bluuebunny/crossref_metadata_2025_split huggingface dataset:
P10.20.B MODELING UNCERTAINTY IN INDIVIDUAL PREDICTIONS OF COGNITIVE FUNCTIONING FOR UNTREATED GLIOMA PATIENTS USING BAYESIAN REGRESSION AND CLINICAL VARIABLES
Authors: Boelders S M , Nicenboim B , Postma E O , Ong L S , Gehring K 
Published: October 2024

Abstract

BACKGROUND
Cognitive functioning is increasingly considered when making treatment decisions for patients with a glioma in view of a personalized onco-functional balance (balancing survival against the preservation of function). Previous research using machine-learning models found that predicting pre-operative cognitive functioning based on clinical variables resulted in accurate predictions for some, but inaccurate predictions for other patients. Therefore, the current study sets out to use Bayesian models to improve predictions while also providing estimates of uncertainty for each individual prediction.

MATERIAL AND METHODS
Pre-operative cognitive functioning was predicted for 340 patients with a glioma across eight cognitive tests. This was done using six increasingly complex Bayesian regression models including hierarchical models conditioned on tumor grade. Models used a comprehensive set of predictors associated with cognitive functioning in the literature. Point-wise predictions were compared against one another and previous work using machine learning. The best-performing model (R2) was interpreted and examples of how Bayesian prediction models can be applied in clinical practice were provided.

RESULTS
Bayesian models outperformed the machine-learning models used in previous work. Predictions, however, remained uncertain. The best-performing model allowed coefficients and intercepts to differ across tumors with a different grade while pulling the estimates toward the population mean. Moreover, the best-performing model included regularizing priors, causing it to use most variables for prediction while not relying strongly on any variable.

CONCLUSION
Bayesian models resulted in better predictions than machine learning models while also providing estimates of uncertainty for individual predictions. For the best possible predictions, tumors with a different grade are best modeled as different, yet related. Moreover, a holistic view of patients’ cognitive functioning is necessary. The uncertainty in individual predictions exemplifies the importance of measures of uncertainty for clinical practice.
P11.03.A BRAIN METASTATIC LESIONS IN THE FRONTAL LOBE NEGATIVELY IMPACT PATIENT ENGAGEMENT
Authors: David S , Cialdella F , Nagtegaal S H J , van Grinsven E E , Philippens M E P , Verhoeff J J C 
Published: October 2024

Abstract

BACKGROUND
Brain metastases (BMs) significantly affect patients’ cognition, which can alter their ability to make informed decisions regarding treatment or engagement in scientific studies. In the COIMBRA (NCT05267158) study, we prospectively collect data from patients with BMs, including clinical assessments, radiological data, and patient-reported outcomes (PROs) pre- and post-radiotherapy. After enrolling in the trial, patients can make a number of decisions to participate in data collection efforts, such as engaging in QoL questionnaires. Here, we explore how lesion distributions or the disconnected white matter, known as the disconnectome, correlates with patient consent to QoL questionnaires.

MATERIAL AND METHODS
Between April 2019 and April 2023, 377 patients with BMs gave consent for COIMBRA and were referred for stereotactic radiosurgery. Of them, 276 consented to provide PROs, while 101 chose not to participate. The T1 MRIs, along with the gross tumor volumes (GTVs) were nonlinearly registered the MNI brain template, using EasyReg from Freesurfer. We used the BCBtoolkit to calculate the disconnected white matter areas. Voxelwise statistical comparison between the PRO consented and non-consented groups was performed with PALM. Family-wise error rate correction was performed to adjust for multiple comparison correction, p-value &lt;0.05 was applied for significance.

RESULTS
The lesion-based analyses revealed a cluster of 3098 mm3, which significantly associated with PRO non-consent, predominantly located in the frontal lobe, specifically within the Frontal Pole (FP) and Cingulate Gyrus (CG), as well as part of the right Middle FG and the Insular Cortex. The disconnectome analysis identified a cluster of 7718 mm3, with disconnections in both sides of the anterior division of the CG, extending to FP and Superior FG. White matter tracts in the Anterior Thalamic Radiation and Forceps Minor are disrupted on both sides. The prefrontal subthalamic regions on both sides also show disconnections. There are no regions identified by either analysis method that show more lesions in the PRO consented group.

