tbuckley/cabot-search huggingface dataset:
LMIC-03. BRAINSTEM RADIATION NECROSIS IN A PATIENT WITH RECURRENT MEDULLOBLASTOMA. SUCCESFULL TREATMENT OF A HIGHLY FEARED COMPLICATION
Authors: Carlos A Leal-Cavazos, Jose A Arenas-Ruiz, Rafael Piñeiro-Retif, Oscar Vidal-Gutierrez
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Medulloblastoma is the most common malignant brain tumor in pediatric population. Standard treatment combines surgery, risk-adapted craniospinal irradiation and chemotherapy. Given the well-known cognitive sequelae in young children associated to radiation, strategies in infants try to avoid upfront radiation. A significant number of patients treated during infancy will ultimately relapse. Re-irradition in relapse setting has proven to be effective in disease control (survival depending on several factors) although there is a concern in exceeding radiation tolerance and risk of toxicity. METHODS Herein, we describe the case of male patient that presented at 1 year of age with a non-metastatic anaplastic medulloblastoma that was completely resected. He received 3 cycles of adjuvant chemotherapy (as per Head Start II), local relapse was detected in tumor bed during evaluation and was completely resected, afterwards he received myeloablative chemotherapy with stem cell rescue and posterior fossa radiation therapy (54 Gy). At 8 months off therapy patient developed spinal relapse in imaging with negative cytology, then treated with spinal irradiation 36Gy without adjuvant chemotherapy. He remained disease free during 12 months, then tumor recur at the right cerebellopontine angle, surgery was complete and there was no evidence of distant disease. Patient received adjuvant local radiation with 30.6Gy followed by chemotherapy (bi weekly bevacizumab + irinotecan). Cumulative maximal dose to brainstem was 84Gy. 2 months after radiation patient presented with extreme sleepiness and imaging findings compatible with brainstem radiation necrosis, symptoms resolved promptly after scheduled bevacizumab. Patient is currently 6-year-old and remains free of disease after 3 years off therapy. CONCLUSION Medulloblastoma treatment in infants is challenging because survival is not the only goal. Future clinical trials will help to better tailored treatment based on molecular biology. Re-irradiation in medulloblastoma has been described as well tolerated but clinician should be aware of its complications and management.
HGG-02. LONG-TERM EFFICACY AND SAFETY OF LAROTRECTINIB IN PEDIATRIC PATIENTS WITH TRK FUSION PRIMARY CENTRAL NERVOUS SYSTEM (CNS) TUMORS: AN UPDATED ANALYSIS
Authors: Sébastien Perreault, François Doz, Rebecca J Deyell, Rejin Kebudi, Anna Nilsson, Karsten Nysom, Birgit Geoerger, Yi-Zhuo Zhang, Vadim Bernard-Gauthier, Natascha Neu, Esther De La Cuesta, Theodore W Laetsch, Cornelis M van Tilburg
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Larotrectinib is the first-in-class, highly selective TRK inhibitor approved for tumor-agnostic use in patients with TRK fusion cancer. We report data on larotrectinib-treated pediatric patients with TRK fusion primary CNS tumors. METHODS Patients aged &amp;lt;18 years with TRK fusion primary CNS tumors enrolled in two clinical trials (NCT02637687, NCT02576431) were included. Responses were independent review committee (IRC)-assessed per RANO. Patients were permitted to stop larotrectinib in the absence of on-treatment progression (wait-and-see) and remain on trial. RESULTS As of July 2023, 38 patients were eligible for efficacy analyses by IRC, including 11 patients with only non-measurable disease at baseline. Median age at enrollment was 7 years (range 0–17). Tumor histologic groups included: high-grade glioma (HGG; n=18), low-grade glioma (LGG; n=12), and other (n=8). Eleven (29%) patients had received ≥2 prior systemic therapies. Overall response rate was 37% (95% CI 22–54): three complete response, 11 partial response, 17 stable disease, five progressive disease, and two not evaluable. The 24-week disease control rate was 74% (95% CI 57–87). Medians for duration of response, progression-free survival, and overall survival (OS) were 17.2 months (95% CI 5.7–not estimable [NE]), 19.8 months (95% CI 11.1–50.8), and not reached (95% CI 32.7–NE), respectively. The 48-month OS rate was 60%. At data cutoff, one patient with HGG and four with LGG entered wait-and-see; median duration of the first wait-and-see period was 20.2 months (range 4–29). One patient with LGG resumed treatment following wait-and-see. Treatment-related adverse events (TRAEs) were predominantly Grade 1/2. No patients discontinued treatment due to TRAEs. CONCLUSION Larotrectinib demonstrated rapid, durable responses and a manageable safety profile in pediatric patients with TRK fusion primary CNS tumors. This supports the wider adoption of next-generation sequencing panels that include NTRK gene fusions when testing pediatric patients with CNS tumors.
