tbuckley/cabot-search huggingface dataset:
TMIC-67. EMERGING ROLE OF EXTRACELLULAR MATRIX STIFFNESS AS A HALLMARK OF GLIOBLASTOMA: INSIGHT TO MECHANICAL MEMORY FORMATION AND PROLONGED INVASION IN THE TUMOR PERIPHERY
Authors: Paola Suarez Meade, Rachel Whitehead, Jean Clemenceau, Emily Norton, Tanmay Kulkarni, Changjin Hong, Caroline Teeter, Manuela Aramburu, Kaisorn Chaichana, Steven S Rosenfeld, Rajappa Kenchappa, Hugo Guerrero-Cazares, Paula V Schiapparelli, Tae H Hwang, Konstantinos Konstantopoulos, Alfredo Quinones-Hinojosa
Journal: Neuro-Oncology (2024)

Abstract The extracellular matrix (ECM) plays a critical role in cancer progression, with its biophysical properties influencing cancer behavior. ECM stiffness can induce long-lasting adaptations in cancer cells, promoting sustained invasion through a process known as “mechanical memory” (MM). Glioblastoma (GBM) exhibits spatial heterogeneity in stiffness, with stiffer ECM found at the tumor periphery where invasive cells reside and promote recurrence. We hypothesize that increased stiffness at the tumor periphery primes GBM cells for sustained invasion through MM. METHODS Cell lines were established from image-guided human GBM samples from tumor margin and core (n=10 patients, 20 cell lines). Cells from random locations were conditioned in physiologically relevant extracellular matrices for two weeks. Human organotypic assay (n=3), Migration Assays, Atomic Force Microscopy (AFM), Immunocytochemistry, Western Blot, and RNA-sequencing (n=6) were performed. RESULTS GBM cells at higher stiff surfaces displayed increased migration (p&amp;lt;0.01). Magnetic Resonance Elastography (n=9) confirmed GBM heterogeneity, with softer cores (0.2-0.5kPa) transitioning to stiffer margins (&amp;gt;2kPa). Organotypic scaffolds mimicking the tumor margin promoted enhanced migration of GFP-labeled GBM cells. Margin cells and cells conditioned on stiffer matrices demonstrated higher migratory potential compared to their core and soft-conditioned counterparts (p&amp;lt;0.05). These trends persist over time and across multiple passages. ECM stiffness exposure causes nanomechanical, cytoskeletal, and transcriptional adaptations. AFM shows that cells from the margin (n=6) are softer (p&amp;lt;0.01) and more deformable (p&amp;lt;0.01). RNAseq identified upregulation of MM-specific genes in GBM margin cells. The mechanosensitive transcription factor YAP1 emerged as a key driver of MM. Notably, YAP1 is targetable by the FDA-approved drug Verteporfin. YAP1 expression was elevated in margin and stiff-conditioned cells (p&amp;lt;0.05). Stiff-conditioned cells and margin cells displayed increased sensitivity to Verteporfin treatment (p&amp;lt;0.05), with treatment significantly reducing margin migration compared to the core (p&amp;lt;0.001). CONCLUSION Stiffer GBM margins promote the formation of aggressive phenotypes through MM. Targeting YAP1 with Verteporfin, a readily available drug, presents a promising strategy to halt GBM invasion and improve patient outcomes.
