tbuckley/cabot-search huggingface dataset:
P01.06.B GLIOMA STEM CELLS REMODEL ASTROCYTES TO FACILITATE GBM PROGRESSION VIA EXOSOMAL ZNF16 ACTIVATED TGF-Β SIGNALING AXIS
Authors: J Dong
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Tumor-associated astrocytes (TAAs) play crucial promoting roles during tissue remodeling of glioma stem cells (GSCs), however, molecular mechanisms regulating astrocytes transformation, as well as glioblastoma progression by TAAs have not been fully clarified. MATERIAL AND METHODS Normal human astrocytes (NHAs) were cultured in vitro and continuously treated with GSC-derived exosomes (GSC-exo). Cellular phenotypes of TAAs were analyzed, expression of TAAs associated markers TGF-β, CD44, and tenascin-C was assayed by Western blot. Bioinformatic prediction of upstream transcription factor of TGF-β was performed and validated by RT-PCR, dual-luciferase reporter assay. Cell-based assay of glioblastoma proliferation and chemo-resistance were performed through flow cytometric assay, Western blot and colony formation assay, respectively. A xenograft tumor model was applied to verify the role of exosomal ZNF16 activated TGF-β signaling axis in vivo. RESULTS Notably, under the influence of GSC-exo, NHAs undergo transformation into tumor-associated astrocytes (TAAs) within three days, expressing hallmark surface markers such as TGF-β, CD44, and Tenascin-C. The transcription factor zinc finger protein 16 (ZNF16) was directly bound to the TGF-β promoter region and enhanced TGF-β expression.This transformation was associated with upregulation of TGF-β in NHAs activated by GSCs exosomal ZNF16. TGF-β is a direct downstream target of ZNF16 in TAAs. Transformed TAAs exhibit morphological changes, enhanced proliferative and migrative capacities, as well as contributing to aggressiveness and chemo-resistance of glioblastoma. In vivo studies disclosed that targeting on GSC-exosomal ZNF16 or TGF-β can suppressive transformation of TAAs and inhibiting their tumor promoting role on glioblastoma progression. CONCLUSION Understanding the intricate mutual interactions between GSCs and astrocytes in glioblastoma microenvironment can shed light on new therapeutic strategy on disrupting GSCs-TAAs crosstalk against glioblastoma progression.
Single-cell transcriptomics reveal potent extrafollicular B cell response linked with granzyme K<sup>+</sup>CD8 T cell activation in lupus kidney
Authors: Chunmei Wu, Shan Jiang, Zechuan Chen, Teng Li, Xixi Gu, Min Dai, Fang Du, Yan Ye, Longhai Tang, Mingyuan Wang, Xiaodong Wang, Ting Li, Shuang Ye, Chunde Bao, Xiaoming Zhang, Qiong Fu
Journal: Annals of the Rheumatic Diseases (2024)

B and T cells constitute the majority of infiltrating lymphocytes in the kidney and represent the local perpetrators in lupus nephritis (LN), but the underlying pathogenic mechanisms are not well elucidated. The aim of this study is to explore the kidney-specific adaptive immune landscape in patients with active LN at the single-cell level.
P10.12.B DEEP LEARNING-BASED NORMALIZATION AND UNMIXING OF HYPERSPECTRAL IMAGES FOR BRAIN TUMOR SURGERY
Authors: D Black, J Gill, A Xie, B Liquet, A Di Ieva, W Stummer, E Suero Molina
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Hyperspectral Imaging (HSI) for fluorescence-guided brain tumor resection enables better visualization of differences between tissues. This can maximize brain tumor resection, improving patient outcomes. However, much of the processing in HSI uses simplified models that are unable to capture the non-linear, wavelength-dependent phenomena that must be modeled for accurate recovery of fluorophore abundances. To overcome these challenges, measured spectra are normalized to account for artifacts and spectrally unmixed to isolate the protoporphyrin IX (PpIX) signal, which indicates malignant tissue. Existing methods are simplistic and based on phantoms and are unable to account for nonlinear effects such as multiple scattering or the inhomogeneous optical properties of the tissue. We propose a deep learning (DL)-based pipeline encompassing normalization and unmixing, which can fully account for the nonlinear effects and produce more accurate distributions of fluorophore abundances. MATERIAL AND METHODS This study proposes two deep learning models for correction and unmixing, which can capture these effects. Both models use autoencoder-like architectures. While one is trained with protoporphyrin IX (PpIX) concentration labels, the other is semi-supervised, learning hyperspectral unmixing self-supervised and then learning to correct the spectra for optical and geometric effects using a white-light reflectance spectrum in a few-shot manner. The models were evaluated on phantom and pig-brain data with known PpIX concentration. RESULTS The supervised and semi-supervised models achieved Pearson correlation coefficients (phantom, pig-brain) between known and computed PpIX concentrations of (0.997, 0.990) and (0.98, 0.91), respectively, whereas the classical approach achieved (0.93, 0.82). On human data, the semi-supervised model gives qualitatively more realistic results than the classical method, better reducing the variance in PpIX abundance over biopsies that should be relatively homogeneous. CONCLUSION These results show promise for using deep learning to improve HSI in fluorescence-guided neurosurgery.
