bluuebunny/crossref_metadata_2025 huggingface dataset:
P10.13.A DEMOCRATIZING QUALITY: A STRATEGY TO MAKE LEVEL OF EVIDENCE ASSESSMENTS QUICK, EASY, AND ACCESSIBLE TO ALL
Authors: Badani A , Grzyb C , Church E W , Glantz M
Published: October 2024

BACKGROUND

Advances in clinical care depend decisively on evidence from high-quality clinical trials. EANO and other international societies have established systematic and transparent methodologies for assessing the quality of clinical trials, but the process is time-consuming and challenging to master. Using advanced computational strategies, we have developed three novel models—an Excel-based calculator, a machine learning (ML) model, and a permutation-based decision tree—designed to facilitate this assessment and make it easily accessible to clinicians and researchers.

METHODS AND MATERIALS

A PRISMA-compliant literature review was conducted to identify all therapeutic human trials involving adult neuro-oncology patients published in the last 12 months in high-impact journals. Articles fulfilling pre-specified inclusion and exclusion criteria were selected and a level of evidence was assigned independently by two investigators, with differences resolved by consensus. Simultaneously, an advanced ML model was created, employing a Support Vector Machine (SVM) algorithm renowned for its efficacy in classification tasks. The SVM model was configured with a 0.2 train-test split to validate its predictive accuracy and recursive feature elimination to evaluate the significance of input features, confirming their equal importance. Additionally, a permutation-based decision tree was developed, where a collaborative team analyzed all possible permutations of questionnaire responses to assign explicit quality ratings through a data-driven decision framework. Finally, an Excel-based tool was developed to calculate the level of evidence. The results of all four assessment strategies were statistically compared.

RESULTS

The ML model was developed and trained on a dataset of 225 categorized research papers and achieved a classification accuracy of 97%. The permutation-based decision tree tool was designed to map all possible questionnaire response permutations to specific trial quality levels, with 11,521 independently graded permutation response pathways. The Excel-based tool was programmed to use a phrase-matching algorithm to identify an evidence level based on a user’s provided answers. The permutation and Excel-based strategies provided excellent classification accuracy but were inferior to the ML model. As we will demonstrate, all three models were easy to use and provided rapid and reliable levels of evidence assessments.

CONCLUSION

By providing open access to these tools to clinicians and researchers and making the level of evidence assessments efficient, consistent, and transparent, we hope to democratize the ability to evaluate published trials, thereby improving the quality of clinical care. We also hope that clinical researchers will utilize these tools to enhance the quality of their clinical trials at the design stage.
P10.17.B IMPACT OF INTENSITY STANDARDISATION AND COMBAT BATCH SIZE VARIATION ON COMBINED CLINICAL AND RADIOMICS PROGNOSTIC MODELS IN PATIENTS WITH UNIFOCAL GLIOBLASTOMA
Authors: Fatania K , Frood R , Mistry H , Short S C , O’Connor J , Scarsbrook A F , Currie S
Published: October 2024

BACKGROUND

Prognostic models for patients with glioblastoma (GBM) may include quantitative image features extracted from MRI (‘radiomics’). Multicentre image acquisition poses a challenge to radiomic feature (RF) reproducibility and MRI intensity standardisation techniques (ISTs) and ComBat may help. Optimal IST and minimum batch size (MBS) for ComBat are uncertain - the latter especially with real-world datasets where few patients are scanned at each site. Our aim was to assess the effect of three popular ISTs in conjunction with varying MBS on prognostic model performance and stability in a real-world, multi-centre GBM patient cohort.

MATERIAL AND METHODS

Patients with IDH-wildtype unifocal WHO grade 4 GBM and pre-operative MRI acquired across multiple geographic locations in the region between 2014-2020 were retrospectively included. Tumours were segmented using deep-learning with manual correction. WhiteStripe (WS), Nyul histogram matching (HM) and Z-score (ZS) ISTs were applied before RF extraction. Post-extraction, RFs were realigned using ComBat using MBS of 5, 10 or 15. Cox proportional hazards models were produced using five strategies to select the four best performing RFs, and the impact of IST and MBS was evaluated with bootstrapping (1,000 repetitions), and measuring model calibration, discrimination, relative explained variation and model fit. Model instability was assessed using bootstrap resampling to produce 95% confidence intervals (95% CIs), feature instability tables and calibration instability plots.

