tbuckley/cabot-search huggingface dataset:
P02.05.A COMPREHENSIVE ANALYSIS OF TUMOR-ASSOCIATED MACROPHAGES IN GLIOBLASTOMA
Authors: X Cai, A Beumer-Chuwonpad, B Westerman, J Garcia Vallejo
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Glioblastoma (GBM) is the most common and extremely aggressive primary tumor of the central nervous system. Tumor-associated macrophages (TAM) can take up around 50% of cells in the tumor microenvironment (TME) of GBM and are thought to play a role in therapy resistance by creating an immunosuppressive TME. Researchers have used the M1/M2 dichotomy to describe the pro- and anti-inflammatory states of TAM, respectively. However, an expanding number of studies have found that this classification strategy oversimplifies the nature of TAM as seen in patients. Therefore, a more comprehensive strategy to represent the continuous spectrum of cellular states of TAM is essential. In this study, we aim to identify the cellular states of TAM, and further explore their impact on clinical outcomes and the TME. MATERIAL AND METHODS A bioinformatic pipeline based on principal component analysis was developed to identify the cellular states of TAM, which addressed the high inter-tumoral heterogeneity of GBM. A public Image Mass Cytometry dataset is used to verify the existence of the TAM states. The correlation analysis and survival analysis were conducted to identify the clinical relevance of the TAM states. Three spatial transcriptomic datasets were used to explore the role of these TAM states in the TME. A vessel/neuron impact index was developed to describe the impact of vessel/neuron on the TME. An 8-color multiplex immunohistochemistry is currently being developed to explore the role of VIM-TAM in the TME with spatial analysis in our cohort with 74 GBM patients. RESULTS Four public GBM scRNA-seq datasets with 94 samples were input into our pipeline. Four TAM states together with a proliferating state were identified: HLA-TAM (HLA-DR, SPP1, APOE, TREM2, C3, CD74), VIM-TAM (VIM, S100A4/6/10, CD44), IL1B-TAM (IL1B, CCL3, CD83), and HSP-TAM (HSP90AA1, BAG3). By mapping TAMs into a 3D plot based on these state scores, we revealed a continuous spectrum of TAM. Prognosis analysis found that the mean IL1B-TAM score showed a protective effect for OS (P = 0.065), while the mean VIM-TAM score had a risk impact on PFS (P = 0.045). Spatial transcriptomic analysis showed that the VIM-TAM is negatively correlated with neural-progenitor-like cancer cells and the neuron impact index. CONCLUSION A continuous spectrum of TAM could be described by these 4 identified TAM states. The IL1B-TAM and the VIM-TAM are predictors for OS and PFS, respectively. Also, the VIM-TAM is related to NPC-like cancer cells and neurons in the TME.
GLP-1 receptor agonists and pancreatic cancer risk: target trial emulation using real-world data
Authors: Lindsey Wang, QuanQiu Wang, Li Li, David C Kaelber, Rong Xu
Journal: JNCI Journal of the National Cancer Institute (2024)

Abstract Background Data on the effects of glucagon-like peptide-1 receptor agonists (GLP-1RAs) on pancreatic cancer incidence are limited and inconsistent. Here we evaluate the association of GLP-1RAs, alone and in combinations, with incident pancreatic cancer risk in a real-world population, stratified by obesity and smoking status. Methods This retrospective cohort included patients with type 2 diabetes mellitus who were prescribed GLP-1RAs or other nonglucagon-like peptide-1 receptor agonist antidiabetes medications between January 2013 and March 2019 and had no prior diagnosis of pancreatic cancer. The incident (first-time) diagnosis of pancreatic cancer during a 5-year follow-up was compared between propensity-score matched cohorts of patients prescribed GLP-1RAs vs other nonglucagon-like peptide-1 receptor agonist antidiabetes medications. Subgroup analyses were performed in patients stratified by the status of obesity and tobacco use disorder. We also compared GLP-1RA combination therapies with monotherapies. Time-to-first-event analysis was performed using Cox proportional hazards and Kaplan–Meier survival analysis, with the hazard ratio and 95% confidence interval calculated. Results The study population comprised 1 636 056 eligible patients including 167 091 prescribed GLP-1RAs and 1 468 965 prescribed other antidiabetes medications. GLP-1RAs were associated with a statistically significant decreased risk for pancreatic cancer incidence compared with each of 6 nonglucagon-like peptide-1 receptor agonist antidiabetes medications with hazard ratios ranging from 0.42 to 0.82. The reduction was greater in patients with obesity and tobacco use disorder than in those without. GLP-1RA combination therapies were associated with lower pancreatic cancer risk compared with monotherapies. Conclusions GLP-1RAs were associated with reduced pancreatic cancer incidence in patients with type 2 diabetes mellitus. Further studies and trials are needed to explore mechanisms and confirm causal effects.