EXTH-44. ENHANCING THERAPEUTIC APPROACHES IN HIGH-GRADE GLIOMAS: SYNERGISTIC EFFECTS OF LSD1 AND KINASE INHIBITION
Authors: Lea M Stitzlein, Faith A Hernandez, Deokhwa Nam, Kareena Patel, Katie Impelman, Alaina L Poche, Xiaoping Su, Joy Gumin, Gangadhara R Sareddy, Frederick F Lang, Joya Chandra
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Glioblastoma (GBM) and Diffuse Intrinsic Pontine Glioma (DIPG) are devastating high-grade gliomas (HGGs) with poor prognoses. Lysine-specific demethylase 1 (LSD1) is a promising therapeutic target and a key regulator in tumor initiation and recurrence. Crosstalk between LSD1 and other signaling pathways, such as the MAPK pathway, frequently hyperactivated in HGG, offers an opportunity to enhance the efficacy of LSD1 inhibitors. This study investigates the combined inhibition of LSD1 and kinase signaling to improve therapeutic outcomes in HGG. METHODS Transcriptional changes following LSD1 knockdown in human GBM cells were analyzed using RNA-seq and GSEA. RPPA and western blotting assessed the impact of LSD1 inhibition on kinase signaling. Pharmacological LSD1 inhibition was tested using NCD38 or bomedemstat in HGG models and normal human astrocytes (NHA). The effects of combining LSD1 inhibitors with kinase inhibitors (osimertinib, afatinib, and ulixertinib) on cell viability were evaluated. Combination treatment was also assessed in orthotopic xenograft models of GBM. RESULTS GSEA revealed LSD1 expression was enriched for gene sets involved in kinase signaling processes. Increased phosphorylated ERK1/2 levels were observed following NCD38 treatment in MDA-GSC17, as shown by RPPA and western blot analyses. The LSD1 inhibitor, NCD38, increased phospho-ERK1/2 levels (72% increase from baseline), while co-treatment with osimertinib mitigated this effect. Combined LSD1 and kinase inhibition (EGFR and ERK inhibition) showed synergistic effects in vitro in GBM and DIPG models but not in the NHA. DISCUSSION Our results demonstrate that kinase activity can be modulated by inhibiting LSD1, potentially leading to a resistant subpopulation. This study underscores the potential of combining LSD1 and kinase inhibition to enhance therapeutic efficacy in HGG, including GBM and DIPG. Future research will focus on elucidating the mechanisms by which LSD1 regulates kinase signaling, aiming to optimize combination therapies.
SURG-31. HYBRID THERAPY FOR NEWLY DIAGNOSED AND RECURRENT GLIOBLASTOMA: STAGED PROCEDURE INTEGRATING OPEN SURGICAL RESECTION WITH LASER INTERSTITIAL THERMAL THERAPY
Authors: Chandler Berke, Adham Khalafallah, Victor Lu, muhammet Gurses, Michael Ivan, Ricardo Komotar, Ashish Shah
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Glioblastoma (GBM) is the most common and aggressive primary malignant brain tumor in adults with a median overall survival (OS) of 15.6 months. Despite advancements, 5-year survival rates have not significantly improved. Laser interstitial thermal therapy (LITT) has been employed to treat both newly diagnosed (nGBM) and recurrent GBM (rGBM) with demonstrable safety and efficacy. Traditionally, LITT has been limited to smaller lesions given physical and thermal constraints. OBJECTIVE We present two case examples of a novel, hybrid treatment approach to GBM, utilizing both surgery and laser ablation as part of a single-staged procedure. METHODS Two geriatric (&amp;gt;65 years) patients with nGBM or rGBM were treated with surgical resection followed by LITT the subsequent day. Both patients underwent preoperative magnetic resonance imaging (MRI) showing multifocal disease with a dominant component, causing mass effect in the second case, and an unresectable component. RESULTS The first case underwent surgical resection of a large, multicentric rGBM in the parieto-occipital region, followed by LITT of an unresectable lesion in the inferior temporal gyrus. The second patient underwent surgical resection of the dominant temporal lobe component, and LITT of the insular component. Neither patient had intraoperative or ablation complications. Both patients had stable postoperative neurological exams and were discharged on the day after ablation, with no new deficits at follow-up. CONCLUSION The prognosis for GBM remains dismal despite significant research and attempts at advancements in patient management. Surgical resection is a critical component of the GBM treatment paradigm. However, surgery alone is not sufficient in many patients. LITT has shown promise for improving GBM outcomes, mainly due to its minimal invasiveness, enhanced immune responses, BBB disruption, and cytoreductive potential. We demonstrate a novel, hybrid approach to GBM using hybrid surgical resection and LITT in a single-staged procedure to overcome traditional constraints of LITT.
