tbuckley/cabot-search huggingface dataset:
LGG-34. THE LANDSCAPE OF GLIOMAS IN CHILDREN, ADOLESCENTS AND YOUNG ADULTS REVEALS INSIGHTS ON GLIOMAGENESIS: A CANADIAN ADOLESCENTS AND YOUNG ADULTS NEURO-ONCOLOGY NETWORK (CANON) STUDY
Authors: Julie Bennett, Adrian Levine, Liana Nobre, Logine Negm, Jiil Chung, Karen Fang, Monique Johnson, Martin Komosa, Stacey Krumholtz, Nuno Miguel Nunes, Mansuba Rana, Scott Ryall, Javal Sheth, Robert Siddaway, Tejus A Bale, Eric Bouffet, Michael Cusimano, Sunit Das, Jay Detsky, Peter Dirks, Matthias Karajannis, Paul Kongkham, Alexandra Giantini-Larsen, Bryan Kincheon Li, Mary Jane Lim-Fat, Andrew Lin, Warren Mason, Alexandra Miller, James Perry, Arjun Sahgal, Sameer Farouk Sait, Derek S Tsang, Gelareh Zadeh, Normand Laperriere, Lananh Nguyen, Andrew Gao, Julia Keith, David G Munoz, Uri Tabori, Cynthia Hawkins
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Gliomas are a heterogenous and common cancer in children, adolescents and young adults (CAYA, ages 0-39 years). Little is known about the biologic and clinical implications of gliomas in AYA limiting our ability to appropriately manage these patients. METHODS We compiled a population-based cohort of patients with glioma aged 0-39 years diagnosed between 2000-2020, performed molecular characterization of the tumors and collected clinical data including therapy and long-term outcome. RESULTS A total of 1456 patients, including 873 AYA patients were included. A pathogenic molecular alteration was found in 98% of AYA samples available. Strikingly, pediatric-type mutations were found in 31% of AYA glioma of which 37% were BRAF V600E and 23% FGFR alterations. Important differences were observed between gliomas in children versus AYAs. First, hemispheric tumors were enriched in AYAs compared to midline tumors in children, especially for RAS/MAPK alterations. Second, increased incidence of high grade tumors in AYA compared to children were observed for BRAF V600E and FGFR mutations (p&amp;lt;0.0001). In contrast, if these alterations were identified in AYA and the tumor was low grade, outcome was improved for BRAF V600E and FGFR mutant tumors in AYAs compared to pediatrics (for BRAF V600E 5 year PFS 55.6% &amp;lt;10 years, 78.1% for 10-20 years and 87.1% for 10-20 years of age, p=0.0002). Third, a specific time window for transformation was observed for each alteration (BRAF, FGFR, IDH). This correlated with different methylation profiles and transcriptional patterns between early midline and late hemispheric tumors. Increased senescence signatures were observed in older patients with low grade RAS/MAPK driven tumors with superior outcome. CONCLUSIONS Different cell of origin and secondary mutations shape tumor behavior and lead to either transformation or senescence during gliomagenesis in CAYA. These can affect early interventions and tailored approaches for gliomas by age and molecular alteration.
IMG-16. DECIPHERING THE NEUROIMAGING SPECTRUM OF AT/RT: A PICTORIAL REVIEW OF ATYPICAL TERATOID/RHABDOID TUMORS
Authors: Fabrício G Gonçalves, Adam E Goldman-Yassen, Sandeep Desai, Richa S Chauhan, Anastasiia Rusyn, Mario Enrique M Carvajal, Agustin Cardenas, Carmen Cerron-Vela, Harun Yildiz, Tassiana Cristhina S Dias, Rong Li, Girish Dhall, James M Johnston
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND This study presents a detailed pictorial review of Atypical teratoid/rhabdoid tumor (AT/RT), a high-grade central nervous system (CNS) malignancy, emphasizing the relationship between neuroimaging characteristics and clinical, molecular, and histopathological aspects. AT/RT is mainly characterized by the biallelic inactivation of SMARCB1 and occasionally SMARCA4 genes. METHODS The review methodically analyzes neuroimaging findings from various imaging techniques, notably MRI. It documents AT/RT appearances in different brain regions, including the cerebellum, cerebellopontine angle cistern, intraventricular, suprasellar, supratentorial, pineal, spinal canal, and cranial nerves. The study integrates these findings with clinical presentation, molecular subtypes (AT/RT-SHH, AT/RT-TYR, and AT/RT-MYC), and pathogenesis, highlighting the connection between imaging features and molecular subtypes. RESULTS The results indicate distinctive neuroimaging characteristics of CNS AT/RT, varying with tumor location and molecular subtypes. Common imaging features include contrast enhancement and signal intensity variations on MRI, including subtype-specific variations. Advanced neuroimaging plays a key role in distinguishing AT/RT from other pediatric CNS tumors, aiding in biopsy and treatment planning. Notably, imaging findings are linked with genetic changes, particularly the involvement of SMARCB1 and SMARCA4, affecting tumor appearance and behavior. CONCLUSIONS This review underscores the significance of neuroimaging in diagnosing and treating CNS AT/RT. The comprehensive analysis of imaging, combined with molecular and histopathological data, offers valuable insights into AT/RT’s heterogeneous nature. This integrative approach is crucial for a better understanding of AT/RT and for the development of more effective, targeted therapies.