P04.02.A DISCOVERY OF NEW METABOLIC PATHWAYS IMPLICATED IN THERAPY RESISTANCE IN GLIOBLASTOMA (GBM)
Authors: A Cingöz
Journal: Neuro-Oncology (2024)

Abstract Glioblastoma stands as the most prevalent and aggressive primary brain tumor. The current treatment regimen involves a combination of radiotherapy and chemotherapy post-surgical tumor resection. However, for most patients, tumor recurrence transpires with a more aggressive phenotype. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) holds promise as it selectively triggers apoptosis in tumor cells, rendering it an attractive therapeutic option. Nonetheless, numerous tumor cells, glioblastoma included, can develop acquired resistance against TRAIL therapy, yet the underlying mechanisms remain poorly elucidated. Apart from resistance to apoptosis, these mechanisms may also encompass non-genetic factors stemming from intracellular dynamics. In our previous research on generating models resistant to TRAIL, we observed differences in the expression of metabolic pathway genes in TRAIL-resistant glioblastoma cells. Our transcriptomic analysis revealed a positive correlation among pathways related to cellular metabolism in these resistant cells. Further examination of this gene family revealed common alterations across various cell lines. Additionally, to delve deeper into the role of cellular metabolism, we conducted in vivo CRISPR/Cas9 screening using a focused library targeting metabolism. We also compared mitochondria densities using MitoTracker dye between sensitive and resistant GBM cells, noting a significant increase in resistant cells. Using the Seahorse Extracellular Flux Analyzer, we measured cellular metabolism activity and observed higher oxygen consumption in resistant cells, indicative of elevated energy levels. Based on these preliminary findings, our study will undergo thorough genetic and metabolomic screening, promising significant insights into cancer metabolism. The identified target genes and metabolites could potentially serve as therapeutic targets for developing novel cancer treatments, particularly glioblastoma.
P16.04.B LONG TERM SURVIVAL AND TOXICITY OUTCOMES IN PEDIATRIC MEDULLOBLASTOMA: SINGLE CENTER EXPERIENCE
Authors: S Kamer, E Karaman, M S Acar, Y Anacak
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Craniospinal radiotherapy(CSRT) is a crucial part of medulloblastoma treatment. Due to the diverse age range of patients and large treatment fields, long term toxicity results, as well as survival outcomes, must be evaluated. This study aims to assess treatment outcomes of CSRT in medulloblastoma patients at a single tertiary center, considering both long-term toxicity and survival. MATERIAL AND METHODS Pediatric medulloblastoma patients who underwent postoperative CSRT between 2000-2021 were included in the analysis. CSRT was planned with 3D CRT technique for all patiens. Craniospinal axis doses were 23,4 Gy for standard risk and 36 Gy for high risk group. Patients received posterior fossa or tumor bed boost according to their risk status. Clinical characteristics and survival outcomes were obtained from follow-up visits. For late toxicity analysis, patients with less than 2 years of follow-up were excluded. Assessments included educational issues, neurological deficits, hearing impairment, endocrinopathy, and growth impairment. RESULTS 120 cases (median age: 7 (2-17)) were analyzed with %61,7 being male. Gross total resection was achieved in 80,8% of cases. Most common histopathologic subtype was classical histology (76.7%). Forty-eight case (40%) was diagnosed in metastatic stage (M+) according to Chang’s classification. 