bluuebunny/crossref_metadata_2025 huggingface dataset:
EXTH-34. ACETYLATION SUPPRESSION MEETS ONCOLYTIC VIRUSES FOR THE TREATMENT OF PEDIATRIC DIFFUSE MIDLINE GLIOMA
Authors: Parthasarathy Akhila , Moure Marc Garcia , He Jiasen , Gillard Andrew , Paparella Alyssa , Shin Dong Ho , Lopez-Rivas Andres , Jiang Hong , Fan Xuejun , Hampton Lethan , Phoenix Timothy , Lang Frederick , Young Nicolas , Alonso Marta , Gomez-Manzano Candelaria , Fueyo Juan
Published: November 2024

Diffuse midline glioma (DMG) remains a devastating pediatric brain tumor without effective treatment. In a recent clinical trial, we demonstrated the feasibility and efficacy of Delta-24-RGD oncolytic virus combined with radiation therapy in patients with newly diagnosed diffuse intrinsic pontine gliomas (NCT03178032). Because the adenoviral protein E1A binds to P300 and redirects acetylation upon virus infection, we hypothesized that combining oncolytic adenoviruses with P300 inhibitors will cause a remarkable shifting in acetylation and the post-translational landscape of DMG, ultimately enhancing the anti-glioma effect of oncolytic viruses. Western blot analyses showed a longitudinal reduction in H3K27ac (89%) and H3K18ac (99%) in a panel of human (TP54 and SF8628) and murine (24B_1 and 26C_7) DMG cells after Delta-24-RGD infection. In addition, using histone fractionation by high-performance liquid chromatography, we detected an increase in total H3 upon adenovirus infection. Mass spectrometry of histones in the human DIPG cell line, TP54 using middle-down approach illustrated post-translational changes across histones, including hypoacetylation of the H3.2K14 mark. To further modify histone acetylation in DMG during Delta-24-RGD infection, we combined virotherapy with C646, a selective and competitive histone acetyltransferase inhibitor of the E1A-binding p300/CBP complex of proteins. In vitro, the combination of Delta-24-RGD with C646 synergistically increased cell death in a panel of human and murine DIPG cell lines (zip-scores ranging from 6.3-11.3 with zip-scores above 10 being indicative of synergy). Ongoing experiments using a panel of adenoviruses expressing E1A with defective P300 binding or expressing a dominant-negative form of P300 or wild-type P300 are designed to test the extent to which E1A binding of P300 drives hypoacetylation in DMG upon virus infection. In addition, we are performing in vivo experiments to establish the anti-cancer effect of the combination of Delta-24-RGD and P300 inhibitors in clinically relevant animal models of DMG, with a feasible translation to the clinic.
EXTH-39. A BENCH-TOP MODEL FOR THE OPTIMIZATION OF ULTRASOUND PARAMETERS FOR SONODYNAMIC THERAPY OF GLIOBLASTOMA
Authors: Hovey Robert , Diaz Roberto
Published: November 2024

BACKGROUND

In-vitro studies have demonstrated that low frequency sound waves can interact with hemo-porphyrin molecule to induce the production of reactive oxygen species. This biophysical phenomenon can induce tumour cell death in glioblastoma cells in-vitro. The purpose of this study was to evaluate the production of reactive oxygen species and expression of apoptotic markers in glioblastoma cells in response to varying total treatment time and ultrasound power using a bench-top focused ultrasound (FUS) device.

METHODS

U251 cells were exposed to 5-Aminolevulenic Acid (5-ALA) at varying concentrations for up to 24 hours. The time point with peak proto-porphyrin IX (PPIX) fluorescence was established using fluorescence activated cell sorting (FACS). A transducer utilized at 0.91MHz was placed on an inverted stage with the focus targeted to the bottom of a standard 96-well cell culture plate. Pressure wave delivery was confirmed using a hydrophone. GBM cells were treated with 5-ALA alone, FUS alone, or 5-ALA + FUS and the cells were incubated for 24 hours prior to measuring ROS induction and cell death. ROS was measured using FACS with the CellROX Green Kit for Oxidative Stress Detection and Annexin-V was measured using the Dead Cell Stain Kit.

RESULTS

Peak fluorescence intensity for PPIX in the U251 cell line was found to be induced through incubation with 5-ALA for 24 hours with a concentration 200mg/mL. The fluorescence intensity of PPIX was found to be 313% greater in the treated group compared to the control group. Peak ROS was observed using a 0.91MHz transducer frequency for a total time of 120s with 6W average power. ROS was 61% and 66% greater in the SDT group compared to the FUS and 5-ALA group respectively.

CONCLUSION

Using this bench-top set up we successfully induced ROS and apoptosis in U251 cells. Establishing a reliable in-vitro model will allow us to further investigate the effects of other sonication parameters such as burst length.
EXTH-45. PRECLINICAL EVALUATION OF THE ANTIBODY-DRUG CONJUGATE TISOTUMAB VEDOTIN IN ADULT-TYPE DIFFUSE GLIOMAS
Authors: Sears Thomas , Wang Wenxia , Unruh Dusten , McCord Matthew , Steffens Alicia , Horbinski Craig
Published: November 2024