RESULTS

195 patients were included with median overall survival of 13 months (95% CI 12-14). Increasing the ComBat MBS reduced the sample size available for modelling (195, MBS=5; 159 MBS=10; 129 MBS = 15). HM and WS tended to produce the highest relative increase in model discrimination, explained variation and model fit but IST choice did not influence model stability or calibration. Increasing the ComBat MBS improved model discrimination, relative explained variance and model fit, however it degraded model stability and calibration accuracy. Calibration instability plots showed a greater spread of calibration curves across the bootstrap resamples as the ComBat MBS increased (and sample size reduced), indicating worse calibration accuracy and stability.

CONCLUSION

IST and ComBat MBS had varied effects. Increased ComBat MBS (and reduced sample size) improved most performance metrics but stability and calibration deteriorated. HM and WS tended to increase most model performance metrics and did not negatively influence stability. Our real-world, multi-centre data showed that while ComBat may improve multi-centre radiomics models, it requires data to be excluded, with negative results for sample size and stability and unknown consequences for patients imaged in smaller centres.
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

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

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

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

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

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

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

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

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<0.01). In case of unresponsiveness to glucocorticoids, intravenously immunoglobulins (IVIg) is the most effective treatment followed by plasma exchange (PLEX) (p<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.
P12.20.B [18F]FDG PET/CT BRAIN SCAN IN THE EVALUATION OF NEUROTOXICITY IN PATIENTS WITH DIFFUSE LARGE B-CELL LYMPHOMA TREATED WITH CAR-T
Authors: Asadurova S , Lorenzo C , Simó M , Ariño H , Vilaseca A , Zabalza A , Iacoboni G , Carpio C , Barba P
Published: October 2024

BACKGROUND

Neurotoxicity is one of the serious and life-threatening complications of CAR-T treatment in patients with diffuse large B-cell lymphoma. Our objective is to identify the findings in brain PET/CT, their evolution over time, and their clinical correlation. We also aim to compare the sensitivity of PET/CT with magnetic resonance imaging (MRI).

MATERIAL AND METHODS

This prospective study includes 33 patients with diffuse large B-cell lymphoma treated with CAR-T therapy. Whole-body and brain [18F]FDG PET/CT scans were performed pre-treatment and 30 days post-therapy. In cases of suspected immune effector cell-associated neurotoxicity syndrome (ICANS), urgent structural imaging (CT or MRI) and [18F]FDG PET/CT brain scans were conducted, among other tests.

RESULTS

The mean age was 62±12 years, with a male-to-female ratio of 19:14. 70% of patients (23/33) developed grade 1, 2, or 3 cytokine release syndrome (CRS). 27% (9/33), all with prior CRS, showed symptoms of ICANS (3/9 G1, 3/9 G2 and 3/9 G3 ICANS). The most common symptoms were tremor, disorientation, and bradypsychia, starting on average on the 7th day post-infusion (range 1 to 10). Urgent [18F]FDG PET/CT brain scans were performed on 7 of the 9 ICANS patients, showing diffuse cortical hypometabolism compatible with encephalopathy in 5 (5/7) and no significant findings in 2/7. At the 30-day post-treatment evaluation, complete normalization was observed in 2/5 patients, improvement with persistent mild global cortical hypometabolism in 2/5, and one patient (1/5) died before the 30 days (with G3 ICANS and severe cortical and subcortical hypometabolism on PET imaging). Urgent brain MRI was performed on the 7 patients with ICANS and urgent [18F]FDG PET brain scans, and it was normal in 5/7 and pathological in 2/7 (both with grade 3 ICANS).

CONCLUSION

[18F]FDG PET/CT brain scan is useful for the diagnosis and follow-up of patients with CAR-T related neurotoxicity (ICANS) and shows greater sensitivity than MRI. Future studies should determine the relationship between acute phase PET findings and long-term prognosis.
P13.02.A A CLINICALLY RELEVANT IN VIVO MODEL RECAPITULATES THE LATE EFFECTS OF RADIOTHERAPY IN CHILDHOOD MEDULLOBLASTOMA SURVIVORS
Authors: Egnuni T , Castle J , Shaw G , Weller D , Fielder E , Singh M , Skinner R , von Zglinicki T , Clifford S , Miwa S , Hicks D , Short S C
Published: October 2024

BACKGROUND

Medulloblastoma (MB) is the most common malignant brain tumour in children, with a 5-year survival rate of up to 80%. However, survival is often accompanied by debilitating late-effects that occur as a result of the cranial-radiotherapy. Survivors typically experience increased frailty, reduced physical functioning and impaired neurocognitive functioning. Here, we describe a clinically relevant in vivo model that recapitulates age-equivalent MB radiotherapy dose, and the resulting late-effect profile with potential for future intervention studies.