MDB-101. TARGETING CTPS1 AND NUCLEOTIDE BIOSYNTHESIS PATHWAYS AS A NOVEL THERAPEUTIC APPROACH IN MYC-AMPLIFIED MEDULLOBLASTOMA
Authors: Matthew Hathaway, Hawa Jagana, Isabella Terrones, Aya Miyaki, John Hemenway, Michael Meechan, Kate Gadek, Barbara Slusher, Myron Evans II
Journal: Neuro-Oncology (2024)

Abstract Although leukemia is the leading pediatric oncology diagnosis, brain tumors are the leading cause of pediatric cancer-related death. Medulloblastoma (MB) is the most common pediatric brain tumor, representing approximately 20% of all diagnoses. MYC-amplified Group 3 medulloblastoma (G3 MB) tumors are the deadliest, with a &amp;lt; 50% 5-year overall survival rate. High risk patients receive large doses of chemo- and radio- therapy (CT/RT) with most survivors experiencing debilitating neurological and cognitive sequelae making the identification of novel targets of the utmost importance. Utilizing whole-genome CRISPR screening, we identified the enzyme CTPS1 as a strong G3 MB-specific vulnerability. Further analysis revealed dependencies on other enzymes in the de novo pyrimidine synthesis pathway, which is corroborated by recent metabolic studies. Targeted knockdown of CTPS1 restricts sphere formation and reduces proliferation of G3 MB tumor lines. Treatment with a specific CTPS1 inhibitor reduced proliferation but did not induce cell death, suggesting a cytostatic mechanism. Previous work has shown that triggering an imbalance in pyrimidine and purine levels leads to replication stress and activation of the ATR/CHK1 pathway. Both genetic and pharmacologic inhibition of CTPS1 leads to CHK phosphorylation, allowing for cell survival despite lack of dNTPs. Previously, the CHK1 inhibitor, prexasertib, demonstrated robust brain accumulation and targeting of G3 MB in pre-clinical models. Dual inhibition of CHK1 and CTPS1 synergizes to significantly reduce cell viability in vitro and tumor growth in vivo. We further demonstrated robust synergy of CHK1 inhibition with either glutamine antagonists or other inhibitors of the de novo pyrimidine synthesis pathway, prolonging in vivo survival in an orthotopic xenograft G3 MB model. The results of this investigation confirm CTPS1 as a novel target in G3 MB, pinpoint a dependency on de novo pyrimidine rather than purine biosynthesis, and identifies a novel rational combination for treatment in MYC-amplified MB patients.