The gene F3, encoding Tissue Factor (TF), is expressed in many cancers and contributes to their malignancy. Our previous work showed that, among adult-type diffuse gliomas, IDH wild-type (IDHwt) glioblastomas (GBM) express more TF than IDH mutant (IDHmut) gliomas (PMID: 27664011, 30266764, 31222125). Tisotumab vedotin (TV), an anti-TF antibody conjugated to monomethyl auristatin E, is a therapeutic designed to target cells expressing TF. We therefore sought to determine the therapeutic potential of TV in IDHwt vs. IDHmut gliomas. TV was more active against cultured IDHwt GBM cells than IDHmut glioma cells (P<0.0001). This activity was increased by 55% with daily washout of the soluble TF secreted by IDHwt GBM cells. TV extended the survival of mice intracranially engrafted with IDHwt GBM by 34% (37.5 days vs. 28 days for IgG control, P=0.006), but not mice with IDHmut glioma (30.5 days, P=0.88). TV also reduced the growth of IDHwt GBM flank xenografts by 58% (P=0.045). Unconjugated tisotumab had no antitumor effect intracranially or in the flank. All 12 flank-engrafted mice treated with tisotumab, and 9/12 mice treated with TV, developed large hematomas in and around the flank xenografts, compared to 0/12 IgG-treated mice (P<0.001). Similarly, a semiquantitative analysis showed that intracerebral hemorrhage was more extensive in tisotumab/TV- treated GBM12 mice than in IgG-treated GBM12 mice (P=0.046). These data indicate that TV targets high TF-expressing IDHwt GBM, but not low TF-expressing IDHmut glioma, that its activity is predominately through the vedotin conjugate rather than inhibition of TF signaling, and that it may have some effect against TF-expressing IDHwt GBM, but intracerebral hemorrhage may be a concern.
EXTH-46. TESTING PRECISION GENOMICS-GUIDED THERAPY IN A MODEL OF ANAPLASTIC PLEOMORPHIC XANTHOASTROCYTOMA: DUAL INHIBITION OF CDK4/6 AND MEK
Authors: Koenig Jenna , Saadatzadeh M Reza , Bailey Barbara J , Pandya Pankita H , Dobrota Erika A , Coy Kathryn , Kennedy Felicia M , Sinn Anthony L , Tailor Jignesh K , Angus Steven P , Damayanti Nur P , Pollok Karen E
Published: November 2024

Typical survival for pediatric high-grade gliomas remains less than 18 months despite recent improved understanding of the molecular drivers of these tumors. Hyperactivating MAPK and CDK4/6 pathway mutations are common and targetable alterations implicated in tumorigenesis and malignant transformation in pediatric glioma. We have established and characterized a novel patient-derived xenograft (PDX) model, RHT128, from a pediatric patient diagnosed with the high-grade glioma anaplastic pleomorphic xanthoastrocytoma (APXA). The molecular landscape of PDX RHT128 exhibits molecular fidelity to the patient’s tumor. Clinical precision genomics analysis of the tumor revealed a novel BRAF chromosomal rearrangement and CDKN2A/B deletion. Based on this molecular signature, the patient was treated with MEK inhibitor trametinib as a monotherapy and, following progression of disease, with CDK4/6 inhibitor ribociclib. However, the tumor continued to progress. In this study our objective is to simultaneously target the CDK4/6 and MAPK pathways in RHT128 and determine to what extent this combination therapy minimizes emergence of therapeutic resistance. Single-agent efficacy assessments in a subcutaneous RHT128 model, showing significant dose-dependent reduction in tumor volume after treatment with abemaciclib (p<0.05), palbociclib (p<0.01), and the blood-brain barrier-permeable MEK inhibitor mirdametinib (p<0.0001). Analysis of the global kinome in CDK4/6 inhibitor-treated PDX tissues compared to vehicle treatment using multiplexed-inhibitor bead chromatography–mass spectrometry demonstrated effective inhibition of CDK4/6. Moreover, this analysis revealed dose-dependent alterations in the MAPK and PI3K pathways and modulation of critical neurotransmitter pathways in treated tissues. Future studies will explore efficacy of these MEK and CDK4/6 inhibitors in combination and in our BRAF wild-type and BRAF V600E variant APXA models to gain further mechanistic insights. The pervasiveness of alterations to the MAPK and CDK4/6 pathways in pediatric gliomas make this approach promising for further study in a broader range of these deadly tumors.
EXTH-56. INVESTIGATING THE EFFECTS OF INDIRUBINS IN PEDIATRIC DIFFUSE HIGH GRADE GLIOMA MODELS
Authors: Clark Jasmine , Lawler Sean , Jimenez-Macias Jorge , Vaughn-Beaucaire Philippa , Zhang Shengliang , El-Deiry Wafik , Lulla Rishi
Published: November 2024

Diffuse midline glioma (DMG) is a highly invasive and fatal pediatric brain tumor that arises from glial cells within the pons of the brainstem. Despite focal radiation treatment, DMG continues to have a poor prognosis, with a median survival of less than 10 months. A significant challenge in treating DMG is the blood-brain barrier (BBB), which tightly restricts access to therapeutic agents, preventing drugs from reaching the brain at effective concentrations. Previous studies from the Lawler lab have shown that the indirubin derivative 6-bromoindirubin-3′-acetoxime (BIO-acetoxime/BIA) has anti-invasive properties and can enhance survival in glioblastoma xenograft models. We investigated the effects of BIA on pediatric glioma models using various assays. In an in vitro scratch migration assay, BIA significantly slowed cell migration at a concentration of 1µM in pediatric glioma cells over 72 hours. Additionally, BIA was shown to modulate tumor vasculature and improve drug delivery to tumors by targeting tight junctions in tumor-associated endothelium. BIA treatment increased dextran uptake into 3D BBB models and lowered endothelial cell permeability in vitro by reducing the expression of tight junction proteins, as shown by staining and a decrease in TEER values. Furthermore, BIA’s anti-angiogenic effects were demonstrated through staining, showing significant alterations in angiogenesis-related protein expression. To assess potential synergistic interactions, a drug screen was performed on a panel of pediatric glioma cell lines identifying several FDA-approved drugs that combine well with BIA. Drugs identified in the screen are currently under investigation. Our hypothesis is that BIA could be an effective therapeutic agent for DMG by targeting tumor invasion, angiogenesis, and improving drug potency and delivery through modulation of endothelial cell tight junctions. Future studies will focus on elucidating the underlying mechanisms and developing drug formulations for in vivo studies to assess the translational potential of this approach.
EXTH-61. TOWARDS A QUANTUM THERAPY FOR GLIOBLASTOMA: A NEW THERAPEUTIC PARADIGM IN MEDICINE
Authors: Jain Akhil , Gosling Jonathan , Liu Shaochuang , Wang Haowei , Stone Eloise , Chakraborty Sajib , Jayaraman Padma-Sheela , Smith Stuart , Amabilino David B , Fromhold Mark , Long Yi-Tao , Pérez-García Lluïsa , Turyanska Lyudmila , Campora Simona , Cicero Alessandra Lo , Ghersi Giulio , Rahman Ruman , Rawson Frankie
Published: November 2024