P14.02.B A MULTICENTER, RANDOMIZED, CONTROLLED TRIAL OF FOCUSED-ULTRASOUND-MEDIATED BLOOD-BRAIN BARRIER DISRUPTION PLUS SYSTEMIC PEMBROLIZUMAB FOR PATIENTS WITH NSCLC BRAIN METASTASES (LIMITLESS)
Authors: M S Ahluwalia, A Ozair, K S Sahni, N Sanai, A Sahgal, M W McDermott, K Nwaogu, L Dye, G F Woodworth, N Lipsman
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND The efficacy of systemic therapies for brain metastases (BM) is hindered by the blood-brain barrier (BBB), whose disruption is associated with improved systemic drug delivery. Low-intensity focused ultrasound (LIFU), combined with IV microbubble oscillators, leads to non-invasive disruption of BBB. This can potentially enhance intracranial drug delivery of systemically administered immune checkpoint inhibitors like pembrolizumab. Given that non-small lung cancer (NSCLC) remains the most common etiology behind BM, this randomized controlled trial (RCT) aims to evaluate the safety and efficacy of LIFU-mediated BBB disruption combined with systemic pembrolizumab for NSCLC BM. MATERIAL AND METHODS LIMITLESS is an ongoing, prospective, multicenter, parallel-arm, open-label RCT that randomizes patients with NSCLC BM on pembrolizumab monotherapy prescribed as per standard-of-care to LIFU plus pembrolizumab (arm 1) or pembrolizumab alone (arm 2) in a 2:1 ratio. Included patients have age ≥18 years, normal organ function, KPS ≥70, EGFR- and ALK-negative primary tumor, and ≤3 BM with ≥1 BM meeting measurable disease criteria as per RANO-BM. Patients on both arms receive standard-of-care therapy, while those on arm 1 also undergo LIFU before each dose of pembrolizumab (200 mg IV every 3 weeks). Patients undergo pre-treatment brain MRI, followed by IV administration of microbubbles for enhanced sonication effects. MR-guided BBB disruption is then performed using a transcranial 220 kHz LIFU device with real-time acoustic feedback-based power control for maintaining effective microbubble activation. Pembrolizumab is infused immediately after the sonication, and a repeat MRI is done 24-48 hours later to assessment to treatment effects. The primary study outcome is the overall objective response rate (ORR) at 6 months as assessed using RANO-BM criteria. Using a Bayesian design for power analysis, a superior ORR of 60% is assumed for the LIFU arm versus 30% in the control arm for a total sample size of N = 96, 64 participants in LIFU and 32 in the control arm, for 80% power using a two-sided chi-square test with an alpha of 0.05. For the upper-bound estimate, ORR of 45% in the LIFU arm and 30% in the control arm, the study needs N = 369 participants: 246 in LIFU arm and 123 in control arm. The secondary outcomes are best objective response rate and median time-to-response per treatment arm. Exploratory outcomes are median progression-free survival (PFS), overall survival (OS), median intracranial PFS, median extracranial PFS, and quality of life. RESULTS Patient enrollment commenced in 2022 and is ongoing. CONCLUSION Findings from this trial will be critical to overcoming the historic challenges presented by the BBB to efficacious CNS drug delivery (ClinicalTrials.Gov Registration: NCT05317858).
