tbuckley/cabot-search huggingface dataset:
NIMG-24. PRECISION GLIOBLASTOMA MANAGEMENT USING MET AND FMISO PET SCANS
Authors: Keisuke Miyake, Masaki Tatano, Takahiro Kanda, Kenta Suzuki, Daisuke Ogawa, Tetsuhiro Hatakeyama
Journal: Neuro-Oncology (2024)

Abstract OBJECTIVE Positron Emission Tomography (PET) may be useful in diagnosing glioblastoma, determining resection areas, and evaluating therapeutic efficacy. This study evaluated the usefulness of PET scans using 11C-Methionine (MET) to assess amino acid metabolism and 18F-Fluoromisonidazole (FMISO) to assess hypoxic regions in glioblastoma treatment. METHODS Thirty glioblastoma patients who underwent MET and FMISO PET studies from July 2013 to March 2024 were included. Patients underwent the Stupp regimen post-tumor resection and were treated with temozolomide (TMZ) and bevacizumab (Bev) upon recurrence. PET scans were performed before and after two courses of Bev treatment. Changes in tumor to normal ratio (TNR) for MET, tumor to blood ratio (TBR) for FMISO, and metabolic tumor volume (MTV) for both MET and FMISO were evaluated. Progression-free survival (PFS) and overall survival (OS) were compared based on the rate of change in MTV for MET and FMISO. RESULTS The residual volumes (contrast-enhanced MRI, MET, and FMISO) with a MET removal rate of &amp;gt;90% were 0.08 ml, 0.1 ml, and 0.08 ml, respectively. For FMISO removal rates of &amp;gt;90%, residual volumes were 0.36 ml, 1.54 ml, and 0.05 ml, respectively. Groups with a decreased rate of change in MET MTV had significantly better outcomes: PFS (months) 10.7 vs. 2.8 (p=0.19) and OS (months) 18.6 vs. 4.9 (p=0.09). In the FMISO groups, decreased TBR change rates correlated with better outcomes: PFS (months) 16.6 vs. 2.5 (p&amp;lt;0.01) and OS (months) 22.8 vs. 4.9 (p&amp;lt;0.01). MTV change rates also showed significant differences in outcomes: PFS (months) 10.5 vs. 3.7 (p=0.76) and OS (months) 14.9 vs. 7.0 (p=0.87). CONCLUSION Higher MET removal rates correlate with fewer contrast-enhanced MRI and FMISO accumulation areas, suggesting MET as a reliable tumor removal indicator. Both MET and FMISO PET scans are valuable in determining glioblastoma treatment response.
NIMG-23. A NOVEL APPROACH TO PERFUSION MRI STUDIES IN BRAIN TUMOR PATIENTS USING ENDOGENOUS DEOXYHEMOGLOBIN AS A CONTRAST AGENT: A PROOF-OF-CONCEPT STUDY
Authors: Vittorio Stumpo, Ece Su Sayin, Jacopo Bellomo, Oliva Sobczyk, Christiaan Hendrik Bas van Niftrik, Martina Sebök, Michael Weller, Luca Regli, Zsolt Kulcsar, Athina Pangalu, Andrea Bink, James Duffin, David D Mikulis, Joseph A Fisher, Jorn Fierstra
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Assessment of resting perfusion in brain tumors is clinically relevant and relies on dynamic susceptibility contrast magnetic resonance imaging using gadolinium contrast. Preliminary studies have introduced the use of controlled hemoglobin desaturation by means of a transient hypoxic stimulus during echo-planar imaging(EPI) as a surrogate for gadolinium for resting perfusion assessment in healthy subjects. In this proof of concept study, we investigated whether this approach is feasible in brain tumors and warrant further validation. METHODS A computer controlled gas blender was used to induce transient and standardized hypoxic stimulus in isocapnic conditions during EPI acquisition in a heterogenous cohort of tumor patients. The induced blood-oxygen-level-dependent(BOLD) signal changes determined by transit of a bolus of deoxygenated blood in the brain vasculature were used as a surrogate of gadolinium to calculate cerebral blood volume(CBV), cerebral blood flow(CBF) and mean transit time(MTT) using a global arterial input functions obtained through the BOLD signal measured over the middle cerebral artery as previously described by Poublanc et al. Perfusion parameters were calculated in the whole-brain voxel-by-voxel and in automatically segmented region of interest(ROI) using SPM, AFNI, Verbena softwares and MATLAB in-house written scripts. RESULTS Nine patients were included. MTT, rCBV, rCBF were calculated voxel-per-voxel. Obtained maps were overlayed on the co-registered T1 MRI scans and compared to T1CE and FLAIR to identify perfusion patterns in tumor ROIs (contrast enhancement, edema, necrosis). The deoxy-hemoglobin BOLD MRI perfusion were compared to clinical DSC-MRI when available and showed high qualitative agreement. CONCLUSION Transient and precise hemoglobin desaturation by controlled hypoxic gas modulation is safe and repeatable in brain tumor patients. The induced BOLD signal change allows measurement of resting perfusion, which qualitatively closely mimic gadolinium perfusion in different brain tumors. Deoxyhemoglobin-based perfusion warrant further quantitative validation against gadolinium in a larger cohort of heterogenous tumor patients.
