bluuebunny/crossref_metadata_2025_split huggingface dataset:
P10.19.A MACHINE LEARNING-BASED PREDICTION OF INPATIENT CARE COSTS FOR PATIENTS WITH BRAIN METASTASES: A REAL-WORLD ANALYSIS
Authors: Ozair A , Mukherjee D 
Published: October 2024

Abstract

BACKGROUND
Brain metastases (BMs) represent a significant cause of cancer-related morbidity and mortality. While BM-related healthcare costs have been previously described, predictive analytics based on recent data, particularly for inpatient care, remain unavailable. This study sought to evaluate inpatient care costs (IPCCs) of patients with BMs and perform predictive modelling through supervised machine learning (sML) using a contemporary, commercial claims database.

MATERIAL AND METHODS
This retrospective study, reported following STROBE and TRIPOD+AI reporting guidelines, included adult patients (aged 18-65 years) in the United States (US) with BMs included in the MarketScan Commercial Claims and Encounters Database who received inpatient care during January 2016 to December 2021. Eligible patients were identified using ICD-10 codes. IPCC measures were adjusted using the Medical Care component of the 2023 Consumer Price Index. Primary study outcome was total IPCC, represented by adjusted gross total payments. After log-transformation performed due to data skew, sML was carried out using Random Forest algorithm with 1000 iterations with a 70:30 training-test data split, followed by residual analysis and evaluation of predictive performance using root-mean-squared error (RMSE), out-of-bag error (OOBE), and calibration curve. Multivariable linear regression (MLR) modelling was carried out for sensitivity analyses.

RESULTS
A total of 25117 unique admissions across 13477 BM patients were included, with median (IQR) age of 57 years (51-61). Gross median (IQR) CPI-medical-care-adjusted values per admission were: total payments $28,119.51 (16847.45-55111.67); hospital payments $24,678.74 (14601.66-47864.84); and payments to principal physician $884.80 (441.07-2434.15), being 3.6% (IQR 1.9-6.8) of total payment. Median inpatient length of stay was 4 days (IQR 2-8). The ML model had an OOBE of 0.61 and, using test data, an RMSE of 0.85, indicating robust performance.

CONCLUSION
Contemporary IPCCs for BM patients in the US are substantial but driven minimally by payments to principal physician for services rendered. sML may be utilized to successfully predict IPCC for patients with BMs.
P11.04.A FAILURE TO PREDICT FUNCTION FROM STRUCTURE IN GLIOMA PATIENTS: LESSONS FROM TRANSLATING NEUROSCIENCE METHODS TO A CLINICAL POPULATION
Authors: Smolders L , De Baene W , van der Hofstad R , Florack L , Rutten G 
Published: October 2024

Abstract

BACKGROUND
Predicting function from structure is central to optimizing the onco-functional balance in neurosurgical planning: if we can predict changes in function due to changes in structure, we may be able to predict the functional outcomes of surgery. In recent years, this challenge has been formulated in terms of predicting Functional Connectivity (FC) from Structural Connectivity (SC), both derived from advanced MRI. Several recent studies claim high individual-level accuracy in predicting FC from SC on healthy subjects. We investigated whether these approaches could be extended to the prediction of FC from SC in glioma patients.

MATERIAL AND METHODS
Three recent studies with promising results were considered for adaptation. To ensure correct implementation, we reproduced their methods on 1000 healthy subjects of the Human Connectome Project (HCP), a data set used in all three studies. We also retrospectively included 242 glioma patients from the Elisabeth-TweeSteden hospital (Tilburg, The Netherlands) to investigate if the studies’ methods could be translated to this population. SC was derived from tractography on diffusion-weighted MRI, while FC was derived from resting-state functional MRI. Performance was calculated as the average individual-level correlation between FC predicted from SC and FC derived from fMRI, and assessed with 10-fold cross-validation, using 90% of the data for training and 10% for validation. To compare performance on the two different data sets in a meaningful way, we constructed a baseline predictor that calculates the group average fMRI-derived FC of the training set and uses this single matrix as predictor for the validation set.

RESULTS
We replicated the prediction performance of 0.71 reported by the first of the three studies using HCP data. On the glioma patient data, we achieved a performance of 0.43. However, we found that for both data sets, the group average predictor outperformed the prediction model presented by the study, achieving a performance of 0.84 and 0.56 respectively. Subsequently, we found that the group average predictor matched the prediction performance reported by the other two studies.