P10.11.B CLINICAL APPLICATION OF MACHINE-BASED DEEP LEARNING IN PATIENTS WITH RADIOLOGICALLY PRESUMED ADULT-TYPE DIFFUSE GLIOMA GRADE 2 OR 3
Authors: T Gómez Vecchio, A Neimantaite, O Solheim, J Pallud, M S Berger, G Widhalm, J Bartek jr., I Y H Gu, A S Jakola
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Diffuse lower-grade gliomas (dLGG) are nowadays characterized by the IDH mutation. Presumed dLGG are typically non or minimal enhancing tumors, with hyperintensity in T2w-images. However, one third of the radiologically presumed dLGG turn out to be patients with IDH wild-type and have a disadvantaged prognosis. The aim of this study was to reduce clinical uncertainty applying deep learning (DL) to the prediction of IDH mutation in patients with radiologically presumed dLGG. MATERIAL AND METHODS 314 patients were retrospectively recruited from six neurosurgical departments in Sweden, Norway, France, Austria, and the United States. Collected data included patient’s age, sex, tumor molecular characteristics (IDH, and 1p19q status), and routine preoperative radiological images. A clinical model was built using multivariable logistic regression with the variables age and voxel-based tumor location. Four DL architectures used in glioma research were chosen for comparison, the best performing DL model was selected with a grid search. In the final test, the clinical model and the DL model were scored with an unseen validation dataset consisting of 155 patients from the Erasmus Glioma Dataset. RESULTS The mean age in the training and validation cohorts were 45.0 (SD 14.3) and 44.3 years (SD 14.6). The training and validation cohorts were similar, except concerning the variables sex (53.5% vs 64.5% males, p-value 0.03) and IDH status (30.9% vs 12.9% IDH wild-type, p-value &amp;lt;0.01). Scored accuracy, sensitivity, specificity, positive predicted value, negative predicted value, and area under the curve for clinical model: 0.86, 0.90, 0.55, 0.93, 0.46, and AUC 0.86; DL model: 0.68, 0.66, 0.80, 0.96, 0.26, and 0.82; combined model: 0.78, 0.77, 0.85, 0.97, 0.35, and AUC 0.87; combined model (specificity tuned): 0.62, 0.58, 0.90, 0.98, 0.24, and AUC 0.87. CONCLUSION We present a large cohort of patients with non or minimal enhancing presumed dLGG studied with DL. Compared to acceptable results in the clinical model, the DL model showed lower sensitivity and higher specificity. Furthermore, when these models were combined, the AUC was slightly improved also showing good results at a high specificity cutoff. However, the DL model failed to deliver additional gain over the clinical model. DL models should be further improved if they are to become clinically applicable.
P18.53.A USING THE PATTERN OF 5-AMINOLEVULINIC ACID (5-ALA) POSITIVE RESIDUE TO PREDICT THE OUTCOME OF GLIOBLASTOMA PATIENTS
Authors: V Manik, V Sim, M MacDonald, A Mannava, C Soumpasis, D Kalaitzoglou, K Ashkan, R Bhangoo, R Gullan, L Brazil, O Al-Salihi, F Vergani, K Chia, A Swampillai*, J P Lavrador*
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Glioblastoma multiforme (GBM) portends poor prognosis despite multiple attempts at finding newer therapies. The current standard of care remains maximal safe resection. 5-ALA guidance helps to maximise the resection extent but complete removal is not always possible. It is unclear, if the residual 5-ALA pattern can predict the outcome of patients with GBM. MATERIALS &amp; METHODS Patients with GBM treated at our centre between January 2018 - July 2019 were included if they had 5-ALA based tumour excision &amp; were planned for adjuvant treatment per Stupp. Patient, tumour &amp; treatment related factors were collected. Operation notes were reviewed to determine the pattern of 5-ALA residual &amp; classified as no residue if there was no visible 5-ALA left at the end of resection; focal residue if 5-ALA positive tissue left involved 1-2 walls; or diffuse residue if all walls were involved. Date of relapse &amp; date of death were collected to compute progression free survival (PFS) &amp; overall survival (OS) respectively. Data was analysed in SPSS™ v29, Kaplan Meier curves were used for survival analysis with log rank testing to compare between groups. RESULTS Total of 23 eligible patients were identified. Median age was 58 (32 - 70), majority were males (n=15). No residual 5-ALA was seen in 12, 8 had focal &amp; 3 had diffuse residual. There was moderate correlation (f=0.453, p=0.03) between 5-ALA residual &amp; the extent of resection however the positive (58.3%) &amp; negative (63.6%) predictive values were low. The quantity of 5-ALA residual, no or focal residual vs diffuse residual, was predictive of overall survival 18.2 vs 9.3 months (p &amp;lt; 0.001) as well as progression free survival 10.9 vs 4.5 months (p = 0.006). The impact on overall survival was maintained even when the groups were stratified with age (65 and above or less than 65, p=0.006) or with their MGMT status (unmethylated or methylated, p=0.002). Cox proportional hazard showed that older age (p=0.004), unmethylated MGMT (p=0.031), intra-operative ventricular involvement (p=0.005) &amp; diffuse 5-ALA residue (p=0.003) all had a negative impact on overall survival. A sub-group analysis, did not show any difference between the no residual and focal residual 5-ALA groups for OS (p = 0.548) or PFS (p = 0.498). CONCLUSION Diffuse pattern of 5-ALA residual had a negative impact on the oncological outcome of patients treated with 5-ALA guided maximal safe resection followed by oncological treatment, even when adjusted for established risk factors like age &amp; methylation status. *-joint authors