HGG-01. DURABLE RESPONSE TO IMMUNOTHERAPY IN AN ADOLESCENT PATEINT WITH CONSTITUTIONAL MISMATCH REPAIR DEFICIENCY CMMRD AND SYNCHRONOUS THREE PRIMARY MALIGNANCIES
Authors: NAHLA Aly Mobarak, Fahad Alotabi, Ali Abdullah O Balbaid, Wafa Al Shakweer, Rana Alrasheed, Salman Turbush A AlMalki, Musa Alharbi, Ali H AlFakeeh
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Familial Cancer Syndrome FCS is of particular concern in Saudi Arabia due to the high rates of consanguinity. Constitutional mismatch repair deficiency Syndrome (CMMRD) is an autosomal recessive FCS with a wide spectrum of malignancies Caused by Biallelic germline mutations in one of 4 mismatch repair genes (MLH1, PMS2, MSH2, and MSH6). METHODS we report 13 yr. Saudi boy, previously healthy with multiple café-au-lait (CAL) macules, and Consanguineous parents with a positive family history of Malignancy. presented with progressive headache, vomiting, abdominal pain, weight loss, and microcytic anemia. MRI Brain showed a Large left hemispheric necrotic mass, MRI abdomen: Circumferential gastric body wall thickening Distal transverse colon intraluminal polypoid mass, and liver hypodense lesion. He had a Resection of the brain tumor and Upper GI endoscopy + colonoscopy with polypectomy: which showed an Ugly gastric ulcer, and multiple colonic polyps. RESULTS Brain tumor molecular pathology: Gliosarcoma WHO grade 4 with negative IHC expression in PMS2 protein, hypermutant tumor with somatic PMS2 ATRX, TP53, NFI, and PIK3R1 genes mutation. stomach biopsy confirmed invasive gastric adenocarcinoma and Colonic polyp biopsy: Tubulovillous adenoma. Genetic testing Detect pathogenic Biallelic germline PMS2 mutation. He received adjuvant focal Brain radiation therapy 59.4Gy/33 F concurrent with immunotherapy (PD-1) inhibitor Nivolumab. Follow-up Abdominal imaging showed excellent response to immunotherapy with no significant residual lesion. MRI of the brain showed surgical bed multi-cystic lesions with thick nodular enhancement suggestive either of radiation necrosis vs. progressions/pseudoprogression. repeated MRI confirmed further progression of the enhancing surgical cavity lesion which was unresectable. CTLA-4 Inhibitor ipilimumab was added to Nivolumab to optimize therapy. UpToDate our patient is clinically stable on Maintenance Nivolumab with no side effects. CONCLUSION Our case confirms immunotherapy’s efficacy for treating CMMRD-related cancers, which can improve survival while reducing toxicity from less effective conventional therapies.
LGG-03. PREDICTIVE VALUE OF ACQUIRED NYSTAGMUS FOR PEDIATRIC BRAIN TUMOR ASSOCIATED VISUAL IMPAIRMENT: A RETROSPECTIVE STUDY
Authors: Sophie Teeuwen, Rianne Oostenbrink, Giorgio Porro, Lisethe Meijer
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Visual impairment (VI), defined as visual acuity (VA) loss or visual field (VF) defects, is common in pediatric brain tumors of the optic pathway and may impact the quality of life. VI is a challenge to establish, especially in young children. However, pediatric brain tumor patients might concurrently have acquired nystagmus (AN), which can easily be observed. The aim of this study was to investigate whether AN is predictive of VI in pediatric brain tumor patients. If correlated, AN could be an early warning sign for brain tumor related VI, warranting MRI scanning to prevent further visual deterioration, thus decreasing morbidity and mortality. METHODS Data on tumor characteristics, VA (in LogMAR), VF, (type of) AN and other ophthalmic investigations were collected from the medical records of pediatric brain tumor patients in the Máxima Pediatric Brain Tumor Ophthalmology cohort (MP-BT-O cohort). These characteristics between children with (nystagmus group) and without (control group) AN were compared to determine the predictors of VI. RESULTS The MP-BT-O cohort consists of 389 children (≤18y) with a brain tumor who had visual assessment, 95 children had AN (24.4%). The mean best corrected visual acuity (BCVA) was 0.10 LogMAR [CI 0.06-0.14] in the control and 0.50 LogMAR [CI 0.35-0.66] in the nystagmus group (p&amp;lt;0.001). Nystagmus type was found to be a significant predictor of VI (p&amp;lt;0.001). Specifically horizontal AN (a decrease in BCVA of 0.75 LogMAR, p&amp;lt;0.001) and mixed AN (a decrease in BCVA of 0.61 LogMAR, p&amp;lt;0.001) were independent predictors of VI, corrected for tumor location (p=0.04) and age at diagnosis (an increase in BCVA of -0.02 LogMAR per year, p&amp;lt;0.001). CONCLUSIONS Acquired nystagmus, especially horizontal and mixed nystagmus, is an independent predictor of VI in pediatric brain tumor patients and should be interpreted as a warning sign for the presence of VI.
