tbuckley/cabot-search huggingface dataset:
QOL-30. DIETARY CONSIDERATIONS FOR PEOPLE WITH NF1: A SYSTEMATIC REVIEW OF THE LITERATURE
Authors: Rajvi Babaria, Arjun Yogaratnam, Stavriani Makri, Carlos Romo
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Neurofibromatosis type 1 (NF1) is a neurocutaneous genetic condition. Limited pre-clinical and clinical data suggests that certain metabolic disturbances, body composition differences and nutritional deficiencies may be more prevalent in people with NF1. Data on the role of dietary patterns in people with NF1 and their effects in NF1-related manifestations is scarce. METHODS A systematic literature review was conducted; the MeSH database of PubMed was utilized to identify controlled vocabulary and key words associated with NF1, diet, and nutrition. These terms were combined using boolean operators to query PubMed, Embase, PLOS One, and Cochrane. The inclusion criteria consisted of articles in English, full text available, human studies, published between 2000-2024. The results were screened and key details were extracted. RESULTS 394 published articles were identified, out of which 15 met the inclusion criteria. 379 papers were excluded due to duplication or not meeting all inclusion criteria. Manuscripts included case reports, case series, retrospective and prospective studies, including a phase 2a clinical trial that only included six participants. Topics included vitamin D and bone metabolism, nutritional supplements, glucose metabolism, and nutritional intake. CONCLUSIONS Data regarding the effects of diet or nutritional supplements in people with NF1 is limited. Available studies suggest that a diet composed of therapeutic elements, including but not limited to, medium-chain fatty acids, calcium, and vitamin D, aids in bone growth and density, and muscle lipolysis. A single clinical trial suggests that L-carnitine supplementation is safe and feasible and might result in improved functional muscle performance in children with NF1. These conclusions might only be applicable to a small population of people with NF1 and did not result in conclusive significant clinical benefit. Further research is needed to better comprehend the role that nutrition plays in patients’ quality of life.
NIMG-71. T2 RELAXIVITY AND DIFFUSION TENSOR METRICS IN THE PREDICTION OF PROGRESSION-FREE SURVIVAL IN NON-RECURRENT HIGH GRADE GLIOMA
Authors: Aaron Rulseh, Heidrun Zajickova, Josef Vymazal
Journal: Neuro-Oncology (2024)

Abstract High grade glioma (HGG) is the most common primary brain tumour; we aimed to evaluate T2 relaxivity and diffusion tensor imaging (DTI) metrics in the prediction of progression-free survival. Seventy-two non-recurrent HGG subjects (IDH: MUT=10, Unknown=20) followed at our institution after surgery and combined chemo-radiotherapy were included. All data used were prior to progression as per RANO criteria; only the first 2 years of follow up was included in the analyses. T2 relaxation rates (1/T2) were calculated voxel-wise assuming mono-exponential decay. Diffusion data were corrected from two opposite phase encode acquisitions and DTI metrics evaluated included FA, MD, p, q, and L1. Whole- and half-brain (ipsilateral/contralateral) masks were generated by brain extraction and registration; data extracted from these masks were analyzed using python 3.8 with the exception of numerous histogram features extracted using fsl tools. Radiomics features were also extracted using the pyradiomics package. The lofo-importance package was used for feature selection. A multi-level approach was used to reduce the initial 32,000 MRI features to a final number of 443; from these, the 50 highest-ranked features were used further. Within-subject feature engineering was then performed including 1–4 step forward and backward lag, lag difference, as well as area, maximum, mean and cumulative sum. Non-MRI features included available demographic, histological and treatment-related data. A LightGBM classification model was used for the prediction of progression within 90 days; the data were grouped by subject, such that each subject was present only in training or testing datasets. Hyperparameters were tuned using randomized search cross validation, and the final model using 5-fold cross validation reached a mean ROC-AUC of 0.89. Our results show the potential of quantitative MRI features derived from qualitatively unremarkable images within the progress-free interval to identify subjects at risk of imminent progression.