SURG-20. DEVELOPING ENDOSCOPIC RESECTION OF COLLOID CYSTS: A 25-YEAR EXPERIENCE IN 200 PATIENTS
Authors: Umberto Tosi, Arsalan Haghdel, Kyle Zappi, Rafael Uribe, Sergio Guadix, Francis Villamater, Mark Souweidane
Journal: Neuro-Oncology (2024)

Abstract Endoscopic resection is a legitimate treatment alternative for third ventricular colloid cysts. Increasing experience and the development of new surgical instruments and techniques have allowed this approach to reach clinical prominence. In this study, we review our 25-year experience with endoscopic resection of colloid cysts, assess factors predictive of operative success, and critically analyze our evolving clinical practice. Therefore, a prospective database was used to review all patients that had endoscopic removal of a third ventricular colloid cyst between 1995 and 2021. Demographics, imaging features, presenting symptomatology, operative approach, surgical outcomes, and complications were analyzed in 5-year intervals to determine changing patterns over time. Bivariate analyses were carried out to understand factors predisposing to outcome. Kaplan-Mayer curves were used to analyze time-to-recurrence. Over this 25-year continuum an increase in the proportion of treated patients who were asymptomatic (p &amp;lt; 0.001) was observed. The rate of recurrence and length of stay all decreased over time (p &amp;lt; 0.001) – now, with median length of stay of 1 day. The rate of complete cyst removal (CCR) increased (p &amp;lt; 0.001). Rate of major complications or need for postoperative CSF diversion remained low. Bivariate analyses indicated how incomplete cyst removal (ICR) was associated with recurrence. In conclusion, our 25-year experience posits endoscopic resection as an increasingly safe approach to third ventricular colloid cysts, with low recurrence rates and negligible complications. These results are attributed in-part to a continuous adaptation related to instrumentation, technique, perioperative strategy, and experience.
EXTH-09. GENE MODIFICATION OF HEMATOPOIETIC STEM AND PROGENITOR CELLS FOR IMPROVEMENT OF IMMUNOTHERAPIES FOR MALIGNANT GLIOMAS
Authors: Laura Falceto Font, Dan Jin, Bayli DiVita Dean, John Figg, Connor Francis, Alexandra Reid, Kaytora Long-James, Brianna McDonald, David Hilferty, Hector Mendez-Gomez, Duane Mitchell, Zubaidan Tuerdi, Evelyne Lauret, Catherine Flores
Journal: Neuro-Oncology (2024)

Abstract Patients living with high-grade gliomas have a poor survival prognosis. Furthermore, standard of care treatment for these malignant gliomas has not significantly improved in the past decades. Our laboratory previously demonstrated that the combination of two different immunotherapies with HSPCs provided a significant survival benefit in preclinical brain tumor models, however, this therapeutic combination is still not 100% curative. We hypothesized that gene modification of HSPCs could add additional therapeutic benefit to immunotherapies for the treatment of resistant gliomas. Hematopoietic stem and progenitor cells (HSPCs) have been widely used in different clinical settings due to their ability to self-renew and differentiate into all immune cell lineages. In recent years, HSPCs have been the target of a variety of gene editing research efforts to decipher the most effective method for gene modification to use for therapeutic purposes. After comparison with previously established methods, we optimized a protocol for the successful editing of murine HSPCs and human CD34+ cells. Using Cas9 mRNA and sgRNAs in HSPCs, we achieved up to 80% reduction in gene expression. This method is superior to others due to its efficient, quick, inexpensive, and reliable nature. We also showed that, by knocking-down IL-6R in HSPCs, we can drive their differentiation into dendritic cells, while decreasing MDSCs and macrophages. Furthermore, gene-modified HSPCs are also capable of bone marrow reconstitution of lethally irradiated mice. Currently, we are testing whether the combination of gene-modified HSPCs with immunotherapy provides additional survival benefit to unmodified HSPCs with immunotherapy in a resistant murine glioma model.
