tbuckley/cabot-search huggingface dataset:
OTHR-20. MINIMALLY-INVASIVE MOLECULAR DIAGNOSIS OF INFILTRATING BRAINSTEM GLIOMAS THROUGH CEREBROSPINAL FLUID CELL-FREE DNA SEQUENCING
Authors: Katherine Hill*, Alexandra Giantini-Larsen*, Richard A Hickman, Bridget M Holle, Burcin Agridag Ucpinar, Tina Alano, Seyram Doe-Tetteh, Sara DiNapoli, Cecile Riviere-Cazaux, Terence C Burns, Sofia Haque, Robert Young, Sunitha Thakur, Tejus Bale, Marc K Rosenblum, Jamal Benhamida, Snjezana Dogan, Chad Vanderbilt, Laetitia A Borsu, Dara Ross, Jason Chang, Caroline Barbosa Zampieri, Maria Donzelli, Andrew Lin, Ira J Dunkel, Kim Kramer, Sameer Farouk Sait, Mark M Souweidane, Jeffrey P Greenfield, Michael F Berger, Maria E Arcila, Marc Ladanyi, Ingo K Mellinghoff, Matthias A Karajannis, Alexandra M Miller
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Accurate molecular diagnosis of infiltrating brainstem tumors, including diffuse midline gliomas and IDH mutant astrocytomas, is essential for prognostication and optimal therapy. Surgical biopsy of the brainstem carries risk of permanent neurological deficits and may yield insufficient or non-diagnostic tissue. We hypothesized that minimally invasive “liquid biopsy” analyzing circulating tumor cell-free DNA (cfDNA) in cerebrospinal fluid (CSF) could represent an alternative molecular diagnostic modality. METHODS We performed MSK-IMPACT, a New York State Department of Health authorized hybridization capture-based next-generation panel DNA sequencing clinical assay on 44 CSF samples from 37 unique patients with brainstem tumors. Ages at time of CSF collection ranged from 1–47 years (median: 29 years). For samples in which diagnostic alterations could not be detected, we performed a series of secondary analyses for known hotspot mutations such as H3F3A, IDH1/2, and BRAF, including manual review for mutant reads below the official clinical reporting threshold, as well as droplet digital PCR (ddPCR). RESULTS Among 44 samples included in this study, 10/44 (23%) samples had mutations detected by MSK-IMPACT using standard clinical calling criteria and 14 of the remaining 34 samples (41%) had supporting evidence of a diagnostically relevant mutation based on manual review. Testing by ddPCR was performed on 11 samples (based on DNA availability), uncovering 4 additional mutations. Overall positive diagnostic yield was 64% (28/44). In biopsied patients, CSF confirmed disease-defining mutations in 80% (16/20) of CSF samples, including H3F3A K28M (9/10; 90%) and IDH1/2 (5/6; 83%). Among 24 unbiopsied patients, a disease-defining mutation was identified in 60% (15/25) of CSF samples. CONCLUSIONS Analysis of CSF cfDNA in patients with brainstem tumors has a high diagnostic yield and obviates the need for tissue biopsy in a majority of patients. A tiered testing approach using next-generation sequencing and ddPCR assays helps maximize diagnostic information and sensitivity.
MDB-106. MEDULLOBLASTOMA TUMOR MICROENVIRONMENTS SHOW INTRA- AND INTER-TUMORAL HETEROGENEITY ON SPATIAL TRANSCRIPTOMICS
Authors: Franklin Chien, Marina Michaud, Mojtaba Bakhtiari, James L Ross, Chanel Schroff, Matija Snuderl, Tobey MacDonald, Manoj Bhasin
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Medulloblastoma defines a heterogeneous set of neuroepithelial neoplasms of the posterior fossa. Four groups of medulloblastoma are recognized: wingless (WNT), sonic hedgehog (SHH), group 3, and group 4. The tumor microenvironment (TME) influences tumor progression and response to therapy and has emerged as a growing target for the study of novel therapeutic approaches. METHODS We show spatial gene expression architecture through 10X Visium Spatial Sequencing on 16 formalin-fixed paraffin-embedded (FFPE) samples representing all molecular groups of medulloblastoma. Spatial transcriptomics data is correlated with clinical parameters, including M-stage at diagnosis, tumor histological classification, and outcomes data including survival and relapse status. RESULTS Spatial sequencing demonstrates both intra- and inter-tumoral TME heterogeneity across molecular subgroups. Unsupervised clustering and uniform manifold approximate projection illustrate clusters of distinct spatial gene expression representing cell states from different components of the TME, including tumor-associated astrocytes (TAA), macrophages (TAM), and vascular endothelium. Medulloblastoma cells constitute the majority of cells and express marker genes representing different stages of neuronal differentiation and cell cycle. Pathway analysis reveals the enrichment of pathways associated with cell motility (RHO GTPase, MET, MAPK signaling), heat shock response, growth factor signaling, and adaptive immune response (TLR, MHC-II signaling). In addition, molecular pathways known in medulloblastoma, including NF-kB and TP53 regulatory pathways, were also enriched. Neighborhood-enrichment analysis reveals the co-localization of TAMs and TAAs in close spatial relationship with mitotic progenitor-like medulloblastoma cells. Additionally, these two cell types constitute a greater proportion of the TME in patients at relapse compared to initial diagnosis. CONCLUSION Spatial transcriptomics enables new insight into the heterogeneity of the medulloblastoma TME. Notably, our analysis elucidates the spatial association of TAMs and TAAs with proliferating tumor cells and an increased abundance of these cell types following relapse. These initial results support the role of TAMs and TAAs in medulloblastoma progression.