HGG-03. TRUNCATING MUTATIONS IN PPM1D COOPERATE WITH PI3K ALTERATIONS TO DRIVE PEDIATRIC DIFFUSE MIDLINE GLIOMAS
Authors: Adam F Kebede, Eric Morin, Ipsita Kundu, Olivia Blumenshine, Veronica Rendo, Timothy N Phoenix, Pratiti Bandopadhayay
Journal: Neuro-Oncology (2024)

Abstract Mutations in PPM1D – coding for the phosphatase WIP1 - are present in 8 -12% of all Diffuse Midline Glioma (DMG), H3 K27-altered – a universally fatal subtype of pediatric high-grade tumors. PPM1D mutations are mutually exclusive with TP53 mutations and mainly lead to a truncation of its C-terminal regulatory domain. Truncated PPM1D (PPM1Dtr) has increased protein stability and impairs the p53-dependent DNA Damage Response (DDR) by dephosphorylating its numerous targets (e.g p53, H2A.X, CHK1) which contributes to its oncogenicity. However, because wildtype p53 is present in PPM1Dtr tumors, its activation is suppressed but not completely ablated suggesting that PPM1D mutant tumors may evolve differently from p53 mutant ones. Our analysis of whole genome sequencing datasets indeed found that PPM1D mutations uniquely co-occur with alterations in the PI3K/mTOR pathway suggesting potential cooperativity in enhancing tumorigenesis. Using mouse neural stem cells (mNSCs) as an isogenic model system, we have engineered specific combinations of oncogenic alterations to study their impact on cell proliferation, PI3K/mTOR pathway activation and response to DNA damage and replication stress. We find that PPM1Dtr cooperates with PIK3CA alterations to increase proliferation and signaling through the PI3K/mTOR pathway. Notably, in an in utero electroporation model, mutant PIK3CA accelerates the development of high-grade tumors that infiltrate deep into the brainstem. Our study also indicates a vulnerability to inhibition of the PI3K/mTOR pathway in PPM1Dtr-PI3K co-altered tumors. Future work will aim at 1) exploring the mechanism of cooperation and impact on replicative stress response and 2) developing and testing a rational therapeutic strategy for PPM1D-mutant tumors.
MDB-102. CDK8 IS A DEPENDENCY IN GROUP 3 MEDULLOBLASTOMA AND COMBINES WITH BET BROMODOMAIN INHIBITION
Authors: Isabella Terrones, Hawa Jagana, Matthew Hathaway, John Hemenway, Ashmitha Rajendran, Jay Conrad, Myron Evans
Journal: Neuro-Oncology (2024)

Abstract Medulloblastoma (MB) is the most common pediatric CNS malignancy with varying prognoses depending on subgroup diagnosis. Group 3 MB displays the poorest overall prognosis, specifically in cases characterized by MYC hyperactivation. Current standard treatment can cause lifelong debilitating side effects, therefore the identification of targeted therapeutic agents will be critical in enhancing patient survival and bypassing therapy-induced aftereffects. We utilized the Pediatric Cancer Dependency Map to identify CDK8 as the most striking dependency in MB compared to all other pediatric malignancies. Further analysis revealed dependencies on its cognate cyclin, Cyclin C, and other members of the CDK8 kinase module (CKM). The CKM functions as a transcriptional regulator, phosphorylating RNAPol2 and other transcription factors. Interestingly, CDK8 dependency correlates with MYC amplification status in cell lines suggesting it to be a strong dependency in G3 MB. CDK8 expression, both RNA and protein, is highest in G3 tumors. We depleted CDK8 both genetically and pharmacologically and demonstrated downregulation of MYC expression in tumor cells and decreased cell survival. We next tested the efficacy of a CDK8 kinase inhibitor currently in clinical trials. Treatment with SEL-120 reduced cell proliferation and viability in vitro and inhibited tumor growth in vivo. This effect was limited to G3 models, as SEL120 showed little efficacy in SHH MB. Analysis of gene expression revealed that targeting CDK8 did not affect MYC-dependent gene expression but led to de-repression of differentiation genes regulated by PRC2. We further observed a global de-repression of H3K27me3 in cells treated with CDK8i. Finally, we tested the first ever blood-brain barrier penetrant CDK8i which mimics the activity of SEL-120 and potently synergizes with BETi, which antagonizes MYC signaling. In summary, we have identified and validated CDK8 as a novel target in G3 MB and identified a possible synergistic combination to move forward in clinical trials.