52.5% of the cases were classified as high-risk group. Median follow-up was 64 months (4-252). 5- and 10-year overall survival was estimated to be 71.6% and 63.3% respectively. For the recurrence free survival; 5- and 10-year estimates were 68.5% and 61.6%. High risk group correlated adversely with overall survival (p&amp;lt;0.01). In follow-up, recurrence was detected in 41 cases (34.2%) with a median of 16 months (1-52). Recurrence sites included 22 cases in the primary site, 8 cases in the spinal region, and 11 cases in both region. Although a higher recurrence rate was observed in the high-risk group (41.2% vs. 26.3%), difference was not statistically significant. Seventy-five cases underwent late toxicity analysis, with 72% exhibiting at least one late toxicity. Educational issues were found in 36% of cases, permanent neurological deficit in 34.7%, hearing impairment in 32%, endocrine insufficiency in 40%, and growth impairment in 49.3%.Higher spinal dose (p:0,019), age ≤8 (p:0,011) and female sex (p:0,034) correlated with growth impairment. Endocrinopathy was significantly more prevalent in children over 12 years of age (p=0.032). During follow-up, three cases developed secondary malignancies: one meningioma and two papillary thyroid carcinomas. CONCLUSION CSRT is an effective treatment modality for pediatric medulloblastoma and must be meticulously administered in order to achieve acceptable survival outcomes and minimize late toxicity. Long-term follow-up is crucial for monitoring late adverse effects and recurrences in patients.
P02.06.B CROSSTALK BETWEEN GLIOMA AND MYELOID SHAPES DISTINCT TUMOR MICROENVIRONMENT IN SPINAL CORD, BRAIN STEM AND CEREBRUM
Authors: Y Wang
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Occurring in the cerebrum, brainstem, and spinal cord, glioma are the most common primary malignant tumors in the central nervous system. Currently, there is a increasing understanding of the microenvironment of cerebral gliomas and brainstem gliomas, and clinical trials of immunotherapy for them are also ongoing. However, research on the microenvironment of spinal cord glioma is still lacking, Their immunotherapy potential deserve further exploration. MATERIAL AND METHODS We performed single-cell sequencing of fresh tissues from 8 cases of spinal cord DMG. Through integrating public scRNA data from 19 brain glioblastoma cases and 9 cases of DIPG samples, we did an integrated analysis of 199,696 human glioma, immune, and other stromal cells at the single cell level. Further analysis of cell communication revealed the distinct interaction between glioma cells and different cells in the microenvironment, especially tumor infiltrating macrophages. RESULTS Single cell analysis indicates that the main participants in the glioma microenvironment are tumor cells and tumor infiltrating macrophages; In addition, compared to midline gliomas, brain gliomas contain a higher proportion of lymphocytes. Interaction analysis revealed that spinal cord gliomas can regulate the infiltration of macrophages in spinal cord gliomas through the THY1-ADGR5 axis and higher expression of IGF1 by macrophages, promoting the proliferation and invasion of gliomas with IGF1R. CONCLUSION This study provides insights into molecular, spatial, and functional heterogeneity of glioma and glioma-associated immune cells in GBM, DIPG and spinal cord DMG, suggesting that selectively modulating tumor-related immunosuppressive regulatory networks might reprogram the microenvironment and provide an immunotherapeutic strategy for treating glioma.