CONCLUSION
None of the three studies improved upon the basic group average predictor, indicating that none of the predictive models represent a meaningful individual mapping from SC to FC. We consider it likely that the construction of SC or FC is currently not accurate enough at individual level to capture meaningful variation in individuals, either due to excessive noise in resting-state fMRI or due to inadequate accuracy in individual-level parcellations. In conclusion, a failure of promising methods to work on clinical populations may not be caused by population-specific difficulties, but by subtle problems with the methods themselves, only revealed upon careful scrutiny of the implications of the presented quantitative results.
P11.08.A RESECTION OF GLIOMA FROM CLASSIC BROCA’S AREA IS FEASIBLE DUE TO PERITUMORAL AND DISTANT FUNCTIONAL LANGUAGE REORGANIZATION
Authors: Rutten G , Verheul J , Brouwers B , De Baene W 
Published: October 2024

Abstract

BACKGROUND
Historically, Broca’s area has been assigned a critical role in motor language functions. Although there has never been consensus about its precise anatomical definition, most experts consider the left pars triangularis and pars opercularis as the core of classic Broca’s area. Electrocortical mapping and functional MRI (fMRI) routinely find naming and speech sites in this region. However, case reports and small series have indicated that gliomas can often be resected from Broca’s area without new or permanent language deficits, suggesting that in these patients there is functional reorganization due to tumor growth. To test this hypothesis, we compared the organization of the language system in patients with a glioma that encompassed classic Broca’s area (‘Broca group’) to patients with a glioma outside of Broca’s area (‘non-Broca group’).

MATERIAL AND METHODS
We retrospectively selected 13 patients from a prospective dataset of consecutive glioma patients (2010-2024) that had infiltration of left pars triangularis (n=13) and pars opercularis (n=8). There was additional infiltration of the middle frontal gyrus (n=4), insula (n=4), superior temporal gyrus (n=1) or ventral premotor cortex (n=1). All of these Broca group patients were operated under awake conditions with electrical stimulation mapping to delineate motor and language areas. Standardized preoperative MR imaging for all glioma patients included a language fMRI.

RESULTS
Broca group patients had either an oligodendroglioma (7 low grade, 1 high grade) or astrocytoma (3 low grade, 2 high grade). Clinical debut was a seizure (n=10), mild language (n=1) or cognitive (n=2) deficits. In 4 patients there were mild clinical language deficits prior to surgery. In 11 patients there were temporary language deficits after surgery (4 due to seizures) that resolved over time to initial clinical performance. All Broca group patients had a language dominant left hemisphere as deducted from clinical symptomatology and intraoperative mapping results. In none of these patients, electrocortical mapping found functional (language) sites over the tumor part in the pars triangularis and pars opercularis, and these areas were consequently resected. fMRI language maps of Broca versus non-Broca patients (n=276) showed lower activation in ipsilesional inferior frontal gyrus but higher activation in contralesional inferior frontal gyrus.

CONCLUSION
Language is represented differently in patients with a glioma in Broca’s area as compared to non-Broca glioma patients. Peritumoral and distant functional reorganization likely explains why gross total resection in classic Broca’s area is feasible and safe.
P11.10.B THE SYNDROME OF THE SUPPLEMENTARY MOTOR AREA: CLINICAL COURSE AND PREDICTORS OF OUTCOME AFTER RESECTION OF PREMOTOR LESIONS
Authors: Teske N , Jung L B , Nöldeke J O , Weig T , Blobner J , Forbrig R , Tonn J , Kunz M , Thon N , Karschnia P 
Published: October 2024

Abstract

BACKGROUND
The syndrome of the supplementary motor area (SMA) frequently occurs after resection of lesions in the premotor cortex or its associated white matter tracts. Brain plasticity involving the interhemispheric connectivity including the contralateral SMA region might be crucially involved in the development of and recovery from SMA syndrome. We herein aimed to identify predictors of outcome by quantifying pre-operative structural alterations in the non-affected contralateral hemisphere.

METHODS
We retrospectively searched our institutional database for patients developing SMA syndrome after undergoing resection of lesions localized in the SMA region between 2013 and 2023. Clinical characteristics, imaging data, and neurological outcomes were collected. Structural network analysis was performed using the previously validated morphometric inverse divergence (MIND) network. MIND estimates a patient’s axonal connectivity and cortical cytoarchitectonics based upon the comparison of the patient’s MRI with a large cohort of more than 10,000 healthy controls.