BIOS-07. GRADUAL METABOLIC ALTERATIONS RESTRUCTURE THE SPATIAL ARCHITECTURE AND IMMUNITY IN GLIOBLASTOMA
Authors: Jan Kueckelhaus, Jasim Kada-Benotmane, Oliver Schnell, Jürgen Beck, Giulia Villa, Dieter-Henrik Heiland
Journal: Neuro-Oncology (2024)

Abstract The organized layered structure of the human neocortex contrasts sharply with the chaotic architecture of malignant CNS tumors. The heterogenous nature of glioblastoma (GBM) poses significant challenges to research and treatment, given that effective strategies require consistent biological patterns. Here, we leverage recent advances in spatial biology, integrating spatially resolved transcriptomics and metabolomics to identify drivers of GBM-specific architectural evolution. We performed spatial metabolomics (MALDI) and transcriptomics (Visium n=43 and MERFISH n=25) on glioblastoma patients, with computational analysis conducted using the SPATA2 R package. Our findings reveal that most spatial recurrent patterns in glioblastoma emerge in a gradient-like organization, particularly influenced by proximity to areas of necrosis and hypoxia. Samples without hypoxic regions demonstrated less spatial organization. Metabolomic and transcriptomic profiling indicated enhanced responses to hypoxia, reduced cell proliferation, and elevated expression indicative of the S phase in cell division near necrotic regions. The vicinity to hypoxic areas was associated with increased extracellular matrix remodeling and epithelial-to-mesenchymal transition, suggesting that the invasive capabilities of GBM cells originate from these hypoxic niches. By further integrating spatially resolved TCR-sequencing, we identified that hypoxic gradients drive defined T cell responses with a higher likelihood of T cell dysfunction within a distance of 235 µm (sd: 132 µm) to hypoxia. This suggests that the presence of necrosis, hypoxia, and hypoxia-associated metabolites could serve as potential predictive markers for T-cell behavior and exhaustion in glioblastoma. Our study offers an in-depth analysis of the influence of two prevalent niches in glioblastoma: necrosis and hypoxia. We reveal that the complex architecture of glioblastoma is not solely dictated by genetic randomness and stochastic occurrences but is significantly influenced by spatial proximity to key factors like necrosis and hypoxia. This insight contributes to an evolving model that seeks to unravel the intricate biology underpinning this formidable disease.
TMOD-31. SINGLE-CELL PROFILING AND CHARACTERIZATION OF PATIENT-DERIVED XENOGRAFT GLIOBLASTOMA MODEL IN HUMANIZED MICE
Authors: Jun Takei, Ken Furudate, Opeyemi Iwaloye, Yoshiko Nagaoka-Kamata, Madison T Blucas, Stella U Azolibe, Chloe E Jepson, Kiyotaka Saito, C Ryan Miller, Erwin G Van Meir, Masakazu Kamata, Satoru Osuka
Journal: Neuro-Oncology (2024)

Abstract Glioblastoma (GBM) is the most common and aggressive malignant brain tumor in adults, and the current standard therapy has limited efficacy. To develop effective therapies, it is desirable to develop an animal model that can replicate the tumor heterogeneity and immune microenvironment of human GBM. Here, we describe a novel GBM mouse model established with a patient-derived xenograft (PDX) in humanized mice harboring a nearly complete human immune environment. Humanized mice were generated by engrafting human CD34+ hematopoietic stem cells from umbilical cord blood into immunocompromised mice (NSG, NSG-SGM3, and NOG-EXL) after myeloablation. NSG-SGM3 is a triple transgenic mouse encoding human IL3, GM-CSF, and SCF on the NSG strain background. NOG-EXL is a NOG strain with human IL3 and GM-CSF expression. These cytokines foster the development of the human myeloid lineage and its differentiation. NSG-SGM3 and NOG-EXL were superior in immune cell reproducibility, especially myeloid cells. Radioresistant PDX GBM cells established after repeated irradiation were injected into the forebrain of humanized mice and the same immunocompromised mice without humanization. Human PDX GBM cells formed aggressive tumors with similar growth speed in the humanized mice compared to non-humanized mice; however, their dissemination to the spinal cord was significantly suppressed in humanized mice, suggesting that human immune cells impact the spinal dissemination of GBM cells. Single-cell RNA sequencing analysis revealed infiltration of human CD4+ T, CD8+ T, NK cells, and macrophages, as well as infiltration of regulatory T and exhausted CD8+ cells into the brain tumor, reflecting the immunosuppressive landscape of recurrent human GBM. Furthermore, we found that tumor heterogeneity was increased in humanized mice compared to non-humanized mice. There was a notable rise in neural progenitor-like cell populations, indicating tumor adaptation to immune pressures. This novel GBM-PDX humanized mouse model might be highly beneficial for analyzing the interaction between human tumor cells and human immune cells, and evaluating the effect of immunotherapies.