NIMG-20. DWIBS FOR PRIMARY CANCER DETECTION IN INTRACRANIAL METASTASIS: TWO CASE REPORTS
Authors: Yuki Koyahara, Norihiko Saito, Nozomi Hirai, Yu Hiramoto, Satoshi Fujita, Haruo Nakayama, Morito Hayashi, Keisuke Ito, Satoshi Iwabuchi
Journal: Neuro-Oncology (2024)

Abstract INTRODUCTION Diffusion Weighted Whole Body Imaging with background body signal Suppression (DWIBS) is an imaging technique that encompasses comprehensive imaging of the entire body through diffusion-weighted imaging (DWI). In recent years, it has been increasingly utilized for investigating the etiology of fever or primary cancer. Here we present two cases of DWIBS for searching for primary cancer in patient with intracranial metastasis. CASE PRESENTATION Case1: A 60-year-old man presented with headache and diplopia and was admitted to our hospital. MRI revealed a tumor in the clivus exhibiting contrast enhancement. Endoscopic transsphenoidal surgery confirmed the diagnosis of squamous cell carcinoma. DWIBS demonstrated high intensity in a region similar to the esophagus seen on contrast-enhanced CT, leading to the diagnosis of brain metastasis from esophageal cancer. Case 2: A 50-year-old man presented with left facial paralysis and left hemiplegia and was admitted to our hospital. MRI revealed a tumor in the right middle frontal gyrus. Craniotomy confirmed the diagnosis of adenocarcinoma. Although the primary cancer remained unidentified upon initial examination, subsequent investigations revealed it originated from the lung. DWIBS showed high intensity in a region similar to the lung. DISCUSSION While FDG-PET is commonly utilized for cancer detection, its invasiveness and limitations prompt consideration of alternative modalities such as DWIBS. Recently there are some studies that have shown DWIBS to be superior to FDG PET in detecting esophageal and lung cancers. Thus, DWIBS may serve as a viable option for primary cancer screening in hospitals or communities where access to FDG PET is limited. CONCLUSION Its non-invasive nature makes DWIBS an appealing option for primary cancer detection, and further advancements are anticipated.
NIMG-37. “SYNTHETIC” PERFUSION MRI WITH ADJUSTABLE ACQUISITION PARAMETERS IN BRAIN TUMORS USING DYNAMIC SPIN-AND-GRADIENT-ECHO ECHOPLANAR IMAGING
Authors: Francesco Sanvito, Jingwen Yao, Nicholas Cho, Catalina Raymond, Donatello Telesca, Whitney Pope, Richard Everson, Noriko Salamon, Jerrold Boxerman, Timothy Cloughesy, Benjamin Ellingson
Journal: Neuro-Oncology (2024)

Abstract INTRODUCTION Dynamic susceptibility contrast (DSC) perfusion MRI can assess normalized relative cerebral blood volume (nrCBV) and percentage of signal recovery (PSR) in brain tumors, which can aid in differential diagnosis, molecular profiling, and identification of disease progression. However, CBV-optimized and PSR-optimized protocols differ in terms of acquisition parameters. Additionally, DSC dependency on acquisition parameters limits the universalizability of diagnostic cutoffs for nrCBV and PSR across institutions and scanners. This study aims to generate “synthetic” DSC datasets with adjustable synthetic acquisition parameters using dynamic spin-and-gradient-echo echoplanar imaging (dynamic SAGE-EPI) to: 1) simultaneously generate nrCBV and PSR with optimal acquisition parameters, 2) compare DSC datasets with heterogeneous external cohorts. METHODS Thirty-eight patients with contrast-enhancing brain tumors were prospectively imaged with dynamic SAGE-EPI during a non-preloaded single-dose contrast injection. Multiple synthetic DSC datasets with desired pulse sequence parameters were generated using the Bloch equations applied to the dual-echo gradient-echo (GE) data extracted from dynamic SAGE-EPI datasets, with or without optional preload simulation. For each patient, synthetic protocols were set to match guideline-compliant CBV-optimized protocols, PSR-optimized protocols, and protocols used in external cohorts from the literature, for comparison. RESULTS Dynamic SAGE-EPI allowed for simultaneous generation of CBV-optimized and PSR-optimized DSC datasets with a single contrast injection. Conversely, suboptimal PSR computation from guideline-compliant CBV-optimized protocols resulted in rank variations within the cohort (Spearman’s ρ=0.83-0.89, i.e. 31%-21% rank variation). Treatment-naïve glioblastoma exhibited lower parameter-matched PSR compared to the external cohorts of treatment-naïve primary CNS lymphomas (PCNSL) (p&amp;lt;0.0001), supporting a role of synthetic DSC for multicenter comparisons. CONCLUSIONS Dynamic SAGE-EPI allows for simultaneous generation of CBV-optimized and PSR-optimized DSC data with a single injection, facilitating use of a single perfusion protocol for all DSC applications. This approach may also be useful for comparisons of perfusion parameters across heterogeneous multicenter datasets.