MATERIAL AND METHODS

Thirty-six male C57BL/6J juvenile mice at 35 postnatal days (PND) were randomly allocated into 3 equal groups (G1-G3). G1 mice received sham treatment; G2 mice received 10 fractions of 3Gy whole brain cranial-radiotherapy (CRT; human-equivalent of 37.5Gy EQD2) and G3 mice received CRT with 3x 3Gy of posterior fossa boost (PFB) in addition (48.75Gy EQD2). The Small Animal Radiation Research Platform (SARRP) was used to deliver radiation using a 10mm x 10mm collimator with gantry running from - 60° to 60°. Frailty, physical functioning and neurocognitive impairment were longitudinally assessed using frailty index (FI), grip strength test, rotarod test, Y-maze and Barnes maze up to PND394.

RESULTS

No mice died from acute radiation toxicity and there was no significant difference in either survival or body weight loss among all treatment groups. There was no significant difference between G2 and G3 mice in most of the assessments, suggesting receipt of PFB caused no additional deficits. Assessment of frailty showed significantly higher FI in mice that received CRT at PND97 (p=0.001), PND130 (p=0.0001), PND191 (p=0.007) and PND233 (p=0.002) compared to the sham group. CRT treated mice had significantly reduced grip strength at PND233 (p=0.006; grip strength test) and poor body balance and co-ordination at PND172 (p=0.003; rotarod). Assessment of working memory using the Y-maze showed a significant memory deficit in CRT group at PND266 compared to sham treated group (p=0.009). Barnes-maze short-term memory (STM) and long-term memory (LTM) assessment at 24 hours and 7 days after training, respectively, showed significantly decreased LTM (p=0.029) but not STM (p=0.392) in CRT treated group compared to sham treated mice.

CONCLUSION

Our in vivo model showed that juvenile mice tolerated high doses of CRT. We demonstrated increased frailty, physical and neurocognitive impairments that coincides with the late-effect profile observed in CRT treated childhood MB survivors. Importantly, this clinically relevant in vivo model provides a baseline model for the future appraisal of interventions to alleviate the late-effects experienced by childhood MB survivors.
P13.05.B DYNAMICS OF POST-RADIOTHERAPY MORPHOLOGICAL CHANGES IN THE BRAIN
Authors: Turcas A , Tipcu A , Homorozeanu B , Cernea D , Turcas A , Leucuta D , Achimas-Cadariu P
Published: October 2024

BACKGROUND

Radiotherapy is essential in achieving local control for many brain tumours. However, it carries the risks of toxicities, including neuro-cognitive decline, with potential impact on quality of life. Several brain areas and structures are involved in cognition, but their radiosensitivity and clinical response to radiotherapy is not yet fully understood, and no dose-thresholds are yet established. We studied the dynamics of morphological changes on MRI imaging of 18 brain structures following radiotherapy and investigated predictive factors of their occurrence. Identifying such imaging biomarkers could help develop sparing strategies and improve treatment planning.

MATERIAL AND METHODS

We included 40 patients treated for gliomas in a tertiary cancer center between 2018-2022 and contoured a set of 18 structures on T1-MRI sequences acquired at 3, 6, 9 months, 1 and 2 years after treatment. Dosimetric data were extracted from dose-volume histograms of the delivered plan, and for each structure the baseline volume and volumes in dynamics were noted. Correlations were tested by calculating the Spearman coefficient (rho) and comparisons between different groups were made using the paired Wilcoxon test, with statistical significance for p<0.05

RESULTS

The mean age at diagnosis was 47 years. All patients underwent pre-radiotherapy surgical resection. Twenty tumors were left-sided, 18 on right-sided, 1 infratentorial and 1 on the midline. Radiotherapy regimens were normo-fractionated (1.8-2Gy/fr) in 67.5% of cases, and the rest were hypofractionated (>2.67Gy/fr). Most structures registered a slight increase in volume at 3 months, followed by a gradual decrease over the two-year follow-up A correlation was observed between the dynamics of Hippocampal and Putamen volumes with Dmean, with loss of 0.55% of Hippocampal volume with each additional 1 Gy added to Dmean (rho = -0.293, p = 0.054) and 0.45% decrease in Putamen volume for every additional 1 Gy for Dmean (rho = -0.373, p = 0.018). The magnitude of volumetric changes was not significantly associated with dose per fraction, patient age, or overall treatment time.

