tbuckley/cabot-search huggingface dataset:
OTHR-05. ROLES OF GEMCITABINE-OXALIPLATIN (GEMOX) ADD-ON THERAPY IN INFANT-TYPE BRAIN TUMORS: A SINGLE CENTER EXPERIENCE
Authors: Barbara Castelli, Carla Fonte, MIlena Guidi, Marco Di Nicola, Laura Giunti, Anna Maria Buccoliero, Chiara Caporalini, Flavio Giordano, Mirko Scagnet, Veronica Tintori, Ludovico D’Incerti, Lorenzo Genitori, Marco Tellini, Iacopo Sardi
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Combined gemcitabine and oxaliplatin (GemOx) was evaluated in recurrent pediatric solid tumors, showing safety but limited activity. In neuro-oncological infant patients, chemotherapy intensified to high doses (HDC) represents the cornerstone, avoiding radiotherapy toxicities. We describe the roles of GemOx towards autologous transplantation in infant-type brain tumors. METHODS From May 2017 to January 2024, at the Meyer Children’s Hospital IRCCS in Florence, six children (median age 19 months, sex equally distributed, three high-grade gliomas, a metastatic medulloblastoma MM, a pineoblastoma, a choroid plexus carcinoma CPC) completed GemOx after induction chemotherapy delivered according to Italian program for malignant brain tumors under 3 years. GemOx was administered to achieve clinical and neuroradiological permissiveness to HDC and to raise the possibility of second look neurosurgery. RESULTS Gemcitabine 1000 mg/m2 and Oxaliplatin 100 mg/m2 were given every 14-28 days for 1-6 cycles. At re-assessment, maximum every four cycles, disease control was optimal (five stable diseases and one partial response according to RECIST criteria). After GemOx, one patient was also subjected to further neurosurgery. The treatment was overall well tolerated, except for Common Terminology Criteria for Adverse Events (CTCAE) grade 4 platelet toxicity in two patients (one of whom also developed hydrocephalus CTCAE 3 and hyponatremia CTCAE 4 during treatment). All patients were safely exposed to HDC (1-2 courses). MM and CPC patients progressed respectively 4 ad 19 months after the end of GemOx. The latter underwent second look neurosurgery, and a radiotherapy course was delivered to both, considering the achievement of permissive age. To date all patients are alive. CONCLUSIONS In brain infant-type malignant tumors strategies are limited due to the extremely vulnerable age. GemOx treatment should be considered a reasonable and safe option waiting for intensified treatment, especially in radiotherapy delaying programs, and it should result incisive in the therapeutic or palliative choice.
GCT-22. MEDICAL AND SURGICAL VARIABLES ASSOCIATED WITH RELAPSE IN CENTRAL NERVOUS SYSTEM (CNS) NONGERMINOMATOUS GERM CELL TUMORS (NGGCTS): SECONDARY ANALYSIS OF STRATUM 1 OF THE CHILDREN’S ONCOLOGY GROUP ACNS1123 PHASE 2 CLINICAL TRIAL
Authors: Sumanth Nagabushan, Rachel Yan, Tong Lin, Arzu Onar-Thomas, Mark M Souweidane, Girish Dhall
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND ACNS1123 was a Phase 2 trial that evaluated the survival benefit of whole ventricular irradiation (WVI) instead of craniospinal irradiation in children with localized CNS NGGCTs who achieved a complete/partial radiographic response (CR/PR) to induction chemotherapy with negative tumor markers (beta-HCG/AFP) in serum and cerebrospinal fluid (CSF). Patients who did not achieve a CR/PR were considered inevaluable and removed from study therapy post-induction. METHODS In unplanned, exploratory analyses, we evaluated the association of age &amp;lt;15/&amp;gt;15-years at diagnosis, tumor location (pineal/suprasellar/bifocal/ventricular), tumor markers (beta-HCG/AFP) in serum and cerebrospinal fluid (CSF) at baseline (&amp;gt;/&amp;lt;1000), and rate of decline during induction in CR/PR and &amp;lt;CR/PR patients. Since most evaluable patients with relapse experienced distant failure in the spine, we assessed the impact of surgical variables, such as endoscopic third ventriculostomy (ETV)/biopsy/resection/combination, on spinal relapse in patients with or without disease progression. RESULTS 66 of 107 eligible patients achieved CR/PR with negative tumor markers while 41 patients did not. Bifocal tumors appeared to demonstrate a higher hazard for disease progression compared to suprasellar tumors (Hazard Ratio=5.4; p=0.0279). Otherwise, we did not find an association with progression-free-survival for any of the analyzed medical variables. Of 66 evaluable patients who received WVI, eight patients experienced relapse, with all patients demonstrating disease in the spine. No significant association was detected between any surgical variable (ETV/biopsy/resection) and spinal failure among evaluable patients who did or did not relapse; however, we had very limited power for these analyses due to very few events. CONCLUSION Current reliance on conventional parameters appears inadequate to identify biomarkers of response as well as relapse. Innovative approaches such as comprehensive genomic profiling of primary and recurrence tumor specimens could inform somatic clonal evolution and potential targeted therapies.