TMET-09. SEX-BIASED ROLE OF TUMOR-ASSOCIATED MACROPHAGES IN GLIOBLASTOMA IRON METABOLISM
Authors: Aurosman Pappus Sahu, Kondaiah Palsa, Ganesh Shenoy, Becky Slagle-Webb, James R Connor
Journal: Neuro-Oncology (2024)

Abstract Glioblastoma (GBM) is an aggressive brain cancer that is extremely difficult to treat. GBM is sexually dimorphic in nature, where females are less susceptible to developing GBM, respond to therapy better, and get a survival advantage. Sex-biased differences in tumor iron metabolism play a significant part in making this disease sexually dimorphic. Macrophages constitute a significant population in the GBM tumor microenvironment and are key players in tumor iron homeostasis. Here, we examine macrophage iron homeostasis as a potential driver of sex biases in glioblastoma using bone marrow-derived macrophages (BMDM) isolated from C57BL/6 mice. Immunoblot analysis revealed higher ferritin L-chain (FTL) expression in male BMDM than in females (Fold change: 3.18, P = 0.02). Flow cytometric analysis revealed that male BMDMs had a significantly higher labile iron pool (LIP) (Fold change: 1.62, P = 0.0081). We used a stable isotope of iron (Fe57) to determine macrophage iron uptake by ICP-MS, and observed that male BMDMs have a higher iron uptake (fold change: 1.623, P = 0.0018) than females. These results indicate that macrophage iron metabolism is sexually dimorphic in nature. Next, we used a transwell co-culture system to study how macrophages regulate the iron status of GL261 cells. We found that GL261 cells had significantly lower H-Ferritin (FTH1) expression when co-cultured with male BMDMs (Fold change: 0.789, P = 0.0045). However, this decrease in ferritin didn’t result in a decrease in cellular LIP. We discovered that there was an increase in secreted ferritin in the GL261 culture media. Further experiments with Fe57-loaded GBM cells showed that this increase in secreted ferritin correlated with increased iron release from the GL261 cells. These results indicate that tumor-associated macrophages may regulate tumor iron homeostasis by inducing ferritin-bound iron release from GBM cells in a sex-biased manner.
TMIC-70. CORRELATION OF LLT-1 AND NLRC4 INFLAMMASOME AND ITS EFFECT ON GLIOBLASTOMA PROGNOSIS
Authors: JeongMan Park, Yu Jin Kim, Dongkil Kim, JeongMin Sim, Kwang bog Cho, Kyunggi cho, Ju Hyung Moon, Kyoung Su Sung, Dong Hyun Lee, Jaejoon Lim
Journal: Neuro-Oncology (2024)

Abstract PURPOSE LLT-1 is a well-known ligand for the natural killer (NK) cell inhibitory receptor NKRP1A. Here, we examined NLRC4 inflammasome components and LLT-1 expression in glioblastoma (GBM) tissues to elucidate potential associations and interactions between these factors. METHODS Nine GBM tissues were collected for experiments and RNA sequencing, while fifty-two tumor core tissues were collected for RNA sequencing. Expression of LLT-1 and other proteins was assessed by immunofluorescence. Computational analyses utilized RNA-seq data from 296 and 52 patients from the Chinese Glioma Genome Atlas and CHA medical records, respectively, using survival, non-negative matrix factorization clustering, Gene Ontology enrichment, and protein-protein interaction analyses. Receptor-ligand interactions between tumor and immune cells were confirmed by single cell RNA sequencing analysis. RESULTS In GBM tissues, LLT-1 was predominantly colocalized with Glial fibrillary acidic protein (GFAP) -expressing astrocytes, but not with microglial markers like Iba-1. Additionally, LLT-1 and activated NLRC4 inflammasomes were co-expressed mainly in intratumoral astrocytes, suggesting an association between LLT-1, NLRC4, and glioma malignancy. High LLT-1 expression correlates with poor prognosis, particularly in the mesenchymal subtype, and is associated with TNF and NOD-like receptor signaling pathway enrichment, indicating a potential role in tumor inflammation and progression. At the single-cell level, mesenchymal-like malignant cells were highly enriched in the TNF, NLR, and IL-1 signaling pathways compared to other malignant cell types. CONCLUSION We revealed an association between NLRC4 inflammasome activity and LLT-1 expression, suggesting a novel regulatory pathway involving TNF, inflammasomes, and IL-1, potentially offering new anti-glioma approaches by enhancing NK cell-based treatments.
