tbuckley/cabot-search huggingface dataset:
MDB-63. AN INTERNATIONAL META-ANALYSIS OF SHH MEDULLOBLASTOMA SUBTYPES DEFINES A CLINICALLY SIGNIFICANT HIGH-RISK VARIANT OF SHH-SUBTYPE 3
Authors: Edward C Schwalbe, Martin Sill, Hiro Suzuki, Frederic Charron, Michael D Taylor, Stefan M Pfister, Steven C Clifford
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND The distinction of MBSHH into four methylation-dependent subgroups was recognized by the WHO in 2021. However, these subgroups have not previously been defined by international experimental consensus and their clinico-molecular features and behavior have not formally been investigated in large cohorts. We aimed to robustly identify SHH subgroups through analysis of MBSHH with DNA-methylation profiling. METHODS A cohort of 683 MBSHH, confidently classified using the Heidelberg classifier v12.5, was assembled for analysis from multiple international studies. To define subgroups, we applied consensus sampling-based clustering approaches to tumor methylomes, including assessment of confidence in class-definition and inter-technique concordance. The clinico-molecular features of consensus subgroups were investigated. RESULTS Lowest complexity analysis supported the division of MBSHH into the 4 WHO-subtypes. SHH-1 and SHH-2 were associated with lower age and infrequent mutations of PTCH1/SUFU; SHH-2 was distinguished from SHH-1 by enriched MBEN histology, absence of chromosome 2 gain, less frequent metastasis and more favorable overall-survival. SHH-4 presented in older children and adults (3-57; median 24 years), and was primarily defined by mutations in U1-snRNA (67/72). Consensus analyses supported the division of SHH-subgroup-3 into three. Importantly, the SHH-3C subtype was associated with a coalescence of high-risk features (LCA histology, TP53mut, MYCNamp/GLI2amp) alongside 3p, 10q and 17p loss, and had dismal survival. The remaining SHH-3A/B subtypes were characterized by 9q loss, frequent focal amplifications of TERT and PPM1D, and equivalent better survival. CONCLUSIONS This study affirms the distinction of MBSHH into 4 major subgroups. For infant disease, SHH-2 is a favorable-risk marker. For childhood-MBSHH, the SHH-3C subtype provides a molecular definition of high-risk that subsumes other previously-defined high-risk disease markers (LCA, MYCNamp, TP53mut) into a unified high-risk disease group. The other SHH-3 subtypes behave similarly and are favorable-risk. These subtypes have potential to enhance molecularly-guided risk-stratification in routine diagnostics, to improve patient outcomes and quality-of-life.
HGG-46. PEDIATRIC RADIATION-INDUCED GLIOMA PATIENT SAMPLES AND NOVEL PATIENT-DERIVED MODELS REVEAL TRANSLATIONALLY RELEVANT TREATMENT SUSCEPTIBILITIES AND POTENTIAL GERMLINE RISK FACTORS
Authors: John DeSisto, Aaron Knox, Mathew Slade, Gabrielle Link, Yonghua Zhuang, Andrew Donson, Kristen Miller, Elinor Barsh, Michael Arnold, Gregory T Armstrong, Smita Bhatia, Sana D Karam, Natalie Serkova, Rajeev Vibhakar, Nicholas Foreman, Adam L Green
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Pediatric radiation-induced glioma (RIG) is an incurable secondary high-grade glioma (HGG) afflicting up to 4% of children who previously received cranial radiotherapy (RT) for other malignancies. RIG accounts for up to 10% of pediatric brain tumor deaths. It has no known genetic risk factors nor effective treatment and is uniformly fatal, partly due to extremely limited available models. Our recent molecular characterization of patient samples showed that while RIG and primary pediatric HGG share histological similarities, their genetic alterations and gene expression profiles differ. METHODS We obtained germline DNA sequencing from 28 RIG patients and 112 matched controls who received RT but did not develop RIG. In addition, we developed cell culture and