LGG-01. PROGNOSTIC UTILITY AND CHARACTERISTICS OF MIB-1 LABELING INDEX AS A PROLIFERATIVE ACTIVITY MARKER IN CHILDHOOD LOW-GRADE GLIOMA: A RETROSPECTIVE OBSERVATIONAL STUDY
Authors: David Gorodezki, Julian Zipfel, Nägele Thomas, Martin Ebinger, Martin U Schuhmann, Jens Schittenhelm
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND The prognostic utility of MIB-1 labeling index (LI) in pediatric low-grade glioma (PLGG) has not yet conclusively been described. We assess the correlation of MIB-1 LI and tumor growth velocity, aiming to contribute to the understanding of clinical implications and the predictive value of MIB-1 LI as an indicator of proliferative activity and progression-free survival (PFS) in pediatric low-grade glioma. METHODS MIB-1 LI of a cohort of 172 pediatric low-grade gliomas were comprehensively characterized. Correlation to tumor growth velocity, assessed by sequential MRI-based three-dimensional volumetric analyses, and PFS was analyzed. RESULTS Mean MIB-1 LI accounted for 2.7 % (range: &amp;lt;1 – 10) and showed a significant decrease to 1.5 % at secondary surgery (p =.0013). A significant difference of MIB-1 LI in different histopathological types and a correlation to tumor volume at diagnosis could be shown. Linear regression analysis showed a correlation between MIB-1 LI and preoperative TGV (R² =.55, p &amp;lt;.0001), while correlation to tumor growth velocity remarkably decreased after incomplete resection (R² =.08, p =.013). Log-rank test showed no impact of MIB-1 LI on 5-year PFS after incomplete (MIB-1 LI &amp;gt; 1 vs ≤ 1%: 48 vs 46 %, p =.73) and gross-total resection (MIB-1 LI &amp;gt; 1 vs ≤ 1%: 89 vs 95 %, p =.75). CONCLUSIONS This data confirms a correlation of MIB-1 LI and radiologically detectable tumor growth velocity in PLGG for the first time. Compared to preoperative tumor growth rates, a crucially decreasing correlation of MIB-1 LI and tumor growth velocity after surgery may result in limited prognostic capability of MIB-1 LI in pediatric low-grade glioma.