RESULTS
We identified 27 patients with a mean age of 39.2 ± 17.7 years who developed SMA syndrome following resection of premotor lesions, including 13/27 patients (48.1%) who underwent tumor resection for primary brain tumors and 14/27 patients (51.9%) who underwent focal resection for intractable lesional epilepsy. Postoperative SMA syndrome was most characterized by contralateral upper extremity hemiparesis (19/27 patients, 70.4%) and aphasia in case dominant hemisphere involvement (13/13 patients, 100%). Patients with a primary brain tumor had generally more severe symptoms, and were less likely to fully recover from SMA syndrome after 7 days compared to epilepsy patients (full recovery: 2/13 [15.4%] versus 9/14 [64.3%] patients, p = 0.018). At last follow-up after a median time of 5 months (IR 3-16 months), most patients (23/27, 85.2%) experienced a full recovery of SMA syndrome, with no difference between patients with tumors or epilepsy (p = 0.999). Preoperative contralateral intra-hemispheric connectivity was similar between patients receiving tumor or focal resection (0.183 vs 0.177, p = 0.295). However, imaging analyses point towards baseline affection of the SMA connectivity network in patients with brain tumors as characterized by reduced cortical thickness of the contralateral frontal lobe and the cingulate gyrus compared to epilepsy patients.

CONCLUSION
While full recovery from SMA syndrome is common, SMA syndrome is frequently less severe and more transient in patients with epilepsy. This might be due to more severe affection of contralateral SMA network in tumor patients due to the infiltrative nature of the disease. Imaging analyses might assist in identifying network affections at baseline to guide informed discussions with patients and caregivers.
P12.06.A DESCRIPTIVE AND FUNCTIONAL ASSESSMENT OF MHC I-BOUND PEPTIDES PRESENTED ON EXTRACELLULAR VESICLES OF GLIOBLASTOMA CANCER CELLS IN RESPONSE TO ONCOLYTIC VIRUS IMMUNOTHERAPY
Authors: Bronisz A , Kiel K , Balakrishnan A , Przybylski M , Chiocca E , Godlewski J 
Published: October 2024

Abstract

BACKGROUND
Immunopeptide-based therapies offer the potential for cancer care breakthroughs, necessitating effective mass spectrometry utilization in preclinical research. Despite advancements in identifying cancer-specific antigens, personalized medicine faces challenges due to antigen scarcity, demanding heightened detection sensitivity. Additionally, limited patient tissue availability requires expanding antigen-presenting material through cell culture techniques.

MATERIAL AND METHODS
Disparate treatment responses are challenging for heterogeneous glioblastoma. Integrating next-gen sequencing and ex vivo patient stem-like cell (GSC) culture, our model mirrors disease heterogeneity and patient-specific responses to HSV1 oncolytic virus (OV) immunotherapy currently under clinical trials for glioblastoma patients. We developed a high-throughput assay using GSCs and immune cells to identify MHC I receptor-bound immunopeptides as response effectors utilizing 27 immune response markers-based flow cytometry.

RESULTS
GSCs (n=6), infected ex vivo with OV (after 12h at MOI=0.1), yielded EVs via ultracentrifugation. Global proteomic profiling mass spectrometry of EV detected 5,203 proteins, with TAP1, a pivotal player in loading viral peptide antigens onto MHC class I, as the most EV-enriched protein post-OV infection. MHC I was significantly enriched in EV, covering up to 0.1% of all EV proteins, allowing the detection of 2,276 MHC I-bound immunopeptides (out of a total of 45,963 peptides detected). Functional analysis of EVs’ immunological properties via ex vivo PBMC activation assays revealed OV-deregulated EV secretome, with upregulated proteins associated with immune response activation leading to increased activity of NK cells, DCs, NKTs, and CD8+ T cells subpopulations. The effect was diminished by MHC I antibody neutralization.