BACKGROUND

A cell operates as an interconnected bioelectrical circuit, utilising electron transfer processes for intracellular communication, with cytochrome c (Cyt c) playing a pivotal role. The redox processes of Cyt c, occurring via electron tunnelling, are essential for its translocation into the cytosol and modulation of its conformation to bind apoptotic protease activating factor 1. This highlights the need for novel technologies capable of interacting with these processes at the atomic scale to control downstream effects and induce apoptosis in cancer cells.

METHODS

We demonstrate that ‘bio-nanoantennae’, when supplied with an electrical current, enable quantum biological tunnelling for electron transfer (QBET) and facilitate cellular apoptosis in patient-derived IDH wild-type glioblastoma from both the infiltrative tumour margin and proliferative core. The bio-nanoantennae were constructed from gold nanoparticles functionalised with reduced Cyt c and zinc porphyrin as a redox couple.

RESULTS

Electrical polarisation of these bio-nanoantennae via resonant alternating currents in preclinical glioblastoma cells led to decreased metabolic activity and reduced cell viability by oxidizing Cyt c, thus inducing cellular stress. No significant effect was observed in healthy human astrocyte counterparts. The cytosol localised bio-nanoantennae induced differential gene expression related to ion channels, apoptosis, cancer proliferation and tumour suppression upon activation, in tumour relative to astrocyte cell populations. The bio-nanoantennae were also tested in 3D glioblastoma spheroid models, showing similar effects, and in vivo studies demonstrated a significant reduction in glioblastoma xenograft tumour size.

CONCLUSION

We propose that bio-nanoantennae modulate the redox state of Cyt c under an electrical field through QBET. To validate this, we investigated the tunnel junction energy and plasmon resonance scattering, and developed a mathematical model to explain the system’s behaviour. This innovative wireless electrical–molecular nanodevice, capable of inducing cancer cell apoptosis, paves the way for further applications of quantum signalling as a new (non-pharmacological) therapeutic paradigm.
EXTH-62. FOCAL ADHESION KINASE (FAK) IN CHROMOSOME 8 GAIN-ASSOCIATED MALIGNANT PERIPHERAL NERVE SHEATH TUMORS (MPNST)
Authors: Wang Guangfeng , Borcherding Dana , Oztosun Gorkem , Zhang Xiaochun , Yang Liuzhan , Gannu Trisha , Hirbe Angela
Published: November 2024

OBJECTIVES

Malignant peripheral nerve sheath tumors (MPNST) are aggressive sarcomas often associated with Neurofibromatosis type 1 (NF1), a genetic syndrome driven by overactivation of the RAS pathway. MEK inhibitors (MEKi) target downstream components of the RAS pathway and have been approved for NF1 patients with plexiform neurofibromas (PN). However, MPNST often develop resistance to MEKi. Our lab recently discovered the critical role of chromosome 8 (Chr8) genes in MPNST. The Chr8 gene, protein tyrosine kinase 2 (PTK2), also known as focal adhesion kinase (FAK) is overexpressed in multiple cancers, suggesting its importance in tumor progression. In this study, we aim to evaluate FAK as a therapeutic target for MPNST and investigate the FAKi and RAF/MEKi combination.

METHODS

A CRISPR gRNA screen was used to identify Chr8 genes involved in MPNST survival. The effect of FAK shRNA knockdown and a FAK inhibitor (FAKi), alone or combined with a MEKi, in MPNST cells was assessed using IncuCyte proliferation assays and multiple murine models.

RESULTS

The CRISPR gRNA screen identified 57 genes on Chr8 important for MPNST cell survival, including PTK2/FAK. Knockdown of FAK by shRNA in MPNST inhibited cell proliferation in vitro and reduced tumorigenesis in vivo. Consistently, the FAKi defactinib significantly inhibited the proliferation of MPNST (IC50-values: 1.72-4.65μM). Moreover, the defactinib/avutometinib combination was synergistic in vitro and the combination of FAKi with RAF/MEKi reduced tumor growth more that either drug alone in Chr8-gain MPNST PDX models. Avutometinib induced compensatory activation of FAK, while defactinib/avutometinib combination decreased phosphorylation of FAK, ERK1/2 and STAT3, and augmented cleavage of Caspase-3 and PARP-1, shown using the WES protein simple system.