IMMU-18. ENHANCING GD2.CAR T CELL THERAPY FOR DIFFUSE MIDLINE GLIOMA WITH LSD1 AND HDAC INHIBITORS
Authors: Rebecca L Murdaugh, Meghan Shekar, Brittany R Eberl, Jack R Tremblay, Rosemary U Richard, Linh Nguyen, Bilal Omer, Jamie N Anastas
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Chimeric antigen receptor T cells against the glycolipid GD2 (GD2.CARTs) have shown promise against Diffuse Midline Glioma (DMG) in clinical trials but are not yet curative. Previous studies in neuroblastoma demonstrate that histone deacetylase inhibitor (HDACi) treatment can increase GD2 on tumor cells and improve targeting by GD2.CARTs. Our lab previously found that simultaneous HDACi and lysine-demethylase 1 inhibitor (LSD1i) treatment in DMG cells causes synergistic alterations in gene expression and reduces DMG growth. Here, we find that treating GD2-low DMG cell lines with combinations of LSD1i and HDACi improves DMG response to GD2.CARTs. METHODS Surface expression of GD2 before and after LSD1i/HDACi treatment were analyzed using immunofluorescence microscopy and flow cytometry. The cytotoxicity of GD2.CARTs against DMG cells was determined from co-culture experiments and in patient-derived orthotopic xenograft models using flow cytometry and bioluminescent imaging. RESULTS Since low target antigen expression is one mechanism by which tumor cells can escape CAR T cell therapy, we profiled GD2 expression on 9 different H3K27M-mutant DMG cell lines. This analysis shows that only 5 of the 9 cell lines exhibit high GD2 expression while the remaining 4 lines have low GD2 expression. When treating these cell lines with GD2.CARTs, we find that low GD2 expression on DMG cells correlates with tumor cell escape and resistance to GD2.CARTs. Treating GD2-low DMG cells with LSD1i+HDACi increases GD2 expression and enhances tumor cell targeting by GD2.CARTs in subsequent co-culture assays. Further studies in mice bearing GD2-low DMG tumors were initially GD2.CART-insensitive but showed reduced tumor growth when pre-treated with LSD1i+HDACi before intravenous GD2.CART infusion. CONCLUSIONS These studies suggest that variable GD2 expression is a major driver of DMG resistance to GD2.CARTs and that LSD1i+HDACi pre-treatment may improve DMG patient responses to GD2.CART therapy by increasing target antigen expression.