CTNI-76. A PHASE 1/2 DOSE ESCALATION AND EXPANSION STUDY OF SONODYNAMIC THERAPY WITH SONALA-001 IN COMBINATION WITH NON-ABLATIVE MR-GUIDED FOCUSED ULTRASOUND IN SUBJECTS WITH PROGRESSIVE OR RECURRENT GLIOBLASTOMA
Authors: Dimitris Placantonakis, Mathew Grabowski, Terry Burns, Nicholas Butowski, Ryan Clanton, Lenora Henry, Wyatt Potter, Stuart Marcus, Ely Benaim
Journal: Neuro-Oncology (2024)

Abstract Recurrent glioblastoma (rGBM) is a lethal brain tumor with no effective standard of care option and an extremely poor prognosis (median survival 6 to 8 months after first recurrence). Sonodynamic therapy (SDT) is a non-invasive combination therapy that utilizes a drug, aminolevulinic acid HCL (SONALA-001, ALA), and a device, the Exablate 4000 Type 2.0 to deliver MR-guided focused ultrasound (MRgFUS). Preclinical studies have shown that SDT activates protoporphyrin IX (PpIX) to generate reactive oxygen species that lead to tumor cell death and improved survival in animal glioma models. A first-in-human Phase 0 trial (NCT04559685) indicated that ALA SDT was well-tolerated and not associated with off-target cellular or radiographic effects and provided direct evidence of reactive oxygen species formation and targeted tumor cell death in recurrent high-grade glioma (rHGG). SDT-202 is a Phase 1/2 multicenter, open-label, dose escalation and expansion study (NCT05370508) of iv SONALA-001 (ALA) in combination with MRgFUS for SDT in patients with progressive or recurrent GBM. Dose escalation will include an initial drug and energy dose escalation of ALA SDT utilizing an accelerated titration design with single subject cohorts for dose level cohorts 1 and 2, followed by cohort 3 with 3 + 3 design for additional dose escalation. SONALA-001 is administered 6 to 9 hours prior to MRgFUS treatment. Once the RP2D is determined, Phase 2 dose expansion will enroll approximately 36 additional subjects to assess safety and efficacy of repeated cycles of ALA SDT at the optimized RP2D. Endpoints of this study are safety evaluation, maximum tolerated dose (MTD), recommended Phase 2 dose (RP2D), and determination of pharmacokinetic (PK) parameters. The Phase 2 portion will further characterize safety of RP2D along with evaluation of efficacy with PFS6 (mRANO), ORR, CBR, DOR, DOCR, TTR, and OS. Preliminary PK and safety results will be presented.