CONCLUSION

These results demonstrate the potential therapeutic efficacy of FAK inhibitors, both alone and in combination with RAF/MEKi, for the treatment of MPNST.
EXTH-64. MECHANISMS OF MITOCHONDRIAL COMPLEX-I SENSITIVITY IN GBM
Authors: Dasgupta Biplab , Horchar Matthew , Gawali Mruniya , Desai Pankaj , Choi Kwangmin , D’Alessandro Angelo
Published: November 2024

The biguanide metformin that is widely used for the management of Type 2 diabetes is being evaluated as an anti-neoplastic agent in cancer trials including GBM (NCT02780024, NCT03243851). The mechanisms of action of metformin as an anti-neoplastic agent is still being investigated, but recent studies have unequivocally demonstrated that its therapeutic effects in tumor cell growth and signaling are dependent on inhibition of mitochondrial complex I. Based on the success of metformin in combination therapy in some cancers, new generation of mitochondrial complex I inhibitors (MCI-i) such as IM156, IACS-010759, are currently under investigation. Diffusion of metformin across the plasma membrane occurs slowly. Its entry is facilitated by two transporters OCT1 and OCT2 that are not well expressed outside the liver and kidney. This presents a problem due to its lack of accumulation in other tissues at therapeutic concentrations. Therefore, identification of tumor subtypes that respond better to lower concentrations of metformin may be leveraged for targeted metformin therapy. Metformin GBM trials may be unsatisfactory since there are no molecular markers to distinguish metformin responders from non-responders. Identification of molecular markers may greatly improve metformin and other MCI-i-based therapy in GBM. By examining TCGA data and experimental analysis, we have identified that PDHA, that catalyzes pyruvate to acetyl Co-A, is a predictive molecular marker for MCI-i sensitivity in GBM and potentially beyond GBM. PDHA expression varies widely in patient tumors, potentially due to differential methylation. We are performing joint pathway analysis by examining differentially expressed genes and stable isotope tracing studies to determine distinct metabolic signatures in the two subsets of GBM. We are also performing Classification And Regression Tree (CART) analysis on a cohort of sixty primary GBM lines and tissues to predict if PDHA expression provides a binary outcome for MCI-i sensitivity.
EXTH-66. ONCOLYTIC ADENOVIRAL INFECTION SYNERGIZES WITH IMMUNE CHECKPOINT INHIBITION TO MEDIATE INTRACRANIAL TUMOR CONTROL IN DISPARATE MODELS OF MELANOMA BRAIN METASTASES
Authors: Du Yi , Singh Sanjay , Tawbi Hussein , Davies Mike , Lang Fred , Gomez-Manzano Candelaria , Fueyo Juan , Alvarez-Breckenridge Christopher
Published: November 2024

Amongst all solid cancers, melanoma brain metastases (MBM) have the highest likelihood of metastasizing to the brain. The emergence of immune checkpoint inhibitors (ICI) for metastatic melanoma have demonstrated increasingly promising results; however, intracranial progression remains a challenging obstacle. Oncolytic viral (OV) therapy leverages tumor cell replication machinery to selectively replicate and kill tumor cells and promote anti-tumor immunity. We propose this OV strategy can be applied to MBM through direct tumor infection that simultaneously sustains a distant antitumor immune response. To counteract immunosuppressive features of the tumor microenvironment (TME), a third-generation oncolytic adenovirus (Delta-24-RGDOX) has been developed which expresses the immune stimulatory OX40 ligand (OX40L). We quantified the cytotoxic capacity of Delta-24-RGDOX and its ability to achieve immunogenic cell death (ICD) in vitro along with cerebral organoid co-culture models. Additionally, we used a series of syngeneic murine melanoma models to explore local and systemic antitumor immunity following Delta-24-RGDOX infection. Delta-24-RGDOX inoculation achieved viral infection, OX40L cell surface expression, tumor cell cytotoxicity, and ICD in vitro. Viral oncolysis was recapitulated in a cerebral organoid melanoma co-culture model with concomitant alterations in microglia activation and detection of viral transcripts within microglia using single cell RNA sequencing, suggesting a viral-clearing role of microglia within the TME. Local tumor clearance was achieved in orthotopic intracranial models following direct intracranial viral inoculation alone, and in combination with ICI. Lastly, we demonstrated improvement in overall survival in a synchronous subcutaneous/intracranial B16F10 model where the subcutaneous tumor was treated with Delta-24-RGDOX in combination with ICI. In summary, Delta-24-RGDOX achieves viral infection, oncolysis, and ICD following infection of melanoma cell lines. These findings translated in multiple in vivo models including immune cell activation and systemic antitumor immunity against uninfected MBM. Future studies are needed to explore the role of immune cell trafficking, myeloid cell modulation, T cell priming, and clonal expansion withing locally infected and the distant melanoma TME.
EXTH-67. ONCOLYTIC ADENOVIRAL INFECTION OF CHORDOMA ACHIEVES TREATMENT EFFICACY THROUGH IMMUNOGENIC CELL DEATH AND TUMOR MICROENVIRONMENT ALTERATION
Authors: Wu Xizi , Ledbetter Daniel , de Almeida Romulo Andrade , Singh Sanjay , Conley Anthony , Wang Wein-Lien , Lazar Alex , Lang Fred , Gomez-Manzano Candelaria , Fueyo Juan , Alvarez-Breckenridge Christopher
Published: November 2024