EXTH-05. STEM CELL-BASED THERAPEUTIC STRATEGY FOR LEPTOMENINGEAL METASTASIS OF SOLID CANCERS
Authors: Yohei kitamura, Nobuhiko Kanaya, Susana Moleirinho, Ryota Tamura, Ryo Ueda, Hikaru Sasaki, Masahiro Toda, Khalid Shah
Journal: Neuro-Oncology (2024)

Abstract Leptomeningeal dissemination (LMD), known as carcinomatous meningitis, presents an extremely poor prognosis with an average life expectancy of 4-6 weeks. Although whole brain/spinal cord irradiation and intrathecal injection of anticancer drugs are sometimes performed, their effects are limited, so new therapeutic strategies for LMD are urgently needed. Based on the following greatest advantage of stem cell (SC) based therapeutic strategy for LMD, we tested its efficacy in LMD of various solid cancers; LMD is a condition in which cancer cells spread within a huge single space without separation, and the SCs with the characteristic of cancer tropism and chemotaxis can reach cancer cells easily; Repetitive intrathecal injection of therapeutic agents for patients is an invasive and risky procedure, but SCs can continuously secrete/release therapeutic agents into the cerebrospinal fluid after a few injections and increase local concentration of therapeutic substances. We have shown that treatment using engineered SCs may be effective treatment option against LMD from breast cancer, lung cancer, and malignant melanoma. Specifically, we reported that engineered allogeneic SCs which simultaneously targeting epidermal growth factor receptor (EGFR) and death receptor (DR) has efficacy for LMD of triple negative breast cancer and non-small cell lung cancer. Also, we reported that SCs releasing oncolytic herpes virus, granulocyte-macrophage colony-stimulating factor (GM-CSF), and single-chain variable region fragments (scFv) against programmed death receptor-1 (PD-1) has efficacy in LMD of malignant melanoma. Overall, we believe that SC therapy has the potential to become a new therapeutic option for LMD in the future.
Frailty screening with comprehensive geriatrician-led multidisciplinary assessment for older adults during emergency hospital attendance in Ireland (SOLAR): a randomised controlled trial
Authors: Aoife Leahy, Louise Barry, Gillian Corey, Aoife Whiston, Helen Purtill, Elaine Shanahan, Denys Shchetkovsky, Damien Ryan, Monica O'Loughlin, Margaret O'Connor, Rose Galvin
Journal: The Lancet Healthy Longevity (2024)

Multidisciplinary comprehensive geriatric assessment (CGA) improves outcomes in hospitalised older adults but there is limited evidence on its effectiveness in the emergency department. We aimed to assess the benefits of CGA in the emergency department for older adults living with frailty.