MODL-15. CHARACTERIZATION OF SPONTANEOUS CANINE HIGH-GRADE GLIOMA MODELS AS CLINICALLY-RELEVANT SURROGATES OF PEDIATRIC HIGH-GRADE GLIOMA
Authors: Gabrielle Link, Simon Garey, John DeSisto, Markos Antonakakis, Stephanie McGrath, Lyndah Chow, Mathew Slade, Steven Dow, Adam L Green
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND High-grade glioma (HGG) occurring spontaneously in canines shows histological and genetic resemblance to pediatric high-grade glioma (PHGG). Both canine HGG and PHGG are treated with combinations of surgical resection, radiation therapy, and/or chemotherapy, but outcomes for both groups are poor. Studying canine HGG both serves companion dogs and provides an orthogonal preclinical model of PHGG. METHODS Canine HGG lines J3T, SDT3G, and G06A were characterized and compared with H3K27M-mutant PHGG lines DIPG7, DIPG13, and BT245 using neurosphere dilution assay and drug screening with all FDA-approved anti-cancer agents. J3T and SDT3G were orthotopically implanted into mice and monitored using MRI and bioluminescence. RESULTS Like PHGG, the canine lines J3T and SDT3G were highly sensitive to proteasome and XPO1 inhibition; compared to PHGG, the canine lines were most sensitive to protein translation inhibitors and DNA intercalators. Canine HGG lines were not as sensitive to other targeted inhibitors effective in PHGG. Compared to PHGG cell lines, canine cell lines had greater variance in self-renewal capability. J3T and SDT3G were also injected into the cortex of immunodeficient mice. Bioluminescent signal confirmed J3T engraftment one week post-surgery with rapid tumor growth, while SDT3G presented initial engraftment by MRI two weeks post-surgery but did not exhibit sustained growth. DISCUSSION Canine HGG and PHGG showed similar sensitivity to proteasome and XPO1 inhibition; they differed in self-renewal capability and susceptibility to other anti-cancer agents. This could be because canine target proteins often differ from their human counterparts and thus may respond differently to targeted medications designed for humans. Overall, canine HGG provides a novel, primary, immunocompetent surrogate that resembles PHGG and may provide a step for clinical investigation between xenograft models and PHGG trials and/or opportunities for co-clinical trials.
MDB-103. THE SIGNIFICANCE OF CEREBROSPINAL FLUID CYTOLOGY IN SURVEILLANCE FOR RECURRENT MEDULLOBLASTOMA
Authors: Mohammad Hatim Mohammad Abu Arja, Fatih Okcu, Jack Su, Guillermo Aldave, Carrie Mohila, Melissa Blessing, Murali M Chintagumpala
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Surveillance of patients with medulloblastoma includes magnetic resonance imaging of the brain and spine and cerebrospinal fluid (CSF) cytology evaluation. Certain protocols require frequent CSF cytology evaluations off-therapy while others perform CSF cytology only at the time of radiographic relapse. We wanted to determine the incidence of isolated CSF positivity at the time of recurrence and the outcome of these patients. METHODS We performed a retrospective analysis of patients with relapsed medulloblastoma treated at Texas Children’s Hospital between 1997 and 2023. RESULTS Out of 223 patients with medulloblastoma, 45 patients developed recurrences. Twenty-five (55.5%) patients underwent lumbar puncture for CSF cytology at the time of relapse. The radiographic distribution of recurrences was focal (n=7), focal and disseminated (n=6), disseminated (n=11), and negative imaging (n=1). Seven out of the 25 (28%) patients had positive CSF cytology for malignant cells at initial relapse. All seven patients succumbed secondary to disease progression. Among 18 patients who had negative CSF cytology at recurrence, three infant patients at initial diagnosis were disease-free following craniospinal radiation at recurrence. Only one among 25 patients had positive CSF cytology without radiographic evidence of relapse. Among ten patients with focal disease at the time of relapse, seven had negative CSF cytology for malignant cells, and three did not have CSF cytology evaluated at the time of relapse. DISCUSSION Frequent evaluation of CSF cytology to detect recurrence may not be necessary in addition to imaging studies. In our study, it did not influence the outcome of patients with recurrence. Prospective studies are necessary to support periodic CSF surveillance to detect ctDNA, which may allow for early interventions that may influence outcomes in patients with recurrent medulloblastoma who have poor outcomes.