Chordomas are locally aggressive neoplasms of the axial skeleton with recurrence rates approaching 40%. Moreover, recurrent chordomas are nearly impossible to eradicate—highlighting an unmet clinical need. Immunotherapeutic approaches, such as immune checkpoint inhibition (ICI), has been a successful tool to modulate the tumor microenvironment (TME) towards a pro-inflammatory, antitumor state. There is emerging interest in exploring immunomodulatory agents for chordomas. Oncolytic viral (OV) therapy uses genetically modified viruses which selectively replicate in tumor cells, mediate tumor cell lysis, and initiate a pro-inflammatory response within the infected TME. These findings suggest that OV therapy may be a clinically relevant, novel immunotherapeutic approach for chordoma. Using the replicating oncolytic adenovirus Delta-24-RGD, we investigate the efficacy of chordoma treatment using in vitro approaches, ex vivo bone scaffolds, and in vivo murine models. Additionally, we explore the underlying mechanism of OV cytotoxicity, immunogenic cell death, Brachyury modulation, and reshaping of the TME towards a pro-inflammatory state. Across a panel of human chordoma cell lines, Delta-24-RGD achieved viral infectivity, oncolysis and immunogenic cell death. This treatment response was similarly demonstrated in chordoma cultured in bone scaffold models. Delta-24-RGD infection was associated with concomitant Brachyury downregulation within both infected and uninfected chordoma cells in vitro, suggesting a pleiotropic effect following oncolytic viral infection. In vivo models of CH22 chordoma treated with Delta-24-RGD demonstrated shrinkage in tumor volume and enhanced overall survival. Utilizing a human chordoma tissue microarray, the immunosuppressive macrophage marker CD163 was associated with shortened recurrence free survival. Using macrophage/chordoma co-culture, Delta-24-RGD infection achieved a reduction in macrophage expression of CD163. Taken together, Delta-24-RGD demonstrated efficacy in multiple models of chordoma including mice bearing CH22 tumors. The chordoma TME is associated with clinical outcomes and Delta-24-RGD infection reverses a deleterious immunosuppressive immune profile. These studies provide a framework for future clinical trial implementation for patients with metastatic or recurrent chordoma.
EXTH-71. A MECHANISTIC INVESTIGATION INTO AUGER THERAPY: 2-DIMENSIONAL THIN-FILMS TO CHARACTERIZE THERAPEUTIC RANGEIN VITRO
Authors: Al-Husseini Jacob , Upreti Meenakshi , Ha Joseph , Moats Rex , Koos David , Fong Ethan , Baker Clark , Spindler Archie , Johal Malkiat , Chiarelli Peter
Published: November 2024

Metallic nanoparticles can improve the accuracy and effectiveness of conventional radiotherapy in the treatment of solid tumors through a light-matter interaction known as the Auger effect. In this work, we present the assembly of an iron oxide (Fe3O4) nanoparticle (NPs) layer within a biocompatible polyelectrolyte film using ionic self-assembly to enable the spatial separation of NPs from their target cells. Films exhibited uniform nanoparticle coverage as well as strong stability in cell culture conditions. To investigate the applicability of NMDR with non-internalized NPs, conditions with (NP-PEM) and without (PEM) embedded nanoparticles were used to evaluate the therapeutic effect of physically separated nanoparticles on cells cultured on the film surface via a measure of intracellular reactive oxygen (ROS) generation and histone phosphorylation (yH2AX) after irradiation from a 137Cesium source. Cells cultured on NP-PEM demonstrated a 78.4% increase in ROS generation when compared to cells cultured on PEM films. When adjusting for cell count, NP-PEM films induce 70.5% greater ROS generation. In investigating nanoparticle-mediated deposition of radiation (NMDR), these films allow for the determination of the extent of the therapeutic effect when NPs are not internalized into their targeted cells, potentially providing indications with respect to off-target effects. Cells were irradiated on films with nanoparticle distances from 25.9 nm to 97.5 nm to interrogate the NMDR effect size at a range of distances. yH2AX phosphorylation exhibited an exponential decay until 69.8 nm, where there was no difference when compared to nanoparticle-free films. This work highlights the ability of iron oxide NPs to deliver NMDR at a known, quantifiable distance, providing insights for further translational applications.
EXTH-73. TARGETING THE CELL ADHESION CLUSTER OF DIFFERENTIATION 44 TRANSMEMBRANE GLYCOPROTEIN SENSITIZES CRANIOPHARYNGIOMAS TO IMMUNOTHERAPY
Authors: Lujan Arturo , Chakrabarti Jayati , Eschbacher Jennifer , Zada Gabriel , Kim Albert , Little Andrew , Santagata Sandro , Zavros Yana
Published: November 2024

BACKGROUND

Craniopharyngiomas are categorized as an adamantinomatous craniopharyngioma (ACP) or papillary craniopharyngioma (PCP) subtype with distinct histological, pathological and genetic differences. Studies propose the potential therapeutic benefit of targeting PD-L1 and/or PD-1 in both ACP and PCP subtypes using immune checkpoint inhibitors (ICI). The alternative mRNA splice variant of CD44, CD44v9, is expressed on cancer stem cells and plays multiple key roles including drug resistance and tumor cell invasiveness. CD44 positively regulates PD-L1, but the role of this transmembrane glycoprotein in craniopharyngioma tumorigenesis is unknown. Objectives: To replicate the complexity of the craniopharyngioma tumor microenvironment (TME) by developing a novel patient tissue-generated craniopharyngioma in vitro organoid preclinical model for the development of therapeutic strategies. Approach: NanoString CosMx™ Spatial Molecular Imager (SMI) was performed using FFPE tissue sections prepared from patient craniopharyngiomas. Quantification of PD-L1, and stem cell transmembrane glycoproteins CD44v9 and TROP2 was performed using multiplex immunofluorescence (MxIF). Craniopharyngioma patient-derived organoids (CranioPDOs) were generated and co-cultured with autologous immune cells (IMM) generated from patient peripheral blood mononuclear cells. CranioPDO/IMM co-cultures were used to predict the potential therapeutic benefit in response to tyrosine kinase inhibitor cabozantinib (Cabo) plus pembrolizumab (Pembro) or atezolizumab (Atezo) combinatorial therapy.

RESULTS

SMI analysis showed expression of CD44 and TROP2 positive cells, cancer-associated fibroblasts and myeloid-derived suppressor cells (MDSCs) consistent with the staining pattern of PD-L1. MxIF of matched tissues showed expression of CD44v9 and TROP2 within the same CD44 positive spatially mapped cell populations. Combinatorial treatment of CranioPDO/IMM co-cultures with Cabo plus Pembro or Atezo led to depletion of MDSCs correlating with decreased expression of CD44v9 and a significant increase in cytotoxic T lymphocyte proliferation and tumor cell death.