SURG-16. MULTIDISCIPLINARY TREATMENT OF HEMANGIOBLASTOMAS IN CENTRAL NERVOUS SYSTEM AND FUTURE PROSPECTS
Authors: shunsaku takayanagi, Hirokazu Takami, Masashi Nomura, Yosuke Kitagawa, Nobuhito Saito
Journal: Neuro-Oncology (2024)

Abstract Hemangioblastomas (HB) in central nervous system are originally benign tumors. However, they are extremely vascular and appropriate treatment of the feeders and drainers is important when performing HB resection. Approximately 20% of HB cases are thought to be caused by von Hippel-Lindau (VHL) disease. Patients with VHL disease often develop multiple HBs, and it may be difficult to treat them with excision alone. Recently, belzutifan, a molecular targeted drug indicated for treating HB in VHL disease cases, was approved by FDA. In this presentation, we will provide an overview of the multidisciplinary treatment at our facility. METHOD At our facility, we performed 84 cases of excision surgery from 1996 to 2019, and analyzed the results of these treatments. A high-definition 3D fused image was created before surgery to identify the feeders and drainers. Tumor embolization was performed on the feeder, which was thought to be located deep within the surgical field. In addition, gamma knife treatment was performed as appropriate for HBs that did not undergo extirpation. RESULTS The breakdown of cases was 46 with VHL disease and 38 with non-VHL disease. Postoperatively, KPS improved in 55% of cases, and some complications occurred in 18%. Gamma Knife treatment has been performed on 58 cases so far, and the 10-year tumor control rate is approximately 80%. DISCUSSION/SUMMARY This presentation revealed that multidisciplinary treatment is effective for HBs. In the future it is necessary to consider which HB cases belzutifan is useful for and how it should be combined with other treatments.
QOL-28. CANCER-RELATED DISTRESS IN NEURO-ONCOLOGY: PATIENTS INFORM PROGRAM DEVELOPMENT FOR ENHANCING QUALITY OF LIFE
Authors: Amber Fox, Giuliana V Zarrella, Ashlee R Loughan, Autumn Lanoye, Oxana Palesh, F Gerard Moeller, Sarah E Braun
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Brain tumor diagnosis and treatment result in significant negative sequelae, including cognitive decline, fatigue, and psychosocial symptoms. This study aimed to identify brain tumor patients’ sources of cancer-related distress and examine their interest in various treatment modalities targeting cognitive decline to inform program development for this underserved population. METHODS In pursuit of program development, patients with both primary and secondary brain tumors completed an anonymous survey. They reported demographics, tumor characteristics, subjective cognitive functioning; and, rated sources of cancer-related symptom distress (i.e., cognitive changes, fatigue, physical symptoms, motor functioning, balance, mood, and relationship) and interest in treatments targeting cancer-related cognitive decline (i.e., cognitive rehabilitation, mindfulness-based practices, psychotherapy, and medication). Descriptive statistics, t-tests, chi-square, and linear regressions were conducted. RESULTS Among participants (N=137, Mage=49.6±15.8, 58.1% female, 84.8% White), 50.4% endorsed subjective cognitive functioning below the mean (MFACT-Br-CI=22.6±7.5). Nearly half reported significant distress due to cancer-related fatigue (49.6%) and cognitive change (48.9%). Patients’ mean severity of distress due to cognitive decline was significantly greater relative to all other cancer-related symptoms (ps&amp;lt;.001), except fatigue (p&amp;gt;.05). Age, gender, or time since diagnosis were not significant predictors (ps&amp;gt;.05) of distress due to cognitive decline. Most patients with distress due to cognitive change were interested in cognitive rehabilitation (63.6%) and mindfulness-based practices (61.6%), and only 40.4% were interested in medication. Interest in cognitive rehabilitation was not predicted by symptom distress, subjective cognitive functioning, age, gender, or time since diagnosis (ps&amp;gt;.05). Gender was the only significant predictor of interest in mindful movement (b=.18, p=.041), with greater interest among women (χ2(1)=4.65, p=.031). CONCLUSIONS Fatigue and cognitive decline were the most distressing cancer-related symptoms for neuro-oncology patients. These findings emphasize the need for integrated interventions, including cognitive rehabilitation and mindfulness, as well as multi-targeted and individualized treatments for fatigue and cognitive decline in neuro-oncology.