CONCLUSION

In our cohort of patients, we identified a particular pattern of post-irradiation volume dynamics in selected structures, with a slight increase in volume as an acute effect, followed by progressive, dose-dependent, late atrophy. Our results pave the way for further exploration and validation in subsequent studies, including prospective neurocognitive testing and correlation of dosimetric, volumetric and clinical data.
P13.06.A EVALUATION OF BBB PERMEABLE WEE1 AND CHK1 INHIBITORS IN COMBINATION WITH STANDARD OF CARE FOR THE TREATMENT OF GLIOBLASTOMA
Authors: Scholefield E L , Gomez-Roman N
Published: October 2024

BACKGROUND

Glioblastoma (GBM) is a highly aggressive intracranial malignancy of unmet clinical need. Current therapies such as temozolomide (TMZ) chemotherapy exert suboptimal efficacy, necessitating new therapies such as those targeting nuclear kinases, Wee1 and Chk1. Wee1 and Chk1 are master regulators of S phase and G2/M arrest ensuring DNA replication and genomic stability. Wee1 via inhibitory phosphorylation of CDK1 regulates the intra-S phase checkpoint and G2/M arrest, while Chk1 via Cdc25 inhibition controls mitotic entry and replication fork regulation in S phase. Previous studies combining commercially available Wee1 inhibitor AZD1775 and Chk1 inhibitor AZD7762 showed synergism in melanoma cells. However, a prerequisite of GBM therapies is blood-brain barrier (BBB) penetrance for drugs, thus we assessed synergism in combinations of TMZ with novel Wee1 and Chk1 inhibitors specifically developed for BBB penetrance to deduce their potential for use in GBM treatment.

MATERIAL AND METHODS

Primary patient-derived G7 GBM cells grown in stem-enriched conditions were used in medium-throughput ClonoScreen3D assays. 180 cells per well were seeded into Matrigel-coated 3D-Alvetex 96-well plates and incubated for 20 hours prior to drug treatment. Cells were incubated for 13 days before incubation with MTT reagent for manual colony quantification. Drugs tested were TMZ (0-3 µM); Chk1i-a (0-0.31 µM); Chk1i-b (0-0.31 µM); and Wee1i-a (0-0.31 µM) in a half-log serial dilution.

RESULTS

Treatment of G7 cells with Chk1i-b showed the highest single-agent activity (EC50=73 nM, confidence interval (CI)=0.677-0.774), followed by Chk1i-a (EC50 = 125 nM, CI=0.393-0.805) and TMZ (EC50=849 nM, CI=0.042-0.826) as assessed by clonogenic survival assay (CSA). TMZ+Chk1i-a showed the strongest synergism in combination in G7 cells (mean combination index score (CIS)=0.49), followed by Chk1i-a+Wee1i-a (mean CIS=0.52), and Chk1i-b+Wee1i-a (mean CIS=0.74). Wee1i-a+Chk1i-a caused the highest reduction in clonogenicity measured via CSA, while TMZ+Chk1i-a showed the strongest synergism in combination.

CONCLUSION

Our novel BBB-permeable Wee1 and Chk1 inhibitors show synergism inducing higher cell kill in patient-derived G7 GBM stem-like cells. Combinations will next be tested with radiation to deduce radiosensitisation effects. With synergism observed between novel BBB-penetrant Wee1 and Chk1 inhibitors, these drugs show potential in becoming viable new therapies for GBM treatment.
P13.09.B INVESTIGATING THE EFFECTS OF RADIATION FRACTION DOSES ON THE MOLECULAR BARRIER PERMEABILITY OF AN IN VITRO BLOOD-BRAIN BARRIER MODEL
Authors: Ozturk M , Caglar F , KOYLU M , KAMER S
Published: October 2024

BACKGROUND

Brain tumors and metastases are major causes of death. The blood-brain barrier (BBB) makes it difficult to treat these conditions as it prevents drugs from reaching the tumor. We aim to evaluate the BBB’s permeability changes caused by varying radiotherapy doses. This will help develop treatment strategies that can benefit from this impaired function.

MATERIAL AND METHODS

We used an in vitro model of BBB by seeding cells in a 24-well plate with a porous membrane-separated insert. Human umbilical vein endothelial cells (HUVEC) and human astrocyte cells (NHA) were used for seeding. Transendothelial electrical resistance (TEER) measurements verified the accuracy of the model. A device developed by the Department of Physics was used for TEER measurement. Radiation was delivered in single fractions of 2, 4, 6, 8, 16, and 25 Gy. After ionizing radiation, the cells were incubated with the TEER device for 72 hours, with measurements taken every two hours. In addition, glioblastoma (GBM) cell lines were seeded at the bottom of the 24-well plate where the insert was placed to assess drug dose efficiency, which can vary according to membrane permeability. Two different drugs were applied to the irradiated BBB model. Membrane permeability was determined by ELISA, MTT proliferation assay, and cell wound healing assay.