P06.08.B OF TRAVELING HOMEOPROTEINS AND MEDULLOBLASTOMAS
Authors: E Vigneul, F Clotman
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Medulloblastomas (MB) are the most common pediatric malignancies. These WHO grade IV neoplasms are divided into four main subgroups called SHH-activated, WNT-activated, group 3 and group 4. These subgroups are governed by different molecular patterns involving transcription factors (TFs), in particular (TF) Orthodenticle homeobox 2 (OTX2) which, when overexpressed, is a key factor in group 3 and 4 medulloblastoma formations. In addition to being a transcription factor crucial for the proper cerebral and cerebellar embryogenesis, OTX2 is a homeoprotein with intercellular travelling properties. Indeed, via secretion and penetration sequences, OTX2 can travel between cells and influence the tumor neighborhood in a paracrine manner. The objective of this study is to establish the list of traveling homeoproteins associated with the development of MB. MATERIALS AND METHODS We found 57 homeoproteins with demonstrated intercellular transfer capabilities in vivo. We then systematically reviewed the literature and found 89 articles eligible for full-text analysis. RESULTS Ten traveling homeoproteins (CUX1, EN1, ISL1, LHX1, NKX2.2, OTX2, PAX5, PAX6, PAX8 and POU5F1) are involved in medulloblastoma formation. Apart from PAX8, which is underexpressed, all other homeoproteins are overexpressed in medulloblastoma. CONCLUSION This study highlights the role of several traveling homeoproteins in the formation of medulloblastoma. Most of these proteins are overexpressed in MB and have the ability to enter and modify the transcriptional and non-transcriptional mechanisms of surrounding cells. Antibodies targeting these transcription factors, as used in animal models, could become a promising tool to circumscribe the potential chain reaction of deregulation associated with these roaming homeoproteins.
P16.05.A PEDIATRIC NEUROFIBROMATOSIS 1-RELATED AND NOT-RELATED OPTIC PATHWAY GLIOMA TREATED WITH FIRST LINE CHEMOTHERAPY: A SINGLE-CENTER EXPERIENCE
Authors: B Castelli, C Fonte, M Tellini, M Di Nicola, M Guidi, L Giunti, C Marzano, B Tirinnanzi, C E La Torre, A M Buccoliero, F Giordano, V Marchiori, F Maimone, L D’Incerti, G M Bacci, M Scagnet, L Genitori, I Sardi
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Optic pathway gliomas (OPG) are low-grade tumors (LGG) that affect the precortical visual pathway, representing 3-5% of pediatric brain tumors, more often diagnosed before the age of 5 years. Although histologically benign, due to their location and thus their unresectability, they carry considerable morbidity, bringing to progressive visual loss. In up to 20% of cases they are detected in patients with neurofibromatosis type 1 (NF1). Consolidated chemotherapy regimen with or without biopsy or debulking, if feasible, remains so far the standard management, moving to new personalized frontiers. MATERIAL AND METHODS In Meyer Children’s Hospital IRCCS Neuro-oncology Unit in Florence (Italy), from February 2013 to April 2024, for visual impairment at diagnosis or for disease progression, thirty-seven OPG patients (female/male ratio 1.3, median age at onset 4 years) completed the first line LGG chemotherapy (carboplatin-etoposide scheme adopted in our institution, built upon the INT Milan strategy and the standard SIOP LGG trial). Fourteen patients (37.8%) presented NF1-related OPG diagnosis, mostly made on a clinical/neuroradiological data. Response was assessed according to RAPNO criteria. RESULTS Non-NF1 OPG patients debuted at a lower median age (3 years) and mostly in a chiasmatic-hypothalamic location, predominantly with a pilocytic astrocytoma histology and manifested with nystagmus, secondarily with visual impairment. Despite the most frequent pre-chiasmatic involvement, during follow-up NF1 patients surprisingly presented a mean and median higher thickness (μm) of the retinal nerve fiber layer (RNFL) on optic coherence tomography (OCT) compared to non-NF1 patients, tested in the majority of patients (mean right RNFL 74.4 versus 58.0, median 66.0 versus 50.0, mean left RNFL 77.2 versus 55.3, median 73.0 versus 49.5). Four non-NF1 patients progressed during treatment or immediately afterwards. Considering the whole follow-up from the stop therapy (median time 5 years), non-NF1 patients progressed by far much more (15/23, 65.2% with one death versus 2/14, 14.3%). Overall survival was 97.3%. CONCLUSION NF1-related and not related pediatric OPG represent two distinct subgroups, with different clinical and prognostic characteristics. In agreement to other series our data show that non-NF1 OPG are less chemotherapy responsive than NF1-related OPG, surely due to the molecular landscape at the basis of tumor growth, warranting the needing of precision medicine directed to targets also in first- line treatment. A worse OCT outcome was found in the former cohort.