DIPG-76. PEDIATRIC PATIENTS WITH DIFFUSE MIDLINE GLIOMA DEMONSTRATE AN UNEXPECTED PREVALENCE OF GERMLINE VARIANTS IN HOMOLOGOUS RECOMBINATION GENES
Authors: Marion K Mateos, Pamela Ajuyah, Noemi Fuentes-Bolanos, Sam El Kamand, Paulette Barahona, Ann Altekoester, Chelsea Mayoh, Holly Holiday, Jie Liu, Louise Cui, Elke Pfaff, Alan Mackay, Adam Resnick, Mark Pinese, Loretta M S Lau, Dong-Anh Khuong-Quang, Kimberly Dias, Catherine Goudie, Alison Salkeld, Jo Lynne Rokita, David T W Jones, Nikoleta Juretic, Elisha Hayden, Stefan M Pfister, Christof M Kramm, Mirjam Blattner-Johnson, Nada Jabado, Maria Tsoli, Orazio Vittorio, Sabine Mueller, Yiran Guo, Katherine Tucker, Sebastian M Waszak, Sebastien Perreault, Chris Jones, Marie Wong-Erasmus, Mark J Cowley, David S Ziegler
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Pediatric patients with Diffuse Midline Gliomas (DMG), H3K27M altered have a dismal prognosis and novel therapeutic approaches are urgently needed. Factors that drive development of pediatric DMG are unknown. METHODS To determine the prevalence of germline pathogenic/likely pathogenic variants (P/LPV) in DMG, we assembled an international cohort of 252 patients with germline whole genome or whole exome sequencing data, including diffuse intrinsic pontine glioma (DIPG; n=153), from Australian, European and North American centres. RESULTS We identified germline P/LPV in cancer predisposition genes in 7.5% (19/252) of patients, mainly homologous recombination (n=9; BRCA1, BRCA2, PALB2) and Fanconi anemia genes (n=4). Germline P/LPV in mismatch repair genes (MSH2, PMS2) were found in two patients. Two patients each had two separate germline P/LPV. The prevalence of germline P/LPV was not significantly different according to age, location of DMG nor H3K27M mutational status. Furthermore, tumor profiles differed, with absence of somatic drivers in the PI3K/mTOR pathway in patients with germline P/LPV compared to those without (P = 0.023). Knockdown of BRCA1 in DMG cell cultures sensitized tumor cells to PARP inhibition. Reflecting the potential therapeutic relevance of these findings, we describe one H3.3 K27M-mutant DMG patient with a pathogenic germline BRCA2 and FANCE variant and multiple recurrences, who was treated with a PARP inhibitor (olaparib) and immune checkpoint inhibitor, leading to a near complete radiological response after 4 months. CONCLUSION Our study is the largest series to date investigating germline P/LPV in cancer predisposition genes in DMG and provides new therapeutic insights. It is expected that these germline findings will also guide cascade testing for a proband’s relatives. Our data highlight the importance of germline testing in H3K27-altered DMG patients at diagnosis.
MDB-53. SALVAGE CRANIOSPINAL IRRADIATION FOR RELAPSED WNT-PATHWAY MEDULLOBLASTOMA PATIENTS TREATED WITH UPFRONT FOCAL CONFORMAL RADIOTHERAPY AND CHEMOTHERAPY AT INITIAL DIAGNOSIS: LONG-TERM AND MATURE OUTCOMES FROM A PROSPECTIVE DE-INTENSIFICATION STUDY
Authors: Tejpal Gupta, Abhishek Chatterjee, Archya Dasgupta, Sridhar Epari, Ayushi Sahay, Arpita Sahu, Aliasgar Moiyadi, Maya Prasad, Girish Chinnaswamy
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Excellent long-term outcomes (5-year overall survival &amp;gt;90%) in WNT-pathway medulloblastoma (MB) patients have prompted systematic attempts at de-intensification of therapy to mitigate treatment-related toxicities. Mature outcomes of a prospective study (FOR-WNT) treating low-risk WNT-MB children with focal conformal radiotherapy (RT) and adjuvant systemic chemotherapy omitting upfront craniospinal irradiation (CSI) are being reported herein. METHODS Seven children with rigorously-defined low-risk WNT-MB were treated with post-operative focal conformal RT to the index tumor-bed (54Gy/30 fractions) followed by 6-cycles of adjuvant systemic chemotherapy after written informed consent/assent. Survival outcomes were computed using Kaplan-Meier method and reported as point estimate with 95% confidence intervals (CI). The trial was terminated prematurely due to unacceptably high risk of neuraxial failures. RESULTS One child succumbed to chemotherapy-related toxicity while 3 of 7 children were detected with leptomeningeal relapse on surveillance neuro-imaging within 2-years of index diagnosis. Full-dose salvage CSI (35Gy/21 fractions) at relapse followed by further chemotherapy led to excellent clinico-radiological response in all 3 children; however, one child developed further local recurrence and leptomeningeal metastases and succumbed to recurrent/progressive disease despite further aggressive salvage therapy. Five of 7 children including the other two treated with salvage CSI and systemic chemotherapy are alive and continue to remain in remission on long-term follow-up. At a median follow up of 61 months, the 5-year Kaplan-Meier estimates of event-free survival, relapse-free survival, and overall survival were 42.9% (95%CI: 18.2-100%), 50.0% (95%CI: 22.5-100%), and 71.4% (44.7-100%) respectively. CONCLUSIONS Omission of upfront CSI in low-risk WNT-MB is associated with unacceptably high-risk of neuraxial failure. Although full-dose salvage CSI achieves excellent response, remissions are not durable resulting in sub-optimal long-term overall survival. Judicious de-escalation with upfront low-dose CSI (18Gy) is currently being tested in a successor study (FOR-WNT 2).