CONCLUSION

Our preclinical in vitro organoid data support the potential therapeutic benefit of ICI in combination with cabozantinib for the treatment of craniopharyngiomas.
QLTI-12. COST ANALYSIS OF EMERGENCY PROCEDURES FOR BRAIN TUMORS – WHEN YOU CAN WAIT
Authors: Campos Paiva Aline Lariessy , Araujo João Luiz Vitorino , Lovato Renan Maximillian , de Oliveira Jean Gonçalves , Veiga José Carlos Esteves
Published: November 2024

BACKGROUND

Neurosurgery is expensive and requires advanced technology to achieve the best outcomes, especially for brain tumors. Generally patients are prepared during consultations for a brain tumor surgery, with anesthesiology, cardiology, neuropsychology and other specialties evaluations. Ideally, the hospitalization is planned before and patient is admitted only when is in good conditions. However some patients with brain tumors are evaluated in emergency department and sometimes require urgent procedures.

OBJECTIVE

This study aimed to estimate the direct cost of specialized care for adult neuro-oncological patients considering previous scheduled procedures versus urgent surgeries and another factors that may impact decision about nonelective procedures.

METHODS

This observational economic analysis describes the direct cost of care of neuro-oncological patients in Santa Casa de São Paulo, Brazil. Only adult patients with a common primary brain tumor were included.

RESULTS

The global mortality rate considering all patients were 12.7% and 92.3% of them occurred in nonelective procedures. Also these patients had a greater infection rate and period of hospitalization. Because of this we reviewed when a patient with brain tumor really need an urgent procedure. Despite several patients are initially diagnosed through ER investigation, probably the majority could be compensated through ambulatory consultations and after admitted with better conditions. Situations in which emergency surgery are required include acute hydrocephalus and non-compensated intracranial hypertension.

CONCLUSIONS

These patients usually have difficulty access to neurosurgical evaluation and so, only look for health assistance when the disease cause severe disability. Emergency surgeries were associated with an increased rate of infections and mortality. The findings of this study could be used by policymakers for resource allocation and to perform economic analyses to establish the value of neurosurgery in achieving global health goals. severe disability. KEY WORDS: costs; brain tumor; emergency; infections
QLTI-18. TREATMENT AND OUTCOMES OF FRAIL PATIENTS WITH NEWLY DIAGNOSED HIGH-GRADE GLIOMAS: SHOULD WE CONSIDER CHANGING OUR TREATMENT APPROACH?
Authors: Sielski Neil , Reiner Anne , Schaff Lauren , Imber Brandon , Pike Luke , Carver Alan , Pentsova Elena
Published: November 2024

BACKGROUND

Patients with newly diagnosed high-grade glioma (HGG) and low Karnofsky Performance Status (KPS) often face challenges in receiving cancer-directed therapy. They are excluded from prospective trials, limiting the chance of developing novel therapeutic approaches.

METHODS

We retrospectively reviewed charts of patients with functional debility and newly diagnosed HGG who received radiotherapy (RT) while admitted to the inpatient service at Memorial Sloan Kettering between 2013 and 2023. Multivariable analyses were performed which associated patient demographics, KPS, histology, genetic and molecular pathology, RT duration and dose, chemotherapy, palliative/supportive care consultation, and advanced care planning documentation with overall survival (OS) and discharge location, separately.

RESULTS

Fifty-four patients were identified; median age was 68 years (range:21-86) and 28 (52%) were women. Median KPS was 50 (range:30-70). Per WHO 2021 criteria, 47 (87%) were glioblastoma, IDH wild-type and 7 (13%) were HGG not otherwise specified, diagnosed by biopsy in 30 (56%), subtotal resection in 23 (43%), and gross total resection in one. MGMT promoter methylation was performed in 39/54 and was hypermethylated in 15 (38%). All patients received RT and 52 (96%) with concurrent temozolomide; 47/54 (87%) completed planned RT, with the median dose of 4,005 cGy in 15 fractions. 13 (24%) received bevacizumab. The median length of stay (LOS) was 29 days (range:20-65). Only 17 (31%) had palliative care consultation prior to discharge. The median OS (mOS) from the last radiation treatment was 4.21 months (95% CI: 2.73, 6.63). In multivariable Cox and logistic regression, respectively, lower KPS remained the sole factor significantly associated with increased risk of death (p=0.004) and decreased chance of return home (p=0.040).

CONCLUSION

In our patient cohort, treatment was associated with prolonged LOS and poor outcomes. A clinical trial should be considered to evaluate shorter RT courses and early palliative care consultation in this patient population.
QLTI-19. PEDIATRIC NEURO-ONCOLOGISTS NAVIGATING AN ADULT WORLD: A TALE OF TWO CENTERS
Authors: Gampel Bradley , Nasany Ruham Alshiekh , Hill Colin , Kushnirsky Marina , Tejera Dalissa , Muniz Thiago , De La Fuente Macarena , Bennett Julie
Published: November 2024

BACKGROUND

Adolescent and Young Adult Neuro-Oncology(AYA-NO) patients are a distinct cohort with an overlap of tumors found in childhood and adulthood. For adult patients with pediatric-type Central Nervous System tumors, optimal work-flow to manage these patients is unclear.

METHODS

We examine the work-flow of pediatric neuro-oncologists starting AYA-NO clinics within two high volume adult institutions: the University of Miami(Florida, USA) and the Princess Margaret Cancer Centre(Toronto, Canada).

RESULTS

Over 18 months, the AYA-NO clinics managed 167 patients total with several key differences emerging in both institutions between the pediatric and adult work-flows. Adult providers commonly have neurology backgrounds, while pediatric providers mostly have hematology/oncology backgrounds. In pediatrics, providers typically meet the patient inpatient before pathology results, adult providers meet their patients in outpatient settings once histopathology results are available. Outpatient management in pediatric oncology centers typically includes labs, infusion centers, provider rooms, and social workers in one area while adults, due to the larger volume, have these services on separate units. Chemotherapy related differences included the primary provider for inpatient admissions and the emphasis of adult institutions on outpatient administration when feasible. Psychosocial factors such as the variety of caregivers, increased opportunity for patient autonomy in decision-making, and the increased fragmentation in care magnifies the importance of providers forming a strong rapport with AYA-NO patients. End of life care is vastly different including the inability for adult patients to receive palliative treatment in hospice care and the availability medically-assisted death.