GCT-11. CENTRAL NERVOUS SYSTEM GERM TUMORS (CNS GCTS): RESULTS FROM A SINGLE INSTITUTION IN BRAZIL - SÃO PAULO UNIVERSITY
Authors: Juliana S Barreto, Mirela L Campoy, Alessandra M P de Azambuja, Felippe G O Ribas, Felipe H Sanders, Helena E Baraldi, Eduardo Weltaman, Suely F Ferracioli, Leandro T Lucato, Yuri R Casal, Estela M Novak, Thamiris M Gimenez, Mariana M Komatsu, Lilian M Cristofani, Vicente Odone Filho
Journal: Neuro-Oncology (2024)

Abstract INTRODUCTION Central Nervous System Germ Tumors (CNS GCTs) are broadly classified as germinomatous (commonly called germinoma) and non-germinomatous germ cell tumors (NGGCTs) based on clinicopathological and laboratory characteristics, including tumor markers. OBJECTIVES Compare data from patients admitted from 2000 to 2023, with the usual presentation in the literature, identifying possible specific variables. METHODOLOGY Retrospective study involving 27 patients admitted to the institution without previous treatment. RESULTS In western countries, GCTs account for 3% to 4% of primary brain tumors in children, with a peak incidence between 10 and 19 years of age. In Japan and other Asian countries, one series reported that the incidence of GCTs in the CNS consists of approximately 15% of all pediatric CNS tumors. The genetic or environmental reasons for these differences remain unknown. In general, males have a higher incidence of GCT than females. Male patients have a preponderance of primary tumors of the pineal region. The data collected by our institution are compatible with those in the literature. CONCLUSION Our discussion and data analysis on GCTs are comparable to those presented in the literature, with the majority of cases treated being: adolescents between 10 and 15 years old, predominantly male and with a satisfactory response to therapy.
NFS-03. MEDULLOBLASTOMA IN CHILDREN WITH FANCONI ANEMIA: ASSOCIATION WITH FA-D1/FA-N, SHH TYPE AND POOR SURVIVAL INDEPENDENT OF TREATMENT STRATEGIES
Authors: Marthe Sönksen, Denise Obrecht-Sturm, Pablo Hernáiz Driever, Axel Sauerbrey, Norbert Graf, Udo Kontny, Christian Reimann, Uwe Kordes, Rudolf Schwarz, Tobias Obser, Felix Boschann, Ulrich Schüller, Lea Altendorf, Tobias Goschzik, Torsten Pietsch, Martin Mynarek, Stefan Rutkowski
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Outcome of children with medulloblastoma (MB) and Fanconi Anemia (FA), an inherited DNA repair deficiency, has not systematically been described. Treatment is complicated by high vulnerability to treatment-associated side effects, yet structured data are lacking. This study provides a comprehensive overview about clinical and molecular characteristics of pediatric FA MB patients. METHODS Clinical data including detailed information on treatment and toxicities of six previously unreported FA MB patients were supplemented with data of 16 published cases. RESULTS We identified 22 cases of children with FA and MB with clinical data available. Biological subgroup was SHH in all cases with data available (n=9), confirmed by methylation profiling in five patients. FA MB patients exclusively belonged to complementation groups FA-D1 (n=16) or FA-N (n=3). Patients were treated with postoperative chemotherapy only (50%) or radiotherapy (RT)±chemotherapy (27%). 