CONCLUSION
BM lesions in specific frontal lobe regions and disruptions in related white matter tracts significantly lowered patients’ consent fill-in QoL questionnaires. Data collection in research studies, particularly concerning aspects of patients’ mental health, typically relies on voluntary acts such as neuropsychological assessments or the collection of PROs. However, when patients cannot or are unable to participate in such efforts, due to their condition influenced by for example the lesion location, the results are likely to be biased. Clinicians may consider these ‘neural barriers’ in the design of studies and data collection methods, potentially integrating more observational or caregiver-reported measures to obtain evaluation of the patient’s condition.
P11.11.B VALIDITY RELATED EVIDENCE FOR COGSTATE TASKS IN PATIENTS WITH BRAIN METASTASES
Authors: Wefel J S , Tawbi H A , Sulman E P , Sullaway C M , Thomas A L , Noll K R , Tang C , Ferrarotto R , Welsh J , Guha-Thakurta N , Glitza I C , Diab A , Patel S P , Wong M K , Davies M A , Burton E , Chung C , Li J 
Published: October 2024

Abstract

BACKGROUND
Digital approaches to measuring and monitoring cognitive function (CF) are of interest as screening measures to enhance clinical care and clinical research. Validity related evidence for such measures is required prior to adopting these in practice and trials. Four investigator-initiated clinical trials evaluated CF in patients with brain metastases (BM) with both clinically validated CF tests and experimental computerized CogState (CS) tasks. Construct validity of the CS tasks was evaluated.

MATERIAL AND METHODS
140 pts with BM who completed both CF testing and computerized CS tasks prior to treatment were included. Within sample mean/SD were used to convert raw to standardized test scores. The following domains and tests were evaluated: Processing Speed (CS Detection, TMTA, TMTB, Coding), Attention (CS Identification, Digit Span, Coding, TMTA, TMTB), Working Memory (CS One Back, Digit Span), and Learning and Memory (CS One Card Learning and International Shopping List, HVLT-R). Spearman correlations were computed between CF tests and CS tasks, with significance set at the 0.01 level. Impairment was classified as a z-score ≤-1.5 and concordance rates were examined between HVLT-R and ISL.

RESULTS
On average, pts were 58.3 years old(SD 12.9), completed 14.7 years of education(SD 3.0), 48% female, and 84% right-handed. Spearman correlation coefficients between CS tasks and related CF tests were weak to moderate for processing speed (rs=0.39-0.55) and attention (rs=0.34-0.56), weak for working memory (rs=0.28), and weak to strong for learning and memory (rs=0.36-0.69). Spearman correlations were stronger, while intraclass correlation coefficients were moderate, between the ISLT and HVLT-R TR (rs=0.69 and ICC=0.58) and ISLR and HVLT-R DR (rs=0.69 and ICC=0.58). Concordance rates of impairment for the most highly correlated and parallel measures of learning and memory were poor with no to minimal correspondence based on Cohen kappa coefficients (ISLT and HVLT-R TR k=0.11; ISLR and HVLT-R DR k=0.29).

CONCLUSION
Spearman correlations between CS tasks and clinically validated CF tests in similar domains were weak with the exception of highly parallel measures of verbal learning and memory. ICC were less robust and Cohen kappa coefficients was negligible for these measures of verbal learning and memory. The substantial lack of agreement in identifying abnormal episodic memory performance is concerning in terms of utilizing the CS ISL task as a surrogate for the HVLT-R. Further associations between clinical variables and these measures of CF will help to determine ability to assess clinically relevant differences due to disease burden. Longitudinal evaluations will further shed light on sensitivity to treatment and disease effects.
P12.03.B CAN COGNITIVE PERFORMANCE PREDICT NEUROTOXICITY INCIDENCE FOLLOWING CHIMERIC ANTIGEN RECEPTOR T-CELL THERAPY FOR LYMPHOMA?
Authors: Ursu R , Barsan C , Belin C , Cuzzubbo S , Carreau C , El Soudany M , Sivapragassame R , Cristinelli C , Di Blasi R , Ouedrani A , Caillat-Zucman S , Thieblemont C , Carpentier A 
Published: October 2024

Abstract

BACKGROUND
Chimeric antigen receptor T-cell (CAR-T) therapy has revolutionised the landscape of cancer treatment, particularly in haematological malignancies, and while these therapies have demonstrated significant efficacy against malignancies, they are associated with a spectrum of side effects. Cytokine Release Syndrome (CRS) and Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) are unique to CAR-T cell therapy and distinguish it from other forms of autoimmune toxicity. Predicting which patients will develop neurotoxicity remains a challenge. The pattern of ICANS is cognitive dysfunction, suggesting a plausible relationship between cognitive status and neurotoxicity. Understanding the interplay between cognitive function and neurotoxicity may provide valuable insights for early detection. The primary endpoint of this study was to investigate whether the cognitive performance of patients at the time of leukapheresis is associated with the subsequent development of ICANS.