EXTH-08. IVOSIDENIB THERAPY FOR IDH-MUTANT WHO GRADE 4 ASTROCYTOMA
Authors: Brittany Owusu-Adjei, Peter Amenta, Mark Johnson, David Cachia
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Isocitrate Dehydrogenase (IDH) is a commonly mutated gene in gliomas, present in approximately 10% of high-grade gliomas. Its oncometabolite, D-2-hydroxyglutarate, has been implicated in promoting gliomagenesis and epileptogenesis. IDH-1 or IDH-2 mutations confer a more favorable prognosis in gliomas than wildtype IDH, leading to the differentiation between IDH-wild type glioblastoma and IDH-mutant WHO Grade 4 astrocytoma. Although IDH-mutant WHO Grade 4 astrocytomas tend to occur in younger patients and show an improved survival, prognosis remains poor and treatment options are limited. Ivosidenib is a small molecule inhibitor of IDH-1 that has shown promise for treating low-grade IDH-mutant glioma. However, little is known about its efficacy in IDH-mutant WHO Grade 4 astrocytoma. METHODS We present a retrospective case of a 38-year-old male with a WHO Grade 4 astrocytoma. Molecular characterization revealed that it was IDH-mutant, MGMTp methylated, and 1p/19q co-deleted. It was treated with ivosidenib at second recurrence. He was originally treated with gross total resection, followed by radiation and 6 cycles of adjuvant temozolomide. At the time of 1st progression (approximately 19 months postoperatively), he was treated with lomustine at 90mg/m2 but progressed after 2 cycles. Here we report the effects of off label use of ivosidenib. RESULTS Radiological surveillance showed interval decrease in tumor size starting two months after initiation of ivosidenib. The patient remained neurologically intact and no adverse effects were observed. A review of the literature revealed only three studies analyzing the effects of ivosidenib in IDH-mutated WHO Grade 4 astrocytomas with varying results. CONCLUSION The INDIGO trial published last year showed evidence of efficacy in using an IDH inhibitor for low-grade gliomas. The role of these drugs in high-grade IDH-mutated gliomas is currently unknown. Further studies are needed to assess their efficacy in overall and progression free survival, specifically in IDH-mutated WHO Grade 4 astrocytoma.
NIMG-04. MASSIVE THORACIC MENINGOCELE IN A PATIENT WITH NF1
Authors: Pushan Dasgupta, Ian McCutcheon, John Slopis
Journal: Neuro-Oncology (2024)

Abstract Thoracic meningoceles are uncommon but when seen are often associated with neurofibromatosis 1 (NF1). Here we present a unique case where a massive thoracic meningocele presented with chest pain in a patient with NF1. A 56-year-old female with a diagnosis of NF1 presented with pain in the entire chest wall. She described the pain as circumferential around the entire chest “like a barrel”. Cardiology evaluation (with echocardiography) revealed no pulmonary hypertension or other cardiac disorder. MR angiogram of the chest also revealed no intrathoracic vascular structural abnormality. Inflammatory myopathy was considered to explain the pain but electromyography was unremarkable as were creatine kinase and erythrocyte sedimentation rate. MRI of thoracic spine demonstrated a large thoracic meningocele involving the spinal canal from T5-T10 and extending into the left hemithorax with measurements of 11.5 x 6.1 x 12.5 cm. Imaging was also notable for leftward displacement of the spinal cord toward the meningocele starting at the T6 level and extending to the T9 level with kyphosis of the thoracic spine centered on the block vertebral bodies forming the T7-T8 levels. Significant posterior scalloping was evident from T6-T10 with attendant dural ectasia. Neurosurgical consultation recommended no intervention to correct the meningocele as plication carried a risk of producing a subarachnoid-pleural fistula from the meningocele into the pleural space of the thoracic cavity. This case adds to our understanding of how unique and diverse the presentations of NF1 can be, and of the surgical challenges posed by NF1-associated meningoceles.