P14.23.B USE OF BIOPSY-DERIVED TUMOR ORGANOIDS FOR PERSONALIZED DRUG TESTING IN RECURRENT GLIOBLASTOMA
Authors: A Wöllner, R Warta, J Cao, A Paul, M Arquilla, G Jungwirth, W Wick, A von Deimling, S Krieg, A Unterberg, M Jakobs, C Herold-Mende
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND To date, there are no systemic treatment options for patients suffering from recurrent glioblastoma with a proven efficacy. Furthermore, often surgical resection is not any more possible and patient tumors have acquired an increased chemo- and radioresistance. Patient-derived tumor organoids (TOs) provide a new exciting tool to test individual treatment responses. Aim of this study was to develop a protocol and to test the feasibility to perform personalized TO-based drug testing using the rare material from stereotactic biopsies. MATERIAL AND METHODS Patient-derived TOs were prepared based on single cell suspensions from tumor material obtained either from open glioblastoma resections serving as a reference data set (n=37) or from stereotactic biopsies of 8 patients. Drug response curves (6-9 dose points) were performed for nine selected drugs including temozolomide, lomustine, etoposide and temsirolimus, which are commonly used in clinical practice. Viability and metabolic activity were measured using CellTiterGlo (Promega). Half-maximal inhibitory concentrations (IC50) were calculated by GraphPad Prism software. Medical records were reviewed for survival and routine molecular information such as the MGMT promoter methylation status. RESULTS Drug testing performed on TOs derived from open resections allowed to adjust the concentration test range for each drug, as well as to determine the range of drug vulnerability. Additionally, we found a significant association between increased temozolomide sensitivity of TOs and both, MGMT methylation and increased survival. However, in 59% of the cases, no high sensitivity to any of the drugs was observed, and only 17% were highly sensitive to more than one drug. Subsequent drug testing on TOs derived from biopsies of recurrent glioblastoma revealed sensitivity in 3/8 cases against one (n=2) or two (n=1) of the drugs. However, sensitivity against drugs varied substantially in a patient-individual manner. CONCLUSION Taken together, we successfully developed a workflow to test drug sensitivity on glioblastoma-derived tumor organoids even from the low starting material obtained from stereotactic biopsies. Association of clinical outcome and MGMT methylation with temozolomide sensitivity corroborated the strength of this approach. Furthermore, patient-individual treatment responses strongly suggest for a future personalized drug testing.
P14.24.A USE OF OMMAYA RESERVOIR FOR INTRATHECAL CHEMOTHERAPY AND DISEASE MONITORING IN ROUTINE CLINICAL PRACTICE: ASSESSMENT OF SAFETY AND EFFICACY
Authors: E Harahsheh, S Shah, R Butterfield, C Ariete, M Lyons, C Krishna, S Fortin-Ensign, R Zimmerman, B R Bendok, M M Mrugala
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Leptomeningeal disease (LMD) carries poor prognosis with an average survival of 3-6 months after diagnosis. Ommaya reservoirs (OR) are an accessible alternative to serial lumbar punctures for delivery of intrathecal chemotherapy (IC) and disease monitoring but are not widely used. Intraventricular administration of chemotherapy may be associated with superior efficacy and improved patient comfort. The purpose of this study was to assess safety and efficacy of IC and disease monitoring via OR in routine clinical practice. MATERIAL AND METHODS Patients who received at least one administration of IC via OR for LMD between 2017 and 2022 were included. Demographics, treatment type, complications and outcomes were recorded. RESULTS We identified 22 patients (17 females, 5 males) with mean age 50.9 ± 14.8 years. The primary tumors were: breast (12), leukemia (3), ovarian carcinoma (3), CNS lymphoma (1), urothelial carcinoma (1), spinal melanocytoma (1), and high-grade glioma (1). A total of 208 OR injections were performed [median was 9 OR injections per patient, interquartile range (IQR) (5, 13)]. Five patients (23%) experienced mild adverse events of grade 2 or lower by Common Terminology Criteria for Adverse Events. Overall risk of adverse event from injection was 3.4% (7/208). Eight patients (36.3%) converted into negative CSF cytology (median 1 month following first injection), and 18 patients (82%) had clinical or radiological progression of their LMD (median 2 months following first injection). Eleven patients (50%) died of their LMD during follow-up. Median OS and PFS from the first injection were 5.3 months [95% CI 4.8-NE (not estimable)] and 4.3 months [95% CI 1.8-16.0], respectively. CONCLUSION Use of OR in routine clinical practice is a safe and feasible option and should be strongly considered for treatment and frequent disease monitoring of patients with LMD, especially in the era of circulating tumor cells analysis. The median OS in our cohort is comparable to prior published series.
