bluuebunny/crossref_metadata_2025_split huggingface dataset:
IMMU-46. MONITORING T-CELL DYNAMICS AND CHECKPOINT EXPRESSION IN THE IMMUNE MICROENVIRONMENT OF PEDIATRIC HIGH GRADE BRAIN TUMORS: THE MIMIC PROGRAM
Authors: Meesters-Ensing Joyce , Carvalheiro Tiago , Kranendonk Mariëtte , Van Baarsen Kirsten , Hoving Eelco , Calkoen Friso , van der Lugt Jasper , Nierkens Stefan 
Published: November 2023

Abstract

BACKGROUND
Pediatric high grade brain tumors (pHGBT) pose a significant challenge due to limited treatment options and poor prognosis. Understanding the immune landscape, in particular T cell profiles and functionality, is of high interest as numerous immunotherapeutic approaches focus on or utilize T-cells. This study aimed to characterize T-cell phenotypes and their potential for immunotherapeutic interventions in tumor fragments (obtained from cavitron ultrasonic surgical aspiration (CUSA)) and tumor tissue (biopsy), in comparison with peripheral blood, collected from pHGBT patients.

METHODS
Spectral flow cytometry was employed to characterize the presence of T-cell subsets and their functional phenotype.

RESULTS
T cells were detected in all materials with similar CD8/CD4 ratios. At diagnosis, T-cells in the tumor microenvironment exhibited significantly increased expression of PD1, LAG3 and TIM3 checkpoint receptors compared to peripheral blood. This difference was more pronounced in biopsy samples compared to CUSA fragments. T-cell composition and phenotype in peripheral blood were similar to healthy adult controls at diagnosis. However, during therapy, the T-cell compartment showed a shift towards a higher CD8/CD4 ratio, accompanied by increased activation markers (CD25, CD69) and checkpoint receptor expression . Notably, CD8+ T-cells in both peripheral blood and tumor microenvironment showed high production of Granzyme B.

CONCLUSION
Our findings demonstrate that despite the high expression of checkpoint receptors on CD8+ T-cells, these cells retain the capability to produce significant amounts of Granzyme B, indicating their potential for cytotoxic activity. Furthermore, variations in checkpoint receptor expression on T-cells were observed when comparing CUSA fragments to biopsy material. Functional assays will further validate these findings and elucidate the functional status of these cells. Understanding the function of T-cells within the tumor microenvironment is essential for designing novel combination therapies to enhance T-cell cytotoxicity against pHGBT.
IMMU-48. SOLUBLE CIRCULATING IMMUNE CHECKPOINT MOLECULES IN MALIGNANT BRAIN TUMORS
Authors: Ryba Alice , Maire Cecile , Drexler Richard , Kolbe Katharina , Heinemann Sarina , Pantel Klaus , Gempt Jens , Westphal Manfred , Ricklefs Franz L , Wikman-Kocher Harriet , Riethdorf Sabine , Lamszus Katrin , Mohme Malte 
Published: November 2023

Abstract
Immune checkpoint therapy has been shown to be effective in several types of cancer, and tumor-directed immune activation is also a promising strategy in glioblastoma (GBM) patients. Our goal was to discover alterations in the circulating immunome of GBM patients and other cerebral tumor entities to identify soluble immune biomarkers and novel therapeutic targets. We analyzed 30 markers in plasma of 208 patients and healthy donors, using bead-based multiplex assays and flow cytometry. In a smaller cohort we further applied a high-sensitivity discovery biomarker platform with 368 markers. We included patients with 1) primary GBM (n=68), 2) recurrent GBM (n=25), 3) cerebral metastases (NSCLC, n=61; breast cancer, n=19), 4) meningioma (n=15) as well as 5) healthy donors (HD, n=20). We detected a distinct immune signature in the peripheral blood of patients with GBM, which was defined by an increased prevalence of soluble immune checkpoint markers (sCD27, sPD-L2, sGal-9), whereas soluble chemokines (CX3CL, CXCL12) were underrepresented. This signature was similar in primary and recurrent GBM, but differed markedly from other cerebral tumor entities as well as from HD. Primary GBM, but not their recurrent counterparts, additionally exhibited increased levels of neurotrophic factors (BDNF, b-NGF) and signs of immune activation with significantly increased levels of IL-18. The biomarker discovery platform further identified 76 proteins that were specifically regulated in GBM compared to HD, offering the potential to serve as biomarkers for disease activity. GBM patients with higher levels of BDNF displayed a significantly shorter survival than patients with lower levels (9.33 vs. 21.90 months; p=0.0001). Likewise patients with high concentrations of VEGF survived significantly shorter than those with low concentrations (12.97 vs. 21.90 months, p=0,0166). Taken together, we were able to delineate a specific immune profile of soluble markers in GBM patients compared to other cerebral tumor entities and to healthy individuals.
IMMU-50. DIFFERENCES IN GUT MICROBIAL COMPOSITION BETWEEN PEDIATRIC BRAIN TUMOR PATIENTS AND HEALTHY CONTROLS – THE MIMIC PROGRAM
Authors: Hoogendijk Raoull , van den Broek Thijs , Carvalheiro Tiago , Lammers Julie , Legemaat Monique , Quaedvlieg Miguel , van Mastrigt Esther , de Zoete Marcel , Top Janetta , Mueller Sabine , Kline Cassie , Calkoen Friso , van der Lugt Jasper 
Published: November 2023