LGG-40. TYPE II RAF INHIBITOR TOVORAFENIB IN RELAPSED/REFRACTORY PEDIATRIC LOW-GRADE GLIOMA (PLGG): REVERSIBLE DECREASES IN GROWTH VELOCITY IN THE PHASE 2 FIREFLY-1 TRIAL
Authors: Cassie Kline, Angela J Waanders, David S Ziegler, Lindsay B Kilburn, Karsten Nysom, Jasper van der Lugt, Timothy E Hassall, Nicolas U Gerber, Devorah Segal, Valérie Larouche, Dong-Anh Khuong-Quang, Jordan R Hansford, Sarah E S Leary, Pablo Hernáiz Driever, Simon Bailey, Sébastien Perreault, Geoffrey McCowage, Olaf Witt, Patricia A Baxter, Hyoung Jin Kang, Jung Woo Han, Darren Hargrave, Andrea T Franson, Michal Yalon Oren, Helen Toledano, Mohamed S Abdelbaki, Nada Jabado, Nicholas G Gottardo, Nicholas S Whipple, Susan N Chi, Liat Oren, Enrica E K Tan, Sabine Mueller, Karen D Wright, Samuel C Blackman, Jiaheng Qiu, Dolores Podesta, Ashley Walter, Daniel Da Costa, Peter Manley, Lisa McLeod, Daniel B Landi
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND: Tovorafenib is an investigational, selective, CNS-penetrant, type II RAF inhibitor. The ongoing FIREFLY-1 (NCT04775485) phase 2 study (Kilburn LK, et al. Nat Med. 2023) of tovorafenib in BRAF-altered pLGG resulted in antitumor activity and manageable safety. Decreased growth velocity (GV) was observed; this is an update on GV changes in skeletally immature children receiving tovorafenib. Methods A planned safety analysis was completed on August 8, 2023 on 137 patients (Arm 1: 77 &amp; Arm 2: 60). Additional follow-up on all cases of decreased GV (an AESI) reported to the global safety database (GSDB) as of January 19, 2024 is provided. Results Overall, 29% had decreased GV from baseline (BL); 19% had ≥50% decrease. Of the 40 with this AESI, 75% had pre-existing neuromuscular or endocrine comorbidities potentially affecting normal growth, including 6 on GnRH-analogues for precocious puberty and 9 with BL heights 2 SDs above/below average for age and sex. Nineteen had on-treatment bone age assessments; none showed bone age advancement from BL or premature growth plate closure. No osteopenia or abnormal fractures reported. All 10 who discontinued or interrupted tovorafenib for ≥3 months for any reason (mean follow-up: 5.8 months), with off-treatment growth measurements available, showed post-treatment annualized GV (AGV) recovery (average AGV: on-treatment, 1.1 cm/y; off-treatment, 8 cm/y), with some exceeding expected average AGV for age. A 4-year-old boy with 1.2 cm/y AGV on-treatment had 12.3 cm/y AGV off-treatment (follow-up: 2 months). Five additional events of decreased GV in patients not on study FIREFLY-1 were reported to the GSDB; 4 of 5 had ≥3 months of off-treatment follow-up, all 4 recovered GV. Conclusions Decreased GV has been observed in patients on tovorafenib. Preliminary follow-up data in those who interrupted treatment show consistent evidence of GV recovery and preservation of growth potential on bone age studies.