CTIM-35. PD-1 BLOCKADE WITH CAMRELIZUMAB IN RELAPSED/REFRACTORY PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA
Authors: Jing-Jing Ge, Cheng Li, Shao-Pei Qi, Chen-Chen Kong, Chi Zhao, Feng-Jun Xue, Jun-Ping Zhang
Journal: Neuro-Oncology (2024)

Abstract Primary central nervous system lymphoma (PCNSL) are rare extranodal large B-cell lymphomas. There are no standard-of-care treatment options for patients with relapsed and refractory PCNSL and the overall prognosis is poor. We conducted a phase 2 clinical trial to evaluate the efficacy and adverse events of PD-1 antibody camrelizumab in relapsed/refractory PCNSL. Enrolled patients received camrelizumab 200mg intravenously every 2 weeks. The primary endpoint was overall response rate (ORR). Here we present results of 20 relapsed PCNSL patients who treated with camrelizumab. Among them,12 were male and 8 were female. The median age was 57 years (range 25-67 years). Fourteen patients were available to evaluate efficacy. After camrelizumab treatment, 4 got complete response (CR), 3 got partial response (PR), 1 got stable disease, and 6 got progressed disease (PD). The ORR was 50%. The median progression-free survival (PFS) was 19.3 weeks (95% CI, 3.1-35.5). 24 week PFS rate was 40%. For the 7 patients who got CR/PR, got a long sustained response, with a median PFS of 93.6 weeks (range 17-211.6+ weeks). One patient developed pseudoprogression 2 months after initiation of treatment. By the last follow-up, 18 patients discontinued treatment (10 PD, 4 complete treatment, 3 withdrawal of informed consent, 1 lost follow-up). Eleven patient got PD. Nine patients received chemotherapy and 5 received radiotherapy after PD. PD-L1 expression, microsatellite stability and mutation burden of the tumors were detected in 9 patients, and all the three factors were not correlated with efficacy. The main drug-related adverse reaction was cutaneous capillary hyperplasia. None of the patients dropped out of the study due to adverse reactions. Our data suggest that camrelizumab is active in relapsed/refractory PCNSL and support further investigation of PD-1 blockade in PCNSL.
DISP-12. AN ECONOMIC STUDY OF NEURO-ONCOLOGICAL PATIENTS IN A LARGE DEVELOPING COUNTRY – A COST ANALYSIS
Authors: Aline Lariessy Campos Paiva, João Luiz Vitorino Araujo, Renan Maximillian Lovato, Alex Michel Daoud, Jean Gonçalves de Oliveira, José Carlos Esteves Veiga
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Neuro-oncological patients require specialized medical care. However, the data on the costs incurred for such specialized care in developing countries are currently lacking; these data are relevant for international cooperation. OBJECTIVE This study aimed to estimate the direct cost of specialized care for an adult neuro-oncological patient with meningioma or glioma during hospitalization in the largest philanthropic hospital in Latin America. 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 Due to differences in the system records, the period analyzed for cost estimation was between December 2016 and December 2019. A group of patients with meningiomas and gliomas was analyzed. The estimated mean cost of neurosurgical hospitalization was US$4,166. The cost of the operating room and intensive care unit represented the largest proportion of the total cost. A total of 17.5% of patients had some type of infection, and 66.67% these occurred in nonelective procedures. The mortality rates during emergency procedures were 12.7% and 92.3%. CONCLUSIONS Emergency surgeries were associated with an increased rate of infections and mortality. The findings of this study could be used by stakeholders and policymakers for resource allocation and to perform economic analyses to establish the value of neurosurgery in achieving global health goals. KEY WORDS: costs; brain tumor; glioma; meningioma.