MODL-06. USING HYDROGEL MODELS TO RECAPITULATE THE TUMOUR-IMMUNE MICROENVIRONMENT OF AGGRESSIVE GROUP 4 MEDULLOBLASTOMA TUMOURS
Authors: Isabelle Forder-Denham, Ian Kerr, Andrew M Jackson, Beth Coyle
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Medulloblastoma is the most common malignant childhood brain-tumour, predominantly affecting children between the ages of one and nine. It is divided into four molecular subgroups amongst which, Group 3 (G3) and Group 4 (G4) subgroups have the worst prognosis. Subgroups possess distinct extracellular-matrix (ECM) and tumour immune microenvironments (TIME) directly influencing therapy-response and metastasis. Current models of medulloblastoma fail to precisely recreate the complex, subgroup-specific TIME and do not mimic intricate immune-tumour heterotypic signalling facilitating immune-evasion. Here we use a HyStem-hydrogel which forms a hyaluronan-rich environment mimicking the natural brain architecture. This overcomes several limitations of current MB models, allowing customisation of subgroup matching of ECM components, adjustable ECM-stiffness and co-culturing of immune cells. METHODS HyStem-hydrogels were co-assembled with ECM components (with/without laminin) and G4 medulloblastoma cell line CHLA-01-MED. Hydrogels were imaged every three-days using an EVOS M7000 system and assessed for cell-viability with PrestoBlue every seven days. Co-culture laminin-supplemented HyStem hydrogels were established with M1-like or M2-like resting/activated macrophages and their growth tracked in the same manner. On day twenty-eight, hydrogels were fixed and stained for markers of cellular proliferation (Ki-67), ECM (laminin, vitronectin) and macrophage markers. Media from hydrogel co-cultures was collected and ELISAs permofmed to assess cytokine production. RESULTS Hydrogels with/without laminin both remained viable and stable for 28 days. Laminin-supplemented hydrogels displayed a mixed laminar-nodular phenotype which mirrored the heterogenous nature of G4 patient-tumours. Co-culture of CHLA-01-MED cells with activated-macrophages led to cytokine production and altered growth patterns. CONCLUSION We show that HyStem hydrogels recapitulate biologically relevant behaviour of aggressive G4-MB tumours in vitro and represent a promising model for G4-tumours. Future research will involve inclusion of additional brain relevant cells/ECM components and comparisons to a fully customisable peptide-amphiphile hydrogel.
IMG-33. EXPLORING RARE CASES OF SUBEPENDYMAL GIANT CELL ASTROCYTOMA (SEGA) IN PATIENTS WITH AND WITHOUT TUBEROUS SCLEROSIS COMPLEX (TSC): EXPERIENCE FROM INDONESIA
Authors: Mohamad Yanuar Amal, Ludi Dhyani Rahmartani, Eka Susanto
Journal: Neuro-Oncology (2024)

Abstract INTRODUCTION Subependymal giant cell astrocytoma (SEGA) represents a rare type of brain tumor that predominantly manifests in individuals with tuberous sclerosis complex (TSC), a genetic disorder characterized by the growth of benign tumors in various organs. In radiology, SEGA exhibits distinct imaging characteristics in various modalities such as magnetic resonance imaging (MRI) and computed tomography (CT). Radiological features include well-defined intraventricular masses with variable enhancement patterns and associated hydrocephalus. Moreover, SEGA typically demonstrates signal characteristics consistent with glial tumors on MRI, aiding in differentiation from other intraventricular lesions. In TSC patients, SEGA often arises in association with other typical manifestations such as cortical tubers and subependymal nodules, facilitating diagnosis through multimodal imaging approaches. In contrast, SEGA occurring in non-TSC individuals presents challenges in diagnosis due to its rarity and lack of associated clinical features. CASE PRESENTATION Two patients with tuberous sclerosis complex exhibit intraventricular masses suggestive of SEGA, confirmed by histopathological results. Another patient, one patient with an intraventricular mass was suspected to have choroid plexus papilloma based on MRI findings; however, additional features correlated with SEGA. Histopathological examination subsequently confirmed the diagnosis of SEGA. CONCLUSION Radiological evaluation plays a crucial role in the assessment of SEGA, guiding treatment decisions and prognostic considerations. This abstract provides an overview of the radiological findings of SEGA in the context of TSC and non-TSC populations, highlighting the importance of imaging in managing this uncommon brain tumor.