LGG-38. UNRESECTABLE PEDIATRIC LOW-GRADE GLIOMAS OF THE BRAIN: TARGETED THERAPY COMPARED WITH STANDARD CHEMOTHERAPY AS FIRST-LINE TREATMENT
Authors: Marta Molteni, Antonio Verrico, Antonia Ramaglia, Andrea Rossi, Francesca Bagnasco, Martina Fragola, Gianluca Piccolo, Claudia Mercuri, Gianluca Piatelli, Gabriele Gaggero, Patrizia De Marco, Maria Luisa Garrè, Claudia Milanaccio
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Pediatric low-grade gliomas (pLGG) frequently harbor MAPK-pathway mutations that determine poor response to standard chemotherapy (sCt). Targeted agents against BRAF-V600E mutation (MAPK-i) are emerging as molecularly driven treatments. Few studies have compared sCt with MAPK-i. We aimed to compare response and progression-free survival (PFS) of unresectable brain pLGG treated with sCt or MAPK-i. MAPK-i were used in first line or at relapse. METHODS We conducted a single-center observational retrospective study of all brain pLGG consecutively diagnosed and treated at Gaslini Children’s Hospital between January 2008 and December 2021. Treatment was assessed using RAPNO criteria at 6, 12-18 months, and at last follow-up. MRI studies were reviewed by two experienced neuroradiologists. RESULTS Seventy-one patients were enrolled: 66 received sCt and 10 MAPK-i (5 in first line, 5 after sCt failure). All patients who received MAPK-i were BRAF-V600E mutated. Groups were homogeneous for tumor location and dissemination. sCt group was enriched for pilocytic astrocytoma, MAPK-I group for ganglioglioma. sCt patients were younger. SCt lasted 12-18 months, MAPK-i were continuously given. Tumor size reduction was 19.5% at 6 months and 40.5% at 12-18 months for sCt group; 48% at 6 months and 43.5% at 12-18 months for MAPK-i group. SCt determined at least stable disease in 74.2% of patients; 60% of responders reached the best response at 6 months, 40% at 12-18 months. 5y-PFS was 40.3% (median time for progression: 2.5 years). MAPK-i determined at least stable disease in all patients at first evaluation with long-lasting response (median time of follow-up: 5.1 years). CONCLUSIONS In our study sCt was effective in inducing response but prolonged disease control is not always achieved. BRAF-V600E mutated patients upon MAPK-i start gained a rapid disease control with long-lasting response, also if they have been pretreated. Acknowledgement: this study was supported by ARTUCEBA ONLUS.
IMG-13. PREDICTION OF PEDIATRIC MEDULLOBLASTOMA SUBGROUPS USING CLINICO-RADIOMIC ANALYSIS
Authors: Ariana M Familiar, Anahita Fathi Kazerooni, Adam Kraya, Komal Rathi, Nastaran Khalili, Deep Gandhi, Hannah Anderson, Aria Mahtabfar, Jeffrey B Ware, Arastoo Vossough, Phillip B Storm, Adam C Resnick, Ali Nabavizadeh
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Pediatric medulloblastoma is an aggressive brain tumor and tailored treatment has the potential to lead to better patient outcomes. The WHO 2021 classification of medulloblastoma involves an integrated diagnosis that incorporates genetically defined characteristics, including molecular subgroups (WNT-activated, SHH-activated TP53 wildtype, SHH-activated TP53-mutant, and non-WNT/non-SHH). Clinically acquired radiology (MRI) imaging characteristics could provide a non-invasive, pre-treatment biomarker for such subgroups faster than standard methylation-based turn-around times, and for use in countries where methylation is not available. METHODS Herein, we utilize a multi-institutional dataset of multi-parametric, clinical MRIs of pediatric medulloblastoma patients from the Children’s Brain Tumor Network (median age = 8.9 years) to assess the predictive value of patient-level radiomic and clinical factors. 89 subjects with treatment-naïve T1w/T1w contrast-enhanced/T2w/FLAIR images and molecular subgroups (derived from methylation profiling or RNA sequencing) were included (SHH=18, WNT=10, non-SHH/WNT=61). Radiomic features were extracted from a radiologist-defined volumetric (3D) segmentation for each subject separately (including solid tumor, cystic, and peritumoral edema regions). Clinical variables included sex, age at diagnosis, and metastatic disease. 20 top performing features were selected based on an ANOVA between features/classes and subsequently used to train and evaluate three separate classification models based on radiomic, clinical, or clinico-radiomic features (Linear SVM; leave-one-subject-out cross-validation). RESULTS The combined clinico-radiomic model had the top performance (AUC=0.83) followed by radiomic (0.78) and clinical (0.5) for predicting SHH/WNT vs. non-SHH/WNT groups. Predictive radiomic features included intensity-based statistics (T1w, T2w, T1w-CE), texture (T2w), and morphological shape characteristics. CONCLUSIONS Our findings show potential for early prediction of molecular subgroups using baseline imaging that could lend to faster decision-making in patient treatment planning. Future work aims to evaluate the inclusion of histological characteristics for a full integrated diagnostic approach as well as assessment of prognostic value of the combined multi-omic features.