MATERIAL AND METHODS
We report here on a prospective study of an adult patient population with aggressive B-cell lymphoma treated with CAR-T cell therapy at our centre between May 2020 and November 2023. All patients underwent neurological examination, cerebral MRI and global cognitive assessment using the Montreal Cognitive Assessment (MoCA) test with a cut-off of less than 26 points. We retrospectively recorded total metabolic tumour volume (TMTV) and International Prognostic Index (IPI) at lymphodepletion. Biological data including lactate dehydrogenase (LDH), albumin, ferritin and C-reactive protein (CRP) were also collected at the time of treatment. A retrospective analysis of pre-infusion serum neurofilament light chain (NfL) levels at the time of the decision to proceed with CAR-T cell therapy and at the time of treatment was performed.

RESULTS
156 patients, median age 64 years (range 21 to 79 years), 55 females / 101 males, all treated for lymphoma, were included in this study. The mean MoCA score was 26 (range 12 to 30 points), 63 patients (40%) had a MoCA test below the cut-off at baseline. Following infusion of CAR T cells, 32% of patients developed ICANS within 6 days (grade 1-2: 72%; grade 3-4: 30%). The most common sign of neurotoxicity was cognitive impairment. In univariate analyses, the occurrence of ICANS was not significantly associated with baseline cognitive performance (p 0.58). As the study is ongoing, an update on the results will be available at the EANO meeting.

CONCLUSION
Neurotoxicity associated with CAR-T therapies occurs in one third of patients. This study does not suggest an association between the occurrence of ICANS and baseline cognitive performance. Despite progress in understanding the mechanisms underlying neurotoxicity, predicting its occurrence remains a challenge.
P12.04.A CAR-ENGINEERED PRIMARY NK CELLS SHOW PROMISING EFFECTS AS TARGETED THERAPY AGAINST EGFR-POSITIVE GLIOBLASTOMA
Authors: Roller B , Reindl L , Strassheimer F , Ziegener L , Elleringmann P , Kiefer A , Röder J , Steinbach J , Wels W , Ullrich E , Burger M 
Published: October 2024

Abstract

BACKGROUND
Glioblastoma (GB) is the most frequent primary brain tumor with a dismal prognosis despite multimodal treatment regimens. Effector cells such as T cells or natural killer cells (NK) carrying tumor-specific chimeric antigen receptors (CAR) hold promise for the development of more effective treatment strategies. CAR-engineered derivatives of the human NK cell line NK-92 targeting EGFR or EGFRvIII showed potent antitumor activity against glioblastoma cell lines in vitro and in vivo. Nevertheless, NK-92 does have limitations when compared to primary NK cells, such as the required irradiation prior to application in humans.

MATERIAL AND METHODS
To overcome this restriction, we evaluated the suitability of peripheral blood derived human primary NK cells (pNK) as carriers for a CAR targeting the common GB antigen epidermal growth factor receptor (EGFR) and the tumor-specific EGFR variant EGFRvIII. pNK cells from healthy donors were transduced with a lentiviral vector encoding the cetuximab-derived 225.28.z CAR (CAR-pNK), which recognizes an epitope common to both receptors. Specific tumor cell lysis by the CAR-pNK cells was then investigated in FACS-based cytotoxicity assays with GB cells expressing EGFR, EGFRvIII, or both target antigens. In addition, we tested in vivo CAR-pNK cell therapy in the subcutanous and intracranial LNT-229/EGFRvIII glioblastoma xenograft models.