RESULTS

There was a significant decrease in TEER values in all dose groups after irradiation compared to the control group (p<0.001). No significant difference was found when fraction doses were evaluated (p=0.639). The most significant dose-independent decrease occurred between hours 2 and 6. It was noted that the change in the rate of resistance decline increased in direct proportion to the dose. Temozolomide (TMZ), used to evaluate the proliferation of GBM cell lines seeded on the bottom after irradiation, was effective on GBM cell proliferation, and the lowest dose for effective permeability was 4 Gy. In the cell wound healing experiment performed as an indicator of repopulation and repair capacity, it was observed that while bridging started in the early hours after irradiation in the TMZ-treated groups at low fraction doses, there was no wound closure at the end of 72 hours at high fraction doses. When the results of ELISA measurements made after the application of trastuzumab (TRAS), which is 750 times larger than TMZ, were evaluated, TRAS levels below 500 ng/ml were found at doses of 2, 4, and 6 Gy. TRAS levels of 1500 ng/ml were measured at doses of 8, 16, and 25 Gy.

CONCLUSION

Our study demonstrates that different doses of ionizing radiation combined with chemotherapy may increase tumor access to therapeutic agents and evaluates the time course of this relationship. We conclude that permeability through the BBB is related to molecular weight, which increases proportionally with increasing dose fraction.
P13.11.A OUTCOMES FOLLOWING CYBERKNIFE FOR VESTIBULAR SCHWANNOMA: THE ST. BARTHOLOMEW’S HOSPITAL EXPERIENCE
Authors: Christodoulou P , Hill T , de Luna P , Parasekevopoulos D , McFeely G , Dean C , Bowles S , Cook J , Rozati H , Plowman P N , Burton K , Rashed S , Pollock J , Shoakazemi A , Lewis R
Published: October 2024

BACKGROUND

Vestibular schwannomata (VS) represent <10% of brain tumours. Treatment strategies are surveillance, surgical resection, stereotactic radiosurgery (SRS) or fractionated stereotactic radiotherapy (SRT). Since 2019 SRS/SRT has been delivered with CyberKnife (CK) at Barts. After analysis of dosimetry and verification, the GTV to PTV margin was reduced from 1mm to 0mm, and dose prescribed to the 50% isodose for a single fraction, or 65% if fractionated, with the aim of maintaining tumour control rates whilst sparing additional toxicity. PRV to OARs remained 1mm in both groups.

MATERIAL AND METHODS

patients were treated with 1mm GTV to PTV expansion (Group 1) and the remaining 57 patients were treated without additional PTV margin (Group 2). Post-treatment imaging and clinic letters were reviewed to assess rates of tumour control and reported adverse events. Results of reducing the PTV margin were compared with previous practice and against the International Stereotactic Radiosurgery Society (ISRS) guidelines. Median follow-up was 32.5 months, range 9 - 56 months.

RESULTS

All patients in group 1 were treated with 21Gy in 3 fractions. 16 patients in Group 2 (24%) were treated with a single 12Gy fraction. The median dose was 21Gy in 3 fractions, with no patients treated over more than 5 fractions. Change in PTV prescription did not affect tumour control rate. At the point of reporting, tumour control was achieved in 64/66 patients. 1 patient from group 1 proceeded to microsurgical resection at 3 months. The second patient, from group 2, declined surgery and continues with close surveillance. The majority of patients experienced no side effects (38 patients). The most common acute toxicity was headache (33% in group 1 vs 26% group 2), reduced hearing (33% vs 16%) and facial/trigeminal nerve deficit (11% vs 9%). Of those who experienced acute toxicity, for 17 patients (45%) it persisted for greater than 12 weeks, equally distributed between facial/trigeminal nerve deficits, reduced hearing or dizziness. Persistent toxicity was more common in Group 1 (55% vs 21%). 2 patients required V-P shunt insertion after treatment (one from group 1 and one from group 2).

CONCLUSION

Given the limitations of our small retrospective analysis it appears that CK is an effective and safe treatment for VS. Our rate of tumour control is comparable to international standards with improved rates of hearing preservation (79% vs 67%). Our data suggest reduced treatment margin does not have an impact on tumour control but is associated with reduced toxicity. The toxicity rates in group 2 are consistent with expected toxicity from published data. Long-term follow-up is required to further evaluate tumour control and late effects.