CONCLUSION

Pediatric neuro-oncologists building AYA-NO workflows within adult settings can provide unique expertise for AYA-NO patients with pediatric-type tumors. Growing AYA-NO clinics can benefit from allocating AYA CNS specific resources such as chemotherapy/targeted therapy provider education, a dedicated hospital/clinic space, chemotherapy nursing, a care coordinator, and a social worker with experience treating this patient population.
QOL-03. CAREGIVER PROGRAM IN NEURO-ONCOLOGY: UCSF EXPERIENCE CARING FOR MORE THAN 4,000 CAREGIVERS OVER THE LAST 10 YEARS
Authors: Taylor Jennie , Page Margaretta , Almaraz Eduardo Rodriguez , Vo Anh Huan , Velasco Candice , Angelo Desiree , Demayo Cherrie , Chang Susan
Published: November 2024

BACKGROUND

Caregivers of patients with primary brain tumors are at high risk for distress as they navigate caring for their loved one with both a cancer diagnosis and neurologic disorder. The UCSF Gordon Murray Neuro-Oncology Program, the first of its kind, addresses caregiver needs and is fully integrated into clinical care, providing personalized care and programming to address common challenges and foster resilience. The Program includes a nurse, administrator, and social worker. Referrals occur at the initial clinic appointment; from clinical staff; and caregivers of patients with GBM receive proactive outreach. Dedicated programming provides educational materials around common concerns and building community through support groups, annual retreats and family camp. We report our practical experience of the Program serving over 4,000 caregivers.

METHODS

Total number of individual caregivers were included from 01/2014 – 12/2023. Detailed demographics were extrapolated during clinical interviews from a subset. Caregiver concerns and interventions were extracted from the medical records between 01/2017 – 12/2023.

RESULTS

The Program serves an average of 400 caregivers and 800 encounters annually. Demographics revealed 66% females; 77% between 41-64 years of age; 60% spouse; 89% working full time; and 30% with children at home. The most common concerns were informational (42%), followed by emotional (25%), and practical (23%). Examples of informational concerns included desire for resources, understanding treatment plan/side effects, and patient behavioral changes. Emotionally, they feel overwhelmed, uncertain, and sad. Practical concerns included physically caring for patients and issues around medical insurance, disability, and finances. Most common intervention was providing emotional support (40%).

CONCLUSIONS

Caregivers of patients with primary brain tumors are at high risk of distress and have unique needs. Our practical 10 year experience of a dedicated, fully integrated, caregiver program highlights real world concerns of caregivers and identifies opportunities to develop tailored interventions to address these needs.
QOL-04. THE UNDER-UTILIZATION OF PALLIATIVE CARE SERVICES BY PATIENTS WITH GLIOBLASTOMA HIGHLIGHTS THE IMPORTANCE OF DISCUSSIONS AROUND PALLIATIVE CARE: A CROSS-SECTIONAL STUDY WITH CARE PARTNERS OF PATIENTS WITH GBM RECRUITED FROM FACEBOOK SUPPORT GROUPS
Authors: Robbins Lauren , James Elizabeth , Ennis Samantha , Wallace Marlee , Vreeling Anna , Lutz Barbara , Minns Laurie
Published: November 2024

Glioblastoma (GBM) is a terminal brain cancer that has a rapid onset and results in symptoms such as headaches, vomiting, seizures, anxiety, depression, agitation, speech impairment, memory impairment, infections, brain bleeds, mobility changes, changes in sleep patterns, and cognitive changes. Palliative care helps patients diagnosed with an incurable or chronic disease manage physical, social, and psychological symptoms and has been shown to increase survival for patients with cancer. Previous data of former care partners of patients with GBM indicated only 30% of patients used palliative care whereas 90% used hospice. To better understand the reasons for underutilization of palliative care patients with GBM, 38-question survey about the use of palliative care, type of medical center where treatment occurred, and discussions with care team members about palliative care was given to current care partners recruited from Facebook support groups in February 2024. Inclusion criteria: current primary care partner of a patient with GBM, over the age of 18, and willing to participate (IRB exempt; H24-0393). The care partner was excluded if their patient was no longer living. Of the 77 current care partners, 56 reported they did not use palliative care as part of their care team. The use of palliative care was similar among care facilities (community hospital, major medical center, university hospital, brain tumor center). When care team members discussed palliative care with patients and their care partners (n=21), 71% of the dyads used palliative care. When care team members did not discuss palliative care (n=56), the use of palliative care was much lower at 7%. Interestingly, 55% of respondents reported they would benefit from knowing more about ways to increase physical and emotional support. This data suggests discussions around palliative care increase the use of palliative care services among patients with GBM and their care partners.
QOL-06. OPTIMIZING NEUROFIBROMATOSIS CARE: A COMPREHENSIVE ECONOMIC EVALUATION OF A SPECIALIZED EXPERTISE CENTER’S IMPACT ON PATIENT OUTCOMES
Authors: Boubekri Sara , Greciet Nicolas , Annani Maria , Rousseau Julien , Labidi Moujahed , Haffaf Zaki El , Boudreau Isabelle , Saliba Issam , de Haan Emma , Tremblay Danny , Lapointe Sarah
Published: November 2024