23% did not receive adjuvant therapy. Excessive treatment-related toxicities were frequent. Severe hematological toxicity occurred in 91% of patients treated with alkylating chemotherapy, while non-alkylating agents and RT were less toxic. 14 patients (63.6%) developed 20 other malignancies, of which ten occurred before, five simultaneously with and five after MB diagnosis. Median overall survival (OS) was 1 year (95%CI 0.3-1.9). 1-year-progression-free-survival (PFS) was 26.3±10.1% and 1-year-OS was 42.1±11.3%. Adjuvant therapy prolonged survival (1y-OS/1y-PFS 0%/0% without adjuvant therapy vs. 53.3±12.9%/33.3±12.2% with adjuvant therapy, p=0.006/p=0.086), with no difference whether the patient had received chemotherapy only or RT±chemotherapy. CONCLUSIONS MB in FA patients is strongly associated with SHH activation and FA-D1/FA-N. Despite the dismal prognosis, adjuvant therapy may improve survival. Non-alkylating chemotherapy and RT are feasible in selected patients with careful monitoring of toxicities and dose adjustments. Unlike in standard MB protocols, focal RT may be considered in FA MB patients. Curative therapy for FA MB-SHH remains an unmet medical need.
BIOM-01. CARBONIC ANHYDRASE IX INTERPLAY WITH LOCAL AND SYSTEMIC IMMUNE RESPONSE IN PEDIATRIC BRAIN TUMORS
Authors: Monika Kapitancuke, Donatas Petroska, Agne Petrosiute, Asta Luciunaite, Svitrigaile Grinceviciene, Daumantas Matulis, Saulius Rocka, Dainius Rinkevicius, Ramunas Raugalas, Jelena Rascon
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Brain tumors (BT) remain the leading cause of death among childhood cancers. There is an urgent need to identify novel targets in these patients. BT progression depends on the adaptive responses to hypoxia. Carbonic anhydrase IX (CAIX) helps cancer cells survive in a hypoxic environment and can be potentially as a therapeutic target. The role of CAIX in the interplay between the tumor and immune cells requires in-depth investigation to design effective therapies. METHODS Fresh BT, blood, and intraoperative cerebrospinal fluid (iCSF) samples were collected prospectively from pediatric patients, who underwent brain tumor surgery at Vilnius University Hospital Santaros Klinikos from March 2022 to December 2023. All tumor types were included. Immunohistochemistry (IHC) and flow cytometry (FC) were performed to analyze the expression of CAIX and selected immunological markers in the fresh tumor, iCSF and peripheral blood mononuclear cells (PBMCs). Soluble CAIX content in serum and iCSF was assessed by ELISA. In addition, a retrospective analysis of previously diagnosed pediatric glioma specimens was performed by IHC. RESULTS Twelve patients with heterogeneous BT types have been enrolled prospectively and 17 patients with glioma were reviewed retrospectively. Glioma accounted for 72% (21/29) of all samples. IHC showed that 57% of gliomas were positive for CAIX as well as a moderate correlation between the CAIX score and the expression of CD44, CD206, and CCR2 markers. PD-1/PD-L1 expression was negligible. In the prospective cohort, 83% (10/12) of BT tissue was positive for CAIX by IHC and FC. Soluble CAIX was detectable in 40% of iCSF samples, but not in serum. We found a correlation trend of CAIX expression in the fresh tumor cells and iCSF with increased CCR2 expression on CD45+ PBMCs. CONCLUSIONS This interim analysis showed a correlation between CAIX tumor expression and immune biomarkers, prompting further investigation by enrolling more patients.