IMG-11. RADIOGENOMIC ANALYSIS INFORMS ON IMMUNOLOGICAL PROFILES, PROGNOSIS, AND TREATMENT RESPONSE IN PEDIATRIC LOW-GRADE GLIOMA
Authors: Anahita Fathi Kazerooni, Adam Kraya, Komal S Rathi, Meen Chul Kim, Arastoo Vossough, Varun Kesherwani, Nastaran Khalili, Ariana Familiar, Deep Gandhi, Neda Khalili, Hannah Anderson, Mateusz Koptyra, Phillip B Storm, Jeffrey B Ware, Jessica Foster, Sabine Mueller, Michael J Fisher, Adam C Resnick, Ali Nabavizadeh
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Pediatric low-grade gliomas (pLGGs) have variable prognosis and treatment responses. Complete resection cannot be achieved for all tumors, especially for highly infiltrative or deep-seated tumors, necessitating additional therapy, from chemotherapy to targeted inhibitors. We integrated imaging-derived phenotypes with genotypic traits from transcriptional analysis, offering an in-depth characterization of pLGG immune microenvironment, progression risk, and likelihood of multiple treatments. METHODS Analyzing 549 treatment-naïve pLGGs with multiparametric MRI and RNA sequencing, we identified distinct immunological groups using XCell scores based on immune cell infiltration. We developed a radiomic signature using conventional MRI and machine learning techniques (support vector machines with a linear kernel and nested cross-validation) to distinguish the ‘immune-hot’ group, and incorporated diffusion MRI to improve signature accuracy. Additionally, a clinicoradiomic model predicting tumor progression risk and treatment response was trained, integrating clinical and radiomic data. Transcriptomic analysis was conducted to identify pathways correlated with clinicoradiomic risk, predictive of pLGG progression. RESULTS Three immunological groups were revealed, the ‘immune-hot’ group characterized by poor prognosis due to a high concentration of pro-tumorigenic M2-polarized macrophages, despite a higher preponderance of T-lymphocytes. The radiomic signature effectively distinguished the ‘immune-hot’ group with balanced accuracies of 76.8%/86.0% in discovery/replication sets, improved by diffusion MRI to 81.5%/84.4%. The clinicoradiomic model showed concordance indices of 0.71 (discovery) and 0.77 (replication), predicting patient progression risk. Significant differences (p=0.0010) were found in clinicoradiomic risk scores between patients undergoing one versus multiple treatments post-diagnosis, linking higher scores to a likelihood of multiple treatments. Transcriptomic pathways associated with higher clinicoradiomic risk highlighted the importance of fatty acid oxidation, a tumor-promoting mechanism that drives adaptive resistance to cytolytic immune cell effectors. CONCLUSIONS This first large-scale radiogenomic analysis in pLGGs aids in prognostication, assessing progression risk, predicting treatment response to standard-of-care therapies, and stratification of patients to identify potential candidates for novel therapies targeting aberrantly regulated pathways.
MODL-02. ESTABLISHING THE TIME-DEPENDENCE OF CDK4/6 INHIBITOR EFFICACY IN PEDIATRIC BRAIN TUMORS AND FEASIBILITY OF METRONOMIC INTRATHECAL DELIVERY IN A PRECLINICAL MODEL
Authors: Brice Martin, Sergio Guadix, Rekha Sathian, Madeline Laramee, Abhinav Pandey, Ishani Ray, Selina Chen-Kiang, Amy Wang, Ramana Davuluri, Nadia Dahmane, Craig Thomas, Mark Souweidane
Journal: Neuro-Oncology (2024)

Abstract This comprehensive study delves into the intricate dynamics of CDK4/6 inhibitors (abemaciclib, ribociclib, palbociclib) efficacy in the context of pediatric brain tumors, with a specific focus on establishing the temporal dependencies of their effectiveness. Beyond elucidating the time-dependent aspects, the research also explores into the feasibility and safety considerations associated with a metronomic intrathecal delivery with Palbociclib. This involves a thorough examination of pharmacokinetics and an analysis of liver and renal function through a panel assessment in vivo. By methodically exploring the optimal dosing within the brain after administration of Palbociclib via a systemic or intrathecal administration; the study aims to provide nuanced insights into enhancing therapeutic outcomes for pediatric brain tumors. Ultimately, we also provide a mechanistic understanding of the inhibition of CDK4/6 over time using RNAseq analysis; and an assessment of the efficacy of the proposed metronomic intrathecal delivery strategy in a preclinical mouse model of leptomeningeal ATRT. This multifaceted study not only expands our understanding of the temporal dynamics of CDK4/6 inhibitors but also lays the foundation for informed decision-making regarding the potential of this innovative therapeutic delivery method in the realm of pediatric brain tumor treatment.