CONCLUSIONS
Designed a high-throughput immune phenotype assay, employing a training cohort of GSCs and immune cells as donors and recipients, respectively, pinpointed MHC I receptor-bound immunopeptides and TAP1 overexpressed in response to OV infection as mechanistic effectors of the immune response. Methodological innovation of zooming on EV fraction instead of whole cell material allowed us to bypass the limitations of antigen and patient material scarcity by offering a higher MHC I presenting surface in the material devoid of bulky cellular protein complexes. EV-MHC immunoprecipitation proteomic approach thus correlates personalized clinical interventions with prognostic therapy-outcome assays, stratifying patients for new immunotherapeutic regimens. Supported by National Science Centre Poland grants: 2021/41/N/NZ6/02682 (K.K.), 2022/45/B/NZ5/04226 (A.B.), 2020/39/B/NZ5/02893, 2021/41/B/NZ6/02436 (J.G.), and the National Agency for Academic Exchange grant: PPN/PPO/2019/1/00001 (J.G.).
P12.07.A DEVELOPING NOVEL, MORE STRINGENT EVALUATION PLATFORMS TO ACCELERATE RESEARCH TRANSLATION AND INCREASE SURVIVAL FROM BRAIN CANCER
Authors: Chen Y , Bax S , Prior V , Hsu K , Kramer B , Goodhand T , MacLeod J , McCowage G , Gore S , Gowrishankar K , O’Neill G 
Published: October 2024

Abstract

BACKGROUND
The high grade gliomas (HGG) are a collection of lethal brain tumours. Currently available therapies are unsuccessful and patient survival rates have not significantly improved over the last ~ 50 years. Preclinical models currently in use poorly predict subsequent activity in phase I trials and over-estimate anti-tumour activity in HGG. Fundamental research from many labs, including our own, has shown that the normal tissue environment controls cancer invasion, signalling and response to therapy. Yet most preclinical assays lack this vital element. We have developed a brain-organoid co-culture model to test potential Chimeric Antigen Receptor (CAR) T-cell therapies for brain cancer.

METHODS
We grew stem-cell generated cortical brain organoids derived from human embryonic stem cells (hESCs) using a directed organoid protocol to ensure uniform organoid generation. Organoids were then combined with spheroids of HGG cells that were transduced with lentiviral vector to express luciferase. Tumour cell viability was assessed by xCelligence electrical impedance assay or by IVIS Lumina imaging of luciferase activity in 3D cultures. Cytokine-mediated T-cell killing was confirmed by ELISA.

RESULTS
We evaluated Ephrin receptor A2 (EphA2)-directed CAR T cells in EphA2-positive HGG, comparing response in target cells grown in 2D monolayers, as 3D spheroids and as 3D spheroids co-cultured with cortical brain organoids. Critically, we show that CAR T cell efficacy reduces with increasing model complexity.

CONCLUSION
Thus the inclusion of the normal tissue in the form of the organoid modulates therapy response, and the co-cultures provide an important platform for evaluating novel therapies for brain cancer. The use of such biomimetic models may not only provide a more realistic reflection of in vivo responses but also increase successful transition of treatments to patients.
P12.08.B DUAL-CAR T CELLS AGAINST NKG2D LIGANDS AND VEGFR2 ACCUMULATE IN ORTHOTOPICALLY IMPLANTED GLIOMA AND PROLONG SURVIVAL OF IMMUNOCOMPETENT GLIOMA-BEARING MICE
Authors: Mastall M , Dunkel G , Weiss T , Okada N , Weigelin B , Weller M , Roth P 
Published: October 2024

Abstract

BACKGROUND
Glioblastoma is the most common malignant brain tumor with a devastating outcome. Novel therapeutic strategies are currently explored including the use of chimeric antigen receptor (CAR) T cells. However, in glioblastoma an impaired tumor infiltration by CAR T cells, antigen heterogeneity and an immunosuppressive tumor microenvironment remain significant obstacles. NK group 2D (NKG2D)-CAR T cells efficiently lyse glioma cells and confer a survival benefit of glioma-bearing immunocompetent mice upon intratumoral administration. This effect is less prominent after intravenous injection, suggesting an insufficient trafficking of CAR T cells into the tumor. Vascular endothelial growth factor receptor 2 (VEGFR2)-CAR T cells were shown to accumulate in murine glioma upon intravenous administration and to have anti-glioma and anti-angiogenic activity. However, VEGFR2 expression in glioblastoma is heterogenous. Here, we generated Dual-CAR T cells targeting VEGFR2 and NKG2D ligands.

METHODS
Murine VEGFR2, NKG2D, Mock or Dual-CAR T were generated by retroviral transduction. In vitro, their activity was explored in co-culture assays. Glioma cells were orthotopically implanted into brains of immunocompetent mice and the infiltration of intravenously administered CAR T cells was assessed by in vivo fluorescence molecular tomography (FMT), ex vivo flow cytometry as well as 3D light-sheet microscopy (3D-LSFM).