IMMU-49. TARGETING ALTERNATIVE SPLICING VARIANTS TO STIMULATE ANTI-TUMOR IMMUNITY IN A NOVEL SYNGENEIC MOUSE MODEL OF DIFFUSE HEMISPHERIC GLIOMA, H3 G34-MUTANT
Authors: Anthony Wang, Geoffrey Owens, Yang Pan, Wi-Jin Kim, Matthew Sun, Sophie Peeters, Janet Treger, Alexander Lee, Amber Armellini, Brian Na, Richard Everson, David Daniels, David Nathanson, Linda Liau, Robert Prins, Yi Xing
Journal: Neuro-Oncology (2024)

Abstract The prognosis for pediatric high-grade gliomas associated with mutations in the H3-A3 histone gene is very poor. To investigate whether peptide-pulsed dendritic cells (DC) together with checkpoint blockade might be a potential treatment modality for diffuse hemispheric glioma, H3 G34-mutant (DHG), we have developed a novel mouse model, and utilized a novel bioinformatics pipeline to identify tumor-associated peptide antigens (TAs). We used the RCAS/tv-A system to target the expression of H3/G34R and PDGFb, and to knock out p53 in neural progenitors in transgenic C57BL/6 neonatal mice. Three independent cell lines were obtained that expressed transcripts associated with oligodendrocyte and interneuron lineages, and formed lethal tumors after intracranial implantation. To identify TAs, we implemented a new computational workflow to identify nonapeptides generated from alternative splicing of mRNAs that were highly enriched in the tumor transcriptomes of two DHG patients, and predicted to bind the HLA-A*2:01 class I allele carried by these patients. Three of the candidate peptides were conserved in the mouse and also predicted to bind the H2-Kb MHC I allele carried by C57/BL6 mice. Using our syngeneic mouse model, we showed that DCs pulsed with these peptides together with anti-PD1 mAb provided a significant survival benefit compared with checkpoint inhibitor and DCs pulsed with peptides that were not predicted to bind the H2-Kb allele. Splenocytes isolated from successfully treated mice were analyzed through bulk TCR sequencing, and in comparison with control mice and publicly-accessible TCR libraries, 6 highly-represented TCR clonotypes were identified only in treated mice. In summary, we demonstrate that effective TAs can be extracted from RNAseq data, and can be targeted with DC vaccination to generate a systemic anti-tumor cytotoxic T cell response to eliminate DHG in a novel immunocompetent mouse model.
IMMU-65. TARGETING AXONAL GUIDANCE DEPENDENCIES IN GLIOBLASTOMA WITH ROBO1 CAR T CELLS
Authors: Chirayu Chokshi, Benjamin Brakel, Muhammad Vaseem Shaikh, Martin A Rossotti, Chitra Venugopal, Kevin R Brown, Kevin A Henry, Jason Moffat, Sheila K Singh
Journal: Neuro-Oncology (2024)

Abstract Resistance to genotoxic therapies and subsequent disease recurrence are hallmarks of aggressive cancers, including glioblastoma (GBM). Here, we uncover functional drivers of post-treatment recurrent GBM using genome scale CRISPR-Cas9 screens accompanied by integrative genomic analysis. Using patient-matched pre- and post-treatment GBM models, our findings uncover large-scale reorganization of functional dependencies at tumor recurrence and implicate protein tyrosine phosphatases 4A2 (PTP4A2) as a novel driver of tumorigenicity in recurrent GBM. Small molecule inhibition and phospho-proteomic analyses reveal a novel PTP4A-ROBO1 signaling axis that modulates tumor invasion, self-renewal and proliferation in recurrent GBM. Since a pan-PTP4A targeting small molecule suffers from poor blood-brain-barrier penetrance, we engineered a novel second generation chimeric antigen receptor (CAR) targeting human ROBO1, a cell surface receptor enriched across GBM specimens. Not only do ROBO1 CAR T cells exhibit a potent and specific anti-tumor effect in vitro, a single dose of ROBO1 CAR T cells doubles median survival in a patient-derived xenograft (PDX) model of recurrent GBM. Expansion of ROBO1 CAR T cells to other invasive brain cancers leads to tumor eradication in ~50% of mice in PDX models of pediatric medulloblastoma and adult lung-to-brain metastases. Together, we provide insights into functional remodeling of GBM at recurrence and present a multi-targetable PTP4A-ROBO1 signaling axis with potential across multiple malignant brain tumors.