OTHR-27. NARRATIVE MEDICINE APPLIED: A STUDY ELUCIDATING HOW ONE NEURO-ONCOLOGY TEAM GRAPPLES WITH DISTRESS
Authors: Kathy Riley, Alison L Toback, Kelsey Knight, Tammy Wimer, Scott L Coven, Jignesh K Tailor, Alex H Lion
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Absorbing the cumulative weight of neuro-oncology patient stories in isolation leads providers to experience burnout and distress that some in our study called “debilitating.” Sands, Stanley, &amp; Charon (2008) describe the field of pediatric oncology as one that “taunts professionals with the random unfairness” of grave childhood illness. They reason that clinicians in this demanding field may benefit from narrative training to build empathy, teamwork, and resilience. Narrative medicine is a rigorous and evidence-based field of study that utilizes the method of close reading of literature and art to engage providers in discussion and personal reflection. In narrative medicine workshops, participants immerse themselves in a text or image, contemplate their experiences and their relation to the text, write in response to a prompt, and share their writings with one another (Charon, et al., 2017). METHODS This study sought to understand how narrative medicine workshops conducted in a pediatric neuro-oncology clinical setting impacted individual team members, as well as inter- and intra-team relationships. Data collection for the study included pre- and post-surveys, qualitative interviews, and observation notes recorded by workshop facilitators. Researchers applied Clark’s (2014) framework of three distinct levels – relationship to oneself, relationship to the patient, and relationship to others on the team – to development of pre- and post-survey and qualitative interview questions. RESULTS Although quantitative data failed to demonstrate that the workshops reduced participant distress, qualitative research generated evidence that the very act of participating in narrative medicine workshops provided a safe space for providers to discuss job-related distress, breaking down hierarchical barriers and moving them toward what one participant called “professional intimacy.” CONCLUSIONS This research suggests that engaging in narrative medicine practice as a healthcare team may in and of itself alleviate distress and foster healing dialogue in a stressful clinical environment suffused with pain and loss.
DIPG-42. PHASE 1/2 CLINICAL TRIAL OF OMBIPEPIMUT-S IN JAPANESE PEDIATRIC PATIENTS WITH RECURRENT/REFRACTORY DIFFUSE INTRINSIC PONTINE GLIOMA, GLIOBLASTOMA, OR HIGH-GRADE GLIOMA
Authors: Yoshiko Hashii, Hiroyuki Fujisaki, Keita Terashima, Hiroaki Goto, Keizo Horibe, Kazuhiko Sugiyama, Takaaki Yanagisawa, Atsushi Kikuta, Hiroshi Kawamoto, Naoya Hashimoto, Junichi Hara, Haruo Sugiyama
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Pediatric patients with recurred/relapsed diffuse intrinsic pontine glioma (DIPG), glioblastoma, or high-grade gliomas (HGGs) have a dismal prognosis. The present study investigated the impacts of 1) the absolute count of Wilms tumor 1 (WT1)-specific cytotoxic T cells (CTLs) at the initiation of WT-1 specific peptide vaccine (Ombipepimut-S) consisting of a killer peptide—adegramotide, a helper peptide—nelatimotide, and adjuvant MontanideTM ISA 51 VG and of 2) cumulative steroid dose on patients’ survival. We aimed to explore the optimal timing for initiating this cancer immunotherapy for them. METHODS The absolute counts of WT1-specific CTLs and lymphocytes were examined at the initiation of vaccination. This first-in-child phase 1/2 study investigated survival (overall survival [OS] and progression-free survival [PFS]), as well as cumulative steroid dose until day 28 after vaccination initiation and immune responses according to the Kaplan-Meier method and receiver-operating curve (ROC) analysis, respectively. RESULTS 18 patients (median age: 8.9 years [range: 2.8–18.7]), 11 (61.1%), 5 (27.8%), and 2 (11.1%) had DIPG, glioblastoma, and HGG, respectively) were intradermally injected with ombipepimut-S. WT1-specific immune responders accounted for 70.6% of patients. Median OS was significantly longer (P = 0.024) in WT1-specific immune responders (9.9 months [6.0−33.4]) than in nonresponders (4.9 months [2.2−16.5]). Under a low cumulative steroid dose (&amp;lt; 0.66 mg/kg body weight), ombipepimut-S significantly extended both OS (P=0.0015) and PFS (P=0.007). Immune responders tended to show the higher absolute counts of WT1-specific CTLs (P=0.091) and lymphocytes (P=0.087) at the initiation of vaccination. CONCLUSIONS Ombipepimut-S exhibited antitumor activity, and this cancer immunotherapy appeared to be preferably initiated when the patient’s immunity is relatively preserved immediately after the completion of standard therapy for primary disease or before the tumor recurs or relapses.