P20.24.A THE WIDE HISTOLOGICAL SPECTRUM OF ZFTA FUSED WITHOUT RELA FUSION SUPRATENTORIAL EPENDYMOMAS: FROM SARCOMA-LIKE TO EMBRYONAL TUMOR-LIKE
Authors: S Xi, Z Chen
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND According to the 5th World Health Organization (WHO) classification of the central nervous system, supratentorial-ependymomas (ST-EPN) RELA-fusion positive was replaced by ST-EPN, ZFTA-fusion positive. This modification reinforces the importance of the ZFTA gene in ST-EPN. The significant histopathological heterogeneity in supratentorial ZFTA fused without RELA fusion ependymomas (not RELA, ZFTA fused EPN) has raised concern recently, which included varied histological patterns. MATERIAL AND METHODS To expand the histological spectrum of not RELA, ZFTA fused EPN, we reported four cases of not RELA, ZFTA fused ST-EPN, and described the histological features of this uncommon entity. RESULTS In our cohort, one case showed small round cells with chondromyxoid or fibrous stromal components forming a sarcoma-like pattern. The second case presented a lobular or sheet-like pattern infiltrating with trapped glia. The tumor cells carried reticular cytoplasm, prominent cell membranes, and irregular wrinkle nuclei. They were strongly positive for cytokeratin, which resembled metastatic cancer. The third case showed an embryonal tumor-like pattern with relatively circumscribed but infiltrated cells, hypercellularity and necrosis were seen. Focal differentiation to neurocytes and ganglion cells could be observed. The tumor cells are partially positive for Neu-N. The last case presented the embryonal tumor-like pattern with highly cellular unstructured primitive areas and high-grade classic EPN histology like the rosettes and fibrillar areas with few nuclei. The first case carried ZFTA-MAML2 fusion, and three instances carried ZFTA-NOCA2 fusion. Three cases underwent DNA methylation profiling and were classified as EPN satellite clusters. The clinicopathological features and molecular alterations are summarized, one of the patients died during the follow-up. CONCLUSION Compared to the ST-EPN, RELA-fusion positive, not RELA, ZFTA fused ST-EPN often presented uncommon histological features, the adult cases often present morphology resembling sarcoma or metastatic cancer, and the pediatric cases present embryonal tumor-like histology. The subtype may carry a worse outcome.
P18.21.A GLIOBLASTOMA AS A METASTATIC DISEASE: A POSSIBLE MOLECULAR PATHWAY OF METASTATIC SPREAD ACCORDING TO THE GENE MUTATION PROFILE
Authors: R Jancalek, M Barak, J Brychta, M Hendrych, J Sana, P Pospisil, T Kazda
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Glioblastoma (GBM) is the most common glial brain tumor in adults. It accounts for nearly 50 % of malignant primary brain tumors and represents a disease with a dismal prognosis. GBM is characterized by rapid infiltrative spread within the central nervous system; however, its metastases are considered sporadic. The molecular background of primary and secondary GBM is yet to be discovered, making it difficult to describe the possible molecular pathway/s of metastatic spread. Due to increasing overall survival rates in GBM patients, extracranial metastasis is becoming more common, making this topic increasingly relevant. MATERIAL AND METHODS We screened a case of spinal GBM metastasis and its molecular background and searched for differences in gene mutation profile between the primary and metastatic disease to outline possible molecular pathways of metastatic spread. RESULTS In this study, we discovered that the alteration of NF1, NOTCH3, and ARID1A could explain, at least in part, the acquired invasiveness and metastatic potential in a GBM case. CONCLUSION This finding underscores the importance of genetic testing in understanding tumor progression and its potential impact on patient oncological management. The project was supported by the NU23-03-00100 grant from the Ministry of Health, Czech Republic.