murine orthotopic patient-derived xenograft (PDX) models from four RIGs. We conducted single-cell RNA-seq (scRNA-seq), drug screening/validation, and CRISPR functional screening on our novel models. RESULTS Germline mutations in TP53, PARP10, POLI, DCLRE1A, and MLH3 were more common in RIG patients than controls (p&amp;lt;0.002). Our matched cell culture and PDX models of RIG represent the genetic diversity of the disease. The PDX models form tumors in 30-120 days and closely recapitulate human RIG by histology and scRNA-seq. They show susceptibility across models to DNA-damaging treatments (etoposide, irinotecan, radiation), as well as MEK, PARP, and proteasome inhibition, with orthogonal supporting findings via CRISPR screening. Several two-treatment combinations also show efficacy and synergy across models, including radiation and trametinib in vivo (logrank p=0.029). Discussion: RIG is an understudied but major cause of pediatric CNS tumor mortality that differs genetically from primary pediatric HGG. Our findings suggest specific germline alterations in DNA repair pathways may put some patients at higher risk of developing RIG after cranial RT. We also introduce the first set of patient-derived RIG models in order to advance translational RIG research, with characterization of translationally relevant treatment susceptibilities.
NURS-22. NAVIGATING DISPARITIES: COMPREHENSIVE CARE AND ACCESS TO CLINICAL TRIALS FOR ADOLESCENTS AND YOUNG ADULTS WITH CENTRAL NERVOUS SYSTEM TUMORS
Authors: Courtney Briamonte, Susan Holtzclaw, Micah Higgins, Carly Hoffman, Michele McHugh, Ashley Meyer, Shannon Raber, Kasey Rangan, Cindy Schmus, Kenny Seidl, Marylynne Strachan, Kaaren Waters, Lanipua Yeh-Nayre
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Central nervous system (CNS) tumors are one of the most common causes of cancer-related death in the adolescent and young adult (AYA) age group. Despite being a prevalent cancer diagnosis, adolescents and young adults continue to be underrepresented in clinical trials. Literature review shows a notable lack of research focused on clinical care, reproductive health, and psychosocial aspects specific to this population. The longstanding issue of low AYA participation in clinical trials persists across various cancer types, with a particular scarcity of data regarding CNS tumors. Notably, the lack of participation in clinical trials has been associated with worse survival outcomes and increase in frequency and severity of treatment-related toxicity, emphasizing the critical impact of this issue on patients’ overall morbidity and mortality. The literature underscores the under-representation of AYAs with CNS tumors in neuro-oncology trials.. METHODS This talk will review challenges faced by adolescents and young adults (AYAs) diagnosed with central nervous system (CNS) tumors.We will discuss the necessity for molecular profiling in the diagnostic workup of CNS patients to delineate tumor biology and guide treatment plans, including clinical trial access. To address the insufficient understanding of best practices for this group, there is a crucial call for expanding access to clinical trials. We will explore barriers to clinical trial access and provide case examples of successful and unsuccessful work with AYA patients with CNS tumors with ideas to improve access. Finally, we will discuss the holistic care of AYAs with CNS tumors through a multidisciplinary approach, incorporating expertise in neuro-oncology, oncofertility, palliative care, and psychosocial aspects within both pediatric and adult care settings RESULTS N/A CONCLUSIONS By the end of this presentation, pediatric RNs and APPs will have an understanding of the differences in caring for this unique population of patients including benefits of enrolling adolescents and young adults with CNS tumors in clinical trials.