PATH-05. MACHINE LEARNING-BASED CYTOLOGICAL ANALYSIS OF CEREBROSPINAL FLUID IN MEDULLOBLASTOMA
Authors: Lennart Maack, Catena Kresbach, Julia Neumann, Jacqueline Tischendorf, Annika Wefers, Philipp Seegerer, Ulrich Schüller, Alexander Schlaefer, Michael Bockmayr
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Metastatic dissemination occurring via the cerebrospinal fluid contributes to the poor prognosis in many medulloblastoma patients. It has high prognostic relevance, and its accurate detection is critical for adequate therapy stratification. However, cytological examination is a difficult, time-consuming task and frequently unreliable. We, therefore, propose a machine-learning pipeline to solve this diagnostic challenge. METHODS A dataset of 303 digitized images of cerebrospinal fluid preparations from 81 medulloblastoma patients was assembled. Based on these data, over 50000 digitized objects, including more than 5000 patches with tumor cells, were classified by experts into 13 clinically relevant diagnostic categories and used for training. The classification was performed using convolutional neural networks, trained with nested-cross validation and different transfer learning strategies. RESULTS The classification into the 13 diagnostic categories was feasible, with an overall accuracy of 75% on the test set and a tumor-specific F1 score of 89%. Most misclassifications occurred between morphologically similar cell types, mainly lymphocytes and activated lymphocytes, monocytes and activated monocytes, as well as tumor cells and atypical cells with borderline cytomorphology. Grouping these cytologically and/or biologically closely related groups increased the overall accuracy to 91%. Pretraining on published cytological datasets of cerebrospinal fluid and bone marrow further increased classification accuracy. CONCLUSIONS Deep learning can reliably detect tumor cells in digitized cytological images from cerebrospinal fluid preparations in medulloblastoma. Implementing explanation methods, an easy-to-use user interface and validation on additional cohorts will further strengthen the robustness of the presented approach.