NIMG-05. ARTIFICIAL INTELLIGENCE-BASED RESPONSE ASSESSMENT FOR PATIENTS RECEIVING LASER INTERSTITIAL THERMAL THERAPY
Authors: Aden Haskell-Mendoza, Ellery Reason, Ariel Gonzalez, Joshua Jackson, Eric Sankey, Ethan Srinivasan, James Herndon II, Peter Fecci, Evan Calabrese
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Laser interstitial thermal therapy (LITT) is a minimally invasive option for tissue diagnosis, cytoreduction, and rapid post-operative return to systemic therapies for patients with brain tumors or radiation necrosis. As ablated tissue remains in situ, post-LITT edema may be associated with apparent increased lesion size and transient clinical worsening, complicating assessment of progression. METHODS All patients receiving LITT at a single center for tumors or radiation necrosis from 2015 – 2023 with ≥ 9 months of MRI follow-up were retrospectively reviewed. A 3D U-net segmentation model implemented in nnU-Net was developed for automated segmentation of Contrast-enhancing Lesion Volume (CeLV) of LITT-treated lesions on T1-weighted post-contrast MR images. CeLVs were analyzed to establish volumetric post-LITT response assessments. RESULTS Across 384 unique MRI exams, 61LITT-treated lesions and 6 control cases of medically-managed radiation necrosis were analyzed. Automated segmentation was qualitatively accurate in 367/384 (95.6%) images. CeLV increased to a median of 68.3% (IQR 35.1 – 109.2%) from baseline at 1 – 3 months from LITT (P = 0.0012) and returned to baseline thereafter. Based on established criteria, volumetric disease progression was defined as lesion expansion 40% from volumetric nadir or baseline. Twenty-one of 56 (37.5%) patients experienced volumetric progression with a progression-free survival of 21.4 (6.0 – 93.4) months. Patients experiencing volumetric progression had lower mOS (17.3 vs 62.1 months, P = 0.0015). CONCLUSIONS We observed a stereotyped increase in CeLV at 1 – 3 months post-LITT, which resolved within 6 months of the procedure. Post-LITT disease response can be reliably and feasibly assessed with criteria that account for this transient CeLV expansion. Automated lesion segmentation may speed adoption of volumetric response assessment criteria to clinical practice.
TMIC-32. INFIGRATINIB INHIBITION OF THE THBS1 PATHWAY IN MELANOMA BRAIN METASTASIS
Authors: Andrew Tran, John Choi, Brandon Bergsneider, Lily Kim, Ethan Schonfeld, Matthew Abikenari, Rohit Verma, Kwang Bog Cho, Michael Lim
Journal: Neuro-Oncology (2024)

Abstract INTRODUCTION Despite promising preclinical studies, BRAF/MEK inhibition with vemurafenib in melanoma brain metastases (MBM) has suboptimal durable response in humans. Thrombospondin 1 (THBS1), a matricellular protein, is upregulated in vemurafenib-resistant metastatic melanoma, and its inhibition reverses BRAF inhibitor chemoresistance. However, the characteristics of THBS1-mediated signaling pathways as well as methods of inhibition require further exploration in the context of MBM. OBJECTIVE To characterize THBS1-mediated signaling pathways in MBM and evaluate the therapeutic potential of targeting THBS1 pathways. METHODS We analyzed human parenchymal MBM samples using publicly available single-cell RNA sequencing (scRNA-seq) data. Protein-protein interaction networks were assessed using the STRING database. Syngeneic B16 melanoma cells were intracranially implanted in C57BL/6J mice and treated with intraperitoneal injection of FGF7/FGFR2 small-molecule inhibitor Infigratinib or PBS (sham). Mice were immunophenotyped using flow cytometry and monitored for survival. RESULTS THBS1 is highly upregulated in immunosuppressive MBM-associated cell populations such as S100A8+ Metastasis-Associated Macrophages and Mesenchymal Stromal Cell-like cells. Gene set enrichment analysis of THBS1-positive cells paradoxically revealed upregulation of inflammation-associated gene sets. Differential expression analysis identified Fibroblast Growth Factor 7 (FGF7) as strongly co-expressed in THBS1-positive MBM cells, and STRING-DB confirmed close protein-protein interactions between FGF7 and THBS1. In vivo inhibition using Infigratinib for FGF7’s receptor, FGFR2, decreased the proportion of monocytic myeloid-derived suppressor cells (M-MDSCs) (P=0.030), increased T-cell activation marker IFN-y (P=0.027) and proliferation marker CD69 (P=0.047), and resulted in improved overall survival (P=0.0001). CONCLUSION MBM scRNA-seq data suggests that THBS1 is associated with inflammation-induced immunosuppression. Inhibiting the FGF7/FGFR2-THBS1 axis with Infigratinib modulates the tumor microenvironment by reducing immunosuppressive M-MDSCs and increasing T cell activation and proliferation. This data supports THBS1 inhibition as a viable therapeutic option that in the future can also be combined with other current immunotherapeutic strategies.