NURS-12. NEURO-RADIOLOGY 101 FOR RNS AND APPS
Authors: Marylynne Strachan, Courtney Baker Briamonte, Micah Higgins, Susan Holtzclaw, Michele McHugh, Ashley Meyer, Shannon Raber, Kasey Rangan, Cindy Schmus, Kenny Seidl, Kaaren Waters, Lanipua Yeh-Nayre, Carly Hoffman
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Magnetic Resonance Imaging (MRI) brain are the gold standard of diagnosing pediatric brain tumors. In pediatrics, MRI’s are often presented at new diagnosis or recurrence at tumor boards, which includes APP and RN’s in a multidisciplinary approach. By providing basic understanding of MRI imaging and sequencing, APP’s and RN’s will be able to participate and understand patient treatment discussions. METHODS During the presentation, we will review the 3 common planes used in MRIs: axial, coronal, and sagittal. We will then discuss the common MRI sequences, including T1, T2, FLAIR, DWI, and post-contrast imaging and discuss which common brain tumors and anatomy are best seen on said sequences. RESULTS NA. CONCLUSIONS By the end of this presentation, pediatric RNs and APPs will have the basic understanding of MRI images and feel more confident to participate in multidisciplinary tumor board discussions.
HGG-52. MULTI-INTEGRIN TARGETING EFFECTIVELY SUPPRESSES DIFFUSE MIDLINE GLIOMA MIGRATION
Authors: Rodrigo Cartaxo, Edwin Nieblas-Bedolla, Michael Niculcea, Madeline Miclea, Ruby ` Siada, Kallen Schwark, Sunjong Ji, Ananya Gera, Robert Doherty, Stefanie Galban, Nicholas Nuechterlein, Toshiro Hara, Jack Parent, Mariella Filbin, Carl Koschmann
Journal: Neuro-Oncology (2024)

Abstract Diffuse midline gliomas (DMGs) are aggressive tumors characterized by infiltration into normal midline brain tissue, hindering surgical resection and contributing to overall morbidity and mortality. We established a novel two-step pooled whole genome CRISPR-Migration screen by using serum-free conditions and laminin-dependent cell attachment, mimicking cell migration on brain vasculature scaffolds, a common feature in glioblastoma (GBM). Comparing DMG and GBM primary cell lines (n=5), genes involved in focal adhesion (ITGB1, CRKL, PARVA, PTK2, FERMT2) were identified as significantly restricting migration in all cell lines. Multi-institutional transcriptomic data revealed an association of expression of these focal adhesion genes with survival primarily in K27M-DMG and pediatric high-grade glioma compared to lower-grade brain tumors, and ITGB1 expression increased with glioma grade. Single-cell RNA-seq and spatial transcriptomic data demonstrated higher expression of ITGB1 in OPC-like/Mesenchymal cells associated with leading edge and microvasculature in both K27M-DMG and GBM tumors. Unexpectedly, knockout of ITGB1 (ITGB1-KO), primarily responsible for cell adhesion to laminin, led to the decreased expression of multiple mitochondrial NADH dehydrogenase genes, and reduced levels of glycolysis and oxidative phosphorylation (OXPHOS) activity. Preliminary mechanistic data linked this phenotype to impaired mitochondrial fusion. Orthotopic implantation of control and ITGB1-KO models of H3K27M-DMG and adult GBM in mouse brains revealed two distinct phenotypes: (1) ITGB1-KO reducing proliferation and significantly increasing survival; and (2) ITGB1-KO leading to upregulation of ITGB3 and ITGB5 in vivo without impacting survival. Cilengitide (αvβ3 and αvβ5 inhibitor) ablated migration of all ITGB1-KO models on vitronectin (secreted by pericytes surrounding blood vessels) in vitro. Ongoing combinatorial therapy with an experimental anti-Integrin Beta 1 antibody (AIIB2, CNS delivered) and Cilengitide is underway with promising early results. In summary, multi-integrin inhibition provides a feasible avenue to curb glioma spread in the brain through impaired focal adhesion as well as blunting mitochondrial glucose metabolism.