JS06.4.A RADIOTHERAPY QUALITY ASSURANCE IN THE ROAM/EORTC1308 ATYPICAL MENINGIOMA RANDOMISED CONTROLLED TRIAL: PROSPECTIVE REVIEW IMPROVES RADIOTHERAPY QUALITY AND CONSISTENCY
Authors: M D Jenkinson, H Mayles, D C Weber, B J Haylock
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND ROAM/1308 is an international randomised controlled phase III trial comparing radiotherapy (60Gy in 30 fractions) to observation following complete surgical resection of atypical meningioma. We embedded prospective radiotherapy quality assurance (RTQA) within the trial with the aim of ensuring consistent radiotherapy planning and delivery. MATERIAL AND METHODS The radiotherapy protocol described the consensus contouring/planning guidelines. Pre-trial assessment included benchmark cases (outlining/planning) and a technology ‘Dummy Run’. Individual case reviews were undertaken. Non-conformities were classed as ‘major’ (undertreatment of dural margins/over treatment of brain or organs at risk) or ‘minor’ (for education). Resubmissions were mandated for all major non-conformities. All plans were approved before radiotherapy delivery. RESULTS The UK RTQA group coordinated European sites. The Australian RTQA group (TROG) reviewed their sites and provided all data to the UK for review. Four radiation oncologists reviewed contours and physicists/dosimetrists reviewed plans. All sites (20 UK, 25 EORTC, 11 TROG) undertook the benchmark/’Dummy Run’ cases prior to opening. Resubmissions were: UK (1 contour, 0 plans), EORTC (2 contours, 6 plans) and TROG (1 contour, 3 plans). Trial communications and outlining workshops were used to provide feedback. Radiotherapy was delivered to 30, 26 and 7 patients at 11 UK, 12 EORTC and 5 TROG sites, respectively. Overall, 25 (40%) patient cases needed resubmitting: 23 (37%) sets of outlines (2 cases twice) and 9 (14%) treatment plans (1 plan twice). CONCLUSION Prospective quality assurance and case review are essential to ensure consistent high-quality radiotherapy and benchmark/’Dummy Run’ alone is not sufficient. RTQA should be used for future trials in rare tumours where centres may only treat a few patients. The consistent high-quality radiotherapy in ROAM/EORTC1308 ensures the primary outcome (progression free survival: to report 2026) will be a robust assessment and any difference between treatment arms cannot be attributed to variation in radiotherapy planning or delivery.
P24.01.A A UK-WIDE SURVEY OF THE HOLISTIC NEEDS OF SELF-IDENTIFIED CLINICALLY VULNERABLE PATIENTS WITH A NEW DIAGNOSIS OF GLIOMA
Authors: C Lorimer, M Jameson, A Thomson, U Ali, H Bulbeck, A Byrne, S Cooper, S Meldrum, S Melhuish, S Mills, I Oberg, S Robson, J Brock
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND A multidisciplinary research group, established by NCRI, identified that research into holistic needs of patients with malignant gliomas and their caregivers remains sparse. A large proportion of patients in this cohort are considered ‘clinically vulnerable’ including older and frail patients. This UK wide survey sought to identify key areas requiring greater research and intervention with a specific focus on the clinically vulnerable subgroup. MATERIAL AND METHODS Patients who identified as clinically vulnerable by themselves or their caregiver and had received a diagnosis of glioma were invited via leaflets and social media platforms to respond to a 21 question online survey, hosted by BrainsTrust. Questions focussed on support, information and treatments offered at initial diagnosis. Quantitative and qualitative data was collected and analysed using descriptive statistics and narrative analysis. RESULTS The survey received 70 responses; 57 patients, 13 caregivers. 47 female, 23 male. The mean age of respondents was 46 (range 21-76 years). 64% of respondents felt listened to by their medical team, however only 43% of respondents felt they fully understood the information they received in the consultation. Only 29% reported remembering all the information they were given once home, fewer than half (47%) of respondents received written information to take away. 50% respondents felt that all and 33% felt that some of their questions were answered by their medical team. Only 50% of respondents reported being assigned a key worker, and 43% felt they could contact their key worker when they needed. Questions regarding specific needs gave great insight into areas where these needs are not being met; 70% wanted support with fatigue, with 36% actually receiving this, 47% wanted support with memory changes but only 19% received this. 49% of respondents wanted involvement from the neuropsychology team, with 26% receiving this. Conclusion: The results of this survey demonstrate areas where brain tumour care services are not meeting the needs of this self-identified clinically vulnerable patient group. Overall there was no category of need that was fully met which identifies the requirement for consistently structured assessment and intervention.