RESULTS
Co-culture experiments demonstrated increased lysis of glioma cells by Dual-CAR T cells compared to VEGFR2-CAR T cells. By ex vivo 3D-FLSM, we observed substantial trafficking of systemically administered VEGFR2-CAR T cell into gliomas in vivo. In two different glioma models, FMT imaging as well as ex vivo flow cytometry revealed that Dual-CAR T cells accumulated to a similar extent at the tumor site as VEGFR2-CAR T cells and around 10-fold more Dual-CAR T cells were detected compared to CAR T cells expressing the NKG2D-CAR alone. Finally, Dual-CAR T cell treatment resulted in reduced growth of orthotopically growing gliomas and significantly prolonged the survival of glioma-bearing mice compared to Mock or NKG2D-CAR or VEGFR2-CAR T cell treatment.

CONCLUSION
Recent advances in CAR T cell optimization are mostly focused on CAR design, CAR generation and improving metabolic fitness, while improvements in CAR T cell trafficking are limited. VEGFR2-CAR T cells exhibited enhanced infiltration into the tumor site in the brain and arming of VEGFR2-CAR T cells with a NKG2D-CAR resulted in prolonged survival of glioma-bearing mice. Therefore, Dual-CAR T cells offer a versatile approach for the treatment of glioblastoma addressing two main hindrances, tumor infiltration and antigen heterogeneity.
P12.18.A UNRAVELLING THE ACUTE, CHRONIC AND STEROID-REFRACTORY MANAGEMENT OF HIGH GRADE NEUROLOGICAL IMMUNE RELATED ADVERSE EVENTS: OUR EXPERIENCE AND LITERATURE FINDINGS
Authors: Malvaso A , Giglio P , Diamanti L , Gastaldi M , Bini P , Marchioni E 
Published: October 2024

Abstract

BACKGROUND
Neurological immune-related adverse events (n-irAEs) are rare side effects of immune-checkpoint inhibitors (ICI). Their incidence is rising in tandem with the expansion of ICI oncological indications. N-irAEs are often severe, carrying a considerable risk of mortality and long-term disability. To date, strong scientific data is lacking to support the management of high-grade n-irAEs. We aim to present an updated depiction of the most documented and well-characterized therapies of high-grade n-irAEs with a particular focus on steroid-resistant clinical forms.

MATERIAL AND METHODS
A systematic literature search in PubMed, Scopus, Embase, and Google Scholar until January 31 2024 was performed, according to PRISMA guidelines. A total of 81 studies were included at least reporting the following details: (I) type of tumor, (II) ICI type, (III) the course of treatment, and (IV) the outcome. High-grade n-irAEs recent management guidelines were compared to real-life clinical settings. The frequency, clinical course and outcome were summarized through qualitative and quantitative analysis using GraphPad Prism Software.

RESULTS
We found a few poorly characterized cases of steroid-resistant n-irAEs and only aggregated data were usually available. The median time to onset of high-grade n-irAEs was 4 weeks (range:1-64 weeks) for both general and steroid-resistant clinical forms. Significant correlations were found between the high-grade n-irAEs phenotype, type of cancer and ICIs administered. Transverse myelitis represents the principal clinical phenotype associated with a higher steroid resistance rate (14-40%), followed by cranial neuropathies (23%) and CNS demyelinating disorders (4-13%). Nivolumab and Pembrolizumab were the ICIs associated most frequently with steroid-resistant irAEs (80-90%, p&lt;0.01). In case of unresponsiveness to glucocorticoids, intravenously immunoglobulins (IVIg) is the most effective treatment followed by plasma exchange (PLEX) (p&lt;0.01), although a proportion of high-grade CNS/PNS n-irAEs require additional immunosuppressants, such as Mycophenolate and/or Rituximab.

CONCLUSION
High-grade n-irAEs generally show clinical improvement following steroids-only therapy and after association therapy. We suggest that the estimated frequency of high-grade steroid-resistant n-irAEs should not be underestimated. Steroid-resistant n-irAEs mostly demonstrate clinical improvement after IVIg or PLEX therapy. Decisions about treatment should be made by a multidisciplinary board that includes the neurologist and oncologist. However, more standardized studies are needed in order to early detect and promptly treat these life-threatening conditions.