QOL-08. HEALTH-RELATED QUALITY-OF-LIFE (HRQOL) IN ADULTS AND CHILDREN WITH NEUROFIBROMATOSIS TYPE 1-ASSOCIATED PLEXIFORM NEUROFIBROMA (NF1-PN) TREATED WITH MIRDAMETINIB: PIVOTAL, PHASE 2B RENEU TRIAL
Authors: Dusica Babovic-Vuksanovic, Angela Hirbe, Christopher Moertel, Hans Shuhaiber, Alpa Sidhu, Kevin Bielamowicz, David Viskochil, Timothy Bell, Michael Weber, Abraham Langseth, Armend Lokku, Lauren Weintraub, Fouad Hajjar, Nick Foreman, Timothy Gershon, Rene McNall-Knapp
Journal: Neuro-Oncology (2024)

Abstract Patients with NF1-PN experience pain and other symptoms that negatively impact functioning and quality-of-life. We present patient- and parent proxy-reported HRQoL outcomes from ReNeu (NCT03962543), a pivotal, phase 2b trial of mirdametinib, an investigational MEK1/2 inhibitor, in adults and children (≥2 y) with NF1-PN causing morbidities. Fifty-eight adults and 56 children received mirdametinib (2 mg/m2 BID; 3-weeks-on/1-week-off, 28-d cycles). Change in HRQoL was assessed by Pediatric QoL Inventory (PedsQL) 4.0 Generic Core Scales from baseline across the 24-cycle treatment phase; change from baseline at Cycle 13 (C13) was a prespecified secondary endpoint. PedsQL is a HRQoL measure for adults and children with a Total Score (TS) and 4 subscales: physical, emotional, social, and school/work. Items are reported on a 0-100 scale (higher scores=better HRQoL). Clinically meaningful improvement was defined as change from baseline &amp;gt;9.7 points for adults, &amp;gt;8.5 points for child self-report, and &amp;gt;9.0 points for parent proxy-report. PedsQL-TS improvement (least-squares mean, LSM [SE] change) from baseline at C13 was 3.9 (1.6; P=.018; n=34) for adults, 4.0 (2.4; P=.096; n=38) for children by self-report, and 5.6 (1.9; P=.005; n=43) by parent proxy-report. PedsQL-TS improvements for adults and children by parent proxy-report (not by children self-report) were observed early (at C5 and C3, respectively) and sustained through C24. Clinically meaningful improvement in PedsQL-TS from baseline at C13 was achieved by 37% (10/27) adults, 45% (13/29) children by self-report, and 47% (15/32) children by parent proxy-report (among patients who could have achieved a clinically meaningful change from baseline). Significant (P&amp;lt;.05) improvement from baseline to C13 was reported for physical (adults, children, and parent proxy-report), school/work (adults), and emotional and social (parent proxy-report) subscales. Adults and children (by parent proxy-report) with NF1-PN had clinically meaningful, early, and sustained improvement in HRQoL over the course of mirdametinib treatment.