RESULTS
When compared to non-transduced pNK cells, CAR-pNK cells achieved enhanced lysis of LNT-229 GB cells expressing EGFR and EGFRvIII. Likewise, markedly increased cytotoxicity of CAR-pNK was observed against the murine EGFR transduced GB cell line GL261 and the human cell lines SKMG-3 and BS153 with intrinsic EGFR gene amplification or expression of EGFRvIII, respectively. Furthermore, we observed delayed tumor growth following a single intravenous injection of CAR-pNK cells in the subcutaneous LNT-229/EGFRvIII glioblastoma xenograft model.

CONCLUSION
In summary, these results demonstrate promising efficacy of primary CAR-NK cells targeting EGFR and EGFRvIII both in vitro and in vivo. Ongoing work is currently evaluating CAR-pNK cell therapy in the orthotopic LNT-229 glioblastoma xenograft mouse model and an in vitro organoid model, which may provide the rationale for early clinical testing.
P12.05.B COMBINED ANTI-ANGIOGENIC TREATMENT TO INCREASE INTRATUMORAL PERSISTENCE OF CAR T CELLS IN LUNG CANCER BRAIN METASTASES
Authors: Blobner J , Eberle C , Dengler L , Herold J J , Xu T , Mueller K J , Teske N , Karschnia P , Ishikawa-Ankerhold H , Subklewe M , Thon N , Tonn J , von Baumgarten L 
Published: October 2024

Abstract

BACKGROUND
Metastatic lung cancer shows a devastating prognosis. Immunotherapeutic approaches including CAR T-cells show promise in hematologic malignancies. However, the presence of immunosuppressive factors within the tumor microenvironment and physical barriers like elevated interstitial pressure due to dysfunctional tumor vessels are one of the main obstacles especially in solid tumors. Therefore, we investigate potential synergistic effects of a combined anti-angiogenic treatment and CAR T cells.

METHODS
Here, we set up an immunocompetent syngeneic orthotopic cerebral metastasis model in mice by combining a chronic cranial window with repetitive intracerebral two-photon laser scanning microscopy (TPLSM). This model allows in-vivo characterization of fluorescent tumor cells and CAR T-cells on a single cell level over time. Intraparenchymal injection of red fluorescent EpCAM-transduced Lewis Lung carcinoma cells (EpCAM/tdtLL/2 cells) followed by injection of EpCAM-directed or undirected CAR T-cells into the adjacent brain tissue was performed. Additionally, aVEGF-A combined with aVEGF-R2 and the respective isotype control were injected intraperitoneally.

RESULTS
Compared to undirected CAR T-cells, mice receiving EpCAM-directed CAR T-cells showed higher intratumoral CAR T-cell densities after intraparenchymal injection. This finding was accompanied with reduced tumor growth and eventually translates into a survival benefit. However, intratumoral CAR T-cell numbers diminish over time indicating insufficient persistence inside of the tumor microenvironment. Additional anti-VEGF-A/VEGF-R2 treatment results in reduced tumor growth after EpCAM/GFPCAR T cell and GFPT cell treatment, respectively. Interestingly, in vivo imaging reveals higher intratumoral CAR T cell numbers after anti-angiogenic treatment compared to isotype controls pointing towards enhanced CAR T cell persistence resulting in a survival benefit.

CONCLUSION
Collectively, our findings indicate that locally injected CAR T-cells may safely induce relevant anti-tumor effects in brain metastases from lung cancer. Additional anti-angiogenic treatment provides a mechanism to enhance intratumoral CAR T cell persistence and reduce tumor growth.
P12.15.B PROGNOSTIC VALUE OF CD8+ T-CELLS INFILTRATION IN GLIOMA PATIENTS TREATED WITH IMMUNOTHERAPY: A SYSTEMATIC REVIEW AND META-ANALYSIS
Authors: Cai X , Westerman B , Wang D , Garcia Vallejo J 
Published: October 2024

Abstract

BACKGROUND
Glioblastoma (GBM) is the most aggressive subtype of glioma with a five-year survival of 7·2 %. Immunotherapy has become a promising approach in the treatment of it. However, no improved prognosis was reached yet in phase III immunotherapy trials of glioma. Highly intertumoral heterogeneity was one of the reasons for this outcome. Hence, identifying patients who will respond to immunotherapy has become a core task in the research of GBM. In non-CNS malignancy, CD8+ tumor infiltrating lymphocytes (TILs) within tumor has been associated with response to immunotherapy and prognosis. However, no consensus was reached regarding the value of CD8+ TILs in predicting glioma patients’ response to immunotherapy. In this meta-analysis, we investigated the prognostic predictive value of infiltrating CD8+ TIL in glioma patients treated with immunotherapy.