Abstract

INTRODUCTION
The gut microbiome has been hypothesized to influence tumor initiation, immune evasion and treatment response in CNS tumor patients via the gut-brain axis, but data remains limited. To begin to address this question, we compared the gut microbial composition in a cohort of pediatric high-grade brain tumor patients with healthy controls.

METHODS
Within the MIMIC program, we prospectively collected fecal samples from 33 pediatric brain tumor patients at diagnosis and 26 pediatric healthy controls (HC) (&lt; 21 years of age). Samples were analyzed using 16S rRNA amplicon sequencing of the V3-V4 region. Group differences were tested through the α- and β-diversity. Additionally, differential abundance (DA) analyses were performed.

RESULTS
Brain tumor patients (16 embryonal and 17 glial) significantly differed in age from HC (median 8 years vs 5 years, p&lt; 0.001). Patient vs HC comparison revealed a comparable α-diversity (Shannon-index p=0.45), but significantly different β-diversity (Permanova test p=0.02). Corrected for age, DA revealed 18 genera with a significant log fold change. Twenty five of 33 brain tumor patients received dexamethasone during or prior to fecal sampling and 32 out of 33 patients received cefazolin, a first generation narrow-spectrum cephalosporin targeting mainly gram-positive bacteria, during surgery and before sample collection. Steroid use within brain tumor patients did not statistically affect α-diversity, β-diversity or DA. However, the impact of intravenously administered cefazolin during surgery on the gut microbiome in brain tumor patients remains unknown.

CONCLUSION
We report significant differences in gut microbial composition between pediatric brain tumor patients at diagnosis and healthy controls. DA revealed clinically relevant differences in Agathobacter , Fusicatenibacter , Eggerthella , and Hungatella. However, differences may be impacted by cefazolin administration. If and how gut microbial composition at diagnosis is associated with treatment efficacy and toxicity is subject to further research within the MIMIC program.
IMMU-53. MONITOR THE IMMUNE MICROENVIRONMENT AND SYSTEMIC IMMUNE EFFECTS IN PEDIATRIC BRAIN TUMORS – THE MIMIC PROGRAM
Authors: Hoogendijk Raoull , Carvalheiro Tiago , Lammers Julie , Kranendonk Mariëtte , Meesters-Ensing Joyce , Stunnenberg Hendrik , Kool Marcel , Bunt Jens , Heutinck Anneke , Adams Lisette , Van Baarsen Kirsten , Nierkens Stefan , Calkoen Friso , van der Lugt Jasper 
Published: November 2023

Abstract

INTRODUCTION
Dismal outcomes of pediatric high-grade CNS tumors demand new therapeutic strategies. A better understanding of the immune system may contribute to designing better immunotherapies for these children. The MIMIC program (Dutch Trial Registry NL8967) is a prospective observational longitudinal cohort study, conducted in patients with newly diagnosed or relapsed high-grade CNS tumors with the aim of characterizing and quantifying changes in immune parameters at diagnosis and during treatment.

METHODS
All patients with a newly diagnosed or relapsed high-grade CNS tumor are included after obtaining informed consent. Patient study material is collected longitudinally and includes tumor tissue (TT), Cavitron Ultra Sonic Aspirator (CUSA) material and optional bone marrow aspiration (BM) at diagnosis and relapse. Cerebrospinal fluid (CSF), peripheral blood (PB) and fecal samples (FS) at diagnosis, 3 months, 6 months, 12 months, relapse and additionally collection of CSF and FS at 14 days. Furthermore, FS is collected from patient siblings as a reference.