BIOM-74. IDENTIFICATION OF EMP2 AS A TARGETABLE BIOMARKER IN GLIOBLASTOMA TUMORS RESISTANT TO ANTI-ANGIOGENIC THERAPIES
Authors: Mahlet Mekonnen, Brian Aguirre, Riddhi Mehta, Anubhav Chandla, Madhuri Wadehra, Isaac Yang
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND The role of Epithelial Membrane Protein-2 (EMP2) in mediating resistance to current anti-angiogenic drugs in the treatment of glioblastoma (GBM) is an intriguing hypothesis that may provide insights into improving the limited survival benefits observed in current therapies. Investigating the interaction between EMP2 and anti-angiogenic drugs such as bevacizumab or Aflibercept could lead to a better understanding of the mechanisms underlying resistance, potentially opening up new avenues for more effective treatment strategies. OBJECTIVE To use EMP2 as a targetable biomarker for anti-VEGF resistance and test combination therapy with anti-VEGF (Aflibercept or bevacizumab), and a novel anti-EMP2 mAb in SB28 and GL261 GBM mouse models. METHODS Tumor tissue was collected prospectively from patients undergoing surgery for suspected glioblastoma and stained for EMP2 and HIF-2a using standard immunohistochemistry. Patients had banked tumor tissue both before and after bevacizumab treatment with 3 months of clinical and radiologic follow-up available. To establish syngeneic models, 10-week-old mice were subcutaneously implanted with murine SB28 or GL261 GBM cells. RESULTS Immunohistochemistry conducted on pre- and post-bevacizumab-treated patient samples revealed an increase in EMP2 and HIF-2a protein expression post-treatment. This increase in EMP2 expression correlated with reduced survival time. Similarly, the in vivo models showed a significant upregulation in both markers in the Aflibercept-treated cohort compared to the control. Treatment with either polyclonal sera to VEGF or Aflibercept failed to reduce tumor load or provide a therapeutic benefit. However, combination therapy with Aflibercept and anti-EMP2 mAb was found to significantly reduce tumor volume and weight in both SB28 and GL261 tumors. These findings highlight the potential effectiveness of combination therapies targeting EMP2 and VEGF in reducing tumor load in GBM. CONCLUSION Our results suggest that EMP2 can be a promising new therapeutic target that can be combined with anti-VEGF treatment to potentially increase overall survival in GBM patients.
EPCO-10. PROTEIN GENERATOR ENABLES PROTEOMICS-BASED SUBTYPING OF IDH MUTANT ASTROCYTOMA
Authors: Hui Wang, Jihong Tang, Xing Liu, Wenhua Fan, Tao Jiang, Jiguang Wang
Journal: Neuro-Oncology (2024)

Abstract The understanding of the proteomic landscape of IDH mutant astrocytoma has been limited in previous studies. To address this knowledge gap, we developed an innovative approach using artificial intelligence (AI) to generate proteomic profiles of tumors based on their transcriptome data. Particularly, we employed a combination of Variational Auto-Encoder and Contrastive Language Image Pretraining techniques to develop an AI model. The model was trained on publicly available databases containing matched RNA and protein data. Leveraging this extensive dataset, we applied the trained model to infer proteomic profiles for over one thousand adult IDH mutant astrocytoma specimens using their transcriptome sequencing data. This novel approach allowed us to explore and identify previously undiscovered subtypes based on the predicted proteomic profiles. As a result, we identified seven distinct clusters: IDHmut-noncodel-Proliferative, IDHmut-noncodel-Mesenchymal, IDHmut-noncodel-Mitochondrial, IDHmut-NFkB-signal, IDHmut-codel-Proliferative, IDHmut-Metabolism, and IDHmut-Neuronal. Of particular clinical significance, the IDHmut-noncodel-Proliferative and IDHmut-noncodel-Immune-Mesenchymal subtypes displayed the worst prognoses, while the IDHmut-Neuronal, IDHmut-NFkB-signal, and IDHmut-Metabolism subtypes exhibited relatively better survival outcomes. Remarkably, within the IDHmut-noncodel-Proliferative cluster, we observed a high prevalence of CDKN2A homozygous deletion, providing a potential explanation for its poor survival prognosis. Conversely, the IDHmut-noncodel-Mesenchymal cluster did not demonstrate any significant genetic events but exhibited elevated expression of mesenchymal marker genes. Furthermore, this cluster displayed notable characteristics, including the presence of gemistocytic differentiated tumor cells and infiltration of activated CD8 T lymphocytes. Moreover, we encompassed an evolutionary analysis of 189 initial-recurrent IDH mutant astrocytoma pairs, and discovered that gemistocytic differentiation represents an early event in tumor progression. In summary, we introduced a novel method utilizing an AI model to generate proteomic profiles, thus enabling the discovery of previously unknown subtypes of IDH mutant glioma with clinical relevance. These findings contribute to a deeper understanding of the molecular landscape of IDH mutant astrocytoma, potentially leading to improved prognostication and personalized treatment strategies.