mice. Blood, spleen, and bone marrow were analyzed when tumors became sizable (Day 18-21). Flow cytometry was utilized to measure total, CD4+, and CD8+ T cell counts, as well as the proportion of T cells expressing surface S1P1.

RESULTS

Compared with mice injected with methylcellulose, mice bearing cerebellar CT2A tumors demonstrated significantly decreased splenic weight, increased total, CD4, and CD8 T cell counts in the bone marrow, and a decreased proportion of surface S1P1 expressing T cells within the bone marrow.

CONCLUSIONS

T cell sequestration within the bone marrow associated with loss of surface S1P1, as previously demonstrated in high grade tumors of the forebrain, also occurs with tumors implanted into the cerebellum, suggesting that the genesis T cell sequestration is independent of location within the brain. Future work on this project will add additional tumor histology to our analysis as well as measuring the effects of S1P1 stabilization on response to T cell activating therapies in these models of cerebellar tumors.
IMMU-17. DEVELOPMENT OF AN INTRACRANIAL CANNULA IMPLANTATION SYSTEM FOR SERIAL LOCOREGIONAL CAR T CELL INFUSIONS IN MICE
Authors: Harvey Kyra , Madsen Peter , Smith Tiffany , Griffin Crystal , Patterson Luke , Vitanza Nicholas , Storm Phillip , Resnick Adam , Foster Jessica
Published: June 2023

Pediatric CNS tumors are responsible for the majority of cancer-related deaths in children. As many tumors lack efficacious treatments, there is a crucial need to develop more promising therapeutic options, such as immunotherapies. Of particular interest is the use of chimeric antigen receptor (CAR) T cell therapy. Current clinical trials are ongoing targeting the cell surface molecules HER2, EGFR, B7-H3, IL13RA2, and the disialoganglioside GD2. While the majority of trials deliver CAR T cells into the cerebral spinal fluid with repeated doses, this has not been completed in preclinical models due to difficulty performing multiple stereotactic surgeries. To evaluate repeated locoregional delivery of CAR T cells in preclinical murine models, we established an indwelling catheter system that recapitulates indwelling catheters currently being used in human clinical trials. Following orthotopic injection and engraftment of tumor cells in mice, intratumoral placement of a fixed guide cannula is completed on a stereotactic apparatus and secured with screws and acrylic resin. Treatment cannulas are then inserted through the fixed guide cannula for repeated CAR T cell delivery. With this system, we tested novel CAR T cells directed against glypican 2 (GPC2), resulting in significant tumor regression in medulloblastoma model 7316-4509 (p<0.01), as well as significantly prolonged survival in thalamic diffuse midline glioma 7316-3058 (p<0.05). Stereotactic placement of the guide cannula can be adjusted to deliver CAR T cells directly into the lateral ventricle or other locations in the brain. This platform offers a reliable mechanism for preclinical testing of repeated intracranial infusions of CAR T cells and other novel therapeutics, offering a superior preclinical model for translation to clinical trials.
IMMU-19. NIVOLUMAB-INDUCED CNS DEMYELINATION IN A 15-YEAR-OLD WITH CLASSIC HODGKIN LYMPHOMA
Authors: Ramirez Alejandra , Jonokuchi Alexander , Hijiya Nobuko , Gomes William , Wesley Sarah , Kaur Gurcharanjeet
Published: June 2023

INTRODUCTION

Nivolumab associated neurologic immune-related adverse events (irAEs) have been reported in less than 1% of patients and mainly in the adult population. Here we present a pediatric case of nivolumab related CNS demyelination. Case description: 15-year-old male with nodular sclerosis stage III classic Hodgkin lymphoma was enrolled to receive chemotherapy following SWOG S1826 protocol. Eight weeks after the first dose of nivolumab, he had a single episode of seizure. Prolonged EEG showed no epileptiform discharges. Levetiracetam was initiated. Initial MRI showed a non-enhancing T2 hyperintense focal cortical thickening in the left primary motor cortex. CSF studies were significant for mild lymphocytic pleocytosis. One dose of nivolumab was held with subsequent doses given. Levetiracetam was continued and follow-up EEGs were normal. Repeat MRI done three months later showed multiple new parenchymal hyperintense lesions including in the anterior temporal lobe with central curvilinear enhancement, and faintly enhancing lesions in the left fusiform gyrus, juxtacortical white matter of the right middle temporal gyrus, and left superior cerebellar peduncle, findings consistent with CNS demyelination. At this time, CSF showed 9 WBCs (94% lymphocytes) and oligoclonal bands with negative cytology and flow cytometry making CNS lymphoma highly unlikely. The last two doses of nivolumab were held and he was started on methylprednisolone. The most recent MRI ten weeks after the last dose of nivolumab showed resolution of the abnormal findings.

DISCUSSION

There is limited published literature about neurologic complications of immune checkpoint inhibitors (ICPis) in the pediatric population. CNS demyelination and other neurologic irAEs should be suspected in patients presenting with new neurologic symptoms who started any ICPi within the past three months and after other causes including disease progression, metastasis, metabolic or infectious disorders have been ruled out. Treatment varies depending on severity but includes discontinuation of the ICPi and steroids.
IMMU-22. ALLOGENEIC NK CELLS SECRETING IL15 AND RESISTANT TO TGF-β Show Antitumor Activity Against Gliobastoma
Authors: Muniraj Nethaji , Chaudhry Kajal , Terao Joshua , Barron Luke , Suri Vipin , Bollard Catherine , Cruz Conrad Russell
Published: June 2023

INTRODUCTION

High grade brain cancers, like most solid tumors, often relapse and are resistant to current therapies. Limited efficacy to cell therapy may be related to intratumoral heterogeneity and the suppressive tumor microenvironment. Hence, we aimed to modify allogeneic natural killer (NK) cells, which can recognize expressed tumor stress ligands, to resist TGF-β and secrete IL15.

METHODS

Cord blood-derived NK cells were expanded and modified to express IL15 and a dominant negative receptor (DNR) against TGF-β. NK cell product activity against the GBM cell line U87MG were evaluated in vitro and in vivo. The behavior of these cells were also analyzed ex vivo, to evaluate the impact (including potential toxicity) of increasing the potency of this allogeneic NK cell product.

RESULTS

While animals injected with NK cells secreting IL15 and expressing DNR successfully cleared tumors 6 days after T cell infusion, we did not observe significant differences in survival between the groups (no treatment control mice vs treated with mock-transduced NK cell vs DNR-transduced NK cells vs IL-15/DNR-transduced NK cells). Therefore, we sought to determine whether cytokine-related toxicity was responsible for death in the setting of tumor clearance. We compared no treatment control mice vs mice treated with mock-transduced or IL-15/DNR-transduced NK cell products. Elevated levels of IL-15 were detected in the plasma of mice treated with IL-15/DNR-transduced NK cells. These elevated IL-15 levels corresponded with NK cell persistence in the brain measured by ddPCR. However, no other cytokines were upregulated.

CONCLUSIONS

We observed improved tumor clearance when NK cells were both protected against immune suppressive TGF-β and were capable of secreting the stimulatory cytokine IL15. We are currently performing additional experiments to determine whether toxicity from IL15 secretion occurs. To potentially mitigate this toxicity we plan to engineer a suicide gene into these constructs.