MDB-110. A NOVEL TRANSGENIC MOUSE MODEL FOR GLI2-AMPLIFIED MEDULLOBLASTOMA
Authors: Najiba Murad, Zhenhua Xu, Xiao Liu, Samuel Rivero-Hinojosa, Prathibhani Gamachchige Ramawickrama, Yanxin Pei
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Medulloblastoma (MB) is one of the most common malignant childhood brain tumors. The sonic hedgehog (SHH) subgroup represents 30% of MBs and can arise from granule neuron progenitors (GNPs). SHH-MB is a diverse subgroup of tumors which often exhibit loss-of function mutations in PTCH1 or SUFU, activating mutations in the receptor SMO and amplification of the transcription factor GLI2. Of note, SHH-MBs harboring GLI2-amplification and associated with P53 mutations have extremely poor prognosis with a 5-year survival rate less than 30%. These tumors are non-responsive to SMO inhibitors, which are the only targeted treatment currently available for SHH-MB. Therefore, the development of novel effective therapies for this disease is urgent. Although GLI2 amplification is detected in SHH-MBs, it is not yet known if GLI2 can drive oncogenic activity in this disease. METHOD To elucidate the mechanisms underlying tumorigenesis, our group has developed a novel transgenic model of GLI2-driven MB by expressing a constitutively active form of GLI2 (GLI2A) in Atoh1+ cells in the developing mouse cerebellum to form tumors. To accomplish this, we crossed R26;Gli2A mice with Atoh1-Cre. RESULTS The resulting tumors faithfully recapitulate human GLI2-amplified MB at the cellular and molecular levels. Inactivation of GLI2A resulted in tumor regression, indicating that GLI2 is not only critical for tumorigenesis, but also required for tumor maintenance, suggesting that targeting GLI2 itself or its downstream targets may be effective to inhibit growth of GLI2-driven MB. Interestingly, activation of GLI2A expression in the neonatal cerebellum was not sufficient to drive tumorigenesis, indicating that GLI2-driven MB arises from more primitive cells in the developing cerebellum. CONCLUSION Taken together, our studies demonstrate for the first time the role of GLI2 as an oncogenic driver of MB and introduce a novel mouse model which can be used to develop targeted therapies for this disease.
IMMU-13. TUMOR INFLAMMATION-ASSOCIATED NEUROTOXICITY (TIAN): A TOXICITY SYNDROME IN PATIENTS TREATED WITH IMMUNOTHERAPY FOR CENTRAL NERVOUS SYSTEM TUMORS
Authors: Jasia Mahdi, Jorg Dietrich, Karin Straathof, Claire Roddie, Brian J Scott, Tom Belle Davidson, Laura Prolo, Tracy T Batchelor, Cynthia J Campen, Kara L Davis, Juliane Gust, Michael Lim, Robbie G Majzner, Julie R Park, Sonia Partap, Sneha Ramakrishna, Rebecca Richards, Liora Schultz, Nicholas A Vitanza, Leo D Wang, Crystal L Mackall, Michelle Monje
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Immunotherapies are increasingly being explored as potential therapeutic modalities for the treatment of central nervous system (CNS) tumors and have unique toxicity profiles. Toxicity syndromes such as cytokine release syndrome (CRS) and immune effector-cell associated neurotoxicity (ICANS) were identified through experiences with chimeric antigen receptor (CAR) T-cell therapies for B cell malignancies; the creation of grading scales for these toxicities standardized the reporting and enabled management. METHODS From our collective experiences in treating patients with immunotherapies for CNS tumors, we have identified a localized neurotoxicity syndrome, distinct from the systemic toxicities of CRS and ICANS, termed tumor inflammation-associated neurotoxicity (TIAN). RESULTS TIAN develops secondary to localized inflammation at the tumor site. From a mechanistic perspective, we identified two types of TIAN: 1) type 1 TIAN arises in the setting of mechanical space constraints when peritumoral edema results in tissue shifts and increased intracranial pressure, which if untreated, can lead to a life-threatening herniation syndrome and 2) type 2 TIAN occurs when local neuronal dysfunction causes transient worsening/new neurological deficits. Whereas type 1 TIAN encompasses the concept of “pseudoprogression,” type 2 TIAN can occur in the absence of edema when neural-immune interactions disrupt local neural function. Patients can have both type 1 and type 2 TIAN simultaneously; understanding the type of TIAN can inform management. To facilitate the uniform reporting and management of TIAN, we created a TIAN grading scale that applies to both types of TIAN. Although, type 1 TIAN is generally associated with higher-grade toxicity, high-grade type 2 TIAN can occur when local inflammation compromises respiratory or autonomic functions. CONCLUSIONS Recognizing TIAN as a distinct, local neurotoxicity syndrome is critical to guiding clinical management and prognostication when treating patients with CNS tumors with immunotherapies.