NURS-19. IMPLEMENTING A NURSING LED WORKING GROUP WITHIN THE PEDIATRIC NEURO-ONCOLOGY CONSORTIUM (PNOC), A TWO-YEAR EXPERIENCE AND EVALUATION
Authors: Shannon Raber, Carly Hoffman, Cassie Kline, Sabine Mueller, Michael Prados, Ashley Meyer
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Incorporation of nurses and advanced practice providers (APPs) creates an opportunity to enhance the work of clinical trial consortia in providing care to children and young adults with central nervous system tumors enrolled on clinical trials. Within PNOC, a formalized APP and nursing working group (“APPNIC”) was established in 2021. Since inception, APPNIC has assigned members to each clinical trial committee, developed support documents to partner with protocols, highlighted supportive care measures, and provided nursing education across all PNOC sites. METHODS A de-identified, electronic Qualtrics survey was distributed to PNOC members in Fall 2023 to evaluate the 2-year impact of APPNIC. Physicians, nurses or APPs, and CRCs were eligible to participate. RESULTS Thirty-six surveys were completed in total from physicians or principal investigators (n=15; PIs), nurses/APPS (n=18), and clinical research coordinators (n=3; CRCs) representing multiple institutions. PI satisfaction with APPNIC was high with all reporting APPNIC to be “somewhat helpful” (40%) or “very helpful” (60%) and most PIs (53%) working directly with APPNIC members. Nurses confirmed they use the protocol roadmaps (87%) and education sheets (80%) generated by APPNIC. Barriers to APPNIC participation continue to indicate scarce resources allowing time for APPs and nurses to participate in hybrid meetings and limited travel funds to attend meetings and conferences. Identified education needs of APPs and nurses include identifying supportive care for novel treatments, understanding developmental therapy strategies, and receiving routine study updates. CONCLUSIONS With high overall satisfaction of PIs and utilization of study deliverables by consortium site members, we plan to continue APPNIC as currently structured. Ongoing efforts to integrate APPNIC members early in protocol development will increase PI and APPNIC member collaboration. Education for APPs and nursing will continue to be a priority, along with investigating mechanisms to increase funding to attend meetings and conferences.
NFS-17. CORRELATIONS BETWEEN OPTICAL COHERENCE TOMOGRAPHY AND MAGNETIC RESONANCE IMAGING IN NEUROFIBROMATOSIS TYPE 1 – RELATED OPTIC PATHWAY GLIOMAS
Authors: Gianluca Piccolo, Ilaria Luongo, Costanza Parodi, Paola Camicione, Luca Carlini, Cristina Chelleri, Maria Savina Severino, Massimiliano Serafino, Marta Molteni, Pasquale Striano, Maria Cristina Diana
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Optic pathway glioma (OPG) is a prevalent tumor affecting children with Neurofibromatosis type 1 (NF1), representing a diagnostic hallmark. OPGs, typically WHO grade 1 pilocytic astrocytomas, are characterized by an indolent course. Diagnosis and surveillance traditionally rely on Magnetic Resonance Imaging (MRI). Routine NF1 pediatric surveillance includes annual eye examinations, encompassing visual acuity (VA) and Optical Coherence Tomography (OCT), with MRI reserved for ophthalmological abnormalities. However, the precise correlation between altered OCT findings and OPG presence or size remains unclear, while the role of MRI in screening is contentious due to cost and anesthesia requirements. METHODS In this retrospective study, we sought to establish correlations between OCT changes and MRI-observed tumor volume in NF1-diagnosed children at a tertiary center. Clinical and ophthalmological data, including VA, fundoscopy, and OCT, were collected. Tumor volumes were assessed using the software Sophia DDMTM for Radiomics in two consecutive MRI scans in a randomly selected cohort of 50 untreated patients. RESULTS Among 409 NF1 patients, 132 (31%) were diagnosed with OPG (48% females = 64), revealing a significant association with plexiform neurofibroma (pNF) (p=0.03), thus indicating an elevated risk of concurrent tumor development. In the subcohort of patients in whom volumetric analysis was performed, the mean age at OPG diagnosis was 5.56 ± 3.59 years. While tumor volume on MRI correlated with VA (p=0.0007), OCT values did not: larger OPGs did not consistently result in thinner retinal nerve fiber layers, suggesting independence between OCT alterations and OPG size. CONCLUSIONS The observed lack of correlation among VA, retinal thickness (OCT), and tumor volume (MRI) underscores the importance of MRI as the gold standard for diagnosis. The strong association between pNFs and OPGs suggests considering whole-body MRI when an OPG is detected, facilitating comprehensive evaluation in NF1 patients.