MATERIAL AND METHODS
PubMed and Web of Science were searched from 1st of January 2000 up to 15th of May 2023. Quality assessment was performed using ROBINS-I and JBI critical appraisal check list. Subgroup analyses were conducted according to clinical indicators. The protocol of the meta-analysis was registered on PROSPERO (CRD42023425790).

RESULTS
A total of 8550 records were identified after the duplicates were removed, with 272 records remained for full text screening. Nine records with 187 GBM participants were included in the meta-analysis. Most of them are from Phase I or Phase II clinical trials. The immunotherapies utilized in these studies included peptide vaccination, oncolytic viral vectors therapy, DC vaccination, immune checkpoint inhibitors, and CAR-NK. Overall, no statistically significant effect of CD8+TIL infiltration was observed on overall survival (OS), progress-free survival (PFS), and survival time after immunotherapy. The subgroup analysis on peptide vaccination showed that patients with high CD8+TIL infiltration tended to have a lower OS (HR = 6·57; 95% CI: 1·12, 38·58; P = 0·037). In the subgroup analyses on male (HR = 12·34; 95% CI: 1·09, 139·18; P = 0·042) and recurrence (HR = 0·08; 95% CI: 0·01, 0·79; P = 0·030), CD8+TIL infiltration showed important effect on PFS.

CONCLUSION
In general, CD8+ TIL infiltration has no prognostic predictive value in GBM patients treated with immunotherapy. However, there is predictive value for OS in the subpopulation of peptide vaccination treated GBM patients.
P12.19.A UNVEILING SYNERGISTIC STRATEGIES: CRISPR-GUIDED OPTIMIZATION OF L19-TNF IMMUNOCYTOKINE THERAPY IN GLIOBLASTOMA
Authors: Sakic I , Uijttewaal E , De Luca R , Puca E , Weller M , Neri D , Elling U , Weiss T 
Published: October 2024

Abstract

BACKGROUND
Glioblastoma poses a formidable challenge due to its intricate intra- and intertumoral heterogeneities and the immunosuppressive milieu it creates. Despite advances, the standard of care remains largely ineffective, underscoring the urgent need for innovative treatment strategies. Tumor-targeted cytokine-based therapies, particularly L19-TNF, represent a promising cancer immunotherapy approach, that is currently being studied in clinical trials for patients with newly diagnosed or recurrent glioblastoma in Europe. Particularly combination therapies based on L19TNF, such as the combination with lomustine, have shown promising activity in preclinical models. However, the most promising combinatorial treatment strategy remains to be determined. To address this, we employed a cutting-edge in vivo CRISPR screening approach to identify synergistic partners and druggable targets that could enhance the efficacy of L19TNF cancer immunotherapy.

MATERIAL AND METHODS
The primary limitation in glioblastoma treatment is the identification of effective drugs. Here, we systematically explored tumor growth dependencies and dominant signaling pathways in an orthotopic murine glioma model in the complex setting of an intact host immune system under immunotherapeutic pressure, using in vivoCRISPR screening. We used a novel CRISPR strategy based on an innovative sgRNA cassette switch-system with unique molecular identifiers (UMIs) for controlled induction of the perturbations in vivo. This accounts for cell-to-cell heterogeneities by allowing single-cell lineage tracing and a timed sgRNA activation by Cre-recombinase activation to reduce off-target effects and overcome the bottleneck created by the orthotopic tumor cell implantation.

RESULTS
Through genome-wide and selective CRISPR screens, we uncovered several novel druggable targets, some previously unexplored in glioblastoma and others which demonstrated efficacy in other tumor entities. Additionally, our investigation provided insights into the mode of action of L19-TNF, while at the same time suggesting possible combination opportunities. Importantly, our study identified four highly promising synergistic drugs currently undergoing preclinical evaluation in glioblastoma mouse models. These findings offer tangible avenues for enhancing the therapeutic efficacy of L19-TNF immunotherapy.

CONCLUSION
Our research represents a significant step forward in the quest for innovative treatment strategies in glioblastoma. The CRISPR screening under immunotherapeutic selection has revealed a spectrum of synergistic partners and paved the way for a rational design of combinatory treatment approaches to maximize therapeutic efficacy, laying the groundwork for future clinical translation.