RESULTS
The MIMIC program has opened in June 2021 in the Princess Máxima Center, the national pediatric oncology center in the Netherlands, including so far 47 patients (out of ~60 eligible patients annually). More than 400 samples, out of which 46 TT, 34 CUSA, 65 CSF, 14 BM, 143 PB, and 105 FS have been collected. All samples are subject to extensive immunological profiling using 70+ markers flow cytometry panels (PB, TT, CUSA, CSF, BM), (spatial single cell) RNA and protein profiling (TT, CUSA, BM), immunohistochemistry (TT), proteomics (CSF and PB), and 16S rRNA or shotgun metagenomic sequencing (FS).

CONCLUSION
The MIMIC program demonstrates the feasibility of obtaining various samples for pediatric high-grade CNS tumors. By incorporating multiple technologies in longitudinal samples, the MIMIC program provides insight into the different immune compartments and their relation to the tumor, forming the base for future clinical trials with immunotherapy.
IMMU-54. PNEUMOCYSTIS JIROVECII PNEUMONIA INFECTION IN A PATIENT WITH ANAPLASTIC ASTROCYTOMA AND RADIATION NECROSIS IN THE SETTING OF CORTICOSTEROID AND PEMBROLIZUMAB USE
Authors: Choi Yoon , Kong Xiao-Tang 
Published: November 2023

Abstract
We present a case with anaplastic astrocytoma and radiation-induced brain necrosis, diagnosed with pneumocystis jirovecii pneumonia(PJP) while receiving corticosteroid and pembrolizumab, an immune checkpoint inhibitor(ICI). ICIs have significantly changed management of many cancer types and are known to be associated with immune related adverse events(irAEs). Recently, concerns have emerged regarding the potential relationship between ICI use and infection risks, and PJP, a rare opportunistic infection, has been reported in patients with ICI treatments with or without corticosteroid use. A 40-year-old man with anaplastic astrocytoma and radiation-induced brain necrosis on corticosteroid and pembrolizumab presented with high fever and tachycardia over three days, and the patient later developed hypoxia and cough. The patient was on dexamethasone for brain radiation necrosis for two months and he received one dose of pembrolizumab two weeks prior to his symptom onset, based on genetic information that showed hypermutated tumor and abnormal DNA mismatch repair protein expression. Chest CT showed abnormal findings from infectious or inflammatory process. Bronchoalveolar lavage sample confirmed positive pneumocystis jiroveci PCR test, confirmed PJP, and he was treated with clindamycin, primaquine, and prednisone. To the best of our knowledge, this is the first reported case of PJP in a patient with primary brain tumor receiving corticosteroid and pembrolizumab. ICIs are being investigated in patients with primary brain tumors and wildly used in patients with malignancies with frequent central nervous system involvements, such as malignant melanomas and non-small cell lung cancers. Awareness of risk for infectious conditions including PJP in patients on ICI treatment, especially with corticosteroid use is crucial for implementing appropriate prophylactic measures and prompt diagnosis and treatment interventions.
IMMU-56. TARGETING NONO IN GLIOMA VIROIMMUNOTHERAPY
Authors: Gillard Andrew , Shin Dong Ho , Jiang Hong , Fan Xuejun , Singh Sanjay , Laspidea Virginia , He Jiasen , Lopez-Rivas Andres , Parthasarathy Akhila , Alonso Martha , Lang Frederick , Fueyo-Margareto Juan , Gomez-Manzano Candelaria 
Published: November 2023

Abstract
Despite aggressive therapies, the median survival for glioblastoma (GBM) patients remains just 7-months after tumor progression. Oncolytic virotherapy is a promising approach to reprogramming the immunosuppressed microenvironment of GBMs facilitating anti-tumor immunity. Delta-24-RGD is an oncolytic adenovirus that has shown favorable results in phase I/II clinical trials (NCT00805376, NCT03178032 and NCT02798406). However, the immune response of the patient functionally cleared the virus, limiting its anti-cancer efficacy to a subset (~20%) of patients. It is known that Non-POU Domain Containing Octamer Binding (NONO) is overexpressed in gliomas and is associated with poor survival of patients. Using bulk RNA sequencing, we showed that the NONO pathway is upregulated 7 folds during adenoviral infection. These results were confirmed by western blot analyses that showed a significant increase in the expression of NONO after Delta-24-RGD infection. We detected cellular and viral members of the NONO interactome using mass spectrometry analyses. Immunoprecipitation assays confirmed those results and showed that NONO binds to adenoviral proteins during infection and associates with the foreign DNA sensor cyclic GMP AMP synthase (cGAS). Using shRNA knockdown, we showed that NONO was required to induce innate immune activation in response to adenovirus infection. Thus, we observed a 180-fold increase in type I interferon after the infection with the virus that was reversed in NONO-null cells. Therefore, NONO is a previously undetected innate immune sensor of adenoviruses in the nucleus. In addition, the fact that NONO binds adenoviral proteins suggests a new double-sensor mechanism involving the detection of both foreign DNA and viral proteins. Interactions between NONO and adenoviral proteins should be considered when designing the next generation of oncolytic adenovirus for the treatment of gliomas.
INNV-16. COMPARISON OF SURVIVAL OUTCOMES OF RECURRENT GLIOBLASTOMA PATIENTS: A COMPARISON BETWEEN PATIENTS ENROLLED INTO CLINICAL TRIALS AND PATIENTS THAT DID NOT ENROLL INTO TRIALS AT FIRST PROGRESSION
Authors: Balasubramanian Geethanjali , Yerramothu Shruti , Youssef Gilbert , Lee Eudocia , Castro Luis Nicolas Gonzalez , McFaline-Figueroa Jose Ricardo , Nayak Lakshmi , Reardon David , Trippa Lorenzo , Wen Patrick , Rahman Rifaquat 
Published: November 2023