ETMR-14. THE SINGLE-CELL LANDSCAPE OF PINEOBLASTOMA IDENTIFIES AN ONCOGENIC PHOTORECEPTOR PROGRAM AS A TUMORIGENIC VULNERABILITY UNIFYING DISTINCT EMBRYONAL CNS TUMOR ENTITIES
Authors: Brian Gudenas, Bernhard Englinger, Anthony P Y Liu, Sheikh Tanveer Ahmad, Miao Zhao, David Meredith, Elke Pfaff, Leena Paul, Jennifer Hadley, Melissa Batts, Paul Klimo Jr., Frederick A Boop, Amar Gajjar, Giles W Robinson, Brent A Orr, Hong Lin, Sanda Alexandrescu, David T W Jones, Fredrik Swartling, Mariella G Filbin, Paul A Northcott
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Pineoblastoma (PB) is a rare and aggressive childhood brain tumor with highly variable outcomes. PB is diagnostically characterized by expression of the photoreceptor identity transcription factor CRX, while tumors can be further classified into molecular subgroups (PB-miRNA1, PB-miRNA2, PB-MYC/FOXR2, and PB-RB1), each marked by unique clinico-molecular features. However, developmental origins of PB subgroup heterogeneity and mechanisms governing malignancy remain unknown. METHODS We assembled a single-nucleus RNA-sequencing cohort (n=25) of primary PB tumors, including cases from all subgroups. A single-cell transcriptional atlas of the mouse pineal gland, covering 11 developmental stages (E11-P21), was created as a reference to map PB subgroup origins. Developmental trajectory analysis in the pineal gland showed a progression from pinealocyte progenitors to an early-, mid- and mature stage of pinealocyte differentiation. RESULTS Cross-species bioinformatics identified significant associations between PB subgroups and pinealocyte progenitors, mitotic cells expressing Crx, Otx2 and Neurod1. Single-nuclei gene regulatory networks in PB tumors identified CRX, OTX2, and NEUROD1 as master regulators of an oncogenic photoreceptor program conserved across PB subgroups. Surprisingly, this photoreceptor program was also highly expressed in retinoblastoma (RETB) and Group3 medulloblastoma (G3-MB). The molecular association between PB, RETB and G3-MB was further supported by DNA methylation and bulk RNA-seq, suggesting up-regulation of the oncogenic photoreceptor program is a unifying molecular connection of distinct CNS tumor entities. Querying this photoreceptor program across the developing pineal gland, retina, and cerebellum, identified conserved yet transient expression within each developmental lineage, suggesting the photoreceptor program may be a developmental vulnerability. In-vivo dependency assays for Otx2 and Neurod1 performed in a novel genetically engineered mouse model of the PB-RB subgroup confirmed their selective essentiality in photoreceptor-positive tumors. CONCLUSIONS Collectively, these findings uncover the photoreceptor program as a shared oncogenic dependency underlying anatomically distinct embryonal CNS tumors and provide a path towards rational clinical translation.
EPEN-23. TARGETING TRISOMY MDM4 INDUCES CELL DEATH IN 1Q+ PFA EPENDYMOMA THROUGH REACTIVATION OF THE P53 PATHWAY
Authors: Annaliese J Calzadilla, Andrea M Griesinger, Andrew M Donson, Enrique Grimaldo, Krishna Madhavan, Irina Alimova, Angela M Pierce, Breauna Brunt, Rajeev Vibhakar, Nicholas K Foreman
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Gain of chromosome 1q (1q+), gives a grave prognosis in pediatric posterior fossa group A ependymoma (PFA). The prevalence of 1q+ in newly diagnosed PFA stands at 25%, escalating to 50% upon recurrence. Conventional therapeutic modalities, such as complete resection and radiation, exhibit minimal efficacy in cases of 1q+ PFA, and the incorporation of additional chemotherapy in clinical trials has failed to yield substantial improvements. In this investigation, we delineate the trisomy-induced overexpression of the MDM4 gene on chromosome 1q as a driver of malignant progression in 1q+ PFA and a viable therapeutic target via idasanutlin, an MDM4 pathway inhibitor. METHODS We are using genetic and pharmaceutical inhibition of the MDM4/MDM2 pathway high-risk PFA 1q+ in vitro and in vivo models to test the efficacy of idasanutlin in a preclinical setting. Treatment effects are measured utilizing growth assays as well as genomic and transcriptomic analysis. RESULTS Our investigation reveals that two 1q+ in vitro models demonstrate a dose dependent sensitivity to idasanutlin compared to normal brain tissue. Upon exposure to idasnutlin, they also have an increase in p21 expression, a critical marker demonstrating reactivation of the p53 pathway, evidenced at both the gene expression and protein levels. Moreover, we found radiation synergistically enhances the efficacy of idasanutlin. Currently, we are evaluating our in vitro results with combination radiation and idasanutlin treatment in our 1q+ PFA preclinical in vivo models. CONCLUSIONS In summary, our study advocates for the exploration of small molecule inhibitors, with a primary focus on the promising idasanutlin compound, as a therapeutic avenue for addressing the challenge posed by ultra-high-risk 1q+ PFA. The compelling preclinical evidence presented herein lays the groundwork for advancing our understanding of the molecular intricacies underlying this malignancy, paving the way for novel and targeted treatment strategies.