HGG-53. MULTI-DIMENSIONAL INTEGRATIVE PROFILING IDENTIFIES BCL2L1 METHYLATION AS A PREDICTIVE BIOMARKER FOR MCL-1 ACTIVITY IN PEDIATRIC HIGH-GRADE GLIOMAS
Authors: Shazia Adjumain, Claire Xin Sun, Gabrielle Bradshaw, Nicole Chew, Vanessa Tsui, Hanbyeol Lee, Melissa Loi, Nataliya Zhukova, Dilru Habarakada, Louise Ludlow, Naama Neeman, Paul Daniel, Ron Firestein
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Pediatric high-grade gliomas (pHGGs) pose a significant challenge as the most aggressive central nervous system tumors in children. The lack of effective treatment and poor survival rates emphasize the critical need for innovative therapies to improve the prognosis of pediatric patients with pHGG. METHODS We executed CRISPR-cas9 knockout (KO) screenings in 65 pediatric and 10 adult high-grade glioma (HGG) cell lines to explore unique functional dependencies associated with pHGGs. Drug assays were carried out to assess the targetability of a gene dependency of interest in pHGG cell lines. Subsequently, Random Forest machine learning algorithm was employed on ‘omics’ datasets to identify biomarkers indicative of drug response. Finally, biomarkers were confirmed through sequencing-based methods across various pediatric cancers. RESULTS CRISPR-cas9 KO screens revealed 8 crucial genes essential for pHGG growth, namely MCL-1, ATIC, DHFR, EED, HDAC2, PARP1, PDK1, PIK3CA and TYMS. Among these, Myeloid Cell Leukemia (MCL-1) was further characterized as it emerged as the top differential genetic dependency in pHGGs. Consistent with this, MCL1 inhibitors exhibited potent anti-cancer activity on 43% of pHGG cell lines. Multi-feature prediction analysis identified 140 features correlated to response. Strikingly, a previously undescribed methylation site within the BCL2L1 locus, cg00300298, ranked in the top 5% of features. Tissue analysis revealed a wide range of other pediatric brain cancers that harbor the BCL2L1 cg00300298 methylation mark as compared to non-malignant brain tissue. Lastly, we validated the utility of BCL2L1 methylation as a predictive biomarker of MCL1 inhibitor sensitivity across a large panel of pediatric brain cancer cell lines. CONCLUSION Using an integrated genomic approach, we identify MCL1 as a distinct therapeutic target in BCL2L1-methylated pediatric brain cancers. This offers a rational approach for stratifying patients who may benefit from MCL1 inhibitors.