Abstract

BACKGROUND
Clinical trials in neuro-oncology use stringent eligibility criteria to select patients. We examined potential differences of survival outcomes in recurrent glioblastoma patients participating in clinical trials compared to trial-eligible patients treated outside of a trial.

METHODS
We reviewed 378 adult IDH-wild-type glioblastoma patients treated for first recurrence at our institution 2014-2020. We retrospectively evaluated patients for clinical trial eligibility based upon review of performance status, laboratory values (e.g. comprehensive metabolic panel, complete blood count), and other common eligibility criteria. Overall survival was defined as time from date of first recurrence to death. Cox proportional hazards modeling were used to evaluate outcomes of trial eligible patients compared to patients who received treatment on a clinical trial.

RESULTS
Among 378 patients, 171 patients (47%) enrolled onto a trial at first recurrence. Amongst 207 non-trial patients, 65 patients were excluded due to ineligibility or missing data. The primary reasons for trial ineligibility was known additional malignancy, thrombocytopenia, KPS &lt; 60, active autoimmune disease, and presence of diffuse leptomeningeal disease. There were 142 (69%) patients deemed trial-eligible per our retrospective screening. In trial-eligible non-trial and trial participants (N=313), trial participation was associated with improved survival (Adjusted-HR 0.58, 95%CI 0.43-0.77, p&lt; 0.001) after adjustment for age (HR 1.02, 95%CI:1.01-1.03, p=0.01), MGMT promoter methylation (HR 0.64, 95%CI:0.47-0.88, p=0.008), KPS at first recurrence (HR 0.99, 95%CI:0.97-1.00, p=0.02), time to first recurrence (HR 1.00, 95%CI:0.999-1.00, p=0.07), surgery at first recurrence (HR 0.96, 95%CI:0.72-1.27, p=0.77), standard 6 weeks radiation upfront (HR 0.47, 95%CI:0.25-0.87, p=0.02), and concurrent temozolomide use upfront (HR 0.71, 95%CI:0.43-1.15, p=0.18).

CONCLUSION
The most common reasons for clinical trial ineligibility in our cohort was additional malignancy, thrombocytopenia and poor performance status. In a single institution recurrent glioblastoma cohort, trial participation was associated with improved survival after adjustment of clinical covariates in this cohort.
INNV-24. MACHINE LEARNING-BASED SPECTROSCOPIC TISSUE DIFFERENTIATION IN FLUORESCENCE-GUIDED NEUROSURGERY
Authors: Black David , Byrne Declan , Walke Anna , Liu Sidong , Ieva Antonio Di , Stummer Walter , Salcudean Tim , Molina Eric Suero 
Published: November 2023