Biomarkers of peanut allergy in children over time
Authors: Ru‐Xin Foong, George Du Toit, Ronald van Ree, Henry T. Bahnson, Suzana Radulovic, Jo Craven, Matthew Kwok, Zainab Jama, Serge A. Versteeg, Helen A. Brough, Kirsty Logan, Michael R. Perkin, Carsten Flohr, Gideon Lack, Alexandra F. Santos
Journal: Allergy (2024)

Abstract Background Various biomarkers are used to define peanut allergy (PA). We aimed to observe changes in PA resolution and persistence over time comparing biomarkers in PA and peanut sensitised but tolerant (PS) children in a population‐based cohort. Methods Participants were recruited from the EAT and EAT‐On studies, conducted across England and Wales, and were exclusively breastfeed babies recruited at 3 months old and followed up until 7–12 years old. Clinical characteristics, skin prick test (SPT), sIgE to peanut and peanut components and mast cell activation tests (MAT) were assessed at 12 months, 36 months and 7–12 years. PA status was determined at the 7–12 year time point. Results The prevalence of PA was 2.1% at 7–12 years. Between 3 and 7–12 year, two children developed PA and one outgrew PA. PA children had larger SPT, higher peanut‐sIgE, Ara h 2‐sIgE and MAT (all p &lt; .001) compared to PS children from 12 months onwards. SPT, peanut‐sIgE, Ara h 2‐sIgE and MAT between children with persistent PA, new PA, outgrown PA and PS were statistically significant from 12 months onwards ( p &lt; .001). Those with persistent PA had SPT, peanut‐sIgE and Ara h 2‐sIgE that increased over time and MAT which was highest at 36 months. New PA children had increased SPT and peanut‐sIgE from 36 months to 7–12 years, but MAT remained low. PS children had low biomarkers across time. Conclusions In this cohort, few children outgrow or develop new PA between 36 months and 7–12 years. Children with persistent PA have raised SPT, peanut‐sIgE, Ara h 2‐sIgE and MAT evident from infancy that consistently increase over time.
HGG-05. GLUCOSE CONJUGATION FOR THE SPECIFIC TARGETING AND TREATMENT OF GLIOBLASTOMA
Authors: Anna Lisa Iorio, Elena Lenci, Chiara Marzano, Bianca Tirinnanzi, Laura Giunti, Carla Fonte, Milena Guidi, Marco Tellini, Barbara Castelli, Marco Di Nicola, Andrea Trabocchi, Iacopo Sardi
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Malignant brain tumors, such as Glioblastoma (GBM), are a major challenge in oncology with a dismal prognosis. This can be in part explained by the inability to deliver more effective drugs, as Doxorubicin (DOX), into the brain because of resistance mechanisms. Malignant tumors as GBM also show an elevated glycolytic rate through glucose transporters and GLUT1 is reported to be the main mediator of BBB glucose uptake. For these reasons, we have developed an innovative approach able to increase drug efficiency and selectivity, by conjugating the anticancer agents DOX to glucose. METHODS Two glycoconjugates (EB73 and EB74) were synthesized, using an oxime-based linkers between position 6 of glucose and carbonyl group of DOX, and characterized for absorbance, fluorescence and binding affinity to ctDNA. The cytotoxic effect of EB73 and EB74 was evaluated in two GBM cell lines (A172 and T98G). These cells were also used to study the effect of glucose deprivation on GLUT1 and breast cancer resistance protein (BCRP) expression. Moreover, cellular uptake of the glicoconjugates was evaluate in an in vitro BBB model and by immunofluorescence (IF) in GBM cells. RESULTS Our results indicated that EB73 and EB74 maintained Ka binding constants comparable to DOX, confirming that functionalization with glucose did not alter DOX intercalation capability and fluorescence. The cytotoxicity results demonstrated that EB74 has the major effect in A172 and T98G DOX-resistant cells starting from 24h of treatment. Moreover, glucose deprivation showed a GLUT1 overexpression and BCRP downregulation in both cell lines improving EB74 efficacy. BBB in vitro model and IF experiments revealed that only EB74 is able to accumulate in cells nuclei as conventional DOX CONCLUSION In conclusion, these results indicated that glycoconjugation of DOX and glucose deprivation may be helpful instruments to increase drugs uptake and effectiveness in aggressive and chemoresistant tumor cells.