MDB-52. MYC-DRIVEN PEDIATRIC BRAIN TUMORS SHARE A COMMON PHOTORECEPTOR IDENTITY
Authors: Miao Zhao, Gabriela Rosén, Anders Sundstrom, Thale Kristin Olsen, Takahisa Furukawa, Brian L Gudenas, Paul A Northcott, Fredrik J Swartling
Journal: Neuro-Oncology (2024)

Abstract Mouse models serve as invaluable tools for improving the understanding and treatment of pediatric brain tumors. We recently published a highly aggressive MYC-driven brain tumor model (GMYC), which exhibits approximately 70% penetrance. Our transcription profiling indicates that GMYC tumors accurately resemble human Group 3 medulloblastoma (MB-G3). Interestingly, a strong photoreceptor program was activated in the tumor model. This is commonly upregulated in MB-G3 but also in pineoblastoma (PB), another malignant pediatric brain tumor. CRX, a transcription factor critical for pineal cell development is also a master regulator for MB-G3 maintenance. By studying early tumor initiation using Crx-lineage tracing and scRNA-seq, we confirmed that GMYC tumors originate from early pinealocytes. Exome sequencing of GMYC tumors further confirmed mutations of epigenetic regulators commonly reported in either PB or MB. To investigate tumor development from photoreceptor-positive progenitors in the developing brain, we performed Crx-lineage tracing with tamoxifen injections, confirming that Crx-positive cells exist in pineal gland progenitors. However, Crx-traced cells also marked granule neurons in the flocculonodular lobe of the cerebellum, which is the suggested site of MB-G3 origin arising from the developing rhombic lip. To investigate if the Myc oncogene can generate different types of pediatric brain tumors in Crx-positive cells, an XMYCT58A-Tomato mouse model was established by crossing Crx-CreERT2; LSL-MycT58A and Rosa26LSL-tdTomato strains. Here, MycT58A was turned on with tamoxifen injection after birth and tumor development followed using the tdTomato reporter. XMYCT58A-Tomato mice developed brain tumors from both the pineal gland and cerebellum after 2-6 months. Histologically, tumors were non-glial (GFAP-, Olig2-), showed neuronal activity (Neurod1+), and stained positive for photoreceptor identity markers (CRX+, OTX2+) similar to both MB-G3 and PB-MYC. Collectively, our data suggest that both MYC-driven MB-G3 and PB-MYC originate from photoreceptor-positive cells, which has implications for developing novel treatments targeting these devastating childhood malignancies.
QOL-39. FATIGUE AS A RISK FACTOR FOR REDUCED SOCIAL CONNECTEDNESS IN PEDIATRIC BRAIN TUMOR SURVIVORS
Authors: Peter Fantozzi, Michael J Fisher, John D Herrington, Yimei Li, Shana E McCormack, Julia Parish-Morris, Matthew C Hocking
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Pediatric brain tumor survivors (PBTS) experience reduced social connectedness, including fewer friendships, less social acceptance, and greater isolation. Identifying modifiable factors contributing to social issues would yield treatment opportunities. Fatigue is common among PBTS and may relate to social challenges. This study evaluated fatigue among PBTS and its associations with various indices of social connectedness. METHODS Survivors (N = 34) of three types of brain tumors—medulloblastoma (N = 11), pilocytic astrocytoma (N = 15), and craniopharyngioma (N = 8)—completed self-reported measures of fatigue and social connectedness. Laboratory studies assessed thyroid function and growth hormone status. Caregivers completed measures of social functioning. Descriptive statistics summarized fatigue and endorsement of fatigue items. ANOVAs, t-tests, and Pearson correlations evaluated fatigue according to various medical factors, and Pearson correlations evaluated associations between self-reported fatigue and indices of social connectedness. RESULTS Over 20% of survivors reported elevated fatigue, with 53% and 35% indicating fatigue interfering with attention and socialization, respectively. We did not detect associations between self-reported fatigue and diagnosis, current age or age at diagnosis, time since end of treatment, or history of chemotherapy or cranial radiation therapy. We did not detect an association between BMI Z-score and collected hormones. Mean T scores on the self-reported peer relationships measure were below the reference mean (M = 45.8, SD = 11.9), with 22% of survivors endorsing concerns. Higher self-reported fatigue was significantly correlated with poorer self-reported peer relationships (r = -.62, p &amp;lt; 0.001) and more parent-reported social impairments (r =.61, p &amp;lt; 0.001). CONCLUSIONS Fatigue is common among PBTS and may interfere with peer relationships. Clinicians should screen for fatigue as a risk factor for reduced social connectedness. Further research is needed to identify predictors of fatigue and social difficulties and determine temporal associations between fatigue and social connectedness.