Abstract
Maximal resection of malignant gliomas is hindered by difficulty in distinguishing tumor margins. Fluorescence-guided resection with 5-ALA assists in reaching this goal. Previously, we characterized five fluorophore emissions that accurately represent any spectrum measured from human brain tumor biopsies with a wide-field hyperspectral device. In this study, the effectiveness of these five spectra was explored for different tumor classification tasks in 891 hyperspectral widefield measurements of 184 patients harboring low- (n=30) and high-grade gliomas (n=115), non-glial primary brain tumors (n=19), radiation necrosis (n=2), miscellaneous (n=10) and metastases (n=8), which corresponds to up to 15000 spectra for a given test. The statistical differences in fluorophore abundances between classes were determined and visualized using dimensionality reduction techniques, including principal component analysis (PCA) and t-distributed stochastic neighbor embedding (t-SNE). Three machine-learning models were trained to classify tumor type (12 classes), grade (3 classes), and glioma margins (3 classes). Five algorithms were tested with varying hyperparameters for each classification task. We explored whether PCA projection onto five different axes than fluorophore abundances can provide more information for visualization and classification. The abundances of the five a priori fluorophore spectra matched or outperformed the five optimal PCA components for all classification tasks. These five axes capture 96-99% of the variance in the dataset. Using random forests and multilayer perceptrons, the classifiers achieved average test accuracies of 74-82%, 79%, and 81%, respectively. All five fluorophore abundances varied between tumor margin type as well as between grades (p &lt; 0.01). For tissue type, at least four of five fluorophore abundances were found to be significantly different (p &lt; 0.01) between all classes. These results demonstrate the differing contribution of fluorophores in different tissue classes tissue, as well as the five fluorophores value as potential optical biomarkers, opening new opportunities for intraoperative classification systems in fluorescence-guided neurosurgery.
INNV-28. SCIENTIFIC LITERACY AND DECISION-MAKING OF PATIENT FAMILIES IN PEDIATRIC NEURO-ONCOLOGY
Authors: Lyons Nicole , Ward Lisa 
Published: November 2023

Abstract
Pediatric neuro-oncology, especially when treating typically terminal tumors such as DIPG, exists in a fluid, complicated state. There exists no standard, effective, and tolerable treatment. This means all patients are on clinical trials for treatment, placing the child’s care on the cutting edge of an already complicated field of research. A concern frequently brought up by parents is the struggle to understand scientific articles about their child's condition. Without a solid foundational understanding of molecular biology, the majority of their time reading research is spent googling terms only scientists are familiar with. A survey of 40 questions was developed and disseminated amongst families of children diagnosed with DIPG/DMG via email, with 64 participants The intent was to investigate what level of relevant scientific literacy the average parent had at diagnosis, during decisions on treatment, and where it is currently. RESULTS: showed at the time of diagnosis, 89.4% of families had never heard of Diffuse Intrinsic Pontine Glioma, let alone understood its mechanisms and treatment options. There is existing patient education, but current education does not go into the level of scientific detail needed. The result shows that 86.5% of families are spending at least 10 hours each week researching conditions outside of doctor appointments. At the time of diagnosis, 84.4% of families have little to no familiarity with clinical trials at all, yet 61.4% of those families are making decisions on participation under a month from diagnosis. The decisions families make impact patients’ quality of life, the development of effective and safe treatments, and if their child passes, their grieving. A better understanding of disease and treatment has been consistently shown to result in better outcomes by a variety of measures. Patient education focused on scientific literacy is desperately needed to match families' decision-making needs.
INNV-31. ADOPTING TUMOR TREATING FIELDS (TTFIELDS) THERAPY FOR GLIOBLASTOMA AND OTHER SOLID CANCERS: CHALLENGES AND OPPORTUNITIES
Authors: Lustgarten Leonardo , Tatsui Claudio , Williams Matthew , Sengupta Soma , Wong Eric 
Published: November 2023

Abstract
Tumor Treating Fields (TTFields) are alternating electric fields generated by a wearable medical device (NovoTTF-200A), delivered to the tumor target by arrays placed on the skin. These fields have multiple biological effects on tumor cells, including mitotic disruption, dysregulated DNA repair, antimigratory effects, and stimulation of antitumor immune response. TTFields therapy was approved for recurrent and newly diagnosed glioblastoma, based on the randomized, pivotal EF-11 and EF-14 studies, respectively. Data from both studies demonstrated favorable outcomes, sustained quality of life, and tolerable safety profile. Side effects are limited to mostly manageable, mild to moderate skin reactions with no increased systemic toxicity. TTFields therapy is also approved for pleural mesothelioma and has met the primary endpoint in the pivotal LUNAR study for metastatic non-small cell lung cancer patients. Despite extensive preclinical data, positive clinical study outcomes, and favorable real-world evidence, adoption of TTFields therapy remains tepid. Here we discuss potential causes and possible solutions to treatment barriers. Based on extensive surveys in the field, we have identified several potential reasons. The first challenge is the perception that open-label studies are less rigorous since sham devices are not used per protocol. The purpose of sham treatments in trials is to minimize placebo effects and/or investigator bias, but RANO criteria is designed to guard against just that. Secondly, dissemination of knowledge underlying innovative therapies often takes time. Unlike chemotherapy and radiotherapy, the mechanistic aspects of TTFields are not typically included in oncology training. Lastly, the benefits of TTFields therapy may be difficult to appreciate due to the required chronic use during maintenance. Therefore, education, additional bench research, and future clinical studies are important for a better adoption of this increasingly important oncological option.