Neurofibromatosis type 1 (NF1), NF2-related schwannomatosis (NF2) and other schwannomatoses represent a spectrum of genetic disorders characterized by the development of tumors on nerve tissues, profoundly impacting patients’ quality of life and posing complex challenges. Recognizing the imperative for comprehensive care delivery, we undertook to implement a Neurofibromatosis Expertise Center (CE) at the Centre hospitalier de l’Université de Montréal (CHUM), Quebec, Canada. Employing a robust analysis framework, we aimed to assess the economic viability of the CE by quantifying the Quality-Adjusted Life Years (QALYs) gained through centralized multidisciplinary neurofibromatosis care (cost-utility ratio = CAD/QALY gained). Leveraging data from validated questionnaires including the SF-6D, our preliminary analysis revealed significant enhancements in patients’ quality of life across diverse domains, including physical pain, visible cutaneous lesions, cognitive dysfunction, hearing loss, malignancies, psychiatric comorbidities, unemployment, physical disability, and social isolation. Notably, among the respondents (N = 115), patients receiving CE services reported a 12% increase in general health compared to a 25% decline among those without CE services. Moreover, 28% of CE patients reported improved overall health compared to 12% of those without CE services. Using the Work Productivity and Activity Impairment questionnaire (WPAI-GH), we found that cohorts followed in CE for ≥ 1 year (N = 45) experienced less work productivity losses compared to the most recent cohort (N = 32), which presented scores exceeding 6 on a 1-to-10 scale. We hypothesize that the establishment of the CE will yield profound improvements in patient health outcomes and alleviate financial strains on the Ministère de la Santé et des Services Sociaux du Québec (MSSS). Therefore, our next steps include discussing a strategy for funding application to the MSSS to ensure the accessibility of necessary care for patients. Continuing data collection and analysis will also provide a more comprehensive overview of patient characteristics and needs.
QOL-11. GBM PATIENTS CONTINUE TO FACE BARRIERS TO PERSONALIZED AND COMPREHENSIVE CARE THAT MAY IMPACT LONGEVITY AND QUALITY-OF-LIFE
Authors: Ostrum Quinn T , Iwamoto Fabio M , Nayak Lakshmi , Duprey Kelli , Pilkington Ed , Ellen Jacob , Robles David
Published: November 2024

We assessed the quality and accessibility of healthcare services provided to Glioblastoma (GBM) patients across the United States through an online survey distributed among the OurBrainBank community and partners and promoted on social media. A total of 297 patients or caregivers completed the survey (85% caregivers; 15% GBM patients). Median age at diagnosis was 57, lower than the national average of 64. 78% of our respondents described having some college education, and 69% had commercial insurance. Preliminary results revealed that 69% were informed about tumor testing. Among those informed, 64% did not have any molecular testing beyond initial diagnostic tests. For all respondents, 65% were not informed about storing tissue for future testing, and 79% reported not having their tissue stored for possible treatments or clinical trial qualification. Additionally, 52% reported no discussion of seeking a second opinion, and 64% reported not being offered enrollment in any clinical trial. Overall, people living with GBM face significant barriers to achieving comprehensive and personalized care. Lack of tumor testing and storage present missed opportunities for future access to emerging therapies that could improve individual outcomes. Over half of patients had no discussion about seeking a second opinion and were not offered enrollment in clinical trials, highlighting significant barriers to accessing life-extending or quality-of-life (QOL) improving treatments. Compared to the general population affected by GBM, survey respondents represented a disproportionately young and urban population, suggesting potential bias in who is able to respond to the survey. This may underestimate the challenges faced by patients with additional barriers. We are implementing strategies to reach a more geographically diverse participant group, particularly in rural areas. Ongoing targeted recruitment will further elucidate barriers to patient-centered care in GBM, with the potential for significant improvements in survival and QOL.
QOL-12. ELECTRONIC ASSESSMENT OF QUALITY OF LIFE IN GLIOBLASTOMA PATIENTS USING THE EORTC-QLQ-C30/ EORTC-BN20 AND THE PROMIS SYSTEM IN CLINICAL PRACTICE
Authors: Walbert Tobias , Schultz Lonni , Snyder James Matthew , Mohn Josh D
Published: November 2024

BACKGROUND

Patient reported outcomes are essential to guide patient-care and to maintain quality of life. We aim to further assess feasibility of computer adaptations of the Patient-Reported Outcomes Measurement Information System (PROMIS) questionnaire in the clinical setting and compare it with outcomes of the EORTC- QLQ-C30 and EORTC-BN20 questionnaires.

METHODS

Newly diagnosed patients with GBM were enrolled to assess feasibility. The PROMIS modules were selected to reflect the HRQoL domains assessed in the EORTC- QLQ-C30 and EORTC-BN20 questionnaires. PROMIS modules selected included anxiety, depression, fatigue, physical function, sleep disturbance, sleep-related impairment, social satisfaction role, applied cognitive ability and global health. EORTC instruments as well as PROMIS was answered to patients in the outpatient setting. Descriptive analysis was performed

RESULTS

43 patients with 124 PROMIS/EORTC responses were included in this analysis. 31 patients completed the survey prior to or within 14 days of start of radiation, 12 patients completed a survey outside of the radiation window, and a total of 60 completed surveys were obtained between both patient groups. The median times to complete the EORTC-QLQ-C30 and the EORTC-BN20 surveys were 4.77 (range=2.05-18.6) and 2.63 (range=1.17- 24.83) minutes respectively. For the PROMIS instruments except global health, the median times to complete different modules ranged from 0.6- 1 minute (range= 0.15-7.77). For global health, the median time was 2.35 minutes (range= 1.02-21.12). Average time to complete all PROMIS questions was 8.65 minutes (range=3.32-66.01).

CONCLUSIONS

Real-time prospective assessment of the EORTC tools is similar to the PROMIS measures. While most response times were short, the ranges suggest that select patients might struggle. Patients were offered to participate online from home for convenience, but low computer literacy, limited internet access and burden of disease might limit participation.